jm burr, g mowatt, r hernández, mar siddiqui, j cook, t...

The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematicreview and economic evaluation

JM Burr, G Mowatt, R Hernández, MAR Siddiqui, J Cook, T Lourenco, C Ramsay, L Vale, C Fraser, A Azuara-Blanco, J Deeks, J Cairns, R Wormald, S McPherson, K Rabindranath and A Grant

Health Technology Assessment 2007; Vol. 11: No. 41

HTAHealth Technology AssessmentNHS R&D HTA Programmewww.hta.ac.uk

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278

FeedbackThe HTA Programme and the authors would like to know

your views about this report.

The Correspondence Page on the HTA website(http://www.hta.ac.uk) is a convenient way to publish

your comments. If you prefer, you can send your comments to the address below, telling us whether you would like

us to transfer them to the website.

We look forward to hearing from you.

October 2007

Health Technology Assessm

ent 2007;Vol. 11: No. 41

Screening for open angle glaucoma

Copyright notice

© Queen's Printer and Controller of HMSO 2007 HTA reports may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising Violations should be reported to [email protected] Applications for commercial reproduction should be addressed to HMSO, The Copyright Unit, St Clements House, 2–16 Colegate, Norwich NR3 1BQ

How to obtain copies of this and other HTA Programme reports.An electronic version of this publication, in Adobe Acrobat format, is available for downloading free ofcharge for personal use from the HTA website (http://www.hta.ac.uk). A fully searchable CD-ROM isalso available (see below).

Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public andprivate sector purchasers from our Despatch Agents.

Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is£2 per monograph and for the rest of the world £3 per monograph.

You can order HTA monographs from our Despatch Agents:

– fax (with credit card or official purchase order) – post (with credit card or official purchase order or cheque)– phone during office hours (credit card only).

Additionally the HTA website allows you either to pay securely by credit card or to print out yourorder and then post or fax it.

Contact details are as follows:HTA Despatch Email: [email protected]/o Direct Mail Works Ltd Tel: 02392 492 0004 Oakwood Business Centre Fax: 02392 478 555Downley, HAVANT PO9 2NP, UK Fax from outside the UK: +44 2392 478 555

NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of £100 for each volume (normally comprising 30–40 titles). The commercial subscription rate is £300 per volume. Please see our website for details. Subscriptions can only be purchased for the current orforthcoming volume.

Payment methods

Paying by chequeIf you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltdand drawn on a bank with a UK address.

Paying by credit cardThe following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard,Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email.

Paying by official purchase orderYou can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK.We cannot at present accept purchase orders from commercial companies or from outside the UK.

How do I get a copy of HTA on CD?

Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (seecontact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.

The website also provides information about the HTA Programme and lists the membership of the variouscommittees.

HTA


JM Burr,1* G Mowatt,1 R Hernández,2

MAR Siddiqui,1 J Cook,1 T Lourenco,1 C Ramsay,1

L Vale,1,2 C Fraser,1 A Azuara-Blanco,3 J Deeks,4

J Cairns,5 R Wormald,6 S McPherson,7

K Rabindranath1 and A Grant1

1 Health Services Research Unit, Institute of Applied Health Sciences,University of Aberdeen, UK

2 Health Economics Research Unit, Institute of Applied Health Sciences,University of Aberdeen, UK

3 Eye Clinic, Foresterhill, Aberdeen Royal Infirmary, UK4 Centre for Statistics in Medicine, University of Oxford, UK5 London School of Hygiene and Tropical Medicine, UK6 Cochrane Eyes and Vision Group, International Centre for Eye Health,

London School of Hygiene and Tropical Medicine, UK7 McPherson Optometrists and Contact Lens Practitioners, Aberdeen, UK

* Corresponding author

Declared competing interests of authors: none

Published October 2007

This report should be referenced as follows:

Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al. The clinicaleffectiveness and cost-effectiveness of screening for open angle glaucoma: a systematicreview and economic evaluation. Health Technol Assess 2007;11(41).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine.

NIHR Health Technology Assessment Programme

The Health Technology Assessment (HTA) programme, now part of the National Institute for HealthResearch (NIHR), was set up in 1993. It produces high-quality research information on the costs,

effectiveness and broader impact of health technologies for those who use, manage and provide care inthe NHS. ‘Health technologies’ are broadly defined to include all interventions used to promote health,prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.The research findings from the HTA Programme directly influence decision-making bodies such as theNational Institute for Health and Clinical Excellence (NICE) and the National Screening Committee(NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in thatthey form a key component of the ‘National Knowledge Service’.The HTA Programme is needs-led in that it fills gaps in the evidence needed by the NHS. There arethree routes to the start of projects. First is the commissioned route. Suggestions for research are actively sought from people working in theNHS, the public and consumer groups and professional bodies such as royal colleges and NHS trusts.These suggestions are carefully prioritised by panels of independent experts (including NHS serviceusers). The HTA Programme then commissions the research by competitive tender. Secondly, the HTA Programme provides grants for clinical trials for researchers who identify researchquestions. These are assessed for importance to patients and the NHS, and scientific rigour.Thirdly, through its Technology Assessment Report (TAR) call-off contract, the HTA Programmecommissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.Some HTA research projects, including TARs, may take only months, others need several years. They cancost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence,undertaking a trial, or other research collecting new data to answer a research problem.The final reports from HTA projects are peer-reviewed by a number of independent expert refereesbefore publication in the widely read monograph series Health Technology Assessment.

Criteria for inclusion in the HTA monograph seriesReports are published in the HTA monograph series if (1) they have resulted from work for the HTAProgramme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search,appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit thereplication of the review by others.

The research reported in this monograph was commissioned by the HTA Programme as project number04/08/02. The contractual start date was in February 2005. The draft report began editorial review inJune 2006 and was accepted for publication in April 2007. As the funder, by devising a commissioningbrief, the HTA Programme specified the research question and study design. The authors have beenwholly responsible for all data collection, analysis and interpretation, and for writing up their work. TheHTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like tothank the referees for their constructive comments on the draft document. However, they do not acceptliability for damages or losses arising from material published in this report.The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

Editor-in-Chief: Professor Tom WalleySeries Editors: Dr Aileen Clarke, Dr Peter Davidson, Dr Chris Hyde,

Dr John Powell, Dr Rob Riemsma and Professor Ken SteinProgramme Managers: Sarah Llewellyn Lloyd, Stephen Lemon, Kate Rodger,

Stephanie Russell and Pauline Swinburne

ISSN 1366-5278

© Queen’s Printer and Controller of HMSO 2007This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals providedthat suitable acknowledgement is made and the reproduction is not associated with any form of advertising.

Applications for commercial reproduction should be addressed to: NCCHTA, Mailpoint 728, Boldrewood, University of Southampton,Southampton SO16 7PX, UK.

Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA.Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. G

Objectives: To assess whether open angle glaucoma(OAG) screening meets the UK National ScreeningCommittee criteria, to compare screening strategieswith case finding, to estimate test parameters, tomodel estimates of cost and cost-effectiveness, and toidentify areas for future research.Data sources: Major electronic databases weresearched up to December 2005.Review methods: Screening strategies weredeveloped by wide consultation. Markov submodelswere developed to represent screening strategies.Parameter estimates were determined by systematicreviews of epidemiology, economic evaluations ofscreening, and effectiveness (test accuracy, screeningand treatment). Tailored highly sensitive electronicsearches were undertaken. Results: Most potential screening tests reviewed hadan estimated specificity of 85% or higher. No test wasclearly most accurate, with only a few, heterogeneousstudies for each test. No randomised controlled trials(RCTs) of screening were identified. Based on twotreatment RCTs, early treatment reduces the risk ofprogression. Extrapolating from this, and assumingaccelerated progression with advancing diseaseseverity, without treatment the mean time to blindnessin at least one eye was approximately 23 years,compared to 35 years with treatment. Prevalencewould have to be about 3–4% in 40 year olds with a

screening interval of 10 years to approach cost-effectiveness. It is predicted that screening might becost-effective in a 50-year-old cohort at a prevalence of4% with a 10-year screening interval. Generalpopulation screening at any age, thus, appears not tobe cost-effective. Selective screening of groups withhigher prevalence (family history, black ethnicity) mightbe worthwhile, although this would only cover 6% ofthe population. Extension to include other at-riskcohorts (e.g. myopia and diabetes) would include 37%of the general population, but the prevalence is thentoo low for screening to be considered cost-effective.Screening using a test with initial automatedclassification followed by assessment by a specialisedoptometrist, for test positives, was more cost-effectivethan initial specialised optometric assessment. Thecost-effectiveness of the screening programme washighly sensitive to the perspective on costs (NHS orsocietal). In the base-case model, the NHS costs ofvisual impairment were estimated as £669. If annualsocietal costs were £8800, then screening might beconsidered cost-effective for a 40-year-old cohort with1% OAG prevalence assuming a willingness to pay of£30,000 per quality-adjusted life-year. Of lesserimportance were changes to estimates of attendancefor sight tests, incidence of OAG, rate of progressionand utility values for each stage of OAG severity. Cost-effectiveness was not particularly sensitive to the


iii

© Queen’s Printer and Controller of HMSO 2007. All rights reserved.

Abstract

The clinical effectiveness and cost-effectiveness of screening foropen angle glaucoma: a systematic review and economicevaluation

JM Burr,1* G Mowatt,1 R Hernández,2 MAR Siddiqui,1 J Cook,1 T Lourenco,1

C Ramsay,1 L Vale,1,2 C Fraser,1 A Azuara-Blanco,3 J Deeks,4 J Cairns,5

R Wormald,6 S McPherson,7 K Rabindranath1 and A Grant1

1 Health Services Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK2 Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK3 Eye Clinic, Foresterhill, Aberdeen Royal Infirmary, UK4 Centre for Statistics in Medicine, University of Oxford, UK5 London School of Hygiene and Tropical Medicine, UK6 Cochrane Eyes and Vision Group, International Centre for Eye Health, London School of Hygiene and Tropical

Medicine, UK7 McPherson Optometrists and Contact Lens Practitioners, Aberdeen, UK* Corresponding author

iv

accuracy of screening tests within the ranges observed.However, a highly specific test is required to reducelarge numbers of false-positive referrals. The findingsthat population screening is unlikely to be cost-effectiveare based on an economic model whose parameterestimates have considerable uncertainty. In particular, ifrate of progression and/or costs of visual impairmentare higher than estimated then screening could be cost-effective. Conclusions: While population screening is not cost-effective, the targeted screening of high-risk groupsmay be. Procedures for identifying those at risk, forquality assuring the programme, as well as adequateservice provision for those screened positive would all

be needed. Glaucoma detection can be improved byincreasing attendance for eye examination, andimproving the performance of current testing by eitherrefining practice or adding in a technology-based firstassessment, the latter being the more cost-effectiveoption. This has implications for any futureorganisational changes in community eye-care services.Further research should aim to develop and providequality data to populate the economic model, byconducting a feasibility study of interventions toimprove detection, by obtaining further data on costsof blindness, risk of progression and health outcomes,and by conducting an RCT of interventions to improvethe uptake of glaucoma testing.

Abstract


v


Contents

List of abbreviations .................................. vii

Executive summary .................................... ix

1 The aim of the review ................................ 1

2 Background ................................................ 3Introduction ............................................... 3The condition ............................................. 4Burden of disease in the UK ...................... 4Current practice for glaucoma detection in the UK ................................... 5Diagnostic and treatment services ............. 6

3 Screening tests for glaucoma .................... 7Description of potential screening tests ..... 7

4 Overview of methods and definitions ....... 13Developing the screening pathways and the economic model ................................... 13Searching for the evidence ........................ 21

5 Epidemiology of open angle glaucoma ...... 25Introduction ............................................... 25Methods ...................................................... 25Results ........................................................ 27Discussion ................................................... 36Conclusions ................................................ 40

6 Screening and diagnostic tests for open angle glaucoma .......................................... 41Introduction ............................................... 41Methods ...................................................... 41Results ........................................................ 44Discussion of results ................................... 77Conclusions ................................................ 83

7 Evidence of effectiveness ........................... 85Screening for prevention of optic nervedamage due to OAG .................................. 85Effectiveness of glaucoma treatment ......... 87Probability of glaucoma deterioration frommild disease to visual impairment ............. 89

8 Economic analysis ...................................... 95Principles of economic evaluation ............. 95Systematic review of cost-effectiveness ofscreening for OAG ..................................... 95Economic evaluation of screening for OAG ............................................................ 105

9 Factors relevant to the NHS, other sectors of the economy and patients ..................... 135Potentially relevant target groups for screening .................................................... 135Estimating the numbers eligible for screening .................................................... 135Consideration of screening performance ... 136Implications for service provision .............. 139Implications for patients and their families ....................................................... 139Summary .................................................... 141

10 Does screening for open angle glaucoma meet the National Screening Committeecriteria? ...................................................... 143The condition ............................................. 143The test ...................................................... 144The treatment ............................................ 145The screening programme ........................ 145Summary .................................................... 147

11 Discussion ................................................... 149Main results ................................................ 149Assumptions, limitations and uncertainties ............................................... 150

12 Conclusions ................................................ 153Implications for healthcare ........................ 153

Acknowledgements .................................... 155

References .................................................. 157

Appendix 1 Markov model for glaucoma ... 171

Appendix 2 Literature search strategies ... 175

Appendix 3 Data extraction form:epidemiology review of open angle glaucoma .................................................... 185

Appendix 4 Included studies: epidemiologyreview of open angle glaucoma ................. 191

Appendix 5 Excluded studies: epidemiologyreview of open angle glaucoma ................. 197

Appendix 6 Characteristics of included studies: epidemiology review of open angleglaucoma .................................................... 205

Appendix 7 Modified QUADAS qualityassessment checklist ................................... 225

Appendix 8 Included studies: screening and diagnostic tests review ......................... 227

Appendix 9 Studies providing data onreliability: screening and diagnostic tests review .......................................................... 235

Appendix 10 Excluded case–control studies:screening and diagnostic tests review ........ 241

Appendix 11 Results of the quality assessment for the individual studies ......... 245

Appendix 12 Characteristics of the included studies: screening and diagnostic tests review .................................................. 249

Appendix 13 Results by type of test: screening and diagnostic tests review ........ 255

Appendix 14 Quality assessment of thesystematic review by Maier and colleagues (2005) .......................................................... 273

Appendix 15 Included studies: glaucomaprogression ................................................. 275

Appendix 16 Glaucoma progression: approach 1 – randomised trials ................. 277

Appendix 17 Glaucoma progression: approach 2 – studies .................................. 279

Appendix 18 Included studies: cost-effectiveness of screening for open angle glaucoma .......................................... 285

Appendix 19 Characteristics of includedstudies: cost-effectiveness of screening for open angle glaucoma ................................. 287

Appendix 20 Complete incremental cost-effectiveness data for each included study ........................................................... 293

Appendix 21 Interim life table ................. 299

Appendix 22 Utility scores ........................ 301

Appendix 23 Cost-effectiveness acceptability curves .................................... 303

Appendix 24 The wider costs of visualimpairment ................................................. 327

Appendix 25 Further details of the estimation of the numbers eligible andineligible for screening .............................. 329

Appendix 26 Number of people in theobservation state over time ........................ 331

Appendix 27 Costs of diagnosis and cases detected for the technician and no-screening strategies ............................... 333

Appendix 28 Diagnostic performance of the technician and no-screening strategies ..................................................... 337

Health Technology Assessment reportspublished to date ....................................... 343

Health Technology Assessment Programme ................................................ 359

Contents

vi


vii


AGIS Advanced Glaucoma InterventionStudy

ASSIA Applied Social Science Index andAbstracts

BHPS British Household Panel Survey

C-20° central 20 degrees of visual field

CCT Current Controlled Trials

CDR cup-to-disc ratio

CDSR Cochrane Database of SystematicReviews

CEAC cost-effectiveness acceptabilitycurve

CENTRAL Cochrane Central Register ofControlled Trials

CI confidence interval

CNTGS Collaborative Normal TensionGlaucoma Study

CRD Centre for Reviews andDissemination

CrI credible interval

D dioptre

DALY disability-adjusted life-year

DARE Database of Abstracts of Reviews ofEffectiveness

DOR diagnostic odds ratio

EMGT Early Manifest Glaucoma Trial

EQ-5D EuroQol 5 Dimensions

FDT frequency doubling technology

FN false negative

FP false positive

GAT Goldmann applanation tonometry

GDx VCC GDx variable cornealcompensation

GHT glaucoma hemifield test

GO glaucoma optometrist

GPS glaucoma probability score

HbA1c glycosylated haemoglobin

HF Harrington–Flock

HMIC Health Management InformationConsortium

HRQoL health-related quality of life

HRT Heidelberg retina tomograph

HSROC hierarchical summary receiveroperating characteristic

IC incremental cost

ICER incremental cost-effectiveness ratio

IGA International GlaucomaAssociation

IOP intraocular pressure

ITT intention-to-treat

MD mean deviation

MDP motion detection perimetry

MPT manual perimetry technique

MRA Moorfields regression analysis

continued

List of abbreviations

List of abbreviations

viii

List of abbreviations continued

NA not applicable

NCT non-contact tonometry

NEI National Eye Institute

NFI nerve fibre indicator

NFL nerve fibre layer

NHS EED NHS Economic EvaluationDatabase

NICE National Institute for Health andClinical Excellence

NR not reported

NRR neuroretinal rim

NS not stated

NSC National Screening Committee

NTG normal tension glaucoma

OAG open angle glaucoma

OCT optical coherence tomography

OKP oculokinetic perimetry

OR odds ratio

PS partial sight

QALY quality-adjusted life-year

QAVY quality-adjusted year of vision

QUADAS Quality Assessment of DiagnosticAccuracy Studies

RCT randomised controlled trial

RDOR relative diagnostic odds ratio

RNFL retinal nerve fibre layer

RR relative risk

RTA retinal thickness analyser

RVM relevance vector machine

SAP standard automated perimetry

SCI Science Citation Index

SD standard deviation

SE standard error

SITA Swedish interactive thresholdalgorithm

SLP scanning laser polarimetry

SROC summary receiver operatingcharacteristic

SSCI Social Science Citation Index

STV&WS Sight Test Volume and WorkforceSurvey

SWAP short-wavelength automatedperimetry

TD total deviation

TN true negative

TP true positive

VCDR vertical cup-to-disc ratio

VFQ Visual Function Questionnaire

VI visual impairment

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.


ix


BackgroundGlaucoma is the leading cause of irreversibleblindness worldwide. Open angle glaucoma (OAG)accounts for about 50% of glaucoma blindness.Prior evaluations of screening effectiveness haveconcluded that there is insufficient evidence torecommend screening for OAG; recent treatmentsappear effective in delaying progression, but long-term health outcomes are uncertain. Screeningprogrammes for OAG have not been adopted inany country. In the UK, glaucoma is detected byopportunistic case finding, usually by communityoptometrists.

ObjectivesThe objectives of this systematic review were:

● to assess whether OAG screening meets the UKNational Screening Committee (NSC) criteria

● to develop a model comparing screeningstrategies with case finding

● to estimate parameters through systematicreviews

● to model estimates of cost and cost-effectiveness● to identify areas for future research.

MethodsScreening strategies were developed by wideconsultation. In the first (‘technician’) strategy, thecohort ‘at risk’ would be invited for examination,based on measurement of intraocular pressure(IOP) and a second ‘test’ (not prespecified). Screenpositives would be referred for specialisedoptometrist assessment. In the second (‘glaucomaoptometrist’) strategy, the cohort would be invitedto a specialised optometrist for assessment.Positives from either strategy would be referred fordiagnosis, by an ophthalmologist, as occurs incurrent case finding (‘no screening’ strategy).

Markov submodels were developed to representthese strategies. Parameter estimates weredetermined by systematic reviews of epidemiology,economic evaluations of screening, and effectiveness(test accuracy, screening and treatment).

Tailored highly sensitive electronic searches wereundertaken. The date of last searches was December 2005.

ResultsIn the UK, the estimated prevalence of OAG is2.1% [95% confidence interval (CI) 1.7 to 2.5],ranging from 0.3% in people aged 40 to 3.3% inpeople aged 70 years. Incidence ranges from 30 to181 per 100,000 person-years for ages 50 and 70years, respectively. Of an estimated half a millionpeople affected, 67% are undetected. Several riskfactors are identified; for ages 40–75 years,prevalence estimates are: people with myopia 2.7%,people with diabetes 3.3% and family history in afirst-degree relative 6.7%. The risk is four timeshigher among those of African ethnicity. Insufficientdata were available to estimate prevalence in otherethnic minority groups in the UK.

Most potential screening tests reviewed had anestimated specificity of 85% or higher. No testwas clearly most accurate, with only a few,heterogeneous studies for each test.

No randomised controlled trials (RCTs) ofscreening were identified. Based on two treatmentRCTs, early treatment reduces the risk ofprogression (hazard ratio 0.65, 95% CI 0.49 to0.87). Extrapolating from this, and assumingaccelerated progression with advancing diseaseseverity, without treatment the mean time toblindness in at least one eye was approximately23 years, compared to 35 years with treatment.

The main determinant of cost-effectiveness wasprevalence. Prevalence would have to be about3–4% in 40 year olds with a screening interval of10 years to approach cost-effectiveness. It ispredicted that screening might be cost-effective ina 50-year-old cohort at a prevalence of 4% with a10-year screening interval. General populationscreening at any age, thus, appears not to be cost-effective. Selective screening of groups with higherprevalence (black ethnicity and family history)might be worthwhile, although this would onlycover 6% of the population. Extension to includeother at-risk cohorts (e.g. myopia and diabetes)

Executive summary

would include 37% of the general population, butthe prevalence is then too low for screening to beconsidered cost-effective.

Screening using a test with initial automatedclassification followed by assessment by aspecialised optometrist, for test positives, wasmore cost-effective than initial specialisedoptometric assessment. The cost-effectiveness ofthe screening programme was highly sensitive tothe perspective on costs (NHS or societal). In thebase-case model, the NHS costs of visualimpairment were estimated as £669. If annualsocietal costs were £8800, then screening might beconsidered cost-effective for a 40-year-old cohortwith 1% OAG prevalence assuming a willingness topay of £30,000 per quality-adjusted life-year. Oflesser importance were changes to estimates ofattendance for sight tests, incidence of OAG, rateof progression and utility values for each stage ofOAG severity. Cost-effectiveness was notparticularly sensitive to the accuracy of screeningtests within the ranges observed. However, ahighly specific test is required to reduce largenumbers of false-positive referrals.

The findings that population screening is unlikelyto be cost-effective are based on an economicmodel whose parameter estimates haveconsiderable uncertainty. In particular, if rate ofprogression and/or costs of visual impairment arehigher than estimated then screening could becost-effective.

ConclusionsImplications for healthcareScreening for OAG met the UK NSC criteria forcondition and treatment, but not for test orscreening. Population screening is not cost-effective, but targeted screening of high-riskgroups may be. Measures systematically to identify those at risk and quality assure the

programme would be required. Adequate serviceprovision for those screened positive would beneeded.

Glaucoma detection can be improved byincreasing attendance for eye examination, andimproving the performance of current testing byeither refining practice or adding in a technology-based first assessment, the latter being the morecost-effective option. This has implications for anyfuture organisational changes in community eye-care services.

Implications for research Further research should aim to develop andprovide quality data to populate the economicmodel, by undertaking the following, in order ofpriority.

First, a feasibility study of interventions to improvedetection; input from qualitative researchers,health economists, health psychologists andtrialists is required to evaluate components of thecare pathway:

● optimal test strategy● acceptability of interventions to improve

attendance and the acceptability of subsequenttesting

● harms and benefits associated with enhancedglaucoma detection strategies.

Secondly, a refinement of the parameter estimatesin the economic model. In particular, further dataon costs of blindness, risk of progression andhealth outcomes are required. A value forinformation analysis would inform where primaryresearch should be directed.

Thirdly, an RCT of interventions to improve theuptake of glaucoma testing, informed by theresults of the prior feasibility studies.

x

Executive summary

This report was commissioned to evaluate theclinical effectiveness and cost-effectiveness of

screening for open angle glaucoma (OAG) in theUK. Specifically, secondary research with economicmodelling was required to assess the extent towhich screening for OAG would meet the NationalScreening Committee (NSC) criteria for ascreening programme and to identify futureresearch needs.

The specific objectives were:

● to review systematically risk factors fordeveloping OAG, and to determine theprevalence and incidence of OAG according toage

● to review systematically the accuracy ofscreening tests for OAG

● to review systematically treatment effectivenessand to extrapolate these effects on long-termvisual outcome

● to identify any potential benefits and harms ofscreening and subsequent management

● to determine the clinical and cost-effectivenessof alternative screening strategies

● to assess whether screening for OAG meetsspecified criteria for a national screeningprogramme

● to describe the impact on the NHS if apopulation screening programme for OAG wereinitiated

● to identify and prioritise areas for futureresearch.


1


Chapter 1

The aim of the review

IntroductionGlaucoma describes a group of eye diseases, inwhich there is progressive damage to the opticnerve leading to impaired vision and blindness ifuntreated. The primary glaucomas (those that arenot a consequence of other eye or systemicdisease) can be classified as OAG or angle closureglaucoma. These two types are distinguished bythe anatomy of the anterior segment of the eye, asillustrated in Figure 1.

Angle closure glaucoma, although less commonthan OAG, is more likely to result in bilateralblindness and is estimated to be the cause of 50%of glaucoma blindness worldwide.1,2 Whilescreening for angle closure glaucoma may beappropriate for other country settings, it is adifferent disease from OAG, with different riskfactors, and different screening tests are requiredfor early detection. The epidemiology of OAG isdescribed in detail in Chapter 5.

This report was commissioned to assess whetherscreening for OAG would be worthwhile in theUK. Screening for OAG among ‘at-risk’ targetpopulations with interval screening offered atselected sites has not been adopted in any country,but a number of ad hoc strategies exists, withclinical guidelines for the detection andsubsequent management of glaucoma.3–7

For screening for OAG to be considered, severalcriteria should be addressed. In the UK, the NSCprovides advice to government on whichpopulation screening programmes should beintroduced. The NSC uses a set of criteria, basedon the original WHO criteria,8 but developed overthe years to take account of new scientificdevelopments. These criteria are available on theNSC website.9 Not all the criteria are relevant toOAG, but most are. In brief, the condition shouldbe an important public health problem, thereneeds to be an acceptable test or combination oftests that are able to detect sufficient people at riskof visual impairment to justify testing largenumbers of people who are not at risk, earlytreatment must be effective and acceptable, andappropriate diagnostic and management facilitiesto care for people with detected glaucoma must beavailable. The benefits of screening must outweighthe risks, and the programme needs to be cost-effective and practically feasible. The NSC, incooperation with the Welsh Assembly, convened aworkshop on screening for glaucoma inSeptember 2001 and a report has been issued.10

The current NSC policy is that screening for OAGis not yet recommended, and the topic is due forreconsideration in 2008.11

A recent health technology assessment report forthe US Preventative Services Task Force found thatscreening can detect early OAG in adults and that


3


Chapter 2

Background

Ciliary body

Trabecular meshwork

Anteriorchamber

Iris

Lens

Flow of aqueous humour

Open angle Closed angle

Cornea

FIGURE 1 Anterior segment of the eye (open angle and closed angle)

early treatment reduces the number of peoplewhose visual field defects progress, but that theevidence was insufficient to determine whether ascreening programme would reduce impairmentof vision or impairment of quality of life.12

New potential screening tests for OAG areavailable,13–17 and recent evidence on theeffectiveness of treatment18,19 justifies a furtherevaluation of the effectiveness of screening forOAG.

The conditionOAG is diagnosed primarily by glaucomatousoptic neuropathy (cupping) and a compatiblevisual field defect, in the presence of an open,normal appearing, anterior chamber angle. Raisedintraocular pressure (IOP) of at least 21 mmHg(two standard deviations above the mean) used tobe considered as a part of the definition of OAG,but population studies have consistently foundthat many people with OAG have an IOP belowthis level.20–24 The risk of developing glaucoma,and for worsening of existing glaucoma, does,however, increase with increasing IOP.25–27 Moreadvanced disease at diagnosis is also associatedwith a higher IOP.23,28

Typical early glaucomatous changes in the opticdisc include localised or generalised thinning ofthe neuroretinal rim, with increased enlargementof the optic cup and an increased cup-to-disc ratio(CDR). As glaucoma advances, there is furtherneuroretinal rim thinning until the cup occupiesmost of the disc area (Figure 2).

Currently, the only treatment for OAG is to lowerthe IOP. This can be done medically, usually witheye drops, or surgically, by laser, or anycombination of these. The effectiveness of OAGtreatments is evaluated in a number of ongoing orcompleted Cochrane reviews,18,29–31 and isdiscussed in Chapter 7.

Burden of disease in the UKGlaucoma is second to age-related maculardegeneration as the most common cause ofblindness in adults in the UK and Ireland.32–35

The statutory definition of blindness is that “aperson should be so blind as to be unable toperform any employment”. There is no equivalentdefinition for partial sight, but it refers to peoplewho are not blind, but who are substantially andpermanently disabled by defective vision.36

Ophthalmologists register new cases of blindnessand partial sight with the local authorities acrossthe UK. Registration is voluntary; it is aprerequisite for receiving certain social securitybenefits, but not for all social service concessions.The recommendations for blind and partial sightregistration, based on the vision of the better eye,are as described in Box 1.

The frequency of glaucoma as a cause of blindnessor partial sight is reported as incidence (newcases) and prevalence (all cases). Registration dataare available for England, Scotland and Wales,37–39

but recent estimates of incident visual impairmentare not available for Northern Ireland. InEngland, Scotland and Wales, 31,676 people were

Background

4

Cup

Neuroretinal rim

Disc

Disc

(a) (b)

FIGURE 2 The optic nerve in OAG: (a) healthy optic nerve (reproduced with permission from AgingEye Times, www.agingeye.net); (b) advanced glaucoma damage (reproduced courtesy of A Azuara-Blanco)

registered as incident visual impairment (blindand partial sight registrations) in 2002/03,although data were not detailed according tocauses of visual impairment.

A detailed analysis of main causes of blindness forEngland and Wales in 1990/91 found thatglaucoma was the main cause in 11.7% of incidentblind registrations and 9.6% of partial sightregistrations for all ages, and a contributing causein another 8% of blind and 4% of partial sightregistrations.34 People may be registered using thespecific term OAG or simply as ‘glaucoma,unspecified’. A more recent analysis of certificationsof visual impairment in England and Wales in1999/2000 found similar proportions, withglaucoma accounting for 10.9% of blindness and10.2% of partial sight registrations, although theanalysis was not detailed according to registrationsspecifically for OAG.32 Applying these proportionsto registration data for 2002/03, it can be estimatedthat 3108–3138 people aged over 50 years werenewly registered with visual impairment (blind andpartial sight) due to glaucoma in England andScotland in 2002/03. There are at least 1192 newregistrations of incident visual impairment due toOAG as the main cause, but the true number maybe higher than this, as some OAG cases wouldhave been registered as glaucoma non-specified.Data for Wales were not detailed according to ageand are not included.

Data on blind and partial sight registration maynot be accurate for several reasons. The criteriafor registration are subjective, some eligiblepeople do not wish to be registered andophthalmologists may not offer registration tothose who are eligible. Analyses of people eligiblefor blind and partial sight registration fromattendees at ophthalmology departments in threecentres in the UK have estimated that up to 50%of individuals eligible for blind or partial sightregistration are not registered.32,40,41 These studies

were consistent in their findings that peopleeligible for partial sight registration were less likelyto be registered than people eligible for blindregistration. People with visual field loss alonewere less likely to be registered than people withimpaired central visual acuity, and peopleundergoing long-term treatment and follow-upwere less likely to be registered or haveregistration delayed compared with people with acondition that was untreatable and not underlong-term follow-up, for example age-relatedmacular degeneration.32,40,41 It is therefore likelythat many more people have visual impairmentdue to OAG than currently recorded in the UKblind and partial sight registration system.

Vision below the level that is required for drivingis a major burden of glaucoma, and is notnecessarily reflected in the visual impairmentstatistics, but is of importance to those affected.The number of people who have been forced tosurrender a driving licence on account ofglaucoma visual field loss is not captured bynational statistics, but would be an importantindicator of the burden of glaucoma.

Current practice for glaucomadetection in the UKIn the UK, community optometrists are the keyproviders of primary eye care; general medicalpractitioners do not usually have access tospecialist equipment or the necessary training andskills to detect glaucoma. The majority (90%) ofreferrals to secondary care ophthalmology assuspect glaucoma are initiated from anoptometrist.42–44 Current detection strategies areopportunistic, based on optometrist case findingor open access where the population tested is self-selecting. In the UK, apart from Scotland, onlyselect groups qualify for a free sight test; suchgroups are people aged over 40 years with afamily history of glaucoma, people aged over60 years and those on income support. Guidelinesexist for a more detailed eye examination in at-risk groups; the optometrist is advised toundertake an assessment of the optic nerve head,perform tonometry and undertake a central visualfield assessment.45 ‘At risk’ is not, however, definedand is at the discretion of the practitioner: a sighttest may not necessarily include testing forglaucoma, and, as such, cases, particularly earlyglaucoma, are missed.

In summary, the current service does notconstitute a formal attempt to reach and test


5


Blindness● Acuity worse than 3/60 ● Acuity better than 3/60, but below 6/60 with a very

restricted visual field

Partial sight● From 3/60 to 6/60 with a full visual field ● Up to 6/24 with moderate restriction of the visual

field● 6/18 or better with a gross visual field defect

BOX 1 Recommendations for blind and partial sight registration

everyone at risk in a defined population and isopportunistic surveillance rather than screening.46

Guidelines are provided by the College ofOptometrists45 about which tests should be doneand when, but these are not mandatory, and assuch a sight test often does not detect glaucoma.Uptake of sight testing by the population isvariable and members of more deprivedcommunities are less likely to seek testing.47 TheGeneral Ophthalmic Services in Scotland havebeen reviewed, and as from April 2006, provisionhas been made to provide free NHS eyeexaminations for all. The thrust of the new serviceis to move away from the current emphasis of asight test on refraction to a broader eye healthassessment appropriate to the patient’s needs,including a more extensive examination toimprove glaucoma detection.

Diagnostic and treatment servicesCurrent, usual practice is that suspect glaucomacases identified by community optometrists are

referred to secondary care for anophthalmologist’s opinion with treatment,observation or discharge as required. Peoplerequiring treatment or observation as high-risksuspects remain under review by anophthalmologist.

With an ageing population and improveddetection, the current diagnostic and managementservice in secondary hospital care is likely tobecome increasingly overloaded. Several schemesare in operation in the UK, which aim to alleviatethe pressure on the hospital eye service andimprove glaucoma care, by using glaucoma-trained optometrists, or nurse practitioners in co-managed shared care treatment andmonitoring schemes, which may be hospital orcommunity based.48–50 National initiatives todefine and develop clinical care pathways forglaucoma are underway.51–54 These, together witha review of general ophthalmic services55 and aconnected information technology system in theNHS, provide the basis for a standardiseddiagnostic and treatment service for glaucoma.

Background

6

Description of potential screeningtestsIdeally, a screening test for OAG should be safe,easy to administer and interpret, portable, quick,acceptable to the people who are to be tested, andsufficiently valid to distinguish between those whodo and do not have OAG.

Tests for glaucoma involve an assessment ofstructural changes at the optic nerve head,functional visual loss by visual field testing and thelevel of the IOP. It is not always possible to make adefinitive diagnosis using these criteria. A personcould have a media opacity precluding a view ofthe optic disc, or visual field testing may not bepossible, and in these circumstances diagnosis ismade on only one of these findings or severevisual loss with raised IOP.56

Many commercial devices, particularly forassessing structural damage, are now available.The following sections describe candidatescreening tests for OAG. The diagnosticperformance of the candidate screening tests isreported in Chapter 6.

Intraocular pressureMeasurement: contact and non-contacttonometryContact tonometry and non-contact tonometry(NCT) are quick, taking about 1–2 minutes pereye.

Contact tonometryThe most widely used and generally acceptedreference standard for measuring the IOP isGoldmann applanation tonometry (GAT). GATuses a prism to apply an external force to thecornea to indent and flatten its surface.57 The twogeneral sources of error with Goldmanntonometry can be categorised as those caused byfaults in the application of the technique andthose related to biological variability of the humaneye, both normal and pathological. Of particularnote is the error induced by variability in thecentral corneal thickness. GAT is mounted onto aslit-lamp, which limits its convenience, and isusually performed by trained optometrists, nursesand ophthalmologists. A clinical background is not

essential; with training a technician can performGAT.

The Perkins tonometer is a portable device that issimilar to the Goldmann tonometer. Like theother portable devices, it is useful in situationswhere a patient cannot be seated at a slit-lamp,such as bedside examinations, the operating room, nursing homes, remote areas and massscreenings.

The Tonopen is an automated handheldapplanation tonometer based on theMacKay–Marg tonometer.58 It is small, light andbattery operated, but may be less accurate thanGAT.

There are potential problems with using contacttonometry in a screening situation in that contactwith the tear film and the cornea may raiseconcerns regarding transmissible disease.Chemical disinfection is required after each test toreduce the risk of cross-infection.

Disposable prisms for Goldmann and Perkinstonometry or disposable covers for the Tonopentip avoid the risk of cross-infection but incuradditional costs. Disposable prism tonometry is,potentially, a reliable alternative to GAT.59

Non-contact tonometryNCTs applanate the cornea with a puff of air.60

Measurement errors are larger in patients whosqueeze their eyelids or who blink rapidly inresponse to the startling jet of air, and in eyes withmoderately elevated IOPs. The advantages ofNCT include speed, no anaesthetic and low riskfor corneal abrasion (hence more suitable fortechnician operation) and, since there is no directcontact with the eye, any infection control issuesare avoided.

Population distribution of IOPIOP in the population is normally distributed with an additional tail towards higher levels ofIOP (Figure 3). The mean IOP in adultpopulations is consistently estimated at15–16 mmHg, with a standard deviation (SD) of2.5–2.8 mmHg.20–22,61–66 Other factors (ethnicity,diabetes, systolic blood pressure, family history of


7


Chapter 3

Screening tests for glaucoma

glaucoma, myopia) influence the population IOPdistribution.67 There is a marked overlap of IOPdistributions between those with and withoutglaucoma. In people with glaucoma the medianuntreated IOP has been estimated to be26 mmHg.62,68

Structural damageStructural damage is assessed clinically by asubjective assessment of the optic nerve head (theoptic disc) and/or by evaluating the retinal nervefibre layer.

Ophthalmoscopy (direct and indirect)Direct ophthalmoscopy (i.e. with a directophthalmoscope), best performed with the pupilsdilated and the room darkened, provides amagnified view of the optic disc. The maindisadvantage is the absence of a stereoscopic view.The examiner has to use indirect cues to allow theinterpretation of the optic disc as a tridimensionalstructure. Furthermore, direct ophthalmoscopydoes not yield a permanent record, and theexaminer is required to draw the optic disc toallow subsequent comparisons.

Binocular ophthalmoscopy has the advantage ofstereopsis, allowing a tridimensional observationof the optic disc. Current practice consists of theuse of a standard slit-lamp biomicroscopyassociated with non-contact lenses (60D or 78D).The possibility of achieving stereopsis depends onthe pupil’s size, which often needs to be dilated,the image is inverted and additional training is

required for accurate interpretation. It is alsopossible to use the slit-lamp in association with acontact lens (e.g. the Goldmann lens), but thistechnique requires the use of a topical anaestheticand a viscoelastic substance between the lens andthe cornea. Despite being more uncomfortable,the image provided is excellent with highmagnification and is not inverted, making foreasier interpretation.

Optic disc photography (monoscopic andstereoscopic)A wide variety of digital and non-digital cameras isavailable to provide colour images of the opticdisc. Photography has the advantage overophthalmoscopy of a permanent recording of theoptic disc, but has the same limitations of ideallyrequiring a dilated pupil and clear media, that is,no significant cataract. Monoscopic photographscan be obtained with a standard fundus camera;however, the tridimensional structure of the opticdisc can only be assessed by stereophotography.Stereoscopic pictures can be obtained withsequential photographs using a standard funduscamera by horizontal realignment of the camerabase when photographing the same retinal image.Alternatively, simultaneous stereoscopic fundusphotographs can be obtained using a camera witha beam-splitting prism to capture two images ofthe fundus taken simultaneously at a fixed relativeangle. Digital stereophotographs may be viewed ina number of ways, using either stereoviewers orflicker glasses, which rapidly alternate the imagebetween the left and right eye of the observer.69


8

10 20 30 40

Mean(16)

+2 SD(21)

P

NG

IOP (mmHg)

Freq

uenc

y

FIGURE 3 Intraocular pressure (IOP). G, glaucoma population; N, normal distribution; P, frequency of distribution of IOP in population.

Population distribution of CDROptic disc changes typical of glaucoma includevertical and generalised thinning of theneuroretinal rim, localised thinning and notching,and displacement of the retinal vessels. Aconsensus definition for glaucomatous opticneuropathy has been proposed whereby a CDRabove which 2.5% of the normal population liedefines the upper limit of normal.56 Optic discparameters, particularly size of the optic disc, varyfor different populations; in Europeanpopulations, the 97.5% centile typically equates toa vertical cup-to-disc ratio (VCDR) of 0.770 and isgenerally considered to be the most usefulparameter for determining glaucoma in thepresence of a visual field defect.56 Cup discasymmetry of 0.2–0.3 could also be used to defineglaucoma.71,72 For subjects in whom a reliablevisual field test is not possible, a cut-off exceedingthe 99.5th percentile (i.e. a VCDR � 0.9), in mostpopulations, would define glaucoma. Cup disc sizevaries between populations with small discs havingsmall cups that may be pathological, and viceversa for large discs. Thus, the division betweennormal and abnormal for optic disc parameters isnot clear, and therefore a screening test based on asubjective assessment of glaucomatous optic nervedamage would require an experienced observer todiagnose glaucoma accurately.

Retinal nerve fibre layer photographyThe appearance of the retinal nerve fibre layer(RNFL) may be documented using high-resolutionblack and white images, where the fibre bundlesare seen as silver striations, most visible in thesuperior and inferior poles of the optic disc(Figure 4). The technique includes the use of agreen or blue filter with either standard or digital

photography. The quality of RNFL image is poorin eyes with small pupils and media opacities.Furthermore, the technique is subjective andrequires an experienced observer forinterpretation. A manual with a reference set ofRNFL images is available to guide technicians inthe reading of such images.73

Quantitative analysis of the optic nerve head andRNFLScanning laser tomographyConfocal laser scanning imaging technology, usedby the Heidelberg retina tomograph (HRT;Heidelberg Engineering, Heidelberg, Germany),exploits the principle of confocal laser scanning toallow quantitative structural information.

The topographic image is derived from multipleoptical sections at consecutive focal depth planes.Each image consists of numerous pixels, with eachpixel corresponding to the retinal height at itslocation. The device is operator dependent in thatthe optic disc margin needs to be defined by acontour line manually placed around the innermargin of the peripapillary scleral ring. Thesoftware calculates stereometric parameters withinthis line. These parameters are computed for thewhole of the optic nerve head, and for sixpredefined sectors.

The HRT II is compact and relatively easy to use,pupil dilation is not required and cataracts do notprevent imaging. Specific training is required incontour line placement, which can be a source oferror in image analysis. Measurement time isabout 10 minutes per eye.13,14 HRT III is nowavailable and does not require manual drawing ofthe contour line.


9


RNFL defecttypical of glaucoma

FIGURE 4 The retinal nerve fibre layer (reproduced courtesy of A Azuara-Blanco)

Population distribution of test parametersThe commercially available HRT II device reportsthe Moorfields regression analysis (MRA) as aclassification system for glaucoma. Thisclassification is based on a normative database of80 normal white participants, with a refractiveerror of less than 6 dioptres (D).74 Theneuroretinal rim (NRR) is thinned in glaucoma,and the MRA has derived limits for normalitybased on the area of the NRR, classified for eachsegment of the optic disc. Three diagnostic classesare given: within normal limits (the NRR area lieswithin the 95% prediction interval of normal),borderline (between 95% and 99%) and outsidenormal limits (beyond 99.9%). This is a statisticalclassification, based on a narrowing of the NRR.The classifications of borderline and outsidenormal limits are considered as indicative of OAG,but definitive diagnosis requires other relevantclinical data.

However, the normative database is based on smallnumbers and may not be valid for non-whitepopulations, people with high refractive error andlarge or tilted optic discs; as such, the resultsshould be interpreted with caution. The HRT IIIincorporates a new, larger, race-specific database.This new normative database consists of 733 eyesof white people and 215 eyes of black people. Thesoftware v3.0 calculates the glaucoma probabilityscore (GPS), a new, automated algorithm thatevaluates both optic disc and parapapillary RNFLtopography to estimate the probability ofglaucoma. The GPS uses a new sophisticatedversion of artificial intelligence known as arelevance vector machine (RVM) that estimates thelikelihood of glaucoma. No contour line orreference plane is used in the GPS calculation, andtherefore it is completely an operator-independentanalysis.

Data are limited on the distribution of HRTparameters in the general population and this isrelevant to the use of the HRT as a screeningdevice for OAG. In the UK, a study evaluatingscreening for eye disease75 is ongoing (theBridlington eye assessment project), where peopleaged over 65 years receive a comprehensive eyeexamination by a trained optometrist, with theexamination including optic disc imaging usingthe HRT II. Women were found to havesignificantly larger rim volume, mean RNFLthickness and cross-sectional area than men, andtended to have smaller cup areas and volumes andcup-to-disc area ratios than men. It is also worthnoting that the performance of the HRT isdependent on the optic disc size.76,77 For HRT II

to be used in a screening situation the diagnosticcriteria for classification as normal and abnormalneed to be appropriately defined. Asymmetricalthinning of the NRR is recognised as one of thediagnostic criteria for OAG. In the sameBridlington population study, a reference rangefor rim to disc area asymmetry in a normal elderlypopulation was defined, with this measure havingthe advantage over other HRT parameters ofbeing independent of age, gender and disc size. Ameasure of between-eye NRR asymmetry could beused to discriminate between normals andabnormals for screening purposes.78

Scanning laser polarimetryScanning laser polarimetry (SLP) measures theRNFL thickness objectively based on thebirefringent properties of the RNFL, which has itsneurotubules disposed in an organised, parallelfashion. This peculiar anatomy leads to a rotationof the plane of polarised light as it passes throughthe RNFL, creating a retardation that is directlyproportional to its thickness. The current model(GDx VCC) introduces variable cornealcompensation to enhance the accuracy of themeasurements. The GDx VCC is user friendly andcompact, and pupil dilation is not required. Atechnician can perform the test. The disadvantageis that eyes with optic disc abnormalities, such aslarge myopic discs with peripapillary atrophy,cannot be imaged reliably. The GDx VCC canacquire images in less than 3 minutes for botheyes.

Population distribution of test parametersThe normative database characterises the normaltridimensional RNFL thickness, and individualpatient profiles are compared with the normativedatabase, thus indicating RNFL loss due todisease. The database also includes data onglaucoma subjects and is the basis of the machineclassifier, the nerve fibre indicator (NFI), forindicating OAG damage. There is a wide range of RNFL thickness values among normalindividuals, with overlap between normal and eyeswith OAG. The GDx NFI is intended to supply theclinician with a method of glaucoma diagnosis,and the higher the NFI the greater the likelihoodthat the eye has glaucoma. A score of 0–30 isconsidered normal, 31–70 indicates that the eye issuspect for glaucoma and 71–100 indicates thatthe eye is glaucomatous. The GDx VCC normativedatabase contains 811 (540 normal, 271glaucoma) patients. Ethnic minorities are wellrepresented on the database: Caucasians andHispanics 70%, African-Americans 18% and Asians 12%.79


10

Optical coherence tomographyThe RNFL thickness is also measured by opticalcoherence tomography (OCT). OCT is an opticalimaging technique capable of providing high-resolution, cross-sectional, in vivo imaging of thehuman retina in a fashion analogous to B-scanultrasonography, but using light instead ofsound.80 The first commercial system was availablein 1996; the latest generation OCT3 system isStratus-OCT. Early OCT systems required a pupilsize of at least 5 mm. OCT3, however, operateswith a 3-mm pupil size, which suggests, like non-mydriatic fundus cameras, that pupil dilation isnot required when operated in a darkened room.Posterior subcapsular cataracts and corticalcataracts can impair measurement.14

Population distribution of test parametersA single score of overall RNFL thickness averagedover 12 clock-hour thicknesses is compared with anormative database derived from responses from350 individuals aged between 20 and 80 years.81

An abnormal result is defined as below 5% levelcompared with the normal population. Thedistribution of OCT parameters has not beendescribed in a population setting.

Retinal thickness analyserThe retinal thickness analyser (RTA), commerciallyavailable since 2000 (Talia), combines a colourdigital fundus camera with a laser-based system(helium–neon laser, wavelength 543 nm) formeasuring nerve fibre layer thickness. One scancovers 3 × 3 mm, which consists of 16 optical capitalcross-sections with the laser. Each cross-section is187 µm apart and 3 mm long. In the posterior polethickness mode, five such scans at the centre, supertemporal and infer temporal, and superonasal andinferonasal areas of the posterior pole, which coveran area of 6 mm × 6 mm, are performed for eachmeasurement. The performance of the RTA isaffected by media opacities.

Visual function testsFrequency doubling technologyThe clinical test procedure measures contrastthreshold in 19 visual field locations within thecentral 20 degrees of the visual field (C-20°). Itcan be used in threshold and suprathresholdscreening mode. In the suprathreshold mode ittakes about 1 minute per eye. Recently, FDTMatrix, a 24-2 version of frequency doublingtechnology (FDT), has been introduced. FDT isportable and user friendly, and moderateuncorrected refractive errors, a common findingin the general population, do not appear tointerfere with FDT testing.

Population distribution of test parametersNormative data were based on examination of 407healthy people, aged between 14 and 85 years, toprovide a basis for establishing the probabilityplots for FDT perimetry.82 Using the C-20°–1algorithm, the initial level presented would bedetected by 99% of the normal population of aparticular age, and is therefore designed to have ahigh specificity. Using the C-20°–5 algorithm theinitial level presented would be detected by 95% ofthe normal population of a particular age and istherefore a test aimed to optimise sensitivity.

Motion detection perimetry This test measures the ability to detect movementin the peripheral retina, which may be impaired inglaucoma. There are several types of stimuli thatcan be used to explore motion sensitivity: a line, adot or a patch of dots. Motion detection perimetry(MDP) takes longer and may be more difficult forpeople to perform than standard perimetry,although its reliability appears not to be affectedby cataract or pupil size. There is, as yet, nocommercially available instrument, and theprinciple of motion detection as a screening toolfor OAG needs further evaluation.83

Oculokinetic perimetryOculokinetic perimetry (OKP) with the Damatochart is a simple and inexpensive visual field testdevice. Damato campimetry consists of 20numbers located on a flat, white card within thecentral 30 degrees of visual field. The subject isrequired to refixate from number to number,sequentially reporting whether the central 1.5-mmblack spot is visible. There is a 40-cm hinged piecethat serves to maintain the appropriate testdistance and occludes the non-tested eye. Anypoint missed, other than the physiological blindspot area, is confirmed once before considering ita true missed point. A modified version iscurrently available (free of charge) on theInternet.84,85 This test, either in card form or webbased, is quick, simple and available, and if ofsufficient diagnostic validity would be valuable as ascreening test.

Short-wavelength automated perimetryShort-wavelength automated perimetry (SWAP) isa modification of automated static thresholdperimetry and is purported to detect very earlyloss of sensitivity in the visual field. SWAP uses ayellow background and large, blue stimuli to testthe blue cones. The blue cone system is slower andhas a low visual acuity (about 20/200). As aconsequence, the stimulus is perceived as fuzzy,and the test is more difficult and time-consuming.


11


Uncorrected refractive errors have less of an effecton the thresholds determined by SWAP, but lensopacities tend to result in profoundly depressedfields that are difficult to interpret.

Population distribution of test parametersGlaucomatous visual field defects include,classically, arcuate scotomas within the central25 degrees, nasal step, diffuse loss of sensitivity,hemispheric loss and eventually only a centralisland of vision remaining. There are manydefinitions of abnormality based on the number ofabnormal points, the pattern of visual field loss,the depth of the defect and the glaucomahemifield test (GHT). Normative databases areestablished for standard automated perimetry14,86

and for the more recent Swedish interactivethreshold algorithms (SITA) based on 330 peoplewith no evidence of OAG.87

The GHT is widely used to distinguish betweenabnormal and normal results on standardautomated perimetry.88 The GHT is based on acomparison of the expected sensitivity in thesuperior hemifield to the inferior hemifield. Onstandard SAP testing, the GHT is reported asabnormally high sensitivity, within normal limits,generalised reduction in sensitivity,borderline/generalised reduction in sensitivity,borderline, and outside normal limits. The lattertwo classifications generally are taken as suspiciousof glaucoma.

Standard automated perimetryStandard automated perimetry (SAP) is consideredto be the reference standard in visual field

examination of glaucomatous patients. SAPestimates the threshold sensitivity of several pointswithin the visual field. The target locations remainconstant and the brightness is modified in astaircase approach to estimate the sensitivity. SAPis able to quantify the reliability, and compare theactual examination with an age-matched normaldatabase. Examination of the visual field inglaucoma is usually limited to the central 30- or24-degree area, since almost all clinically relevantdefects fall within this area. The most commonlyused automated perimeter in the UK inophthalmology clinics is the Humphrey perimeter,now with SITA, which speeds up the testingprocess.

Suprathreshold testing with automated perimetryinvolves the use of stimuli that are of greaterintensity than the presumed threshold at eachlocation. This test strategy does not quantify thedepth of visual field defects, but is much quickerthan threshold testing.

The proportion of people able to undertake thetest reliably, and the need for confirmatory testing,could limit the usefulness of standard automatedperimetry as a screening test. However, perimetrydoes have the advantage of its availability, in thatmost community optometric practices areequipped with automated perimeters.


12

In this chapter an overview of methods ispresented including the clinical pathways

and details of the structure of the economicmodel. This overview is used to provide a structure to the rest of this report. Data related to the issues and methods used are reported in subsequent chapters as described towards theend of the section ‘Economic model’ (p. 15).

Developing the screeningpathways and the economicmodelScreening pathwaysThere are various options for a screeningprogramme. The options were explored bypersonal communication with UK experts in thediagnosis and management of OAG(ophthalmologists and optometrists).

The key questions asked were:

● Who should be invited for screening and howwould these groups be identified?

● Which of the many candidate screening tests orcombinations of tests should be used to screenfor OAG?

● Should level of IOP be used as part of ascreening strategy and, if so, what cut-off of IOPshould be used?

● Where should screening take place and whoshould perform it?

● Should screen-positive people be diagnosed and managed in primary care by optometristsor in secondary care either by ophthalmologistsor a supervised care glaucoma diagnosticservice?

The pathways were presented to the followingpatients and professional groups for refinement: ameeting of the European Glaucoma Society inBrussels, October 2005; a meeting with patientrepresentatives from the International GlaucomaAssociation (IGA) convened in Aberdeen, October2005; and an advisory group to the NSC onscreening for OAG in the UK, convened inNovember 2005. The latter group consisted ofrepresentatives of specialist societies,

ophthalmology, optometry, nurses and a patientgroup.

As described in Chapter 3, many potentialscreening tests are now available. There was noconsensus on which test or combination of testsshould be recommended as a screening test. Asexplained in Chapter 2, the level of IOP does notdefine OAG, but the risk of OAG increases withincreasing IOP and the rate of progression mayalso correlate with higher IOP. There was ageneral consensus on the inclusion of IOP level toidentify people of high risk of developing severeglaucoma, and an IOP of 26 mmHg was generallyagreed as a cut-off. There were concerns that thiswould miss a significant number of cases of low-pressure OAG and therefore an additional test ortests for people with an IOP below 26 mmHgshould be considered.

It was generally agreed that screening should startat 50 years, but for higher risk groups (e.g. peoplewith a family history of OAG or of Africanethnicity), screening at 40 years should beconsidered. It was agreed that identifying siblingsof newly diagnosed OAG was not currentlyfeasible. If such an approach to screening were tobe implemented a register of incident OAG caseswould be required.

The high demand on already stretched hospitaleye departments was highlighted as a concern if apopulation screening programme was introduced.However, for the purpose of this evaluation, theadvisory group to the NSC felt that this projectshould evaluate the performance of the tests andthe impact on the number of cases detected, butthat this should be modelled through the existingdiagnostic pathway where suspected cases arereferred to hospital eye departments as if therewere the capacity to do this. If screening appearedviable, further research would be needed toevaluate the best strategy for managing the newlydiagnosed cases.

The outcomes of these discussions led to thedevelopment of two alternative strategies for ascreening programme, and the economic modelwas developed to compare these with the currentsituation of opportunistic screening.


13


Chapter 4

Overview of methods and definitions

Current case findingCurrent practice involves the opportunisticscreening of individuals presenting to communityoptometrists for an eye test (Figure 5). Individualswho test positive are referred to secondary care fordiagnosis by an ophthalmologist (i.e. the referencediagnosis).

Screening strategiesBoth potential screening strategies consideredwould involve inviting a prespecified cohort of at-risk individuals for screening. At-risk groupsmay be identified on the basis of age and anotherfactor such as family history of OAG or ethnicity.

Screening by invitation to a glaucoma-trainedoptometristIn the first of the screening strategies consideredtesting would be performed by a glaucomaoptometrist (Figure 6). Glaucoma-trainedoptometrists are optometrists who have receivedadditional training in glaucoma diagnosis andmanagement and have been accredited, usually byassessment by a consultant ophthalmologistspecialising in glaucoma. The glaucomaoptometrist would perform a full ophthalmicexamination, measurement of the IOP, andexamination of the optic nerve and visual fields,using the equipment available in the particularoptometric practice. People considered to haveglaucoma, or to be highly suspect of glaucomawould be referred to an ophthalmologist for a

definitive diagnosis, as in current practice. Othersignificant eye pathology might also be identifiedby the glaucoma optometrist, although thispossibility has not been included in the economicmodel described below. Furthermore, with thisstrategy some of the cases of OAG may still beidentified by opportunistic screening.

Screening by a technicianIn the second screening strategy the population tobe screened would be invited to a primary caresetting to undergo a measure of IOP and a singlescreening test by a technician or nurse, who hasreceived some training (Figure 7).

This screening pathway incorporates IOPmeasurement by applanation tonometry, with acut-off of an IOP of at least 26 mmHg being usedto identify groups at higher pretest probability ofdeveloping serious OAG. A second test is used forpeople with an IOP below 26 mmHg. The choiceof second test depends on which of the alternativetests has the best balance of diagnostic accuracy,the proportion of people able to do the test andavailability. People with an IOP of at least26 mmHg, and people with an IOP below26 mmHg and positive on the second test wouldbe referred for diagnostic assessment by aglaucoma-accredited optometrist. People testingnegative on the second test are not referred forfurther testing and are recalled for furtherscreening in the next cycle. As with the first


14

Opportunisticsampling

All Optometrists

No glaucoma

Missed glaucoma

Observation

Positive Glaucoma

No glaucoma

Outcome

Opportunisticsampling

Long-termtreatment

Referencediagnosis

Negative

Untreated, progressiveglaucomaAt least 60%

OAG undetected

At least 1200 new cases ofvisual impairment due to OAG

in 2002/03 in UK

Mild

Moderate

Severe

FIGURE 5 Current case finding

strategy, other significant eye disease would beidentified and ongoing case finding by currentpractice may still identify OAG cases.

Economic modelThe economic model was developed to representthe screening pathways described above. Thepathways indicate that screening would be best

considered as an event that will be repeated atdiscrete time intervals. Furthermore, as glaucomais a chronic condition, which progresses slowlyover time, the model should reflect timing of bothscreening and disease progression. For this reasona Markov modelling approach was adopted. AMarkov model can be used to represent the logicaland temporal sequence of events following the


15


Eligibility

Cohort at risk Accept Glaucoma optometrist PositiveReferencediagnosis

Glaucoma

Mild

Moderate

Severe

Treatment

Mild/PS/blind

Treatment

Opportunisticdetection

(mild/moderate/severe)

No glaucoma

Other eyedisease

NegativeNo glaucoma

Missed glaucomaDecline

Untreated, progressiveglaucoma

Invite for screening

FIGURE 6 Screening by referral to a glaucoma accredited optometrist. PS, partial sight.

Cohort at riskAccept

Screentest(s)a Positive

Glaucomaoptometrist

PositiveReferencediagnosis

Glaucoma

Mild

Moderate

SevereNo glaucoma

Opportunisticdetection

(mild/moderate/severe)

Treatment

Mild/PS/Blind

Treatment

Untreated, progressiveglaucoma

Missed glaucomaDecline

Invite for screening

Eligibility

No glaucoma Negative

Other eye disease

FIGURE 7 Screening by a technician. aTest is IOP and technology. The reference standard is an ophthalmologist in all strategies. IOP � 26 mmHg = screen positive; IOP < 26 mmHg + second technology test positive = screen positive; IOP < 26 mmHg+ secondtechnology test negative = return to standard case finding and rescreen cycle.

implementation of alternative screening strategies.In this study the model is used to provide theestimated costs and outcomes over a selectedperiod of a cohort of patients for differentscreening and/or non-screening strategiesadopted. Three Markov submodels weredeveloped and run in parallel. Each submodelrepresented one of the three strategies outlinedabove. The model parameters and the data arepresented in the section ‘Economic evaluation ofscreening for OAG’ (p. 105). The results of thesesub-models presented in this chapter werecompared to obtain the final cost-effectivenessresults, which are presented in ‘Results of base-case analysis and sensitivity analysis on the base’(p. 115).

The modelTypically, Markov models have states (e.g. Markovstates) in which individuals stay for a period oftime called a ‘cycle’. The cycle must be a periodrelevant to the condition considered (e.g.6 months, 1 year). At the end of each cycle,individuals can remain in the state in which theystarted the cycle or move to a different state. Theprobabilities of moving from one state to anotherare called transition probabilities. In each state,the model will assign costs and benefits for eachindividual according to different interventionsand/or the time spent in the state. In thesemodels, there must be at least one absorbing state,typically death, from which the person will not beable to leave.

Figure 8 shows a simplified version of the modelused for the base-case analysis. In this figure thestates are presented as ovals while the arrows showthe possible directions in which individuals couldmove at the end of each cycle, depending on thetransition probabilities. The states considered inthe model were those thought to reflect possiblepaths for normal and glaucoma individuals. Thetop line in Figure 8 represents the possible path forundiagnosed individuals, while the bottom sectionof the figure reflects the glaucoma progression fortreated patients.

Glaucoma states were defined in terms of severityof disease; namely, observation, glaucoma mild,glaucoma moderate, glaucoma severe and visualimpairment. There is no universally agreedstaging system for OAG, and there are limiteddata on utility values according to glaucomaseverity (see ‘Health state utilities’, p. 112, fordetails). Therefore, an economic projectmanagement group, including three economistsand three ophthalmologists, agreed theclassification of health states. The severity ofdisease was based on binocular visual field loss.The detailed description of binocular visual fieldloss was adapted from a scoring system of theintegrated visual field, whereby uniocular visualfield analyses are integrated into a singlebinocular field without additional testing, reported by Crabb and colleagues.89,90 Thedefinitions of health states are described in Table 1.


16

Dead

Disease progressionundiagnosed

Disease progression,treated patients

Glaucomamoderate

Glaucomamild

Treatmentglaucoma mild

Glaucomasevere

Visualimpairment

Normal

Treatmentglaucomamoderate

Treatmentglaucoma

severe

Observation

FIGURE 8 Markov model for OAG

The treatment states refer to treated disease ateach stage. The modality of treatment, either IOP-lowering eye drops, laser or surgery or anycombination thereof, is not specified for atreatment state. A treatment state refers to anymodality or combination treatment for each stageof severity.

According to whether the individual has or has notgot glaucoma, he or she would start in the modelin a normal state or in an undiagnosed glaucomastate. As time passes, the normal individuals coulddevelop glaucoma (e.g. new incident cases ofglaucoma), while those with glaucoma couldprogress into further stages of the disease untilthey eventually become visually impaired. Thesestates represent the true condition of theindividual. There are three treatment states inFigure 8, which vary according to the severity ofglaucoma being treated. An observation statewhere individuals without a definite diagnosisremain until a further diagnosis decision is madeis also included in the model. The observationstate was built up as ‘tunnel states’; that is, aperson is observed for a definite period withinwhich a decision is made about whether or notOAG is present. More details on the observationstates are provided below.

OAG is not reversible and this is reflected in themodel (Figure 8). It is not possible to return to thenormal state or to a less severe glaucoma statefrom any glaucoma state. The absorbing state inthe model is death. Any individual can move intothis state from any other state within the model.

The model allows for a cohort of the population,some with OAG, to pass through differentstrategies. The intuitive idea behind the model is

to identify the strategy that leads to the largestproportion of individuals with OAG crossing thebridge into treatment (Figure 8). Figures 50–52 inAppendix 1 show complete versions of the model.

The diagnosis of OAG within the modelOphthalmologist involvement within the modelFour types of professional are explicitly consideredin the model. These are the technician, theoptometrist, the glaucoma optometrist (GO) andthe ophthalmologist. The main difference betweenthem within the model is their ability to diagnoseOAG, which varies from a simple reading of anequipment outcome by the technician to theassumed gold-standard assessment by theophthalmologist used in the base-case analysis.

Ophthalmologists are involved as the final stage ofdiagnosis in all three strategies and their diagnosisis considered to be the gold standard in theanalyses presented in this study. Nevertheless, themodel structure allows this assumption to berelaxed if data were to become available. For anyperson assessed by the ophthalmologist thefollowing decision structure is used (Figure 9). Ifthe ophthalmologist’s assessment is positive, theywill decide to treat the patient, although themodel structure allows this to be either a true or afalse positive. If the assessment is negative, therewill be two options: to discharge or to keep underobservation. The decision to place someone underobservation would be appropriate if theophthalmologist felt, for whatever reason, that theindividual was at high risk of developingglaucoma.

As stated above, the final stage of the diagnosis isalways the ophthalmologist. Figure 10 shows thepossible paths for the normal state. Within the


17


TABLE 1 Definitions of glaucoma health states

No glaucomatous impairment Under observation as suspect glaucoma but not on medication and no glaucoma visualfield defect in either eye

Mild glaucoma On treatment, no binocular visual field loss, unilateral glaucoma visual field defectpresent

Moderate glaucoma Up to five missed points (<10 dB) in the binocular central 20° of visual field

Severe glaucoma Binocular visual field loss below UK driving standarda

Visual impairment (includes As per criteria for ‘severe’, except binocular visual field loss includes both the upper partial sight and blind) and lower fields of vision

Adapted from Crabb et al.89,90

a Six or more adjoining missed points (<10 dB), and any additional separate missed point(s) OR a cluster of four or moreadjoining missed points (<10 dB), either of which is either wholly or partly within the central 20° superior or inferiorhemispheric field.

base case all these people will be correctlyidentified as negative for OAG.

Conceptually, if the diagnostic ability of theophthalmologist is less than perfect, then theophthalmologist might incorrectly identify aperson as being positive for OAG and initiatetreatment. In such a situation the person would atthe end of the cycle move into the ‘treatment(normal)’ state or progress into ‘treatment(glaucoma mild)’ state. If the assessment isnegative, the ophthalmologist can decide todischarge the patient or keep the person underobservation. If the person is discharged it ispossible that over the duration of the cycle theymay go on to develop OAG. The likelihood of this happening would be dictated by the expected incidence of OAG over the cycle length(i.e. the annual incidence of OAG). For a personkept under observation it is possible that they will

develop OAG while under observation. Thelikelihood of this happening is again dictated by the annual incidence of OAG. Should theperson develop OAG then this will be diagnosed by the ophthalmologist and treatmentstarted.

Figure 11 shows a similar Markov tree layout forthe ‘glaucoma mild’ state case. In the analysespresented in this report it has been assumed thatall people with mild glaucoma referred to theophthalmologist will be correctly diagnosed ashaving OAG and will commence treatment.Treatment, on average, would be expected todelay the progression of disease, but not preventprogression for all people. For this reason peoplediagnosed with OAG may move into the states of‘treatment (glaucoma mild)’ or ‘treatment(glaucoma moderate)’. The likelihood of movingto either of these two states will be determined by


18

Glaucoma(true positive)

Positive

Negative

Ophthalmologisttest/assessment

No glaucoma(false positive)

Glaucoma(false negative)

No glaucoma(true negative)

Treat

Treat

Not to treat

Not to treat

Observe

Observe

FIGURE 9 Decision pathways for diagnosis by the ophthalmologist

Treatment (normal)Positive


Treatment (glaucoma mild)

NormalDischarge

Observation

Negative

Glaucoma mild

Observation (normal)


FIGURE 10 Ophthalmologist involvement Markov tree: normal state

the annual risk of progression from mild tomoderate disease for treated cases.

Conceptually, if the diagnostic ability of theophthalmologist is less than perfect then it mightbe possible for a person with mild OAG to beincorrectly diagnosed as negative. In such asituation the ophthalmologist might discharge theperson, who would then face the risk ofprogressing to more severe disease. The likelihoodof progression would be equal to the annual riskof disease progression for untreated OAG.

Although only considered as a hypothetical optionwithin the model at present, it may be possiblethat individuals incorrectly diagnosed as negativeare still considered by the ophthalmologist asbeing suspect of OAG. In this situation suchpeople would enter the state ‘observation(glaucoma mild)’. In the initial period underobservation the patient would have the risk of thedisease progressing and moderate OAG

developing. If such progression should occur thenit might be expected to be identified by theophthalmologist and treatment initiated. It is forthis reason that in Figure 11 one of the branchesfollowing observation progresses to ‘treatment(glaucoma moderate)’ and not to ‘observation(glaucoma moderate)’.

Observation state structureThe tree structure for this state is similar, nomatter what health state the person originatesfrom. These states are modelled as a 5-year tunnelstate. Figure 12 shows the structure for the‘observation (normal)’ state. As noted above anddescribed in Figure 8, this is the only observationstate allowed in the analyses presented in thisreport (owing to the opthalmologist goldstandard/perfect information assumption withinthe model).

A person coming from a normal state, who theophthalmologist wishes to observe, would enter


19


Treatment (glaucoma moderate)Positive



Glaucoma mildDischarge(false negative and discharge)

Observation

Negative

Glaucoma moderate

Observation (glaucoma mild)

Treatment (glaucoma moderate)

FIGURE 11 Ophthalmologist involvement Markov tree: glaucoma mild state

NormalJudged normal

Observation (normal)

Glaucoma mild

Observation (normal)Observation

No observation(out of tunnel state)

Judgement remains


Normal

Glaucoma mild

FIGURE 12 Observation (normal) state Markov tree

this ‘observation (normal)’ state. During the cyclelength of this state the ophthalmologist coulddecide that the patient under observation does nothave OAG, or decide to keep the person underobservation. In the first situation, the personwould be discharged as ‘normal’ (i.e. no OAG).However, they would still face the risk ofdeveloping OAG (based on likelihood of itsincidence) and hence might progress into the stateof ‘glaucoma mild’. Should this occur then this willnot be identified unless presenting to theophthalmologist at some future date.

If the ophthalmologist’s judgement does notchange, the person will remain in observation fora maximum of 5 years (five cycles of the model).In any of these years the person would face therisk of developing OAG. If this happens theperson will be automatically detected andtreatment initiated.

Although this state is not possible in any of the analyses presented in this report, Figure 13shows the Markov tree hypothetical situation ofpeople with mild OAG being observed [the‘observation (glaucoma mild)’ state]. Thedifference is that, when diagnosed, in this case as a glaucoma mild patient, the person will not bedischarged but will commence treatment [i.e. enterthe ‘treatment (glaucoma mild)’ state].Furthermore, if the disease progresses to moderateOAG [the ‘treatment (glaucoma moderate)’ state]then this will be identified and the patient will betreated as a glaucoma moderate patient. The restof the structure is similar to that depicted inFigure 12.

The strategies consideredThe model considered one current practicestrategy and the two alternative screeningstrategies as described in Figures 5–7. Currentpractice reflects current glaucoma detection byopportunistic case finding. The two alternativescreening strategies vary in how screening wouldbe organised; for example, an invitation for ascreening examination by a glaucoma-trainedoptometrist or for a simple test assessing either visual field loss or structural damage,together with a measurement of the IOP by atechnician. The Markov models reflecting these pathways are detailed in Appendix 1 (Figures 50–52).

As indicated above, the model has assumed thatthe ophthalmologist is the gold standard andmakes a perfect diagnosis (e.g. specificity andsensitivity equal to 1) but, as described above, themodel structure allows for the relaxation of thisassumption. If the ophthalmologist assessmentresult is negative, the individual could bedischarged or remain under observation (asdescribed above). If positive, the ophthalmologistinitiates treatment.

For all the screening strategies, people are invitedfor screening at preselected screening intervals(e.g. every 3, 5 or 10 years) and they have thechoice of accepting or declining the invitation.Those who accept the invitation would go throughthe screening process, while those who decline theinvitation would follow similar paths to the onethey would follow in no-screening years. For theyears for which screening does not occur it is


20


Treatment(Glaucoma moderate)

Diagnosed

Observation (glaucoma mild)

Treatment(glaucoma moderate)

Observation

Glaucoma mild

Glaucoma moderate

No observation(out of tunnel state)

Not diagnosed

Observation(glaucoma mild)

FIGURE 13 Observation (glaucoma mild) state Markov tree

assumed that people might still be diagnosedusing the same procedures outlined for currentpractice (strategy 1).

Populating the model with parameter estimatesTo provide estimates of relative effectiveness, costand cost-effectiveness data, the model requiresestimated values for a whole range of differenttypes of parameters. Such parameter estimatesshould be derived in a systematic and reproduciblemanner to avoid bias caused by the distorted and selective use of data.91 The assembly of suchdata need not necessarily be comprehensive;rather, effort should be focused on identifying the most relevant data to the decision problem,which was in this case the comparison ofalternative screening strategies for OAG fora UK setting.

A series of systematic reviews and focused searchescovering the different types of data required forthe economic model was therefore conducted. Themethods and results of these are reported in detailin subsequent chapters of this report. In brief, thebroad types of data required to populate theeconomic model relate to:

● the prevalence, incidence and risk ofprogression of the disease; that is, itsepidemiology and natural history (systematicallyassessed in Chapter 5)

● the performance of the different strategies interms of the accuracy of the screening anddiagnostic tests used (systematically assessed inChapter 6); the effectiveness of treatments forthose identified as having OAG (systematicallyreviewed in Chapter 7)

● resource use and unit costs required to estimatethe costs of alternative screening strategies; thespecific parameters and methods used toprovide estimates that are relevant to a UKcontext are described in the section reportingthe detailed methods and results of theeconomic evaluation (‘Economic evaluation ofscreening for OAG’, p. 105)

● Health state utilities; the methods used toidentify UK-specific values are also described in ‘Economic evaluation of screening for OAG’(p. 105).

In addition to these data, the structure andconduct of the economic evaluation could beusefully informed by any previous economicevaluations. A review of such studies, as reportedin ‘Systematic review of cost-effectiveness ofscreening for OAG’ (p. 95), should indicatewhether further assessment of cost-effectiveness is

worthwhile; it might also serve to identify anexisting model that could be readily adapted forthis study, or if the existing economic evaluationsare limited it could provide a firm justification fora new modelling exercise. Thus, a thorough reviewof the strengths and weaknesses of the existingstudies may help to ensure that a model willprovide as useful evidence as possible on cost-effectiveness.

Searching for the evidenceHighly sensitive electronic searches wereundertaken to identify the evidence for this report.Initial searching was undertaken between Januaryand April 2005, with the major searches updatedduring November and December 2005. Asprespecified in the protocol, electronic searcheswere restricted to reports published in the Englishlanguage; reports published only as abstracts wereexcluded. The following databases were searched:

● MEDLINE: 1966 to November week 3 2005● EMBASE: 1980 to 2005 week 49 ● MEDLINE In Process and Non-indexed

Citations: 23 February, 6 December 2005● Science Citation Index (SCI): 1981 to

3 December 2005● BIOSIS: 1985 to 30 November 2005● Cochrane Central Register of Controlled Trials

(CENTRAL): Cochrane Library Issue 4 2005● PsycInfo: 1967 to June week 3 2005● Social Science Citation Index (SSCI): 1981

to 27 June 2005● Applied Social Science Index and Abstracts

(ASSIA): 28 June 2005● Science Direct (American Journal of

Ophthalmology, Ophthalmology only): 1998 toNovember 2005

● High Wire Journals (British Journal ofOphthalmology, Investigative Ophthalmology andVision only): 1998 to November 2005

● Journal of Glaucoma: 2001 to November 2005● NHS Economic Evaluation Database (NHS

EED): November 2005● Health Technology Assessment Database (HTA

Database): November 2005● Database of Abstracts of Reviews of Effectiveness

(DARE): November 2005● Cochrane Database of Systematic Reviews

(CDSR): Cochrane Library Issue 4 2005● Health Management Information Consortium

(HMIC): November 2005● National Research Register: Issue 1 2006● Current Controlled Trials (CCT): March 2006● Clinical Trials: March 2006.


21



22 TA

BLE

2Re

trie

ved

repo

rts

for e

ach

com

pone

nt o

f the

revie

w

Dat

abas

eEf

fect

iven

ess

of

Acc

urac

y an

d Pa

tien

t Ef

fect

iven

ess

Epid

emio

logy

, Ec

onom

ic

Gen

eral

scre

enin

gre

prod

ucib

ility

of

acce

ptab

ility

of

of g

lauc

oma

risk

and

ev

alua

tion

sear

chdi

agno

stic

tes

tsgl

auco

ma

test

ing

trea

tmen

tpr

ogre

ssio

nof

scr

eeni

ng

MED

LIN

E/EM

BASE

985

4939

6230

539

4334

9SC

I77

401

410

44BI

OSI

S67

141

30C

ENT

RAL

6226

18Ps

ycIn

fo35

SSC

I39

ASS

IA28

Scie

nce

Dire

ct/H

igh

Wire

/J G

lauc

oma

112

HM

IC36

NH

S EE

D38

HTA

29D

ARE

20C

DSR

3C

CT

56C

linic

al T

rials

0N

atio

nal R

esea

rch

Regi

ster

54To

tal

1191

5619

164

323

4383

431

198


23


TA

BLE

3N

umbe

r of r

epor

ts s

elec

ted

for f

ull-t

ext

asse

ssm

ent

Dat

abas

eEf

fect

iven

ess

Acc

urac

y an

d Pa

tien

t Ef

fect

iven

ess

Epid

emio

logy

, Ec

onom

ic

Bac

kgro

und

of s

cree

ning

repr

oduc

ibili

ty o

f ac

cept

abili

ty o

f of

gla

ucom

a ri

sk a

nd

eval

uati

on o

f in

form

atio

ndi

agno

stic

tes

tsgl

auco

ma

test

ing

trea

tmen

tpr

ogre

ssio

nsc

reen

ing

MED

LIN

E/EM

BASE

077

25

1540

648

48SC

I0

39–

–21

41

BIO

SIS

014

––

4–

0C

ENT

RAL

03

–0

––

0Ps

ycIn

fo–

–0

––

––

SSC

I–

–2

––

––

ASS

IA–

–3

––

––

Scie

nce

Dire

ct/H

igh

Wire

/J G

lauc

oma

–3

––

––

1H

MIC

023

00

08

5N

HS

EED

––

––

–6

–H

TA0

130

00

06

DA

RE0

00

00

00

CC

T0

00

00

00

Nat

iona

l Res

earc

h Re

gist

er0

00

00

00

Web

/unp

ublis

hed

00

00

21

13To

tal

086

710

1543

367

74


24

Specific searches were undertaken separately foreach component of the report: effectiveness ofscreening, accuracy and reproducibility ofdiagnostic tests, patient acceptance of glaucomatesting, effectiveness of glaucoma treatment,epidemiology, risk factors and progression ofglaucoma, and economic evaluation. In addition,general searches on the topic of OAG wereundertaken within the reviews and trials databases. Table 2 details the databases that were searched for each component, with thenumber of reports retrieved from each search after deduplication against the results of theMEDLINE/EMBASE searches. Appendix 2 details all the search strategies that were used. In addition, reference lists of all included studieswere scanned to identify additional potentiallyrelevant studies. Web pages of appropriateprofessional organisations were also searched for additional background material. The details of the main ones consulted are listed in Appendix 2.

The databases were searched using strategies thatwere tailored to the scope of the individualcomponents of this report:

● Effectiveness of screening: aimed to restrictevidence to randomised controlled trials(RCTs), without language restriction.

● Accuracy and reproducibility of diagnostic tests:aimed to restrict evidence to reports that assesseddiagnostic performance of a selected range oftests. This was supplemented with full-textsearching of selected ophthalmology journals.

● Patient acceptability of glaucoma testing:additional social science databases were searched.

● Effectiveness of glaucoma treatment: a relevantsystematic review,19 published in 2005, wasidentified, therefore searching was restricted toupdating this review.

● Epidemiology, risk and progression: included,but was not restricted to, specific searching forselected risk factors and known majorepidemiological studies.

● Economic evaluation of screening: aimed torestrict evidence to cost-effectiveness andutilities data.

All titles and abstracts identified in these wayswere assessed to identify potentially eligiblestudies. Table 3 provides details of the number ofreports that were selected for full-text assessment.

IntroductionThe aetiology of the majority of cases of adult-onset OAG is not known. Since OAG has noassociated symptoms and is often asymptomaticbefore the development of established visual fieldloss, there is a need to identify groups at a highrisk of developing glaucoma and quantify the levelof risk.

Risk factors have been identified fromepidemiological studies. These are increasing ageand IOP, ethnicity, family history of OAG in a first-degree relative, myopia and diabetes. Identifiablegene mutations are implicated,92–96 but accountfor only about 4% of cases of adult-onset OAG.97

Although certain genetic subtypes are more likelyto progress towards severe disease, based oncurrent knowledge of the inheritance of OAG,genetic screening would not detect a substantialnumber of the currently undetected cases.

The aim of this systematic review was to determinethe incidence and prevalence of OAG in the UKpopulation and to identify the magnitude of riskof OAG attributable to age, ethnicity, familyhistory, myopia and diabetes.

MethodsInclusion and exclusion criteriaTypes of studies and participantsPopulation-based studies, namely cohort andcross-sectional studies, investigating the risk ofdeveloping OAG and the prevalence in the UK,were included. Meta-analyses and systematicreviews of observational population-based studieswere also included. Preliminary searches identifiedfew UK studies and therefore other studiesreporting similar populations, such as European,North American, Canadian or Australasian weresought. Studies in which the population wasdefined at the hospital or clinic-based setting wereexcluded, as participants were not considered tobe representative of the general population.Studies were also excluded when it was notpossible to ascertain the type of glaucoma beingassessed. The review was restricted to English-language publications.

Types of risk factors and outcomesThe following variables were considered as riskfactors for OAG:

● age: 40, 50, 60, 70 years● myopia: mild/moderate (�6 D); high (>6)● ethnicity● diabetes: types 1 and 2● family history: one or more first-degree

relative(s) with OAG● IOP.

The following outcome measures were considered:

● number of OAG cases detected● number of mild, moderate and severe OAG

cases detected● relative risk of OAG for each risk factor

reported● relative risk of mild, moderate and severe OAG

for each risk factor● time to glaucoma diagnosis (mild, moderate

and severe) according to level of IOP.

Data extraction strategyFour reviewers screened the titles and abstracts ofall papers identified by the search strategy. Fulltext copies of all potentially relevant studies wereobtained and four reviewers independentlyassessed them for inclusion. Reviewers were notmasked to the names of studies’ authors,institutions or sources of the reports. Anyuncertainties in the data were resolved bydiscussion between reviewers.

A data extraction form was developed to recorddetails of the design of included studies, year ofpublication, year of study, country of study, samplesize, participation rate, method of recruitment,eligibility criteria, diagnostic criteria for OAG,overall prevalence and prevalence by the riskfactors of interest, relative risk of OAG andincidence (Appendix 3). Data were single dataextracted by the same four reviewers.

Quality assessment strategyTwo reviewers (JB, TL) assessed themethodological quality of the included studies.Any disagreements were resolved by consensus orarbitration. The included studies were assessed to


25


Chapter 5

Epidemiology of open angle glaucoma

see whether they contained the elements shown inTable 4. An acceptable diagnosis required aglaucomatous visual field defect with or withoutglaucomatous optic neuropathy. It was acceptedthat the classification of glaucoma would varybetween studies, and in particular that methodsfor ascertaining visual field loss would havechanged from the studies conducted in the 1960s.A secure record for exposure (risk factor)assessment was considered to be through a clinicalexamination or the examination of records. Theoverall quality of each study was summarised as(A) no major flaws or (B) possible important flaws.Studies were included when they rated ‘A’ in allfields. Exceptions were made to include ‘B’ studieswhen no better evidence was available.

Data synthesisPrevalence and incidence reported for an agerange were attributed to the age category to whichthe midpoint was closest. Study estimates ofprevalence came from definite cases of OAGexcluding probable and/or possible cases. Whenthis information was not provided, it was assumedthat the rate presented in studies was for definitecases.

The prevalence of glaucoma was calculated as thenumber of participants diagnosed with glaucomadivided by the number of participants screened.The prevalence of OAG was calculated for thewhole population, and for those aged 40, 50, 60and 70 years. For each study, a standard error (SE)estimate was produced, using the large samplenormal approximation. Prevalence estimates werepooled using the DerSimonian and Laird randomeffects method.98 A pooled estimate of theproportion of undetected OAG was producedusing the same methods. Since only one study99

reported the prevalence of undetected OAG byage, the overall estimate of undetected OAG wasapplied to each age category to produce crudeage-specific estimates. A crude age-specificestimate of the prevalence of undetected OAG was

calculated by multiplying the pooled prevalenceestimate at that age by the pooled estimate of theproportion of previously undetected cases.

Incidence was summarised for each age categoryas the mean and range for cases per 100,000 yearsat risk. No formal pooling was undertaken. Nostudies provided data with which to estimateincidence for 40 year olds and therefore the valuesfor 50 year olds were used. Incidence estimates forthe UK were determined by dividing the numberof cases newly diagnosed by the number of peopleat risk (population data were obtained from the2001 UK Census).

Crude and adjusted relative risks (or odds ratiosdepending on study design) of OAG for the riskfactors under investigation were abstracted. Wheretwo or more studies contributed data, a randomeffects meta-analysis was undertaken using theDerSimonian and Laird method. If both anunadjusted and adjusted ratio were reported in astudy, an age- and gender-adjusted odds ratio wasused in the meta-analysis. A relative risk wasgenerated when an adjusted odds ratio was notreported and raw data were available.

A pooled prevalence was also calculated for theprevalence of OAG in the high-risk group undereach risk factor. The number at risk in the UKpopulation for each risk factor was determined byapplying the pooled estimate to the 2001 UKCensus. Data obtained from the A-rated studiescontributed to the pooled estimates. Where no A-rated studies were available B-rated studies wereused.

High IOP was defined as one or moremeasurements with readings equal to or above26 mmHg. Other IOP cut-offs were alsoinvestigated. Participants with myopia weredefined as having one or more measurements withrefractive errors greater than 0.5 D, ascertained byeither measurement of present spectacles or a


26

TABLE 4 Quality assessment criteria

Criterion Type of bias

Were participants sampled adequately? Selection(Random sample obtained from a representative population)

Was exposure (risk factor) status obtained from a secure record? Detection(Clinical examination or examination records)

Was the criterion used in the diagnostic classification thorough? Detection(Glaucomatous visual field defect with or without glaucomatous optic neuropathy)

Was the response rate greater than 75%? Attrition

refraction examination. Family history of OAG wasdefined as participants having any first-degreerelative affected by OAG confirmed by clinicalexamination. Diabetes was defined as people ontreatment for diabetes (type 1 or 2) or thosetesting positive on urinalysis, glycosylatedhaemoglobin (HbA1c) or a glucose tolerance test.

ResultsNumber and type of studies includedThe study selection process is summarised inFigure 14. In total, 4383 reports were identifiedfrom the search for studies on epidemiology, riskand disease progression, of which 285 wereselected for full assessment for this review. Ninety-two reports describing 27 studies met the inclusioncriteria for the review. In addition, one meta-analysis was identified. The included studies andassociated references are listed in Appendix 4.

Number and type of studies excluded,with reasons for specific exclusionsA total of 192 reports was obtained butsubsequently excluded because they failed to meet

one or more of the inclusion criteria (Figure 14).The majority of the exclusions were notpopulation-based studies or the population wasnot defined at the geographical level. (SeeAppendix 5 for further details.)

Study quality and characteristics ofincluded studiesQuality of available evidenceThe results of the quality assessment of theincluded studies are summarised in Table 5. Inmost studies (81%), participants were sampledadequately and selected from a relevantpopulation. Suboptimal approaches to diagnoseOAG (e.g. high IOP, absence of a visual test,baring of the blind spot, case records,unstandardised criteria) were used in five studies(19%).100–104 IOP, diabetes and myopia status wereobtained from a secure record (examination orexamination records) in most studies. However,only one (20%)105 obtained family history statusfrom a secure source, by examination of first-degree relatives of detected cases. Sixteen (59%)included studies specified the participation rate tobe greater than 75%; however, this informationwas unclear in seven (26%) studies.


27


4383 initial search

285 selected for full assessment

4098 reports excluded

93 reports included92 population-based reports (describing 27 studies)1 meta-analysis

192 reports excluded119 – not population-based reports or population not defined at the geographical level 41 – subjects not similar to those in the UK: 3 Latino 9 African 16 Asian 13 West Indies28 – no usable results1 glaucoma was self-reported1 reported number of eyes rather than number of subjects 1 fatally flawed1 authors did not report separate data for OAG and CAG

FIGURE 14 Study selection process

Characteristics of included studiesAppendix 6 provides details of the characteristicsof all included studies. Only A-rated studies aredescribed in this section(n = 19).21,22,28,63,64,99,105–117 All but one of theincluded studies105 described a population-basedcross-sectional study. The remaining eightstudies100–104,118–120 are also described inAppendix 6.

Studies included in the review presented variationsin relation to study settings, age of participants,types of exposures measured and the definition ofOAG (Tables 6 and 7). Of the 19 eligible studies,four took place in the UK,21,64,113,116 three in the USA,111,114,122 two each in Australia,63,115

Italy,106,107 Iceland110,117 and Sweden,28,109 andone each in Ireland,108 Spain,99 Greece,112

and The Netherlands.105

The participation rate ranged from 67%121 to92%.21 Four studies did not provide informationon participation rate. Sample size ranged from207116 to 32,918.28

All 19 studies gave details of participants’ age.Eight studies included participants aged 40 yearsold and all but seven studies did not have anupper age limit. Most studies involved mainlywhite populations. However, in one study 45%(n = 2394) of included participants were of blackethnicity.114

The majority of studies selected participants froma population register (census in eight, municipalregister in three and electoral register in one).One study took participants from anotherpopulation-based study.121 Two additional studiesdrew participants from general medical practicegroups113,116 and one recruited participants afterdelivering preliminary publicity campaign cards

inviting people over 40 years of age in Bedford,UK, for a screening examination.64

All studies ascertained glaucoma status by meansof a clinical examination. Questionnaires wereused to ascertain exposure status of participants inthree studies.63,99,114

Disease prevalenceData on prevalence was grouped as undetectedOAG and overall OAG. Undetected OAG refers toparticipants being newly diagnosed at screening.Overall OAG refers to both previously detectedand undetected glaucoma. All 19 studies providedinformation on the prevalence of OAG with themajority reporting undetected prevalence as wellas the overall prevalence (Table 7). Estimates of theoverall prevalence of OAG varied across studies,ranging from 0.421 to 6.6%.117 The pooledprevalence rate from 19 studies was estimated tobe 2.1% [95% confidence interval (CI) 1.7 to 2.5].For previously undetected OAG, the pooledprevalence rate was 1.4% (95% CI 1.0 to 1.9).Fifteen studies contributed to this estimation andvalues ranged from 0.3108 to 3.3%.109 By applyingthe pooled prevalence estimates to the UKpopulation over 40 years of age, it was estimatedthat there are approximately 569,000 peopleaffected by OAG, of which 380,000 are undetectedcases (Table 7, Figure 15). (The proportion ofpeople with undetected glaucoma across thestudies can be found in Appendix 6.)

Disease incidence The incidence of OAG was investigated in threestudies (Table 8).123–125 Two of the studiesestimated the incidence of OAG by conducting apopulation-based cohort study with an observationperiod of 5 years. The other study estimated theincidence of OAG from age-specific prevalencedata. Based on these studies, the incidence rate


28

TABLE 5 Summary of quality assessment of papers (n = 27) reporting cross-sectional studies

Criterion A B Unclear

Were participants sampled adequately and selected from a relevant population? 22 (81%) 5 (19%) 0

Were the criteria used in the diagnostic classification thorough? 22 (81%) 5 (19%) 0

Was IOP status obtained from a secure record?a 9 (90%) 1 (10%) 0

Was family history status obtained from a secure record?a 1 (20%) 4 (80%) 0

Was diabetes status obtained from a secure record?a 3 (75%) 1 (25%) 0

Was myopia status obtained from a secure record?a 3 (100%) 0 (0%) 0

Was the response rate greater than 75%? 16 (59%) 4 (15%) 7 (26%)

a As not all studies report all risk factors, the total number of studies does not add up to 26.


29


TABLE 6 Characteristics of included studies (only A-rated studies)

Study Country Participants Age range No. of Ethnicity (%) Exposuresselection (years) participants

(% uptake) White Black

Anton, 200499 Spain Census 40–79 510 (90) NR NR IOP; family Segovia Study history, age

Bankes, 196864 UK All population 40+ 5,941 NR NR IOP, ageBedford Glaucoma Survey

Bonomi, 2001106 Italy National register 40–80+ 4,297 NR NR Age Egna–Neumarkt Glaucoma Study

Cedrone, 1997107 Italy Census 40–80+ 1,034 NR NR IOP, age

Coffey, 1993108 Ireland Electoral register 50–80+ 2,186 NR NR IOP, age

Dielemans, 1996105 Netherlands Municipal registry 55–75+ 3,062 (72) 98 NR IOP, family Rotterdam Study history,

diabetes, age

Ekstrom, 1996109 Sweden Municipal registry 60–74 760 (91) NR NRTierp Glaucoma Survey

Grodum, 200228 Sweden All population 57–79 32,918 (77) NR NR

Leibowitz, 198022 US Other population- 55–84 2,631 (67) 100 AgeFramingham Eye based studyStudy

Hollows, 196621 UK Census 40–75 4,231 (92) NR NR

Jonasson, 1987117 Iceland Census 43–83+ 751 (81) NR NR Age

Jonasson, 2003110 Iceland Census 50–80+ 1,045 (76) NR NR AgeReykjavik Eye Study

Klein, 1992111 US Census 43–84 4,926 (83) 100 0 IOP, myopia Beaver Dam Eye diabetesStudy

Kozobolis, 2000112 Greece Municipal registry 40–80+ 1,107 (85) NR NR IOP, age

Mitchell, 1997122 Australia Census 49–80+ 3,654 (88) 100 0 IOP, age, family Blue Mountains Eye history, myopiaStudy

Reidy, 1998113 UK General medical 65–100 1,547 (84) NR NR Agepractice groups

Tielsch, 1991114 US Census 40–80+ 5,308 (79) 54.9 45.1 IOP, diabetes, Baltimore Eye family history, Survey ethnicity, age

Weih, 2001115 Australia Census 40–90+ 4,498 (86) 100 0 IOP, family Visual Impairment history, myopia, Project ethnicity, age

Wormald, 1992116 UK Age–gender 65+ 207 (72) NR NRregister

NR, not reported.


30

TABLE 7 Prevalence of OAG in population-based studies

Study ID Diagnostic criteria for OAG Participants Prevalence OAG (%)

Undetected Overall

Anton, 200499 Glaucomatous optic disc stereographs, 510 2.1 2.1Segovia Study suprathreshold field and open angle

Bankes, 196864 Disc, semi-automated field, open angle slit-lamp 5,941 NR 0.76Bedford Glaucoma examination on suspectsSurvey

Bonomi, 2001106 Disc (direct ophthalmoscopy), suprathreshold 4,297 1.5 1.95Egna-Neumarkt field, slit-lamp examinationGlaucoma Study

Cedrone, 1997107 Suprathreshold field, and one of IOP positive or 1,034 2.3 2.5disc positive

Coffey, 1993108 Disc and slit-lamp, suprathreshold field only in 2,186 0.3 1.0suspects

Dielemans, 1996105 Threshold field, open angle and one of positive 3,062 0.6 1.1The Rotterdam Study disc or IOP positive

Ekstrom, 1996109 Disc, threshold field, open angle on slit-lamp 760 3.2 5.7Tierp Glaucoma Survey

Grodum, 200228 Threshold field, disc, open angle on slit-lamp 32,918 1.2 1.5examination

Leibowitz, 198022 Glaucoma visual field defect and any of positive 2,631 NR 1.0The Framingham Eye IOP, or disc or glaucoma historyStudy

Hollows, 196621 Disc, field, slit-lamp (open angle) 4,231 0.3 0.4

Jonasson, 1987117 Glaucoma visual field defect and any of positive 751 NR 6.6IOP, or disc or glaucoma history

Jonasson, 2003110 Disc, IOP, threshold fields (two out of three) 1,045 2.4 4.0Reykjavik Eye Study

Klein, 1992111 Disc (stereoscopic photograph), suprathreshold field 4,926 1.9 2.1Beaver Dam Eye Study

Kozobolis, 2000112 Open angle (slit-lamp examination), disc, nerve 1,107 2.0 2.8fibre defect and visual field defect

Mitchell, 1997122 Disc, open angle, suprathreshold field 3,654 1.2 2.4Blue Mountains Eye Study

Reidy, 1998113 Suprathreshold field, disc 1,547 2.3 3.0

Tielsch, 1991114

Baltimore Eye SurveySlit-lamp examination (open angles), disc, 5,308 1.2 2.5(stereoscopic photography), field

Weih, 2001115 Disc, threshold visual field 4,498 1.1 1.8Visual Impairment Project

Wormald, 1992116 Disc, suprathreshold fields 207 0.5 4.4

Pooled estimate 1.4 2.1(95% CI) (1.0 to 1.9) (1.7 to 2.5)

UK estimate Number Number Denominator: affected affectedTotal population over 40 (2001 Census): 27,116,127 379,626 569,439

for OAG increases with age (Table 9). Incidence ofOAG ranged from 30 to 181 cases per 100,000people per year at 40 and 70 years of age,respectively. By applying the pooled estimate foreach age to the 2001 UK census population, thenumber of new cases in the UK is estimated torange from 263 to 880 new cases for 40 and 70 year olds per calendar year, respectively. It isnoteworthy that sample sizes in the older agecohorts are usually quite small and therefore theestimates presented in Table 9 may not reflect thetrue incidence among older people. In addition,the ageing population in the studies may not berepresentative of the general ageing population.For those reasons, these incidence estimatesshould be interpreted with caution.

Disease severity Five studies provided information on diseaseseverity for participants; however, information wasnot provided separately for the newly detectedcases, and in the majority of cases disease statuswas unclear (Table 10).71,108,114,117,126 In thesecross-sectional studies the percentage of peoplewith moderate disease varies from approximately9%114 to 15.4%.126 Mild disease was reported inonly one study and was estimated to be 12.1%.114

Severe disease was reported in three studies,varying from 4%117 to 14.6%.108 Blind from

glaucoma was reported in four studies, varyingfrom 3%71 to 10.6%.114 There appeared to beheterogeneity between the studies regardingseverity definition and therefore these resultsshould be interpreted with caution.

Demographic risk factorsAgeThe prevalence of OAG by age was reported in 16studies (Table 11). There was no standardisation ofage intervals across studies and therefore directcomparisons were difficult. For the purpose of thisreview, the focus was on age 40, 50, 60 and70 years as cut-offs. All studies consistently showedthat the prevalence of OAG increases with olderage. The overall prevalence of OAG by age was 0.3(95% CI 0.1 to 0.5) in people aged 40 years andincreased steeply with age to 3.3% (95% CI 2.5 to4.0) in people aged 70 years. As the prevalence ofundetected cases stratified by age was not reportedin any of the included studies, it was assumed thatthe proportion of undetected OAG does not varyacross age groups. The prevalence of undetectedOAG was then estimated to range from 0.2 to2.1% in people aged 40 and 70 years, respectively(Table 11). Figure 15 shows the estimated numberof people with undetected OAG in the UK,steadily rising from 1761 at 40 years to 11,000people at 70 years of age.


31


TABLE 8 Incidence estimates stratified by age

Age (years) Study Incidence rate (per 100,000 per year)

40 Mukesh, 2002125 0

50 Mukesh, 2002125 20Podgor, 1983123 40

60 Mukesh, 2002125 120Podgor, 1983123 60de Voogd, 2005124 60

70 Mukesh, 2002125 280Podgor, 1983123 140de Voogd, 2005124 124

TABLE 9 Estimated new OAG cases per year by age cohorta

Age (years) UK population at risk Mean Range UK estimate Range(n) (per 100,000 per year) (population)

40 878,257 30b 20–40 263 176–35150 717,088 30 20–40 215 144–28760 556,794 80 60–120 445 334–66870 486,614 181 124–280 880 603–1408

a Population estimate for all people aged 40–70: 11,054 new cases per year in the UK.b Same incidence as 50 year olds was assumed.

EthnicityThe relationship between ethnicity and OAG wasevaluated in only one study.114 This studyprovided a direct comparison of prevalencebetween black and white ethnicity. Age-specificprevalence rates for OAG among African-Americans ranged from 1.23% (95% CI 0.23 to2.24) in those aged 40–49 years to 9.15%

(95% CI 5.83 to 12.48) in those aged 70–79 years.The relative risk of OAG among the Baltimoreover-40 years black population compared withwhites is estimated to be 3.80 (95% CI 2.56 to5.64). The onset of disease appears to be earlierfor blacks as the number of cases identified forthose aged between 40 and 59 was considerablyhigher than that observed in whites (2.3% and


32

TABLE 10 Severity of glaucoma (newly detected and established cases)

Study Severity (%) Definition of severity

Mild Moderate Severe Blind Unclear

n (%) n (%) n (%) n (%) n (%)

Coffey, 1993108 NR NR NR NR 3 (15) 1 (7) 37 (78) Severe: low vision(<6/18)

Blind: not reported

Dielemans, 199471 NR NR 2 (6a) NR NR 1 (3) 31 (91) Moderate: advanced Rotterdam Study visual field loss in at least

one eye

Blind: visual acuity�20/200 in the bettereye

Jonasson, 1987117 NR NR NR NR 2 (4) 3 (6) 45 (90) Severe: visual field loss

Blind: visual acuity �6/60in the better eye orvisual field less than 10°(legally blind)

Lee, 2003126 NR NR 16 (15a) 6 (6) NR NR 82 (79) Moderate: advanced Blue Mountains visual field loss in at least Eye Study one eye

Severe: bilateraladvanced visual field loss

Tielsch, 1991114 16 (12) 12 (9) NR NR 14 (11) 90 (68) Mild: one visual field Baltimore Eye either typically abnormal Survey or compatible with

glaucoma and cupping ornerve fibre layer loss

Moderate: at least oneabnormal visual field withsome but not perfectcongruence betweenfields and a C/D � 0.8 ora difference between thetwo eyes of �0.3

Blind: end-stage diseasewith visual acuity�20/200 and 100%cupping

a No details of the other eye were given, so disease severity was assumed to be moderate because it was presumed that theauthors would have reported it as bilateral visual field loss (severe disease).


33


TABLE 11 Pooled prevalence estimate stratified by age

Age (years) Study Prevalence (%) (95% CI)

Undetected Overall

40 Anton, 200499 0 0Bankes, 196864 NR 2.0 (0 to 0.4)Bonomi, 2001106 NR 0.4 (0 to 0.8)Cedrone, 1997107 NR 1.4 (0 to 2.9)Kozobolis, 2000112 NR 0Tielsch, 1991114 NR 0.6 (0.1 to 1.0)Weih, 2001115 NR 0.1 (0 to 0.2)

Pooled prevalence 0.2 (0.1 to 0.4)a 0.3 (0.1 to 0.5)

50 Anton, 200499 2.2 (0 to 5.2) 2.2 (0 to 5.2)Bankes, 196864 NR 0.3 (0.1 to 0.5)Bonomi, 2001106 NR 1.4 (0.7 to 2.0)Cedrone, 1997107 NR 1.3 (0 to 2.8)Coffey, 1993108 NR 0.7 (0 to 1.3)Jonasson, 1987117 NR 0.9 (0 to 2.1)Jonasson, 2003110 NR 0.6 (0 to 1.3)Klein, 1992111 NR 1.0 (0.5 to 1.5)Kozobolis, 2000112 NR 2.8 (0.4 to 5.1)Mitchell, 1997122 NR 0.4 (0 to 0.7)Tielsch, 1991114 NR 2.1 (1.3 to 2.8)Weih, 2001115 NR 0.8 (0.3 to 1.3)


60 Anton, 200499 2.2 (0 to 4.7) 2.2 (0 to 4.7)Bankes, 196864 NR 0.9 (0.4 to 1.4)Bonomi, 2001106 NR 2.3 (1.4 to 3.1)Cedrone, 1997107 NR 2.5 (0.8 to 4.3)Coffey, 2003108 NR 1.8 (0.8 to 2.7)Dielemans, 1996105 NR 0.2 (0 to 0.4)Jonasson, 1987117 NR 3.0 (0.6 to 5.3)Jonasson, 2003110 NR 2.8 (1.1 to 4.5)Klein, 1992111 NR 1.1 (0.5 to 1.6)Kozobolis, 2000112 NR 2.5 (0.9 to 4.2)Leibowitz, 198022 NR 0.6 (0.1 to 1.0)Mitchell, 1997122 NR 1.1 (0.5 to 1.6)Tielsch, 1991114 NR 1.3 (0.9 to 1.8)Weih, 2001115 NR 1.9 (1.1 to 2.6)


70 Anton, 200499 3.3 (0.4 to 6.1) 3.3 (0.4 to 6.1)Bankes, 196864 NR 2.8 (1.5 to 4.2)Bonomi, 2001106 NR 4.6 (3.0 to 6.3)Cedrone, 1997107 NR 4.3 (1.7 to 6.9)Coffey, 2003108 NR 3.2 (1.7 to 4.7)Dielemans, 1996105 NR 1.3 (0.7 to 2.0)Jonasson, 1987117 NR 6.1 (2.6 to 9.6)Jonasson, 2003110 NR 8.0 (4.6 to 11.3)Klein, 1992111 NR 2.8 (1.9 to 3.7)Kozobolis, 2000112 NR 2.6 (1.1 to 4.1)Leibowitz, 198022 NR 1.3 (0.5 to 2.1)Mitchell, 1997122 NR 4.2 (2.9 to 5.4)Reidy, 1998113 NR 2.0 (1.0 to 2.9)Tielsch, 1991114 NR 4.6 (3.3 to 5.9)Weih, 2001115 NR 4.2 (2.7 to 5.6)Wormald, 1992116 NR 2.0 (0 to 4.7)


a Owing to the limited evidence on the prevalence of undetected OAG by age, the overall estimate of undetected OAG wasapplied to each age category to produce crude age-specific estimates.

0.25%, respectively). The number of people ofblack ethnicity (Caribbean, African, other andmixed) with OAG in the UK is estimated to beapproximately 9000 for those aged between 40and 75 years. No studies reported data for otherethnic populations.

Ocular risk factorsIOPSeven studies described the prevalence of OAG bya range of IOP levels.63,99,107,108,111,112,127 Acrossthe studies, the proportion of people with OAGwho had an IOP above 21 mmHg was consistentlyhigher than those who had an IOP of 21 mmHgor less (Table 12). The proportion of people withhigh IOP varied widely across studies. However, allbut one99 included cases with previously detectedOAG, and thus already under glaucoma therapy,and therefore underestimate the true prevalenceof OAG in people with high IOP. The reason forthe study by Coffey108 reporting such a lowprevalence of glaucoma among those with highIOP was unclear, although the authors did notreport IOP measurements in 12 of the 36 OAGcases. Prevalence of IOP by higher IOP levels(�26 mmHg) was also investigated. The risk ofhaving glaucoma for those with IOPmeasurements 26 mmHg or greater is estimated

to be 13 times higher than that for those withlower IOP [relative risk (RR) 12.58, 95% CI 5.07to 31.24]; of note was that only newly detectedcases contributed to the estimation of this relativerisk.127

MyopiaPrevalence rates of OAG for those with andwithout myopia were available from four studies(Table 13).128–131 The proportion of people withOAG appeared to be higher in participants withmyopia than in those without myopia. Theprevalence of OAG among people with myopiaranged from 1.4 to 4.3%, with a pooled estimateof 2.7% (95% CI 1.5 to 3.9). The pooled relativerisk of OAG among participants with myopia (anydefinition) compared with non-myopes wasestimated to be 1.88 (95% CI 1.53 to 2.31). Thisresult should be treated with caution as there wasno standardisation on the definition of myopiaacross the studies and therefore the risk for low(<–6 D) and moderate (>–6 D) could not bedetermined.

Non-ocular risk factorsDiabetesThe prevalence of OAG by diabetes status wasreported in four studies that established diabetes


34

0

2000

4000

6000

8000

10,000

12,000

14,000

16,000

18,000

40 50 60 70

Num

ber

with

OA

GOverall OAGUndetected OAG

Age (years)

FIGURE 15 Estimated number of people with OAG in the UK at specific ages

by clinical tests.22,105,122,132 Three of those providedadjusted estimates for odds ratios105,122,132 (Table14). The prevalence of OAG among participantswith diabetes varied from 1.2%105 to 5.5%,122 witha pooled estimate of 3.3% (95% CI 1.8 to 4.8%). Asshown in Table 14, this investigation demonstratedalmost twice the risk of OAG onset among peoplewith diabetes when compared with people withoutdiabetes (RR 1.93, 95% CI 1.38 to 2.69). Thenumber of those with diabetes with OAG in the UKis estimated to be approximately 49,300 for thoseaged over 45 years.

Family historyThe relationship between family history ofglaucoma and OAG was investigated in five

studies.99,130,133–135 Only four presented datasufficiently similar to allow for quantitativesynthesis.130,133–135 However, the RotterdamStudy135 was removed from the analysis becausetheir uptake rate was low (<75%). The includedstudies reported adjusted odds ratios estimates(Table 15). The prevalence of OAG amongparticipants with a positive family history variedfrom 4.2 to 8.6%, with a pooled estimate of 6.7%(95% CI 5.0 to 8.4). The meta-analysis showedthat a family history of glaucoma is associated witha three-fold excess age-adjusted risk of OAG(RR 3.14, 95% CI 2.32 to 4.25) (Table 16). Theseresults should be interpreted with caution, as thesestudies are methodologically weak because familyhistory of glaucoma was based solely on


35


TABLE 12 Prevalence of OAG stratified by IOP

Study Age (years) IOP > 21 mmHg (n/N) IOP �� 21 mmHg (n/N) Undetected OAG (%)

Anton, 200499 40–79 0.37 (3/8) 0.014 (7/497) 100Cedrone, 1997107 40+ 0.34 (21/62) 0.005 (5/1002) 19.2Coffey, 1993108 50+ 0.09 (6/65) 0.0087 (15/1734) 66.7Klein, 1992111 43–84 0.31 (71/232) 0.007 (33/4694) 90Kozobolis, 2000112 40+ 0.28 (28/101) 0.003 (3/1006) 70Mitchell, 199663 49+ 0.2 (27/135) 0.022 (81/3654) 51Tielsch, 1994127 40+ 0.1 (80/775) 0.011 (114/9669) 61

TABLE 13 Univariate and multivariate odds ratios (OR) reported by studies describing the relationship between glaucoma and myopes

Study Crude OR 95% CI Adjusted OR 95% CI Comments

Grodum, 2001128 1.85 1.4 to 2.4 NR NR Myopia: �–2.0 D

Mitchell, 1999129 2.1a 1.2 to 3.8 2.4 1.3 to 4.1 Adjusted for age, gender, family historyof glaucoma, diabetes, hypertension,typical migraine history, steroid use andpresence of pseudoexfoliation; myopia:�1.0 to 3.0 D

Weih, 2001130 NR NR 1.6 0.9 to 6.7 Adjusted for age; myopia: �–0.5 D

Wong 2003131 NR NR 1.6 0.9 to 2.6 Adjusted for age and gender; myopia:�–1.0 D

a Gender adjusted.

TABLE 14 Univariate and multivariate odds ratios reported by studies describing the relationship between glaucoma and diabetes


Dielemans, 1996105 NR NR 3.11 1.12 to 8.66 Adjusted for age, gender and body massindex

Klein, 1994132 NR NR 1.84 1.09 to 3.11 Adjusted for age and gender

Leibowitz, 198022 1.27 0.5 to 2.9 NR NR

Mitchell, 1997122 2.07 1.5 to 4.7 2.12 1.18 to 3.79 Adjusted for age and gender

participant self-report of family history. Thismethod is suboptimal as it relies on the imperfectknowledge among participants (a form of recallbias).

This association remained statistically significantwhen data from the Rotterdam Study135 were alsoconsidered (RR 3.23, 95% CI 2.40 to 4.37). Thisstudy investigated the relationship of OAG withfamily history by means of a nested case–controlstudy and was initially excluded from this analysisbecause of the high degree of uncertaintysurrounding the results owing to its small samplesize. However, it was the only study thatascertained a positive family history by examiningfirst-degree relatives of patients with glaucomaand control subjects from the population-basedRotterdam Study.

DiscussionIn this chapter a systematic review has providedthe basis for estimates of the prevalence of OAG inWestern countries and associated risk factors wereevaluated. The results support an associationbetween OAG and raised IOP, myopia, diabetes,age, family history and black ethnicity. There were

insufficient data to estimate the risk of OAG forother ethnic minority groups in the UK.

Inclusion criteriaGiven the aetiological focus of this systematicreview, study designs such as population-basedcross-sectional and cohort studies were consideredthe most appropriate sources of evidence on theprevalence and incidence of OAG. As Beral136 andDickersin137 pointed out, if associations detectedby those studies are causal, even small increasedrisks are likely to have a large public health impactwhen exposure is common.136,137 Study designssuch as these are, however, subject to manyalternative interpretations because of the scope forthe results to be biased or confounded.138 Inaddition, the published epidemiological literatureis unquestionably heterogeneous.137 Studiesnaturally vary in terms of participants’characteristics or on the methods used to assessexposure and outcomes. The presence of majorheterogeneity among studies in a systematic reviewmeans that the results of any statistical synthesisshould be treated with caution.

Only 19 of the 26 studies identified in this reviewwere considered to be similar enough to allow formeaningful pooling. This selection was based on


36

TABLE 15 Univariate and multivariate odds ratios reported by studies describing the relationship between glaucoma and family history


Mitchell, 2002133 2.7a 1.5 to 4.7 3.18 1.8 to 5.6 Adjusted for age, myopia, ocularhypertension, diabetes and IOP

Tielsch, 1994134 2.48 1.6 to 3.9 2.85 1.8 to 4.5 Adjusted for age and race

Weih, 2001130 NR NR 3.7 2.0 to 6.7 Adjusted for age

Wolfs, 1998135 14.7a 1.7 to 130 16.6 1.9 to 147 Adjusted for age, gender, and thepresence of diabetes or hypertension

a Age and gender adjusted.

TABLE 16 Pooled prevalence estimates and respective adjusted relative risks stratified by ethnicity, IOP, myopia, diabetes and familyhistory

Risk factor Pooled prevalence (%) Pooled adjusted 95% CI Number of studies(95% CI) relative risk

Black ethnicitya – 3.80 2.56 to 5.64 1114

IOP � 26 mmHg – 12.58 5.07 to 31.24 1127

Myopia 2.7 (1.5 to 3.9) 1.88 1.53 to 2.31 4128–131

Diabetes 3.3 (1.8 to 4.8) 2.08 1.44 to 2.99 3105,122,132

Family history 6.7 (5.0 to 8.4) 3.14 2.32 to 4.25 3130,133,134

a African-American.

the consideration that reasonable quality studiesthat might contribute usable data for evidencesynthesis should have an adequate samplingmethod, an acceptable glaucoma definition, anexposure status obtained from a high-quality datasource, and a response rate greater than or equalto 75%.

This systematic review attempted to estimate thecurrent prevalence and incidence of OAG in theUK by applying the pooled estimates to the 2001UK Census population. There are numerousepidemiological surveys assessing the prevalenceof glaucoma, but there are few cohort studies thatprovide estimates of incidence. Only three studieshave been identified to report 5-year incidencerates for a cohort of people. Incidence studies areimportant to identify the risk of developing OAGand the number of new cases among a populationof individuals previously unaffected. Prevalencestudies only measure the risk of having thedisease. To overcome this problem, some studiesderived the incidence from already availableprevalence data.139,140 Using this method,Minassian and colleagues140 in the UK estimated ahigher incidence than that observed in this study(approximately 14,000 as opposed to 11,000).This difference may be because their estimate isbased on a much smaller population, includingonly those aged above 65 years.

The systematic review includes the results of 14studies conducted in eight different Europeancountries, as well as three in the USA and two inAustralia. The breadth of coverage acrossgeographical areas facilitates the consideration ofgeneralisability, although this limited the dataavailable on the risk of glaucoma by ethnicity.

Included studiesOnly four UK surveys21,64,113,116 met the inclusioncriteria, two of which were performed during the1960s. For these two, the level of risk, populationstructure, disease definition and methods ofdiagnosis used may no longer be applicable to thecurrent situation. In addition, the results of studiesperformed outside the UK may not begeneralisable to a UK population owing todifferences in aetiological and cultural factors.Further studies would be useful to assess directlythe prevalence of OAG overall and by the differentrisk factors deemed important for the UK.

The results of the review may be biased if theparticipation rates in the included studies are low.In this review, six of the 19 studies included didnot provide information on participation rates. In

addition, the majority of studies that provided thisinformation did not give details about thecharacteristics of those who did not participate.This provides a potential for bias if the risk ofglaucoma among responders is systematicallydifferent from that of non-responders. If non-responders were to be more likely to be glaucomacases (perhaps because they do not see the benefitof entering the study), then this would lead tounderestimation of the prevalence of OAG in thepopulation.

The results of this systematic review must also beinterpreted in light of the quality of the includedobservational studies. A validated checklist was notused to assess the quality of the included studies;instead, a set of fields had to be satisfied in orderfor a study to be considered good quality with nomajor flaws. The reason for this is that there areno validated checklists available to assess thequality of cross-sectional studies. Some may findthis checklist compact and oversimplified.However, studies failing to provide details oneligibility criteria or where the credibility of study designs was questionable were excludedbefore the quality assessment stage. For example, a cohort study that did not demonstrate theoutcome of interest would have been excludedwith no further quality assessment conducted.Nevertheless, despite efforts to focus only on the best available data for some outcomes (e.g.risk of OAG by family history) B-rated studies hadto be included because of the lack of availableevidence. Furthermore, even where data wereavailable they were not always reported in a format suitable for inclusion in the meta-analysis.For example, Anton and colleagues99 evaluatedthe relationship of OAG to family history ofglaucoma, but results were presented as aproportion of those with OAG who had a positivefamily history. No data were provided on theproportion of people with family history in thetotal sample and, hence, a relative risk could notbe estimated.

One of the main difficulties in ascertaining anestimate of population prevalence and risk factorsfor developing OAG is the lack of a referencestandard definition of OAG. Raised IOP is a riskfactor for developing OAG, but does not define itspresence or absence. In this review, studies wereincluded using a definition of OAG based onglaucomatous visual field loss, but the definition ofa glaucomatous visual field defect variedconsiderably across the studies. Perimetricmethods for ascertaining glaucomatous visual fieldloss have evolved over time. The review included


37


several studies conducted in the 1960s, and thestudies used a range of criteria to define a positivetest; therefore, the definition of a positive casemay vary between observers and studies andaccount for some of the variation in prevalencerates between studies. Differential verification biaswas likely in some of the includedstudies28,64,106–108,110,112 in that only suspects onthe initial screen went on to a more extensivereference standard examination, and thereforesome of the cases may have been missed.Therefore, the prevalence may have beenunderestimated by these studies.

OAG and ageThe association between OAG and age is veryrobust. All included studies show that theprevalence of OAG is higher in older age groups.One of the limitations in the calculation of apooled estimate of prevalence in this review is thefact that the age cut-offs used were different tothose reported in the included studies. Inaddition, specific age points (40, 50, 60, 70) werechosen rather than age ranges, and therefore theassumption that the prevalence is constant across aparticular age range may not be a truerepresentation.

OAG and ethnicityOnly one study included in the review reporteddata on the relationship between ethnicity andOAG.114 The risk of having OAG for African-Americans was found to be approximately fourtimes that for whites. OAG is not only moreprevalent but also appears to be more severe inblack than in white people. This is possiblybecause the onset of disease is earlier for blackpeople than it is for white people.114 The relativerisk was not adjusted for other risk factors andshould therefore be treated with caution. Inaddition, the UK African Caribbean Eye Surveyreported that not only darker skin but also placeof origin in Africa are associated with asignificantly increased risk of disease.120 The riskof glaucoma among black Africans wassignificantly higher than that in black Caribbeans.This study was, however, a B-rated study, in that itwas based on a volunteer sample rather than arandom sample of the population.

Studies conducted in Africa, South America andAsia were not included, as it was felt that the levelof risk in these settings would not necessarily berepresentative of the risk observed in the sameethnic groups living in the UK. Prevalence rates ashigh as 13% and 16% have been observed inCongo141 and Barbados.142

The increased risk associated with black ethnicitymay be a function of the excess co-morbidities inthese populations, including sickle cell disease,systemic hypertension and diabetes.143 There mayalso be ethnic differences in optic discmorphology and an increased susceptibility at agiven IOP level. However, there is likely to beheterogeneity within an ethnic population, and acommon level of attributable risk to being of blackethnicity may not be appropriate for differentgeographical areas and subgroups within an ethnicgroup.144

People of Hispanic ethnicity are also at increasedrisk. In a large US population-based study ofdefinite OAG in Latinos of Mexican ancestry,including more than 6000 participants whounderwent a complete ophthalmic examinationfor determining glaucoma, the prevalence patternof OAG was similar to that observed in those ofblack ethnic origin in the USA and significantlyhigher than in non-Hispanic whites.145

OAG and IOPAcross the included studies the proportion ofpeople with OAG who had an IOP greater than21 mmHg was consistently higher than amongthose who had an IOP less than 21 mmHg. Eventhough a clear association was found betweenOAG and high IOP, it is possible that thisrelationship could be stronger. The reason for thisis that the included studies did not provide aseparate IOP measurement for those participantswho had previously detected glaucoma. It is verylikely that these participants will be receivingpressure-lowering therapy, hence the possibleunderestimation of the prevalence of OAG amongthose with high IOP. One study provided sufficientdata to calculate the relative risk based onprevious undiagnosed cases.127 The sample wassmall and the estimate was unadjusted for otherrisk factors and should therefore be treated withcaution.

OAG and myopiaThere is evidence that people with myopia aremore likely to develop OAG. One of the greatestlimitations in assessing the relationship betweenthese two conditions is the lack of a consensusacross the included studies on the definition ofmyopia. For example, in the Visual ImpairmentProject,115 participants were classified as myopeswhen they had a refractive error worse than–0.5 D, whereas Grodum and colleagues28 used arefractive error equal or worse than –2.0 D toclassify myopes. In addition, differences in thedefinition of glaucoma may lead to an


38

underestimation of the prevalence of OAG amongpeople with myopia. However, overdiagnosis ofglaucoma among people with myopia may also beresponsible for this association, because myopia isassociated with a number of non-glaucomatousvisual field defects and myopic discs can bedifficult to assess for glaucomatous damage.131

Owing to limited evidence it was not possible toestimate the risk of glaucoma in people with lowand moderate myopia and therefore the pooledestimates should be treated with caution.

Structural differences in the myopic optic nervemay make myopic eyes more susceptible toglaucomatous damage.129,131,146 Furthermore,glaucoma and myopia have a strong familial basisand therefore they may share a common geneticlink.129 A dose–response relationship betweenOAG and myopia has been postulated (the higherthe myopia the more likely an individual would beto develop OAG). This relationship can beobserved in the Blue Mountains Eye Study,reporting an odds ratio of 3.3 for those withmoderate to high myopia (�–3.0 D) comparedwith 2.3 in those with low myopia (�–1.0 to<–3.0 D).129

OAG and diabetesCurrently available evidence suggests that there is apositive association between people with diabetesand OAG. The present study identified anincreased risk of OAG in those with diabetes. Theseresults are consistent with those of a meta-analysisperformed in 2004 (OR 1.57; 95% CI 1.13 to2.20).147 This meta-analysis had variations in theeligibility criteria used to select studies comparedwith the present study. Bonovas and colleagues147

included studies that did not establish diabetesthrough a clinical examination as well as studiesthat were conducted in African countries. Thesewere excluded in the review reported in this chapterbecause, in order to avoid detection bias, exposureshould be obtained from a secure record, and alsobecause it is believed that the level of risk of OAGin people in countries of African descent is verydifferent from that observed in other populations.

The results reported in this chapter are consistentwith one population-based cohort studyperformed in Scotland,102 and with onepopulation-based cross-sectional study performedin England.116 Ellis and colleagues102 reported arisk ratio of 1.57 for diabetes, although this resultwas not statistically significant. This study wasexcluded from the analysis owing to inadequatemethods used to select cases of glaucoma.Wormald and colleagues120 reported a risk ratio of

2.2 for diabetes, but this result was also notstatistically significant (95% CI 0.9 to 5.6). Thisstudy was excluded from the analysis because avolunteer sample was used rather than a randomsample and therefore it is likely that a healthyvolunteer effect was present in the results. Themethod of sampling is crucial to the avoidance ofselection bias, and the observed increased risk inpeople with diabetes and myopia may reflect thistype of bias, in that these groups may be more likelyto be tested for glaucoma because they have regulareye tests for diabetic eye disease and for spectaclecare for myopia. The impact of this bias would beto elevate artificially the relative risk of OAG.

OAG and family history All studies identified indicated that an associationexists between OAG and a positive family history.However, none of the included studies proved tobe high quality (i.e. none was rated as ‘A’ in thequality assessment). There was no standardisationon the type of family history reported across thefour included studies.115,133–135 It is possible thatthe level of risk varies according to the type offamily history. For example, Tielsch andcolleagues134 and Mitchell and colleagues133 foundsome variability in the strength of the associationby the type of family member, in which thestrongest association was observed betweensiblings.

Most of the studies relied on verbal reporting offamily history of glaucoma rather than a clinicalexamination of relatives of glaucoma cases,making results prone to misclassification. Suchmisclassification may be due to anunderascertainment of glaucoma cases since thediagnostic criteria used for relatives may havebeen different from those used to diagnose thecases. Moreover, those who had a previousdiagnosis of glaucoma are more likely to recall andtherefore report a positive family history.133,134 Inthe Rotterdam Study, attempts were made tominimise some of these biases by examiningrelatives of glaucoma cases. However, a smallsample size led to wide confidence intervalssurrounding the estimates, giving rise to a highdegree of uncertainty.135

Even though an increased risk of glaucoma amongpeople with a positive family history has beenobserved, the population attributable risk is low.This was estimated in two studies.133,135 Bothestimated a population attributable risk ofapproximately 16%, suggesting that other riskfactors largely determine the occurrence ofglaucoma in the population.


39


ConclusionsKey points:● This systematic review estimates the prevalence

of OAG in a predominantly white populationaged over 40 years to be 2.1% (95% CI 1.7 to2.5). An estimated 67% of cases are notcurrently detected; a prevalence rate of 1.4%(95% CI 1.0 to 1.9) is estimated for those withpreviously undiagnosed disease.

● The overall prevalence of OAG by age rangesfrom 0.3 (95% CI 0.1 to 0.5) in people aged40 years, increasing steeply to 3.3% (95% CI 2.5 to 4.0) in people aged 70 years.

● The incidence of glaucoma is estimated asranging from 30 to 181 per 100,000 person-years for people aged 50 and 70 years,respectively.

● Approximately 569,000 people are affected byOAG, of whom 380,000 are undetected cases.The number of people with undetected diseasesteadily rises from 1800 at 40 years, reachingapproximately 11,000 at 70 years of age. Onecan estimate that there are approximately11,000 new cases of OAG per year.

● The risk of having glaucoma for those with IOPmeasurements 26 mmHg or greater is estimatedto be 13 times higher than that for those withlower IOP.

● The onset of disease appears to be earlier forblack people and the relative risk of OAG forpeople of black ethnicity compared with whitepeople is estimated to be 3.80 (95% CI 2.56 to5.64).

● There is almost twice the risk of OAG onset inpeople with diabetes compared with thosewithout diabetes (RR 1.93, 95% CI 1.38 to 2.69).

● A positive family history of glaucoma isassociated with OAG (RR 3.14, 95% CI 2.32 to4.25). The strongest association is for siblings ofan affected case.

● The proportion of people with OAG appearedto be higher in participants with myopiacompared with those without myopia. Thecombined relative risk of OAG amongparticipants with myopia compared with thosewithout myopia was estimated to be 1.88 (95% CI 1.53 to 2.31).

Strengths and limitations:● This comprehensive systematic review identified

19 eligible studies. Data were sparse for some ofthe review outcomes. For example, only onestudy provided data on the relationship betweenOAG and ethnicity. There were few data for theassessment of disease severity. Even though anumber of studies reported family history, noneof the included studies that contributed to anoverall estimate was of high quality. Therefore,more accurate risk information is necessary forbetter estimates to be developed in relation tofamily history and ethnicity.

● An extensive literature search was conducted,but only published data in English were sought.It is possible that unpublished and non-English-language studies were missed, with the directionof effect in these studies being unknown.

● Strong associations between OAG and increasedage, black ethnicity, high IOP, myopia, diabetesand family history are highlighted. However,the prevalence of glaucoma by certain riskfactors may be overestimated, in particularwhen assessing family history, myopia anddiabetes as potential risk factors, as thesegroups are more likely to have sight tests, andtherefore may be more likely to have glaucomadiagnosed. Also, some studies did not adjustrelative risk estimates to other risk factorvariables.

● Risk factor and OAG definitions variedconsiderably, causing the exclusion of severalstudies because of poor reporting andinadequate criteria.

For future epidemiological studies, a standardiseddefinition of OAG and improved reporting on howthe suspects and definite cases received thereference standard diagnostic assessment arerequired. Efforts should be directed to create acollaborative group with the aim of standardisingdata such that the results can be presented andpooled with similar case definitions for similarpopulations. Ideally, prevalence studies shouldreport IOP measurements for participants withnewly diagnosed (i.e. untreated) glaucoma, to allowthe determination of appropriate cut-offs for IOPas a diagnostic or prognostic indicator of OAG.


40

IntroductionThere are many potential tests or combinations oftests for detecting glaucoma (see Chapter 3). Todate, no single test or combination of tests hasbeen identified as a definitive screening test forglaucoma.

The aim of this systematic review was to evaluatethe accuracy of candidate screening tests and toprovide details of the reliability of the tests andthe proportion of people able to complete eachtest.

MethodsInclusion and exclusion criteriaTypes of studyThe following types of study were included:

● direct (head-to-head) studies in which bothindex test(s), comparator test(s) and referencestandard test are done independently in thesame group of people

● RCTs in which people are randomised to theindex and comparator test(s) and all receive thereference standard test.

Where there was insufficient evidence from directstudies and RCTs, indirect (between-study)comparisons were considered by meta-analysingstudies that compared each single test orcombination of tests with the reference standardtest, and comparing the meta-analyses of thedifferent tests. This type of study design, however,is less reliable than direct studies as differences intest accuracy are susceptible to confounding factorsbetween studies. The following types of study wereconsidered for the indirect comparisons:

● observational studies, including cohort studies,with analysis data on at least 100 participants,in which the sample is created by identifying allpeople presenting at the point of testing(without any reference to the test results)

● case–control studies in which two groups arecreated, one known to have the target disease

and one known not to have the target disease,where it was reasonable to assume that allincluded had undergone the index andreference standard tests.

Population-based studies and studies in a primarycare or hospital-based setting were consideredwhere the participants were likely to berepresentative of a screening situation or of aglaucoma suspect population referred from a GPor an optometric practice. Case–control studieswhere the inclusion criteria were different for casesand controls were excluded; that is, studiescomparing severely diseased people with veryhealthy controls or studies excluding people withother ocular disease such that the spectrum ofdisease and non-disease was unlike that to beencountered in a screening situation. Alsoexcluded were case reports and studiesinvestigating technical aspects of a test.

Target conditionThe target condition was OAG (early, moderate orsevere).

ParticipantsPeople over 40 years of age and those in thefollowing higher risk subgroups were included:

● family history of glaucoma● black race● people with myopia● people with diabetes.

The criteria for defining myopia and diabeteswere loosely applied and definitions used by studyauthors for these conditions were consideredacceptable.

Index and comparator test(s)The tests to be considered fell within three broadcategories:

● structure– ophthalmoscopy– optic disc photography (including non-digital

and digital monoscopic and stereoscopicphotography, and planimetric)


41


Chapter 6

Screening and diagnostic tests for open angle glaucoma

– RNFL photography– HRT version II– GDx VCC RNFL analyser (scanning laser

polarimetry)– OCT– RTA

● function:– FDT– MDP– OKP– SWAP– white-on-white SAP, including suprathreshold

and threshold● IOP:

– GAT– NCT– tonopen.

Comparisons both of individual and combinationsof tests were considered.

Reference standard testThere is no optimal reference standard for thediagnosis of OAG or the classification of itsseverity. OAG is a clinical diagnosis, based onstructural abnormalities of the optic disc and anassociated glaucomatous visual field defect.Progressive structural optic neuropathy has beenproposed as a reference standard.148

Either of two reference standard tests wasconsidered. The primary reference standard testwas confirmed OAG on follow-up. This wasconsidered the best reference standard, although itwas anticipated that few studies would use it.Therefore, also considered were studies where thereference standard was ophthalmologist-diagnosedOAG requiring treatment. This diagnosis can bebased on an assessment of the visual field and/orthe optic disc, but without follow-up confirmation.Each reference standard might include one ormore of the screening tests against which it wasbeing compared.

Studies using a technology-based diagnostic test(s)result alone as a reference standard were excluded.

Types of outcomeTo be included, studies had to report relevant andinterpretable data on one of more of the followingtypes of outcome:

● the absolute numbers of true positives, falsepositives, false negatives and true negatives, ornumbers from which they could be computed,such as the sensitivity and specificity values

● adverse events

● acceptability of the tests to those who receivethem

● reliability of the tests.

If the evidence allowed, it was planned to assesstest performance in early, moderate and severeglaucoma.

Data extraction strategyTwo reviewers (GM, MARS) screened the titles(and abstracts if available) of all reports identifiedby the search strategy. Full text copies of all studiesdeemed to be potentially relevant were obtainedand two reviewers (GM, MARS) independentlyassessed them for inclusion. Any disagreementswere resolved by consensus or arbitration by athird party (JB).

A data extraction form was developed and piloted.One reviewer (GM or MARS) extracted details ofstudy design, participants, index, comparator andreference standard tests, participant flow andoutcome data. In the event of any uncertainty, asecond reviewer (GM or MARS) provided adviceand validated the data extraction.

Quality assessment strategyQuality assessment was performed using theQUADAS tool. QUADAS is a recently developedquality assessment tool for use in systematicreviews of diagnostic studies.149 It was developedthrough a formal consensus method and wasbased on empirical evidence. The originalQUADAS checklist contained 14 questions. TheQUADAS tool was adapted to make it moreapplicable to assessing the quality of studies oftests for detecting OAG. (See Appendix 7 for anexample of the modified checklist.)

Question 1 concerns the representativeness of thespectrum of people assessed by the test (question1 of the original QUADAS checklist). This wassplit into two parts, depending on whether thestudy sample was (1) taken from an unscreenedpopulation with a glaucoma prevalence between>0 and 20% or (2) constructed from previouslyundiagnosed glaucoma patients but representativeof those referred from primary care as suspectglaucoma. Case–control studies were assessed onthe basis of whether the cases and controls couldbe regarded as representative of those detected inprimary care.

Question 2, concerning the reference standard(question 3 of the original QUADAS checklist),was reworded to ask whether the referencestandard was follow-up confirmation of glaucoma


42

(i.e. glaucoma confirmed clinically by thelongitudinal follow-up of the patient), consideredto be the best reference standard against which tomeasure tests for detecting OAG. Given the natureof the reference standard, the QUADAS questionon whether the period between reference standardand index test was short enough to be reasonablysure that the target condition did not changebetween the two tests was omitted (question 4 ofthe original QUADAS checklist).

Questions 3 (partial verification bias), 4 (differential verification bias), 5 (incorporationbias), 6 (test review bias), 7 (diagnostic review bias)and 10 (withdrawals from the study) remainedunchanged (questions 5, 6, 7, 10, 11 and 14 of theoriginal QUADAS checklist). Partial verificationbias occurs when not all of the study participantsare verified by a reference standard. Differentialverification bias happens when some of thepatients receiving the index test are verified by adifferent reference standard. Incorporation biasoccurs when the index test also forms part of thereference standard. Test review bias and diagnosticreview bias happen when interpretation of theresults of the index test is influenced byknowledge of the results of the reference standard,and vice versa.

It should be noted that in relation toincorporation bias (question 5), in glaucoma asituation may occur whereby the index test may bea test of visual function (e.g. FDT) and thereference standard may include a different test ofvisual function (e.g. SAP). In such cases question 5was marked as incorporation bias avoided, takingthe view that although both tests were of visualfunction they were actually different tests.However, in a situation such as this the sensitivityand specificity of the index test may beoverestimated as the tests are measuring similaroutcomes. The same situation may occur withdifferent tests that assess the structure of the eyewhen one is the index test and one forms part ofthe reference standard, e.g. HRT II andophthalmoscopy.

Question 8 is concerned with whether the sameclinical data were available when the test resultswere interpreted as would be available when thetest is used in practice (question 12 of the originalQUADAS checklist). This question was split intotwo parts, depending on whether the study was ascreening or diagnostic accuracy study. It wasassumed that in a screening situation in practicethe index test results alone would be used, but thatfor studies of diagnostic test accuracy (cohort or

case–control) in practice information fromophthalmic examination and/or information onco-morbidity might be used.

Question 9 concerns the reporting of numbers of uninterpretable/intermediate test results(question 13 of the original QUADAS checklist). If uninterpretable/intermediate results occur but are not reported then this may lead to abiased assessment of the test characteristics.Therefore, this question was retained and alsoamended to include whether incomplete tests were reported.

Items relating to the quality of reporting in termsof the description of the selection criteria, theexecution of the index test, and the execution ofthe reference standard test were omitted(questions 2, 8 and 9 of the original QUADASchecklist). Three questions were added to thechecklist on whether the technology of the indextest was still current (question 11), whether thestudy provided a clear definition of what wasconsidered a positive result (question 12), andwhether the definition of a positive test result wasdetermined before the study was carried out(question 13).

Two reviewers (GM, MARS) independentlyassessed the quality of all included studies usingthe modified version of QUADAS. Each of the 13questions was checked as ‘Yes’, ‘No’ or ‘Unclear’.Each item was worded so that a rating of ‘Yes’ wasalways optimal in terms of methodological quality.Any disagreements were resolved by consensus orarbitration by a third party (JB). A ‘higher quality’study was considered to be one that was checkedas ‘Yes’ to questions 1 (patient spectrumrepresentative), 3 and 4 (partial and differentialverification bias avoided) and 6 and 7 (test reviewbias and diagnostic review bias avoided).Sensitivity analysis was planned to assess whetherthe results for higher quality studies differedsystematically from those of the other includedstudies.

Data analysis The results of the individual studies weretabulated and sensitivity, specificity, and diagnosticodds ratios (DORs) calculated. A DOR combinessensitivity and specificity into a single summary ofdiagnostic performance. If more than onethreshold level was reported in a given study aseparate 2 × 2 table was derived for eachthreshold. Separate 2 × 2 tables were alsoproduced for relevant subgroups considered in thestudies.


43


Relative diagnostic odds ratios (RDORs) werecalculated for studies comparing two or more testsin the same participants. A 95% confidenceinterval was calculated under the assumption oftwo independent groups which will be conservative.Insufficient data were reported, however, to allowa paired analysis to be undertaken.

Summary performance of each testSummary receiver operating characteristic (SROC)curves were produced for each test where two ormore studies reported estimates of sensitivity andspecificity. A second set of SROC curves was alsoproduced for a test-specific common cut-off. Fromeach study reporting each test, a cut-off waschosen (the common cut-off) from among thevarious cut-offs reported. The aim was to select acut-off that was broadly similar across studiesreporting that test. The decision on which cut-offto select was made following discussion by twoophthalmologists (JB and RS). Owing to thelimited number of studies identified, statisticalinvestigation of the potential sources ofheterogeneity was not undertaken. The Fdistribution method was used for calculating theconfidence intervals for sensitivity and specificityfor individual studies,150 which were producedusing Metadisc software.151

Meta-analysis models were fitted using thehierarchical summary receiver operatingcharacteristic (HSROC) model152 in WinBUGS1.4.153 This model takes proper account of thediseased and non-diseased sample sizes in eachstudy, and allows estimation of random effects forthe threshold and accuracy effects. The SROCcurves from the HSROC models were produced onthe corresponding SROC plots. Summarysensitivity, specificity and DORs for each modelwere reported as median and 95% credible interval(CrI). Credible intervals are the Bayesian equivalentof confidence intervals. Where two or more higherquality studies were available for a test, a modelusing only these studies was also fitted. Asimplified model, which assumed a symmetricalSROC shape, was used where limited data causedconvergence problems under the full model.

Indirect comparison between testsAll tests with two or more included studies weremodelled together in a single HSROC model tocompare formally the performance of the tests. Asymmetrical SROC model was assumed for all thetests. Pairwise differences in sensitivity andspecificity between tests were assessed from themedian difference and the corresponding 95%credible interval.

Results

Number and type of studies included Appendix 8 lists the 82 studies published in 93reports that were included.

AccuracyForty studies, published in 46 reports, met theinclusion criteria for the screening and diagnosticaccuracy review. There were 20 population-basedstudies representative of a screeningsetting.21,72,99,100,106,112,115,154–170 Twenty studieswere representative of a glaucoma suspectpopulation referred from primary care, of whicheight were cohort studies22,171–177 and 12 werecase–control studies.178–191

Uptake, interpretability, time taken to do testand reliability of testIn addition to the studies included in the review ofscreening and diagnostic test accuracy thatcontributed information on uptake,interpretability of tests, time taken to do the testand reliability of the test, 47 reports also provideddata on these aspects. These studies did notprovide usable outcome data in terms of testaccuracy, but otherwise met the review’s inclusioncriteria.107,109,110,132,192–234 Information on uptake,interpretability and time taken to do the test isgiven in the results section for each test, whilethose studies reporting reliability are listed inAppendix 9.

Number and type of studies excluded,with reasons for specific exclusionsFor the screening and diagnostic accuracy review,5918 titles and abstracts from the specific andgeneral searches were screened, from which 877were selected for full-text assessment. Articles wereexcluded because they failed to meet one or moreof the specified inclusion criteria in terms of studydesign, participants, index tests, referencestandard or outcomes reported. Fifty-seven of thefull-text reports excluded were case–control studieswhose participants were considered to beunrepresentative of those who would attend forscreening and are listed in Appendix 10.

Tabulation of quality of studies,characteristics of studies and evidenceratingQuality of studiesThe results of the quality assessment for theindividual studies are shown in Appendix 11. Thequality assessment of studies reporting the varioustests is discussed in the results section for eachtest.


44

Characteristics of studiesAppendix 12 provides details of the characteristicsof the included studies.

The 40 studies enrolled over 48,000 people, withover 39,000 included in the analysis. The earlieststudy took place in 196321 and the latest in2003/04,156,176 while 21 studies gave no indicationof the period in which they were carried out.Thirteen studies took place in theUSA,22,158,159,162,166,168,170,172,175,181,187–189 nine inthe UK,21,164,176,177,180,182,186,190,191 four inAustralia,115,157,163,173 two each in Italy,106,174 TheNetherlands,169,183 Spain99,179 and Sweden,100,171

one each in Belgium,155 Canada,156 Greece,112

India161 and Norway,154 and one in Canada andFinland.178 Twenty-six studies gave details of thegender of their participants, 51% of whom werewomen.21,22,99,106,112,115,154–157,159,161–164,166,168,170,171,

173–176,183,186,188 The median age of theparticipants across studies was 60.5 years, with anage range from 13 years183 to 97 years.155,157

The reports included a number of majorpopulation-based prevalence surveys, such as theBaltimore Eye Survey,72,159 the Blue MountainsEye Study,157 the Crete, Greece GlaucomaStudy,112 the Dalby Population Survey,100 theEgna–Neumarkt Study,106 the Framingham EyeStudy,22 the Glaucoma Screening Study(GLASS),158,160 the Groningen LongitudinalGlaucoma Study,183–185 the Rhondda ValleyStudy,21 the Rotterdam Study,169 the SegoviaStudy99 and the Visual Impairment Project.115

The included studies reported the following tests: ophthalmoscopy,115,163,164,168,172,177,191

optic disc photography,166,169,175,188–190 RNFLphotography,167,178,188,189 HRT II,156,163,186

OKP,154,170,180,182

SAP,157–159,162–164,166,168,174,176,179,181,182,186

FDT,155,161,163,170,173,176,183–185,187

GAT,21,22,99,100,106,112,157,168,171 and NCT.164,165 Nostudies of GDx VCC, OCT, RTA, SWAP, MDP orTonopen met the inclusion criteria in terms ofreporting of test accuracy outcomes.

Eighteen population-based studies reporteduptake (the percentage of those eligible forscreening who actually attended).21,22,99,100,106,107,

109,110,112,115,132,154,157,159,163,164,168,169 Out of a totalof 58,708 eligible people, 44,653 (76.1%) attendedfor screening (median 82.8%, range 28.3–99.5%)(Table 17). Fifteen of these studies are included inthe screening and diagnostic accuracy review.Three others failed to meet the review’s inclusioncriteria in terms of test accuracy outcomes, but asthey provided data on uptake they have also beenincluded in the table.107,110,132

Tabulation of resultsTests of structureOphthalmoscopyQuality assessmentSeven studies enrolling 7279 people reported thetest accuracy of ophthalmoscopy, including fourpopulation-based studies,115,163,164,168 two cohortstudies172,177 and one case–control study.191

Figure 16 summarises the quality assessment for


45


TABLE 17 Uptake reported by population-based studies

Study Eligible Attended %

Anton, 200499 (Segovia Study) 569 510 89.6Bengtsson, 1980100 (Dalby Population Survey) 1,938 1,511 78.0Bonomi, 2001106 (Egna–Neumarkt Study) 5,816 4,237 72.9Cedrone, 1997107 1,226 1,034 84.3Christoffersen, 1995154 196 195 99.5Ekstrom, 1996109 (Tierp Glaucoma Survey) 838 760 90.7Hollows, 196621 (Rhondda Valley Study) 4,608 4,231 91.8Ivers, 2001157 (Blue Mountains Eye Study) 4,433 3,654 82.4Jonasson, 2003110 (Reykjavik Eye Study) 1,379 1,045 75.8Katz, 1993159 (Baltimore Eye Survey) 6,705 5,308 79.2Klein, 1994132 (Beaver Dam Eye Study) 5,924 4,926 83.2Kozobolis, 2000112 (Crete, Greece Glaucoma Study) 1,300 1,107 85.2Leibowitz, 198022 (Framingham Eye Study) 3,977 2,631 66.2Robin, 2005163 2,486 704 28.3Vernon, 1990164 988 874 88.5Wang, 1998168 530 405 76.4Weih, 2001115 (Visual Impairment Project) 5,520 4,744 85.9Wolfs, 1999169 (Rotterdam Study) 10,275 6,777 66.0Total 58,708 44,653 76.1

these studies. In four of the seven studies theparticipants were considered to be representativeof a screening setting.115,163,164,168 Four studieswere judged to be free from both partial anddifferential verification bias.163,172,177,191 In threeof the seven studies both the index test and thereference standard test were interpreted withoutknowledge of each other’s results.115,163,191 Onlythe study by Robin and colleagues163 met allcriteria specified for higher quality studies.

AccuracyFigure 17(c) shows the sensitivity and specificity,with 95% confidence intervals, for the five studiesreporting ophthalmoscopy at a common cut-off(for details of the common cut-off selected forophthalmoscopy see Appendix 13). There wasstatistically significant heterogeneity across thestudies, most obviously due to the study byTheodossiades and colleagues in terms ofsensitivity177 and Theodossiades and colleagues177

and Wood and colleagues191 in terms of specificity.Both were small studies using subjective criteria to

detect suspect discs in an already suspectpopulation, one being a cohort study177 and theother a case–control study.191 In both studies it wasunclear whether the spectrum of people wasrepresentative of those who would be encounteredin primary care. The study by Wood andcolleagues191 was specifically aimed at identifyingpeople with early/moderate glaucoma.

Figure 17(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. For all cut-offs, sensitivity rangedfrom 11% (cut-off of VCDR � 0.9)163 to 100% (cut-off of VCDR � 0.4),163 while specificity rangedfrom 57% (cut-off of VCDR � 0.4)163 to 99% (discssubjectively graded as normal or suspicious).164 Forthe common cut-off, sensitivity ranged from 41%115

to 91%,177 while specificity ranged from 74%177 to99%.164 The pooled sensitivity, specificity andDOR from the meta-analysis models for thecommon cut-off were 60% (95% CrI 34 to 82%),94% (95% CrI 76 to 99%) and 25.70 (95% CrI5.79 to 109.50), respectively (Figure 17d).


46

0% 20% 40% 60% 80% 100%

Spectrum representative

Reference standard confirmed follow-up

Partial verification bias avoided

Differential verification bias avoided

Incorporation bias avoided

Test review bias avoided

Diagnostic review bias avoided

Clinical review bias avoided

Uninterpretable results reported

Withdrawals explained

Index test technology current

Positive result clearly defined

Positive result defined prior to study

Yes

No

Unclear

FIGURE 16 Ophthalmoscopy: summary of quality assessment


47


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Robi

n, 2

00516

3

The

odos

siade

s, 2

00117

7

Vern

on, 1

99016

4

Wei

h, 2

00111

5

Woo

d, 1

98719

1

Ham

mon

d, 1

97917

2

Wan

g,19

9816

8

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ity

Sensitivity

Robi

n, 2

00516

3

The

odos

siade

s, 2

00117

7

Vern

on, 1

99016

4

Wei

h, 2

00111

5

Woo

d, 1

98719

1

SRO

C c

urve

Vern

on, 1

99016

4

Woo

d, 1

98719

1

The

odos

siade

s, 2

00117

7

Robi

n, 2

00516

3

Wei

h, 2

00111

5

7/1

2

9/1

6

21/2

3

9/1

6

33/8

0

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

831

/842

2

1/27

2

0/27

236

/242

4418

/455

6

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

(a)

(b)

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

5Se

nsiti

vity

(%) (

95%

CrI

) 60

(34

to 8

2)Sp

ecifi

city

(%) (

95%

CrI

) 94

(76

to 9

9)D

OR

(95%

CrI

) 25

.70

(5.7

9 to

109

.50)

Hig

her q

ualit

y st

udie

s N

umbe

r of

stu

dies

1

Sens

itivi

ty (%

) (95

% C

rI)

47 (2

4 to

71)

Spec

ifici

ty (%

) (95

% C

rI)

98 (9

5 to

99)

DO

R (9

5% C

rI)

35.4

0 (1

0.54

to 1

18.8

8)

FIG

UR

E 1

7O

phth

alm

osco

py: (

a) S

ROC

plot

: all

stud

ies,

all

cut-

offs

; (b)

SRO

C pl

ot: c

omm

on c

ut-o

ff; (

c) s

ensit

ivity

and

spe

cific

ity a

t co

mm

on c

ut-o

ff; (

d) p

oole

d es

timat

es. F

N, f

alse

neg

ative

; FP

, fal

se p

ositi

ve; T

N, t

rue

nega

tive;

TP,

true

pos

itive

.

Table 18 shows, where this information wasreported, the type of ophthalmoscopy undertaken,whether or not participants’ pupils were dilated andthe clinical experience of those giving the tests.

Interpretable resultsTen population-based studies reported that 13,341(98.0%) of 13,620 participants providedinterpretable test results forophthalmoscopy,22,100,107,109,112,115,161,163,164,168

while three prospective cohort studies reportedthat 278 (90.0%) of 309 participants providedinterpretable test results,172,177,200 giving an overallrate of 97.8% for all studies. None of the studiesgave details of the time taken to perform the test.

Optic disc photographyQuality assessmentSix studies enrolling over 7800 people reportedthe test accuracy of optic disc photography,including two population-based studies,166,169 onecohort study175 and three case–controlstudies.188–190 Figure 18 summarises the qualityassessment for these studies. In four of the sixstudies the participants were considered to berepresentative of a screening setting166,169 ordiagnostic setting175,188 (i.e. people referred fromprimary care with suspect glaucoma). Five of thesix studies were judged to be free from bothpartial and differential verificationbias.166,169,175,188,189 In four studies both the indextest and the reference standard test wereinterpreted without knowledge of each other’sresults.166,169,175,190 The studies by Vitale andcolleagues,166 Wolfs and colleagues169 and Schultzand colleagues175 met all of the above criteriaspecified for higher quality studies.

AccuracyFigure 19(c) shows the sensitivity and specificity,with 95% confidence intervals, for the six studies

reporting optic disc photography at a commoncut-off (for details of the common cut-off selectedfor optic disc photography see Appendix 13). Thestudy by Wollstein and colleagues190 aimed todetect early-stage glaucoma.

Figure 19(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. For all cut-offs, sensitivity rangedfrom 35% (cut-off of concave slopes and CDR � 0.05 in the vertical than horizontaldirection)189 to 86% (cut-off of VCDR � 0.5),175

while specificity ranged from 59% (cutoff ofVCDR � 0.59)166 to 99.5% (cut-off of concaveslopes and CDR � 0.05 in the vertical thanhorizontal direction).189 For the common cutoff,sensitivity ranged from 65%175 to 77%,166,188 whilespecificity ranged from 59%166 to 98%.175 Thepooled sensitivity, specificity and DOR from themeta-analysis models for the common cut-off were73% (95% CrI 61 to 83%), 89% (95% CrI 50 to99%) and 21.74 (95% CrI 3.07 to 148.30),respectively (Figure 19d).

Table 19 shows, where this information wasreported, details of the optic disc photography,whether or not participants’ pupils were dilatedand the clinical experience of those giving thetests.

Interpretable resultsSeven population-based studies reported that16,957 (85.0%) of 19,950 participants providedinterpretable test results for optic discphotography,110,155,157,159,166,168,169 while fourprospective cohort studies reported that 499(89.7%) of 556 participants provided interpretabletest results,175,202,207,209 giving an overall rate forall studies of 85.1%. One study reported that theaverage test duration was 16 minutes per eye(image acquisition and recording requiring


48

TABLE 18 Type of ophthalmoscopy used

Study Type of Pupils dilated? Clinical experience of those ophthalmoscopy giving/interpreting the tests

Robin, 2005163 Slit-lamp biomicroscopy Not stated Not stated

Vernon, 1990164 Direct ophthalmoscopy Undilated Experienced ophthalmologist

Wang, 1998168 Direct ophthalmoscopy Dilated Not stated

Weih, 2001115 Slit-lamp Dilated Trained clinician

Hammond, 1979172 Direct ophthalmoscopy Undilated Nurses skilled in the use of theophthalmoscope

Theodossiades, 2001177 Direct ophthalmoscopy Undilated Not stated (optometrists)

Wood, 1987191 Direct ophthalmoscopy Dilated Not stated (ophthalmologists)


49


0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 18 Optic disc photography: summary of quality assessment

TABLE 19 Details of optic disc photography

Study Type of optic disc photography Pupils dilated? Experience of thosegiving/interpreting the tests

Vitale, 2000166 Topcon ImageNet simultaneous Dilated Technicians with considerable stereophotography experience carried out the tests

Wolfs, 1999169 Topcon TRC-SS2 simultaneous Dilated Transparencies digitised and analysed by stereophotography technicians

Quigley, 1980188 Colour stereophotographs placed in a Not stated Not statedstereoviewer

Schultz, 1995175 NIDEK fundus camera for Dilated Photographs examined by third-year stereophotographs using Kodak Gold ophthalmology residents100 35-mm negative film. Also stereo slide transparencies obtained using 35-mm Ektachrome 100 film and examined through a stereoviewer

Sommer, 1979189 Colour stereophotographs Not stated Not stated

Wollstein, 2000190 Canon CF6OU colour non-simultaneous Not stated Taken by trained technicians, interpreted stereophotographs using 35-mm Kodak by experienced observers (glaucoma Ektachrome 150 film consultants, glaucoma fellow, clinical

glaucoma technician)


50

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

6Se

nsiti

vity

(%) (

95%

CrI

) 73

(61

to 8

3)Sp

ecifi

city

(%) (

95%

CrI

) 89

(50

to 9

9)D

OR

(95%

CrI

) 21

.74

(3.0

7 to

148

.30)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

3

Sens

itivi

ty (%

) (95

% C

rI)a

74 (3

0 to

95)

Spec

ifici

ty (%

) (95

% C

rI)a

82 (4

5 to

97)

DO

R (9

5% C

rI)a

13.0

8 (2

.22

to 1

00.9

0)

Qui

gley

, 198

0188

Wol

fs, 1

99916

9

Som

mer

, 197

9189

Vita

le, 2

00016

6

Schu

ltz, 1

99517

5

Wol

lstei

n, 2

00019

0

43/5

6

28/3

7

12/1

7

34/4

4

89/1

37

36/5

1

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

200

/238

3712

/510

6

193

/206

8

1/13

8

224

/228

6

8/72

TN/T

N+

FP 00.

20.

40.

60.

81.

0Sp

ecifi

city

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Qui

gley

, 198

0188

Schu

ltz, 1

99517

5 So

mm

er, 1

97918

9

Vita

le, 2

00016

6

Wol

fs, 1

99916

9

Wol

lstei

n, 2

00019

0

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Qui

gley

, 198

0188

Schu

ltz, 1

99517

5

Som

mer

, 197

9189

Vita

le, 2

00016

6

Wol

fs, 1

99916

9

Wol

lstei

n, 2

00019

0

SRO

C c

urve

(a)

(b)

FIG

UR

E 1

9O

ptic

disc

pho

togr

aphy

: (a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

sene

gativ

e; F

P, fa

lse p

ositi

ve; T

N, t

rue

nega

tive;

TP,

true

pos

itive

. aBa

sed

on H

SRO

C m

odel

with

sym

met

ric S

ROC

curv

e.

approximately 4 minutes per eye, after which timethe presence of the patient was no longerrequired, with subsequent calculations oftopographical and pallor parameters requiringapproximately 12 minutes per eye).197

RNFL photographyQuality assessmentFour studies enrolling over 700 people reportedthe test accuracy of RNFL photography, includingone population-based study167 and threecase–control studies.178,188,189 Figure 20 summarisesthe quality assessment for these studies. In two ofthe four studies the participants were consideredto be representative of a screening167 ordiagnostic188 setting. Three studies were judged tobe free from both partial and differentialverification bias.178,188,189 In one study both theindex test and the reference standard test wereinterpreted without knowledge of each other’sresults.178 No study met all the criteria specifiedfor higher quality studies.

AccuracyFigure 21(c) shows the sensitivity and specificity,with 95% confidence intervals, for the four studiesreporting RNFL photography at a common cut-off

(for details of the common cut-off selected forRNFL photography see Appendix 13). Threestudies were set in the USA.167,188,189 The study byAiraksinen and colleagues178 appeared to have ajoint setting of Canada and Finland and it wasunclear whether the spectrum of people wasrepresentative of those who would be encounteredin primary care.

Figure 21(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. Both for all cut-offs and thecommon cut-off, sensitivity ranged from 59%189 to94%,178 while specificity ranged from 60%178 to98%.189 The pooled sensitivity, specificity andDOR from the meta-analysis models for thecommon cut-off were 75% (95% CrI 46 to 92%),88% (95% CrI 53 to 98%) and 23.10 (95% CrI4.41 to 123.50), respectively (Figure 21d).

Interpretable resultsOne population-based study reported that 136(79.5%) of 171 participants provided interpretabletest results for RNFL photography.167 None of thestudies reported the time taken to perform thetest, but it is likely to be similar to optic discphotography.


51


0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 20 RNFL: summary of quality assessment


52

(a)

(b)

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

4 Se

nsiti

vity

(%) (

95%

CrI

) 75

(46

to 9

2)

Spec

ifici

ty (%

) (95

% C

rI)

88 (5

3 to

98)

D

OR

(95%

CrI

) 23

.10

(4.4

1 to

123

.50)

H

igh-

qual

ity s

tudi

es

Num

ber

of s

tudi

es

0

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Aira

ksin

en, 1

98417

8

Qui

gley

, 198

0188

Som

mer

, 197

9189

Wan

g, 1

99416

7

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Aira

ksin

en, 1

98417

8

Qui

gley

, 198

0188

Som

mer

, 197

9189

Wan

g, 1

99416

7

SRO

C c

urve

Som

mer

, 197

9189

Aira

ksin

en, 1

98417

8

Wan

g, 1

99416

7

Qui

gley

, 198

0188

10/1

7

48/5

1

9/1

4

37/5

6

Stud

yTP

/TP+

FN 00.

20.

40.

60.

81.

0Se

nsiti

vity

202/

206

49/

81

102/

122

214/

238

TN/T

N+

FP 00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 2

1RN

FL p

hoto

grap

hy: (

a) S

ROC

plot

: all

stud

ies,

all

cut-

offs

; (b)

SRO

C pl

ot: c

omm

on c

ut-o

ff; (

c) s

ensit

ivity

and

spe

cific

ity a

t co

mm

on c

ut-o

ff; (

d) p

oole

d es

timat

es. F

N, f

alse

neg

ative

;FP

, fal

se p

ositi

ve; T

N, t

rue

nega

tive;

TP,

true

pos

itive

.

HRT IIQuality assessmentThree studies enrolling 1073 people reported thetest accuracy of HRT II, including two population-based studies,156,163 and one case–control study.186

Figure 22 summarises the quality assessment forthese studies. In the studies by Harasymowycz andcolleagues156 and Robin and colleagues163 theparticipants were considered to be representativeof a screening setting. All three studies werejudged to be free from both partial anddifferential verification bias.156,163,186 In all threestudies the index test and the reference standardtest were interpreted without knowledge of eachother’s results.156,163,186 The studies byHarasymowycz and colleagues156 and Robin andcolleagues163 met the criteria specified for higherquality studies.

AccuracyFigure 23(c) shows the sensitivity and specificity,with 95% confidence intervals, for the threestudies reporting HRT II at a common cut-off (fordetails of the common cut-off selected for HRT II

see Appendix 13). In the population-based studiesby Harasymowycz and colleagues156 and Robinand colleagues163 the tests were carried out by anophthalmic photographer and “appropriatelytrained staff ”, respectively, while in thecase–control study by Ieong and colleagues186 thetests were carried out by optometrists and early-stage glaucoma was targeted. The study byHarasymowycz and colleagues156 focused ongroups at high risk of developing glaucoma(people of Caribbean or African descent, or olderthan 50 years of age, or with a family history ofOAG).

Figure 23(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. For all cut-offs, sensitivity rangedfrom 69%186 to 100%,156 while specificity rangedfrom 81%163 to 95%.186 For the common cut-off,sensitivity ranged from 69%186 to 95%,163 whilespecificity ranged from 81%163 to 95%.186 Thepooled sensitivity, specificity and DOR from themeta-analysis models for the common cut-off were86% (95% CrI 55 to 97%), 89% (95% CrI 66 to


53


0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 22 HRT II: summary of quality assessment


54

(a)

(b)

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

3Se

nsiti

vity

(%) (

95%

CrI

)a 8

6 (5

5 to

97)

Spec

ifici

ty (%

) (95

% C

rI)a

89

(66

to 9

8)D

OR

(95%

CrI

)a 50

.93

(11.

48 to

246

.30)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

2

Sens

itivi

ty (%

) (95

% C

rI)a

93 (5

8 to

99)

Spec

ifici

ty (%

) (95

% C

rI)a

85 (4

7 to

97)

DO

R (9

5% C

rI)a

72.8

2 (9

.74

to 7

04.5

0)

00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Ieon

g, 2

00318

6

Robi

n, 2

00516

3

Har

asym

owyc

z, 2

00515

6

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Har

asym

owyc

z, 2

00515

6

Ieon

g, 2

00318

6

Robi

n, 2

00516

3

SRO

C c

urve

Ieon

g, 2

00318

6

Robi

n, 2

00516

3

Har

asym

owyc

z, 2

00515

6

20/2

9

18/1

9

12/1

4

Stud

yTP

/TP+

FN 00.

20.

40.

60.

81.

0Se

nsiti

vity

35/

37

195/

242

223/

251

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 2

3H

RT II

: (a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

se n

egat

ive; F

P, fa

lsepo

sitive

; TN

, tru

e ne

gativ

e; T

P, tr

ue p

ositi

ve. a

Base

d on

HSR

OC

mod

el w

ith s

ymm

etric

SRO

C cu

rve.

98%) and 50.93 (95% CrI 11.48 to 246.30),respectively (Figure 23d).

Interpretable resultsTwo population-based studies reported that 536(94.2%) of 569 participants provided interpretabletest results for HRT II.156,163 None of the studiesreported the time taken to perform the test.

Tests of functionFDT (C-20-1) Quality assessmentThree studies involving 575 people reported thetest accuracy of the FDT C-20-1 test, includingone population-based study170 and twocase–control studies.185,187 Figure 24 summarisesthe quality assessment for these studies. In two ofthe three studies the participants were consideredto be representative of a screening170 ordiagnostic185 setting. The study by Yamada andcolleagues170 was the only one judged to be freefrom both partial and differential verification biasand also the only one in which both the index testand the reference standard test were interpretedwithout knowledge of each other’s results, therebymeeting the criteria specified for higher qualitystudies.

AccuracyFigure 25(c) shows the sensitivity and specificity,with 95% confidence intervals, for the threestudies reporting FDT C-20-1 at a common cut-off(for details of the common cut-off selected forFDT C-20-1 see Appendix 13). The heterogeneityin terms of specificity is mainly due to the highvalue reported by Johnson and colleagues.187 Inthis study both eyes of normal participants (meanage 46 years) and one eye of participants withglaucoma (mean age 64 years) were tested.

Figure 25(a) and (b) show, respectively, the SROCplots for all cut-offs with multiple abnormal testpoints for all studies, and the common cut-off. Forall cut-offs, sensitivity ranged from 65% at fiveabnormal test points185 to 93% at one abnormaltest point,187 while specificity ranged from 86% atone abnormal test point170 to 100% at oneabnormal test point, two abnormal test points ortwo clustered abnormal test points.187 For acommon cut-off of one abnormal test point,sensitivity ranged from 91%185 to 93%,187 whilespecificity ranged from 86%170 to 100%.187 Thepooled sensitivity, specificity and DOR from themeta-analysis models for the common cut-off were92% (95% CrI 65 to 95%), 94% (95% CrI 73 to


55


0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 24 FDT C-20-1: summary of quality assessment


56

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

3 Se

nsiti

vity

(%) (

95%

CrI

)a 92

(65

to 9

9)

Spec

ifici

ty (%

) (95

% C

rI)a

94 (7

3 to

99)

D

OR

(95%

CrI

)a 18

1.20

(25.

49 to

213

9.00

) H

igh-

qual

ity s

tudi

es

Num

ber

of s

tudi

es

1 Se

nsiti

vity

(%) (

95%

CrI

) 92

(75

to 9

9)

Spec

ifici

ty (%

) (95

% C

rI)

86 (8

0 to

90)

D

OR

(95%

CrI

) 70

.84

(15.

94 to

314

.91)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

John

son,

199

9187

Yam

ada,

199

9170

Stou

tenb

eek,

200

4185

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

John

son,

199

9187

Yam

ada,

199

9170

Stou

tenb

eek,

200

4185

SRO

C c

urve

Yam

ada,

199

9170

John

son,

199

9187

Stou

tenb

eek,

200

4185

24/2

6

52/5

6

91/1

00

Stud

yTP

/TP+

FN 00.

20.

40.

60.

81.

0Se

nsiti

vity

183/

214

104/

104

95/

108

TN/T

N+

FP 00.

20.

40.

60.

81.

0Sp

ecifi

city

(a)

(b)

FIG

UR

E 2

5FD

T C-

20-1

: (a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

se n

egat

ive;

FP, f

alse

pos

itive

; TN

, tru

e ne

gativ

e; T

P, tr

ue p

ositi

ve.

99%) and 181.20 (95% CrI 25.49 to 2139.00),respectively (Figure 25d).

Interpretable resultsTwo population-based studies reported that14,569 (96.8%) of 15,057 participants providedinterpretable test results for FDT C-20-1,170,210

while one prospective cohort study reported that27 (87.1%) of 31 participants providedinterpretable test results,214 giving an overall rateof 96.7% for all studies. Four studies reported thetime taken to perform the test,170,185,187,214 whichranged from less than 45 seconds per eye fornormal participants to approximately 2 minutesper eye for those with advanced glaucoma.187

FDT (C-20-5)Quality assessmentFive studies involving 2956 people reported thetest accuracy of the FDT C-20-5 test, includingthree population-based studies155,161,163 and twocase–control studies.173,187 Figure 26 summarisesthe quality assessment for these studies. In two ofthe five studies the participants were considered tobe representative of a screening setting.155,163 Fourof the five studies were judged to be free fromboth partial and differential verification

bias.155,161,163,173 In three of five studies155,161,163

both the index test and the reference standard testwere interpreted without knowledge of eachother’s results. Two of five studies met the criteriaspecified for higher quality studies.155,163

AccuracyFigure 27(c) shows the sensitivity and specificity,with 95% confidence intervals, for the five studiesreporting FDT C-20-5 at a common cut-off (fordetails of the common cut-off selected for FDT C-20-5 see Appendix 13). There was markedstatistically significant heterogeneity across thestudies. In particular, the study by Mansberger andcolleagues161 reported extremely low sensitivity(7%) compared with the other studies. The settingfor this study was rural villages in India.Ophthalmological diagnosis was based on reviewof optic disc photographs and this may haveoverdiagnosed glaucoma.

Figure 27(a) and (b) show, respectively, thehierarchical SROC plots for all cut-offs withmultiple abnormal test points for all studies, andthe common cut-off. For all cut-offs, sensitivityranged from 7% at one abnormal test point161 to100% at one abnormal test point on repeat


57


0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 26 FDT C-20-5: summary of quality assessment


58

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

5 Se

nsiti

vity

(%) (

95%

CrI

) 78

(19

to 9

9)

Spec

ifici

ty (%

) (95

% C

rI)

75 (5

7 to

87)

D

OR

(95%

CrI

) 10

.14

(0.7

2 to

249

.00)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

2

Sens

itivi

ty (%

) (95

% C

rI)a

72 (2

6 to

96)

Sp

ecifi

city

(%) (

95%

CrI

)a 60

(17

to 9

2)

DO

R (9

5% C

rI)a

3.84

(0.7

0, 2

3.81

)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Det

ry-M

orel

, 200

4155

John

son,

199

9187

Kho

ng, 2

00117

3

Man

sber

ger,

2005

161

Robi

n, 2

00516

3

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1 –

Spec

ifici

ty

Sensitivity

Det

ry-M

orel

, 200

4155

John

son,

199

9187

Kho

ng, 2

00117

3

Man

sber

ger,

2005

161

Robi

n, 2

00516

3

SRO

C c

urve

Det

ry-M

orel

, 200

4155

Man

sber

ger,

2005

161

Robi

n, 2

00516

3

John

son,

199

9187

Kho

ng, 2

00117

3

39/6

7

4/5

7

16/1

9

55/5

6

2/2

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

2027

/314

4

168

/194

133

/242

9

3/10

4

7

6/11

1

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

(a)

(b)

FIG

UR

E 2

7FD

T C-

20-5

: (a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

se n

egat

ive;

FP, f

alse

pos

itive

; TN

, tru

e ne

gativ

e; T

P, tr

ue p

ositi

ve. a

Base

d on

HSR

OC

mod

el w

ith s

ymm

etric

SRO

C cu

rve.

testing,173 while specificity ranged from 55% atone abnormal test point163 to 95% at two clusteredabnormal test points.187 For a common cut-off ofone abnormal test point, sensitivity ranged from7%161 to 100%,173 while specificity ranged from55%163 to 89%.187 The pooled sensitivity,specificity and DOR from the meta-analysismodels for the common cut-off were 78% (95%CrI 19 to 99%), 75% (95% CrI 57 to 87%) and10.14 (95% CrI 0.72 to 249.00), respectively(Figure 27d).

Interpretable resultsThree population-based studies reported that2164 (91.8%) of 2357 participants providedinterpretable test results for FDT C-20-5,155,161,163

while one prospective cohort study173 reportedthat 223 (97.8%) of 228 participants providedinterpretable test results, giving an overall rate of92.3% for all studies. Two studies155,187 reportedthe time taken to perform the test, which rangedfrom less than 45 seconds per eye for normalparticipants to approximately 2 minutes per eyefor those with advanced glaucoma.187

FDT (C-20 full threshold and C-20 matrix)Heeg and colleagues,183,184 in a case–control study set in The Netherlands, reported theaccuracy of the FDT C-20 full threshold test. Anabnormal test result was defined as more than onedepressed test point, p < 0.01, in the totaldeviation probability plot (TD > 1). Table 20shows the sensitivity and specificity of the FDT C-20 full threshold test, both for all participants andfor a subgroup excluding those with earlyglaucoma, at cut-offs of TD greater than 1, 2 and3. As would be expected, for both the whole group and also the subgroup, sensitivity washighest (90% and 100%, respectively) at a cut-offof TD greater than 1, while specificity was highest(both 88%) at TD greater than 3. In terms ofquality assessment, the cases and controls werejudged as being representative of a diagnosticsetting.

Spry and colleagues,176 in a cohort study set in theUK, reported the test accuracy of the FDT C-20matrix (Humphrey matrix 24-2). An abnormal testresult was defined as a GHT outside the normallimit and/or p < 0.05 with the pattern standarddeviation global index in one or both eyes. Thestudy reported sensitivity of 100% and specificityof 27%. In terms of the quality of the study, thespectrum of people was considered to berepresentative of a diagnostic setting, it wasjudged to be free from both partial anddifferential verification bias, and both the indextest and the reference standard test wereinterpreted without knowledge of each other’sresults, thereby meeting the criteria specified forhigher quality studies.

OKPQuality assessmentFour studies enrolling 768 people reported thetest accuracy of OKP, including two population-based studies,154,170 and two case–controlstudies.180,182 Figure 28 summarises the qualityassessment for these studies. In three of the fourstudies the participants were considered to berepresentative of a screening154,170 or diagnostic182

setting. The study by Yamada and colleagues170

was the only one judged to be free from bothpartial and differential verification bias and wasalso the only study in which both the index testand the reference standard test were interpretedwithout knowledge of each other’s results, therebymeeting the criteria specified for higher qualitystudies.

AccuracyFigure 29(c) shows the sensitivity and specificity,with 95% confidence intervals, for the four studiesreporting OKP at a common cut-off (for details ofthe common cut-off selected for OKP seeAppendix 13). There was statistically significantheterogeneity, in terms of sensitivity, mainly due tothe study by Harper and colleagues.182 There wasno obvious explanation for this heterogeneity in


59


TABLE 20 Sensitivity and specificity of FDT C-20 full threshold for whole group and subgroup excluding patients with early glaucoma

Cut-off TD Sensitivity (%) Specificity (%)

>1 All participants 90 81Early glaucoma excluded 100 81



terms of the spectrum of people. In three of thefour studies, including the study by Harper andcolleagues, the participants were considered to berepresentative of a screening154,170 or diagnostic182

setting, while the representativeness of theparticipants was unclear in the case-control studyby Damato and colleagues.180 However, in contrastto the other three studies, in the study by Harperand colleagues182 there was minimal instructionand supervision. In preparation for the test, theparticipants were asked to read the testinstructions with no further assistance given,following which they self-administered the test,unsupervised.182

Figure 29(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies and thecommon cut-off. For both all cut-offs and thecommon cut-off, sensitivity ranged from 25%182 to100%,154 while specificity ranged from 78%170 to94%.154,182 One reason for the high sensitivityreported by Christoffersen and colleagues154 wasthat test negatives did not receive a referencestandard test to confirm this but were assumed tobe true negatives, so that the study reported nofalse negatives and therefore a sensitivity of 100%.Yamada and colleagues170 also reported a high

sensitivity rate (95%). However, this studycontained a higher than average prevalence ofglaucoma (10.7%) and it would be expected thatthe sensitivity of the test would therefore be higherin such a population compared with an averageprevalence population. The pooled sensitivity,specificity and DOR from the meta-analysismodels for the common cut-off were 86% (95%CrI 29 to 100%), 90% (95% CrI 79 to 96%) and57.54 (95% CrI 4.42 to 1585.00), respectively(Figure 29d).

Interpretable resultsTwo population-based studies reported that 362(97.1%) of 373 participants provided interpretabletest results for OKP,154,170 while one prospectivecohort study reported that 16 (94.1%) of 17participants provided interpretable test results,212

giving an overall rate of 96.9% for all studies.Three studies reported the time taken to performthe test,154,170,212 which ranged fromapproximately 3 minutes170 to 4 minutes212 per eye.

SAP (suprathreshold)Quality assessmentNine studies enrolling over 10,200 peoplereported the test accuracy of the SAP


60

0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 28 OKP: summary of quality assessment


61


(c)

(d)

(a)

(b)

Com

mon

cut

-off

Num

ber

of s

tudi

es

4 Se

nsiti

vity

(%) (

95%

CrI

) 86

(29

to 1

00)

Spec

ifici

ty (%

) (95

% C

rI)

90 (7

9 to

96)

D

OR

(95%

CrI

) 57

.54

(4.4

2 to

158

5.00

) H

igh-

qual

ity s

tudi

es

Num

ber

of s

tudi

es

1 Se

nsiti

vity

(%) (

95%

CrI

) 95

(74

to 1

00)

Spec

ifici

ty (%

) (95

% C

rI)

78 (7

0 to

84)

D

OR

(95%

CrI

) 62

.23

(8.0

2 to

482

.67)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Chr

istof

fers

en, 1

99515

4

Dam

ato,

198

9180

Har

per,

1994

182

Yam

ada,

199

9170

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Chr

istof

fers

en, 1

99515

4

Dam

ato,

198

9180

Har

per,

1994

182

Yam

ada,

199

9170

SRO

C c

urve

Chr

istof

fers

en, 1

99515

4

Dam

ato,

198

9180

Har

per,

1994

182

Yam

ada,

199

9170

16/1

6

42/5

1

13/5

2

18/1

9

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

160/

171

46/

51

132/

141

121/

156

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 2

9O

KP: (

a) S

ROC

plot

: all

stud

ies,

all

cut-

offs

; (b)

SRO

C pl

ot: c

omm

on c

ut-o

ff; (

c) s

ensit

ivity

and

spe

cific

ity a

t co

mm

on c

ut-o

ff; (

d) p

oole

d es

timat

es. F

N, f

alse

neg

ative

; FP,

false

posit

ive; T

N, t

rue

nega

tive;

TP,

true

pos

itive

.

suprathreshold test, including six population-based studies,157,159,162,164,166,168 one cohortstudy174 and two case–control studies.182,186

Figure 30 summarises the quality assessment forthese studies. In eight of nine studies theparticipants were considered to be representativeof a screening157,159,162,164,166,168 or diagnostic174,182

setting. Four of the nine studies were judged to befree from both partial and differential verificationbias.162,166,174,186 In two of the nine studies boththe index test and the reference standard test wereinterpreted without knowledge of each other’sresults.166,186 Only the study by Vitale andcolleagues166 met the criteria specified for higherquality studies.

AccuracyFigure 31(c) shows the sensitivity and specificity,with 95% confidence intervals, for the nine studiesreporting SAP suprathreshold at a common cut-off(for details of the common cut-off selected for SAPsuprathreshold see Appendix 13). There wasstatistically significant heterogeneity across thestudies that could not be explained by differencesin study design, participants or equipment used.However, the two largest population-based studies,

the Blue Mountains Eye Study157 and theBaltimore Eye Survey,159 involving more than3600 and 4700 people, respectively, reportedsimilar sensitivities and specificities. Of note in thestudy by Vernon and colleagues,164 is that thedefinition of glaucoma excluded people with IOPof 22 mmHg or below.

Figure 31(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. For all cut-offs, sensitivity rangedfrom 25% (sufficient points to drop the indicatorinto the suspicious zone or below)164 to 100% (oneor more points missing),157 while specificityranged from 50% (one or more points missing)157

to 96% (sufficient points to drop the indicator intothe suspicious zone or below).164 For the commoncut-off, sensitivity ranged from 25% (sufficientpoints to drop the indicator into the suspiciouszone or below)164 to 90% (at least four abnormalpoints in any single quadrant),162 while specificityranged from 67% (absolute or relative defects�17)168 to 96% (sufficient points to drop theindicator into the suspicious zone or below).164

The pooled sensitivity, specificity and DOR fromthe meta-analysis models for the common cut-off


62

0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 30 SAP: summary of quality assessment


63


(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

9Se

nsiti

vity

(%) (

95%

CrI

) 71

(51

to 8

6)Sp

ecifi

city

(%) (

95%

CrI

) 85

(73

to 9

3)D

OR

(95%

CrI

) 14

.42

(6.3

9 to

33.

73)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

1

Sens

itivi

ty (%

) (95

% C

rI)

50 (3

7 to

63)

Spec

ifici

ty (%

) (95

% C

rI)

83 (7

6 to

88)

DO

R (9

5% C

rI)

4.86

(2.5

3 to

9.3

3)

(a)

(b)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Har

per,

1994

182

Ieon

g, 2

00318

6

Iver

s, 2

00115

7 Ka

tz, 1

99315

9

Mar

raffa

, 198

9174

Mun

dorf

, 198

9162

Vern

on, 1

99016

4

Vita

le, 2

00016

6

Wan

g, 1

99816

8

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

01

– Sp

ecifi

city

Sensitivity

Iver

s, 2

00115

7

Katz

, 199

3159

Mun

dorf

, 198

9162

Vern

on, 1

99016

4

Wan

g 19

9816

8

Har

per,

1994

182

Ieon

g, 2

00318

6

Mar

raffa

, 198

9174

Vita

le 2

00016

6

77/

87

122/

146

9

/10

3

/12

48/

69

57/

67

21/

29

72/

140

29/

58

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

2587

/356

7

3439

/458

7

9

5/13

5

813

/843

9

7/14

5

136

/145

3

5/37

3

7/42

141

/170

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

Har

per,

1994

182

Ieon

g, 2

00318

6

Iver

s, 2

00115

7 Ka

tz, 1

99315

9

Mar

raffa

, 198

9174

Mun

dorf

, 198

9162

Vern

on, 1

99016

4

Vita

le, 2

00016

6

Wan

g, 1

99816

8

FIG

UR

E 3

1SA

P su

prat

hres

hold

: (a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

se n

egat

ive;

FP, f

alse

pos

itive

; TN

, tru

e ne

gativ

e; T

P, tr

ue p

ositi

ve.

were 71% (95% CrI 51 to 86%), 85% (95% CrI 73to 93%) and 14.42 (95% CrI 6.39 to 33.73),respectively (Figure 31d).

Interpretable resultsSix population-based studies reported that 8368(80.1%) of 10,444 participants providedinterpretable test results for SAPsuprathreshold,157,159,162,164,166,168 while twoprospective cohort studies involving 504participants reported that all providedinterpretable test results,174,208 giving an overallrate of 81.0% for all studies. Four studies reportedthe time taken to perform the test,159,162,164,174

which ranged from approximately 3 minutes164 to15 minutes157,159,162,164,166,168 for both eyes.

SAP (threshold)Quality assessmentFive studies enrolling 1457 people reported thetest accuracy of the SAP threshold test, includingtwo population-based studies,158,163 one cohortstudy176 and two case–control studies.179,181

Figure 32 summarises the quality assessment forthese studies. In three of the five studies theparticipants were considered to be representativeof a screening163 or diagnostic176,179 setting. Fourof the five studies were judged to be free from

both partial and differential verificationbias.158,163,176,179 In one study both the index testand the reference standard test were interpretedwithout knowledge of each other’s results.163 Onlythe study by Robin and colleagues163 met thecriteria specified for higher quality studies.

AccuracyFigure 33(c) shows the sensitivity and specificity,with 95% confidence intervals, for the five studiesreporting SAP threshold at a common cut-off (fordetails of the common cut-off selected for SAPthreshold see Appendix 13). There was statisticallysignificant heterogeneity across the studies. Therewas no obvious explanation for the heterogeneity,although there were differences across the studiesin terms of study design and setting. The sametypes of study (population-based,158,163

case–control179,181) appeared to be homogeneousin terms of specificity but not sensitivity.

Figure 33(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and thecommon cut-off. For all cut-offs for all studies,sensitivity ranged from 58% [mean deviation +pattern SD (least significant), significance levelcut-off 0.005] to 97% (mirror image method),181

(clusters, Low Tension Glaucoma Study,


64

0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 32 SAP threshold: summary of quality assessment


65


(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

5Se

nsiti

vity

(%) (

95%

CrI

) 88

(65

to 9

7)Sp

ecifi

city

(%) (

95%

CrI

) 80

(55

to 9

3)D

OR

(95%

CrI

) 29

.87

(5.5

9 to

159

.30)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

2

Sens

itivi

ty (%

) (95

% C

rI)a

73 (2

8 to

95)

Spec

ifici

ty (%

) (95

% C

rI)a

64 (2

2 to

92)

DO

R (9

5% C

rI)a

4.91

(0.8

2 to

31.

25)

(a)

(b)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Ant

on, 1

99717

9

Enge

r, 19

8718

1

Katz

, 199

1158

Robi

n, 2

00516

3

Spry

, 200

5176

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Ant

on, 1

99717

9

Enge

r, 19

8718

1

Katz

, 199

1158

Robi

n, 2

00516

3

Spry

, 200

5176

SRO

C c

urve

Ant

on, 1

99717

9

Enge

r, 19

8718

1

Katz

, 199

1158

Robi

n, 2

00516

3

Spry

, 200

5176

80/9

6

70/7

2

99/1

06

12/1

9

12/1

5

Stud

yTP

/TP+

FN 00.

20.

40.

60.

81.

0Se

nsiti

vity

77/

84

88/

98

192/

249

180/

242

17/

33

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 3

3SA

P th

resh

old:

(a)

SRO

C pl

ot: a

ll st

udie

s, a

ll cu

t-of

fs; (

b) S

ROC

plot

: com

mon

cut

-off;

(c)

sen

sitivi

ty a

nd s

peci

ficity

at

com

mon

cut

-off;

(d)

poo

led

estim

ates

. FN

, fal

se n

egat

ive;

FP, f

alse

pos

itive

; TN

, tru

e ne

gativ

e; T

P, tr

ue p

ositi

ve. a

Base

d on

HSR

OC

mod

el w

ith s

ymm

etric

SRO

C cu

rve.

p-values),158 while specificity ranged from 52%(GHT “outside normal limit” and/or pattern SDp < 0.05 in one or both eyes)176 to 98% [meandeviation + pattern SD (least significant),significance level cut-off 0.005].181 For thecommon cut-off, sensitivity ranged from 63%[Advanced Glaucoma Intervention Study (AGIS)score �3]158,163 to 97% (mirror image method),181

while specificity ranged from 52% (GHT “outsidenormal limit” and/or pattern SD p < 0.05 in oneor both eyes)176 to 92% (logistic discriminantanalysis applied to 59 points).179 The pooledsensitivity, specificity and DOR from the meta-analysis models for the common cut-off were 88%(95% CrI 65 to 97%), 80% (95% CrI 55 to 93%)and 29.87 (95% CrI 5.59 to 159.30), respectively(Figure 33d).

Interpretable resultsSeven population-based studies reported that4459 (98.7%) of 4520 participants providedinterpretable test results for SAPthreshold,100,107,109,112,158,163,164 while sevenprospective cohort studies involving 940participants reported that all providedinterpretable test results,176,192,194,195,198,201,206

giving an overall rate of 98.9% for all studies. Four

studies reported the time taken to perform thetest,176,195,198,206 which ranged from approximately5 minutes176 to 18 minutes206 for both eyes. Allfour studies used SITA standard or SITA fast.

Tests of IOPGATQuality assessmentNine studies involving 20,308 people reported thetest accuracy of GAT for detecting OAG, includingseven population-based studies21,99,100,106,112,157,168

and two cohort studies.22,171 Figure 34 summarisesthe quality assessment for these studies. In eight ofthe nine studies the participants were consideredto be representative of ascreening21,99,100,106,112,157,168 or diagnostic22

setting. Two of the nine studies were judged to befree from both partial and differential verificationbias.21,100 In no study were both the index test andthe reference standard test interpreted withoutknowledge of each other’s results and no studymet the criteria specified for higher quality studies.

AccuracyFigure 35(c) shows the sensitivity and specificity,with 95% confidence intervals, for the nine studiesreporting GAT at a common cut-off (for details of


66

0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 34 GAT: summary of quality assessment


67


(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

9Se

nsiti

vity

(%) (

95%

CrI

) 46

(22

to 7

1)Sp

ecifi

city

(%) (

95%

CrI

) 95

(89

to 9

7)D

OR

(95%

CrI

) 14

.95

(4.4

8 to

48.

95)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

0

(a)

(b)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Ant

on, 2

00499

Beng

tsso

n, 1

98010

0

Bono

mi,

2001

106

Ekst

rom

, 199

3171

Hol

low

s, 1

96621

Iv

ers,

200

1157

Kozo

bolis

, 200

0112

Leib

owitz

, 198

022

Wan

g, 1

99816

8

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

SRO

C c

urve

Ant

on, 2

00499

Beng

tsso

n, 1

98010

0

Bono

mi,

2001

106

Ekst

rom

, 199

3171

Hol

low

s, 1

96621

Iv

ers,

200

1157

Kozo

bolis

, 200

0112

Leib

owitz

, 198

022

Wan

g, 1

99816

8

Ant

on, 2

00499

Beng

tsso

n, 1

98010

0

Bono

mi,

2001

106

Ekst

rom

, 199

3171

Hol

low

s, 1

96621

Iver

s, 2

00115

7 Ko

zobo

lis, 2

00011

2

Leib

owitz

, 200

022

Wan

g, 1

99816

8

3/1

0

7/1

5

97/1

21

8/1

3

13/2

0

12/8

728

/31

5/5

0

19/6

9

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

495

/500

1393

/149

6

4086

/417

6

324

/400

3827

/421

1

3478

/356

710

03/1

076

442

/524

276

/288

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 3

5G

AT: (

a) S

ROC

plot

: all

stud

ies,

all

cut-

offs

; (b)

SRO

C pl

ot: c

omm

on c

ut-o

ff; (

c) s

ensit

ivity

and

spe

cific

ity a

t co

mm

on c

ut-o

ff; (

d) p

oole

d es

timat

es. F

N, f

alse

neg

ative

; FP,

false

posit

ive; T

N, t

rue

nega

tive;

TP,

true

pos

itive

.

the common cut-off selected for GAT seeAppendix 13). There was statistically significantheterogeneity across the studies, especially forsensitivity, with no obvious explanation.

Figure 35(a) and (b) show, respectively, the SROCplots for all cut-offs for all studies, and for thecommon cut-off. For all cut-offs, sensitivity rangedfrom 3% (IOP > 28 mmHg)157 to 90% (IOP >21 mmHg),112 while specificity ranged from 81%(IOP � 21 mmHg)171 to 99% (IOP > 21 mmHg,99

IOP > 28 mmHg).157 For the common cut-off,sensitivity ranged from 10% (IOP > 21 mmHg)22

to 90% (IOP > 21 mmHg),112 while specificityranged from 81% (IOP � 21 mmHg)171 to 99%(IOP > 21 mmHg).99 The pooled sensitivity,specificity and DOR from the meta-analysismodels for the common cut-off of above21 mmHg were 46% (95% CrI 22 to 71%), 95%(95% CrI 89 to 97%) and 14.95 (95% CrI 4.48 to48.95), respectively (Figure 35d).

Interpretable resultsThirteen population-based studies reported that25,422 (99.1%) of 25,650 participants providedinterpretable test results forGAT,21,22,99,100,106,107,109,112,157,159,168,199,205 while

two prospective cohort studies193,204 involving 135participants reported that all providedinterpretable test results, giving an overall rate of99.1% for all studies. None of the studies reportedthe time taken to perform the test.

NCTQuality assessmentOne population-based study involving 874 peoplereported NCT for detecting OAG.164,165 Figure 36summarises the quality assessment for this study.The participants were considered to berepresentative of a screening setting. The studywas judged to be free from partial verification biasbut not differential verification bias. Furthermore,the index test was interpreted without knowledgeof the results of the reference standard test, butnot vice versa. It should be noted that thereference standard was suboptimal for severalreasons: the authors’ definition of glaucomaexcluded people with IOP of 22 mmHg or belowand included people with IOP above 30 mmHgand ‘required treatment’ without other evidence ofglaucoma damage, and optic nerve evaluation wasbased on direct ophthalmoscopy throughundilated pupils. This study did not meet thecriteria required for a higher quality study.


68

0% 20% 40% 60% 80% 100%














Yes

No

Unclear

FIGURE 36 NCT: summary of quality assessment

AccuracyVernon and colleagues164,165 reported IOP at arange of cut-offs from above 21 mmHg to above 26 mmHg and from one to four pulses per eye. Figure 37(a) and (b) show, respectively, the SROC plots for all cut-offs, and a commoncut-off (for details of the common cut-off selectedfor NCT see Appendix 13). For all cut-offs,sensitivity ranged from 42% (IOP > 26 mmHg,four pulses per eye) to 92% (IOP > 21 mmHg,IOP > 22 mmHg, both four pulses per eye), while specificity ranged from 93% (IOP > 21 mmHg, one pulse per eye) to 99.7%(IOP > 26 mmHg, four pulses per eye). For thecommon cut-off of >21 mmHg, sensitivity was92% (95% CrI 62 to 100%), specificity was 92% (95% CrI 90 to 94%) and the DOR was134.88 (95% CrI 17.15 to 1061.10) (Figure 37cand d).

Interpretable resultsIn addition to the study by Vernon andcolleagues,164 five population-based studies,although not providing usable data for NCT interms of test accuracy, otherwise met the review’sinclusion criteria and provided information oninterpretable results.110,155,161,196,203 The six studiesreported that 6126 (97.1%) of 6308 participantsprovided interpretable test results for NCT, whileone prospective cohort study211 involving 105participants reported that all providedinterpretable test results, giving an overall rate of97.2% for all studies. One study reported that ittook approximately 2 minutes to perform the testfor both eyes.164

SummaryTable 21 shows the summary performance for eachtest at the common cut-off. Sensitivity andspecificity are derived from the 40 includedstudies, while the information on interpretableresults and time taken to perform the test alsoincludes data, where reported, from otherpopulation-based studies and prospective cohortstudies that did not report usable outcomes interms of accuracy, but otherwise met the review’sinclusion criteria. Appendix 13 provides details ofthe sensitivity and specificity for each study, bytype of test.

Only one study reporting true and false positivesand negatives for NCT met the inclusion criteria.Vernon and colleagues164 reported 92% sensitivityand also 92% specificity for NCT at a cut-off ofIOP above 21 mmHg. However, the highsensitivity reported was influenced by the fact thatthe authors’ definition of glaucoma excluded

normal tension glaucoma (NTG). Theperformance estimates should be viewed withcaution as the reference standard was suboptimal.Interpretable results were provided by 97% ofthose taking the test, while the time taken toperform the test averaged 2 minutes for both eyes.

In many of the tests there was statisticalheterogeneity across studies. The FDT C-20-1 testwas associated with the highest sensitivity (92%)and was among the tests with the highestspecificity (94%) (ophthalmoscopy 94%; GAT95%), as well as being associated with a relativelyhigh percentage (97%) of interpretable test resultsand short length of time taken to perform the test(<1–2 minutes per eye).

Higher quality studiesEight studies met the criteria for higher qualitystudies, including six population-basedstudies155,156,163,166,169,170 and two cohortstudies.175,176 Sensitivity analysis was undertakenby examining separately the results of the higherquality studies, using HSROC analysis where morethan one higher quality study reported the sametest (Table 22). For both SAP threshold and FDTC-20-5, the higher quality studies reported lowervalues for both sensitivity and specificity whencompared with all studies, while two FDT C-20-5studies not meeting the criteria for higherquality173,187 reported very high sensitivity values(98% and 100%, respectively). For optic discphotography, compared with all studies, thehigher quality studies reported similar sensitivity(74% versus 73%), with slightly lower specificity(82% versus 89%). For HRT II, compared with allstudies, the higher quality studies reported highersensitivity (93% versus 86%) but slightly lowerspecificity (85% versus 89%).

Studies reporting combinations of testsTwo population-based studies reported thesensitivity and specificity of combinations of testsfor detecting OAG.163,164 Robin and colleagues163

compared the sensitivity and specificity ofsequential testing with FDT C-20-5 followed byHRT II in a population-based study set inAustralia involving 261 people. For FDT,participants with any miss of any severity repeatedthe test. Three definitions of abnormal HRT IIwere assessed: one or more borderline or severeabnormalities, two or more borderline or one ormore severe abnormalities, or three or moreborderline or one or more severe abnormalities.The definitions were based on MRA, which takesinto account the global and sectorial rim area


69



70

(c)

(d)

Com

mon

cut

-off

Num

ber

of s

tudi

es

1Se

nsiti

vity

(%) (

95%

CrI

) 92

(62

to 1

00)

Spec

ifici

ty (%

) (95

% C

rI)

92 (9

0 to

94)

DO

R (9

5% C

rI)

134.

88 (1

7.15

to 1

061.

10)

Hig

h-qu

ality

stu

dies

N

umbe

r of

stu

dies

0

(a)

(b)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

10.

20.

30.

40.

50.

60.

70.

80.

91.

0

1 –

Spec

ifici

ty

Sensitivity

Vern

on, 1

99016

4Ve

rnon

, 199

0164

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

00.

100.

200.

300.

400.

500.

600.

700.

800.

901.

00

1 –

Spec

ifici

ty

Sensitivity

Vern

on, 1

99016

411

/12

Stud

yTP

/TP+

FN

00.

20.

40.

60.

81.

0Se

nsiti

vity

797/

862

TN/T

N+

FP

00.

20.

40.

60.

81.

0Sp

ecifi

city

FIG

UR

E 3

7N

CT: (

a) S

ROC

plot

: all

stud

ies,

all

cut-

offs

; (b)

SRO

C pl

ot: c

omm

on c

ut-o

ff; (

c) s

ensit

ivity

and

spe

cific

ity a

t co

mm

on c

ut-o

ff; (

d) p

oole

d es

timat

es. F

N, f

alse

neg

ative

; FP,

false

posit

ive; T

N, t

rue

nega

tive;

TP,

true

pos

itive

.


71


TA

BLE

21

Sum

mar

y in

form

atio

n fo

r tes

ts in

clud

ed in

the

HSR

OC

met

a-an

alys

is m

odel

sa

Test

No.

of

Sens

itiv

ity

(%)

Spec

ifici

ty (

%)

DO

Rc

(95%

CI)

Mea

n %

inte

rpre

tabl

e T

ime

take

n to

per

form

st

udie

s(9

5% C

rI)

(95%

CrI

)re

sult

s (r

ange

)te

st, p

er e

ye

(min

utes

) (r

ange

)

Oph

thal

mos

copy

560

(34

to 8

2)94

(76

to 9

9)26

(6 t

o 11

0)98

(86

to 1

00)

Not

sta

ted

Opt

ic d

isc p

hoto

grap

hy6

73 (6

1 to

83)

89 (5

0 to

99)

22 (3

to

148)

85 (7

3 to

100

)16

RNFL

pho

togr

aphy

b4

75 (4

6 to

92)

88 (5

3 to

98)

23 (4

to

124)

80N

ot s

tate

dH

RT II

386

(55t

o 97

)89

(66

to 9

8)51

(11

to 2

46)

94 (9

1 to

97)

N

ot s

tate

dFD

T C

-20-

13

92 (6

5 to

99)

94 (7

3 to

99)

181

(25

to 2

139)

97 (8

7 to

99)

<1

to 2

FDT

C-2

0-5

578

(19

to 9

9)75

(57

to 8

7)10

(0.7

to

249)

92 (8

6 to

98)

<1

to 2

OK

P4

86 (2

9 to

100

)90

(79

to 9

6)58

(4 t

o 15

85)

97 (9

4 to

98)

3 to

4

SAP

supr

athr

esho

ld9

71 (5

1 to

86)

85 (7

3 to

93)

14 (6

to

34)

81 (6

0 to

100

)2

to 8

SAP

thre

shol

dd5

88 (6

5 to

97)

80 (5

5 to

93)

30 (6

to

159)

99 (9

1 to

100

)3

to 9

GAT

946

(22

to 7

1)95

(89

to 9

7)15

(4 t

o 49

)99

(97

to 1

00)

Not

sta

ted

NC

T1

92 (6

2 to

100

)92

(90

to 9

4)13

5 (1

7 to

106

1)97

(90

to 1

00)

1

aSu

mm

ary

data

acr

oss

all s

tudi

es ir

resp

ectiv

e of

qua

lity.

bO

ne s

tudy

pro

vide

d da

ta o

n in

terp

reta

ble

resu

lts.16

7

cD

ORs

are

bas

ed o

n al

l stu

dies

usin

g a

com

mon

cut

-off.

dFo

ur s

tudi

es r

epor

ted

the

time

take

n to

per

form

the

tes

t, al

l of w

hich

use

d SI

TA s

tand

ard

or S

ITA

fast

.176,

195,

198,

206

TA

BLE

22

HSR

OC

anal

ysis:

all

stud

ies

com

pare

d w

ith h

ighe

r qua

lity

stud

ies

Opt

ic d

isc

phot

ogra

phy

HR

T I

IFD

T C

-20-

5SA

P t

hres

hold

Sens

itiv

ity

Spec

ifici

tySe

nsit

ivit

ySp

ecifi

city

Sens

itiv

ity

Spec

ifici

ty

Sens

itiv

ity

Spec

ifici

ty

(%)

(%)

(%)

(%)

(%)

(%)

(%)

(%)

All

stud

ies

7389

8689

7875

8880

Hig

her

qual

ity

7482

9385

7260

7364

corrected for global and sectorial disc area anduses three grades: ‘normal’ if all of themeasurements fall within the 95% confidenceintervals, ‘borderline’ if at least one falls between the lower 95% and 99.9% confidenceintervals, and ‘outside normal limits’ if at least one rim area measurement is less than the lower 99.9% confidence interval. Thereference standard consisted of a full clinicalophthalmic examination by an ophthalmologist; a panel of nine glaucoma experts determined the final diagnosis of glaucoma. The combinations of tests reported were: (a) FDT (atleast one abnormality) then HRT II (at least oneabnormality); (b) FDT (at least one abnormality)then HRT II (at least two abnormalities); (c) FDT(at least two abnormalities) then HRT II (at least one abnormality); and (d) FDT (at least two abnormalities) then HRT II (at least twoabnormalities). The highest sensitivity, 79%, wasreported for both (a) and (b) with specificities of88% and 93%, respectively, while the highestspecificity, 95%, was reported for (d) with asensitivity of 74%.

The study by Vernon and colleagues164 alsoreported the sensitivity and specificity ofsequential testing of NCT (Keeler Pulsair)followed by SAP (Henson CFS 2000 26-pointsuprathreshold screening programme) fordetecting OAG. For NCT, the criterion used todefine a positive result was mean IOP of at least22 mmHg. For SAP, a missed point on the 26-point suprathreshold programme required theoperator to extend to a 66-point test. A failed testwas defined as occurring when sufficient pointshad been missed to drop the indicator on thescreen into the suspicious zone or below. Thereference standard consisted of all participantshaving their optic discs graded by an experiencedophthalmologist. There was verification bias inthat those who tested positive on the index testshad a more extensive evaluation. Glaucoma wasdefined as IOP greater than 22 mmHg pluspathologically cupped disc with field loss, or IOP greater than 22 mmHg on two occasions inassociation with two or more of six pathologicaldisc parameters despite normal fields, or IOPgreater than 30 mmHg on two occasions. Theauthors reported a sensitivity of 92% andspecificity of 93% for sequential testing of IOPfollowed by the Henson 26-point suprathresholdscreening programme. It should be noted,however, that the reference standard is suboptimal as reported for this study whenreporting the accuracy of NCT alone in theprevious section.

Studies assessing accuracy for different stages ofglaucomaOne population-based study158 and sixcase–control studies181,182,184,186,190,191 reported theaccuracy of tests for detecting glaucoma atdifferent stages of the disease. Although some ofthese studies did not specifically state this as anaim, they were considered to do so by eitherincluding or excluding people with certain stagesof glaucoma. While the present review’s inclusioncriteria aimed to ensure that study participantswould be representative of a screening population,some studies were accepted that excluded verysevere loss, for example hemispheric loss, orhemianopia or that applied exclusion criteria onvision that were not judged as being undulyrestrictive. These studies were accepted on thebasis that they were in effect providinginformation on test accuracy for different stages ofglaucoma and that the categories of peopleexcluded would generally have already beendetected owing to the severity of their vision loss.For example, Katz and colleagues158 excludedpeople with hemispheric or greater loss, Engerand colleagues181 excluded those with advancedglaucoma and Harper and colleagues182 excludedpeople with more advanced glaucomatous visualfield defects, while all participants with glaucomain the study by Wood and colleagues191 possessedearly/moderate visual field defects. Ieong andcolleagues186 included people with minimalglaucomatous field loss, while Wollstein andcolleagues190 included those with visual fielddefects defined as ‘mild glaucoma’.

As these studies aimed to assess test accuracy indifferent stages of glaucoma, their participantswere representative of a specific severity ratherthan a broad spectrum of disease. Table 23provides details of those studies assessing theaccuracy of tests for different stages of glaucoma,the tests used, the sensitivity and specificityreported by the individual studies, and the pooledsensitivity and specificity from the meta-analysismodels for all studies reporting the tests (for allstages of glaucoma) at the common cut-off (asshown in Table 21).

In two studies186,190 assessing early-stage glaucomaand reporting optic disc photography, HRT II andSAP suprathreshold, sensitivity ranged from 69%(HRT II) to 72% (SAP suprathreshold), whilespecificity ranged from 94% (optic discphotography) to 95% (HRT II; SAPsuprathreshold). Sensitivity was similar for SAPsuprathreshold (72% versus 71%) and optic discphotography (71% versus 73%), but lower for


72


73


TA

BLE

23

Stud

ies

repo

rtin

g di

ffere

nt s

tage

s of

gla

ucom

a

Stud

ySt

age

of g

lauc

oma

Test

Sens

itiv

ity

(%)

Spec

ifici

ty (

%)

Pool

ed s

ensi

tivi

ty (

%)

Pool

ed s

peci

ficit

y (%

) (9

5% C

I)(9

5% C

I)(9

5% C

rI)

(95%

CrI

)

Ieon

g, 2

00318

6Ea

rlyH

RT II

69

(49

to 8

5)95

(82

to 9

9)86

(55

to 9

7)89

(66

to 9

8)SA

P su

prat

hres

hold

72 (5

3 to

87)

95 (8

2 to

99)

71 (5

1 to

86)

85 (7

3 to

93)

Wol

lstei

n, 2

00019

0Ea

rlyO

ptic

disc

pho

togr

aphy

71 (5

6 to

83)

94 (8

6 to

98)

73 (6

1 to

83)

89 (5

0 to

99)

Enge

r, 19

8718

1Ea

rly/m

oder

ate

SAP

thre

shol

d97

(90

to 1

00)a

98 (9

3 to

100

)a88

(65

to 9

7)80

(55

to 9

3)H

arpe

r, 19

9418

2,18

6Ea

rly/m

oder

ate

OK

P25

(14

to 3

9)94

(88

to 9

7)86

(29

to 1

00)

90 (7

9 to

96)

Katz

, 199

1158

Early

/mod

erat

eSA

P th

resh

old

97 (9

2 to

99)

b94

(90

to 9

7)b

88 (6

5 to

97)

80 (5

5 to

93)

Woo

d, 1

98719

1Ea

rly/m

oder

ate

Oph

thal

mos

copy

56 (3

0 to

80)

78 (5

8 to

91)

60 (3

4 to

82)

94 (7

6 to

99)

Hee

g, 2

00518

4M

oder

ate/

seve

reFD

T C

-20

full

thre

shol

d10

0 (9

9 to

100

)81

(75

to 8

6)N

AN

A

NA

, not

app

licab

le.

aSe

nsiti

vity

of 9

7% a

nd s

peci

ficity

of 9

8% a

re fr

om d

iffer

ent

algo

rithm

s.b

Sens

itivi

ty o

f 97%

and

spe

cific

ity o

f 94%

are

from

diff

eren

t al

gorit

hms.

HRT II (69% versus 86%), when compared withthe pooled data from the meta-analysis models forall studies reporting the tests at a common cut-off.The specificities reported by the individual studiesfor each test were higher compared with thepooled data.

In four studies158,181,182,191 assessingearly/moderate-stage glaucoma and reportingophthalmoscopy, OKP and SAP threshold,sensitivity ranged from 25% (OKP) to 97% (SAPthreshold), while specificity ranged from 78%(ophthalmoscopy) to 98% (SAP threshold). Inthese studies, compared with the pooled data fromthe meta-analysis models, sensitivity was higherfor SAP threshold (97% versus 88%) but lower forophthalmoscopy (56% versus 60%) and especiallyfor OKP (25% versus 86%), while specificity washigher for OKP (94% versus 90%) and SAPthreshold (98% and 94% versus 80%), but lowerfor ophthalmoscopy (78% versus 94%). Onepossible explanation for the low sensitivity of OKPput forward by the study authors was that the testwas self-administered and unsupervised, andrelied on self-assessment by the participants.182

In the one study184 reporting a subgroup of thestudy population with moderate/severe-stageglaucoma, sensitivity for the FDT C-20 fullthreshold test was higher (100% versus 90%) withsimilar specificity (both 81%) when compared withthe whole study group.

Studies directly comparing testsOverviewSix studies directly compared two or more of thefollowing tests that were considered to bepotentially feasible for use in a screeningprogramme for detection of OAG: optic discphotography, HRT II, SAP, FDT andGAT.157,163,166,168,176,186 All of the studies comparedSAP with one or more of the other tests (Table 24).

SAP compared with optic disc photographyVitale and colleagues166 compared SAP(suprathreshold programme 1 of the Dicon LD

400 Autoperimeter) with optic disc photography(Topcon ImageNet) in a case–control study set inthe USA involving 249 people. The participantswere selected from survivors of a population-basedsample included in the Baltimore Eye SurveyFollow-up Study.235 Three definitions of anabnormal SAP test were assessed: two adjacentpoints missed, three adjacent points missed, ortwo or more points missed in any location. Criteriaused to define a positive test result for optic discphotography were VCDR greater than 0.59 or rimarea/disc area less than 0.66. Overall, optic discphotography performed better than SAP in termsof sensitivity but worse in terms of specificity.Sensitivity for SAP ranged from 50% [threeadjacent points missed (common cut-off)] to 71%(two or more points missed, any location), whilespecificity ranged from 58% (two or more pointsmissed, any location) to 83% [three adjacentpoints missed (common cut-off)]. Sensitivity foroptic disc photography ranged from 73% (rimarea/disc area <0.66) to 77% [VCDR > 0.59(common cut-off)], while specificity ranged from59% [VCDR > 0.59 (common cut-off)] to 62% (rimarea/disc area <0.66). In terms of themethodological quality of the study, the spectrumof people was seen as representative of those whowould attend for screening, there was no evidenceof partial or differential verification bias, and theresults of the index tests were interpreted withoutknowledge of the results of the reference standardtest, and vice versa. The reference standard forthis study was glaucoma expert opinion based onslit-lamp examination, and dilatedophthalmoscopy to assess the optic disc and nervefibre layer. Therefore, the estimates for theaccuracy of optic disc photography as the indextest may overestimate the accuracy of the test, asthe reference standard, although a different test, isalso a test of structure.

SAP compared with HRT IITwo studies compared SAP with HRT II, withRobin and colleagues163 reporting HRT II as thebetter test, and Ieong and colleagues186 reportingbroadly similar results for both tests. Robin and


74

TABLE 24 Studies directly comparing two or more of: optic disc photography, HRT II, FDT, SAP and GAT

Study Optic disc photography HRT II FDT SAP GAT

Ivers, 2001157 ✕ ✕Ieong, 2003186 ✕ ✕Robin, 2005163 ✕ ✕ ✕Spry, 2005176 ✕ ✕Vitale, 2000166 ✕ ✕Wang, 1998168 ✕ ✕

colleagues163 compared SAP (Central 24-2threshold screening programme of the Humphreyfield analyser) with HRT II in a population-basedstudy set in Australia involving 261 people. TheSAP test was analysed using the AGIS visual fieldtest scoring method. Three definitions ofabnormal HRT II were assessed: one or moreborderline or severe abnormalities, two or moreborderline or one or more severe abnormalities, orthree or more borderline or one or more severeabnormalities. The reference standard was a fullclinical ophthalmic examination and a panel ofnine glaucoma experts determined the finaldiagnosis of glaucoma. Overall, HRT IIperformed better than SAP in terms of bothsensitivity and specificity. Sensitivity for HRT IIranged from 90% (at least two borderline or onesevere abnormality; at least three borderline orone severe abnormality) to 95% [at least oneborderline or one severe abnormality (commoncut-off)], while specificity ranged from 81% [atleast one borderline or one severe abnormality(common cut-off)] to 91% (at least threeborderline or one severe abnormality). Sensitivityfor SAP ranged from 63% [AGIS score �3(common cut-off)] to 90% (AGIS score �1), whilespecificity ranged from 58% (AGIS score �1) to74% [AGIS score �3 (common cut-off)]. In thisstudy the spectrum of people was seen asrepresentative of those who would attend forscreening, there was no evidence of partial ordifferential verification bias, and the results of theindex tests were interpreted without knowledge ofthe results of the reference standard test, and viceversa. The accuracy of both SAP and HRT II asindex tests may have been overestimated as visualfield testing and estimates of CDRs also formedpart of the reference standard.

Ieong and colleagues186 compared SAPsuprathreshold (DICON) with HRT II in acase–control study set in the UK involving 29participants with OAG (including 15 NTG) and 37normal participants, with the tests being carriedout by eight optometrists. This study aimed totarget those with early-stage glaucoma. OAGparticipants with minimal field loss were recruitedthrough glaucoma clinics at Moorfields EyeHospital. Normal participants were spouses orpartners of those with OAG. The referencestandard was glaucoma expert opinion. In termsof the criteria used to define a positive result, forSAP, decisions on whether visual plots were trulydefective were left to the optometrists’ judgement,while for HRT II if either the global or one of sixsegments was flagged abnormal the optic disc wasregarded as suspicious, with borderline

classifications taken as normal. The less affectedeye of OAG participants was analysed, while fornormal participants the eyes analysed alternatedright then left in order of presentation. At thecommon cut-off, sensitivity for SAP and HRT IIwas 72% and 69%, respectively, while specificity forboth tests was 95%. In terms of quality, thespectrum of people was not regarded asrepresentative of screening or diagnosis in thatonly early disease was targeted, there was noevidence of partial or differential verification bias,and the results of the index tests were interpretedwithout knowledge of the results of the referencestandard test, and vice versa. The accuracy of bothSAP and HRT II as index tests may have beenoverestimated, as both visual field testing andoptic nerve examination formed part of thereference standard.

SAP compared with FDTTwo studies compared SAP with FDT, with bothRobin and colleagues163 and Spry andcolleagues176 reporting FDT as better than SAP interms of sensitivity, but worse in terms ofspecificity. Robin and colleagues163 compared SAP(Central 24-2 threshold screening programme ofthe Humphrey field analyser) with FDT C-20-5 ina population-based study set in Australia involving261 people. The SAP test was analysed using theAGIS visual field test scoring method. Fourdefinitions of abnormal FDT C-20-5 wereassessed: one abnormal point, two abnormalpoints, three abnormal points and one abnormalpoint at moderate or severe level. The referencestandard was a full clinical ophthalmicexamination and a panel of nine glaucoma expertsdetermined the final diagnosis of glaucoma.Overall, FDT C-20-5 performed better than SAPin terms of sensitivity but worse in terms ofspecificity. Sensitivity for FDT C-20-5 ranged from68% (one abnormal point at moderate or severelevel) to 84% [one abnormal point (common cut-off)], while specificity ranged from 55% [oneabnormal point (common cut-off)] to 76% (oneabnormal point at moderate or severe level).Sensitivity for SAP ranged from 63% [AGIS score�3 (common cut-off)] to 90% (AGIS score �1),while specificity ranged from 58% (AGIS score �1)to 74% [AGIS score �3 (common cut-off)]. In thisstudy the spectrum of people was seen asrepresentative of those who would attend forscreening, there was no evidence of partial ordifferential verification bias, and the results of theindex tests were interpreted without knowledge ofthe results of the reference standard test, and viceversa. The accuracy of both SAP and FDT C-20-5as index tests may have been overestimated as


75


visual field testing also formed part of thereference standard.

Spry and colleagues176 compared SAP threshold(SITA fast) with FDT C-20 matrix (Humphreymatrix 24-2) in a cohort study set in the UKinvolving 48 people. The reference standardconsisted of an ophthalmic examination includingthe SAP threshold test. The definition of anabnormal test for both SAP and FDT was a GHToutside the normal limit and/or p < 0.05 with thepattern standard deviation global index in one orboth eyes. At the common cut-off, the studyreported sensitivity for SAP and FDT of 80% and100%, respectively, while specificity was 52% and27%, respectively. In terms of the quality of thestudy, the spectrum of people was consideredrepresentative of a diagnostic setting, there was noevidence of partial or differential verification bias,and the results of the index tests were interpretedwithout knowledge of the results of the referencestandard. The results of the reference standardwere interpreted without knowledge of the FDTtest results, but with knowledge of the SAP testresults as this test formed part of the referencestandard. Sensitivity and specificity may beoverestimated as both index tests were visual fieldtests, with one (SAP) also forming part of thereference standard, resulting in incorporation biasfor this test.

SAP compared with GATTwo studies157,168 compared SAP suprathresholdwith GAT, with both reporting that SAP performedbetter than GAT in terms of sensitivity but worsein terms of specificity. Ivers and colleagues157

compared SAP (Humphrey 76-pointsuprathreshold screening test) with GAT in apopulation-based study set in Australia (BlueMountains Eye Study) involving 3654 people.Criteria for a positive SAP test included one,three, five or ten or more points missing, whileGAT was assessed at IOP greater than 22 mmHgand IOP greater than 28 mmHg. The referencestandard for all participants was a detailed eyeexamination and a screening visual field test.Glaucoma suspects received a more thoroughreference standard consisting of a full thresholdvisual field test. Sensitivity for SAP ranged from37% (ten or more points missing) to 100% (one ormore points missing), while specificity rangedfrom 50% (one or more points missing) to 92%(ten or more points missing). At the common cut-off sensitivity and specificity for SAP was 89% and73%, respectively. Sensitivity for GAT ranged from3% (IOP > 28 mmHg) to 14% [IOP > 22 mmHg(common cut-off)], while specificity ranged from

98% [IOP > 22 mmHg (common cut-off)] to 99%(IOP > 28 mmHg). In terms of the quality of thestudy, the spectrum of people was seen asrepresentative of those who would attend forscreening, there was no evidence of partialverification bias in that everyone received areference standard test, but there was evidence ofdifferential verification bias in that only testpositives on the index tests went on to receive amore thorough reference standard. Although theresults of the index tests were interpreted withoutknowledge of the results of the reference standardtest, thereby avoiding test review bias, diagnosticreview bias may have occurred in that the finaldiagnosis of glaucoma was made with knowledgeof the results of the SAP and GAT index tests,potentially biasing the assessment of glaucomastatus. The accuracy of both SAP and GAT asindex tests may have been overestimated, as visualfield testing and IOP measurement formed part ofthe reference standard, so that it was not whollyindependent of the index tests, leading toincorporation bias.

Wang and colleagues168 compared SAPsuprathreshold (Humphrey full field 120screening programme) with GAT in a population-based study set in the USA involving 510 people.The participants were selected from thoseattending an adult primary care clinic at the JohnsHopkins Hospital. SAP was assessed at 17 or moreabsolute or relative defects, while GAT wasassessed at IOP above 21 mmHg. The referencestandard for all participants was a fullophthalmological examination. Only screenpositives were referred for a further definitediagnosis of glaucoma. At the common cut-off, thestudy reported sensitivity for SAP and GAT of 70%and 28%, respectively, while specificity was 67%and 96%, respectively. In terms of the quality ofthe study, the spectrum of people was seen asrepresentative of those who would attend forscreening, there was no evidence of partialverification bias in that all participants received areference standard test, but there was evidence ofdifferential verification bias in that only testpositives on the index tests went on to receive amore thorough reference standard. Although theresults of the index tests were interpreted withoutknowledge of the results of the reference standardtest, avoiding test review bias, it was unclearwhether the reference standard test wasinterpreted without knowledge of the results of theindex tests. The accuracy of both SAP and GAT asindex tests may have been overestimated, as visualfield testing and IOP measurement formed part ofthe reference standard, so that it was not wholly


76

independent of the index tests, leading toincorporation bias.

SummaryTable 25 shows the sensitivity, specificity, DOR andrelative RDOR at the common cut-off for the testsbeing compared directly within studies. In termsof sensitivity, SAP performed better thanGAT,157,168 broadly similar186 or worse163 thanHRT II and worse than optic disc photography,166

FDT C-20-5163 or FDT C-20 matrix.176 In terms ofspecificity, SAP performed better than optic discphotography,166 FDT C-20-5163 or FDT C-20matrix,176 broadly similar186 or worse than HRTII163 and worse than GAT.157,168 DORs for the testsranged from 4 for SAP threshold176 to 75 for HRTII,163 with higher DORs indicating moreconvincing diagnostic evidence.

In terms of RDORs, compared with SAP, GATperformed better168 or worse,157 HRT IIperformed better163 or worse,186 FDT C-20-5163

and FDT C-20 matrix176 performed better, whileoptic disc photography166 showed a broadlysimilar performance. The RDORs in the study byIvers and colleagues157 were statistically significantin favour of SAP suprathreshold over GAT, whilethose in the study by Robin and colleagues163 werestatistically significant in favour of HRT II overSAP threshold.

The studies by Robin and colleagues,163 Vitale andcolleagues166 and Spry and colleagues176 met thecriteria specified for higher quality studies.

However, incorporation bias occurred in the studyby Robin and colleagues163 and Spry andcolleagues176 as the SAP test also formed part ofthe reference standard. There was a possibility ofincorporation bias in the study by Vitale andcolleagues166 as one index test (optic discphotography) and tests that formed part of thereference standard (slit-lamp biomicroscopy) weretests of structure.

Indirect comparisons in a single HSROC modelThe results of the indirect comparison of the tentests are given in Table 26. Out of the largenumber of comparisons only four for sensitivityand two for specificity showed a statisticallysignificant difference between tests. There wasevidence that the sensitivity of FDT C-20-1 washigher than ophthalmoscopy (–30, 95% CrI –62 to–0.01) and GAT (45, 95% CrI 17 to 68), and thatSAP threshold (41, 95% CrI 14 to 64) and HRT II(39, 95% CrI 3 to 64) had a higher sensitivity thanGAT. For specificity, there was evidence of a higherlevel for GAT than for FDT C-20-5 (–19, 95% CrI–53 to –0.2) and SAP threshold (–14, 95% CrI –37 to –1). Several other comparisons were close tobeing statistically significant. No one test (or groupof tests) was clearly more accurate than the others.

Discussion of resultsMain findingsThe included studies reported tests of structure(ophthalmoscopy; optic disc photography, RNFL


77


TABLE 25 Sensitivity, specificity, DOR and RDOR at the common cut-off for studies directly comparing tests

Study Test Sensitivity (%) Specificity (%) DOR RDOR (95% CI) (95% CI) (95% CI) (95% CI)

Ivers, 2001157 SAP suprathreshold 89 (80 to 94) 73 (71 to 74) 20 (10 to 39) 1GAT 14 (7 to 23) 98 (97 to 98) 6 (3 to 12) 0.31 (0.12 to 0.78)

Ieong, 2003186 SAP suprathreshold 72 (53 to 87) 95 (82 to 99) 46 (9 to 237) 1HRT II 69 (49 to 85) 95 (82 to 99) 39 (8 to 198) 0.85 (0.08 to 8.54)

Robin, 2005163 SAP threshold 63 (38 to 84) 74 (68 to 80) 5 (2 to 13) 1HRT II 95 (74 to 100) 81 (75 to 85) 75 (10 to 574) 15.01 (1.57 to 143.82)FDT C-20-5 84 (60 to 97) 55 (49 to 61) 7 (2 to 23) 1.31 (0.27 to 6.43)

Spry, 2005176 SAP threshold 80 (52 to 96) 52 (34 to 69) 4 (1 to 18) 1FDT C-20 matrix 100 (78 to 100) 27 (13 to 46) 12 (1 to 222) 2.83 (0.11 to 72.91)

Vitale, 2000166 SAP suprathreshold 50 (37 to 63) 83 (76 to 88) 5 (3 to 9) 1Optic disc photography 77 (62 to 89) 59 (50 to 67) 5 (2 to 11) 0.99 (0.36 to 2.75)

Wang, 1998168 SAP suprathreshold 70 (57 to 80) 67 (59 to 74) 5 (2 to 9) 1GAT 28 (17 to 40) 96 (93 to 98) 9 (4 to 19) 1.89 (0.70 to 5.13)

RDOR = index test DOR/SAP DOR. RDOR calculated as all direct studies had SAP as one of the tests. Values of RDOR > 1 indicate that the test performed better than SAP in the study and values < 1 indicate that the test performedworse than SAP.For details of the common cut-off selected for each test see Appendix 13.


78

TABLE 26 Pairwise indirect comparisons of the 10 tests

Comparisona Difference between tests

Sensitivity, median (95% CrI) Specificity, median (95% CrI)

Ophthalmoscopy versusOptic disc photography –12 (–46 to 20) 6 (–7 to 21)RNFL photography –14 (–50 to 26) 6 (–7 to 30)HRT II –24 (–57 to 14) 5 (–9 to 30)FDT C-20-1 –30 (–62 to –0.01)* 0.3 (–11 to 18)FDT C-20-5 –11 (–49 to 32) 19 (–2 to 53)OKP –20 (–54 to 19) 4 (–9 to 26)SAP suprathreshold –10 (–43 to 20) 9 (–4 to 22)SAP threshold –26 (–58 to 2) 14 (–2 to 37)GAT 15 (–22 to 47) –0.06 (–12 to 7)

Optic disc photography versusRNFL photography –2 (–31 to 34) –0.05 (–17 to 24)HRT II –12 (–38 to 22) –1 (–18 to 24)FDT C-20-1 –18 (–42 to 6) –6 (–21 to 12)FDT C-20-5 1 (–30 to 40) 12 (–10 to 47)OKP –8 (–35 to 27) –2 (–18 to 21)SAP suprathreshold 2 (–23 to 25) 3 (–13 to 17)SAP threshold –14 (–38 to 7) 8 (–11 to 31)GAT 27 (–4 to 53) –6 (–21 to 3)

RNFL photography versusHRT II –10 (–45 to 25) –1 (–25 to 24)FDT C-20-1 –16 (–50 to 10) –5 (–29 to 13)FDT C-20-5 3 (–36 to 44) 12 (–16 to 47)OKP –6 (–43 to 30) –1 (–26 to 22)SAP suprathreshold 4 (–31 to 29) 3 (–21 to 18)SAP threshold –12 (–46 to 12) 8 (–17 to 32)GAT 29 (–10 to 57) –6 (–30 to 4)

HRT II versusOKP 4 (–29 to 38) –1 (–26 to 22)FDT C-20-1 –6 (–38 to 17) –4 (–29 to 14)FDT C-20-5 12 (–23 to 52) 13 (–16 to 49)SAP suprathreshold 14 (–18 to 36) 4 (–21 to 19)SAP threshold –2 (–34 to 18) 9 (–18 to 33)GAT 39 (3 to 64)* –5 (–30 to 5)

OKP versusFDT C-20-1 –10 (–42 to 14) –3 (–26 to 14)FDT C-20-5 9 (–29 to 49) 14 (–13 to 49)SAP suprathreshold 10 (–24 to 34) 5 (–18 to 19)SAP threshold –6 (–39 to 16) 10 (–15 to 34)GAT 35 (–2 to 62) –4 (–26 to 5)

SAP suprathreshold versusFDT C-20-1 –20 (–40 to 3) –8 (–22 to 9)FDT C-20-5 –1 (–29 to 38) 10 (–12 to 45)SAP threshold –16 (–37 to 5) 5 (-12 to 28)GAT 25 (–2 to 50) –9 (–22 to 0.3)

SAP threshold versusFDT C-20-1 –4 (–23 to 18) –13 (–36 to 6)FDT C-20-5 15 (–11 to 53) 5 (–23 to 41)GAT 41 (14 to 64)* –14 (–37 to –1)*

FDT C-20-1 versusFDT C-20-5 19 (–10 to 57) 18 (–6 to 53)GAT 45 (17 to 68)* –0.4 (–18 to 8)

FDT C-20-5 versus GAT 26 (–16 to 57) –19 (–53 to –0.2)*

a A versus B = A – B.* Statistically significant difference.

photography, HRT II), visual function (FDT, OKP,SAP) and IOP (GAT, NCT). Other tests wereconsidered, including those of structure (GDxVCC, OCT, RTA), visual function (SWAP, MDP) orusing Tonopen to measure IOP. However, nostudies using these tests met the inclusion criteriain terms of reporting of test accuracy outcomes.

Despite the huge volume of literature, no good-quality studies were found providing a positiveresponse to all questions on the modified QUADASchecklist. Eight studies were rated as higher qualityin that the spectrum of people was consideredrepresentative of a screening or diagnostic setting,and partial and differential verification bias andtest and diagnostic review bias were avoided.

Analyses were performed at a number of differentlevels:

● HSROC model for each test at all cut-offs and acommon cut-off

● HSROC model for tests reported by two ormore higher quality studies at a common cut-off

● analysis of studies reporting combinations oftests

● analysis of studies reporting the accuracy oftests for stages of glaucoma

● analysis of studies directly comparing two ormore tests in the same population

● indirect comparison of all tests from allincluded studies at a common cut-off.

From the available data, the following tests wereconsidered to be potentially feasible for use in ascreening programme for detection of OAG: opticdisc photography, HRT II, FDT, SAP and GAT.Direct comparison studies provide the most robustestimates of comparative test accuracy. Only sixstudies directly compared two or more of thesetests, with all studies including SAP as one of thetests.157,163,166,168,176,186 In these studies, at thecommon cut-off, in terms of sensitivity, SAPperformed better than GAT,157,168 broadlysimilar186 or worse163 than HRT II and worse thanoptic disc photography,166 FDT C-20-5163 or FDTC-20 matrix.176 At the common cut-off, in terms ofspecificity, SAP performed better than optic discphotography,166 FDT C-20-5163 or FDT C-20matrix,176 broadly similar186 or worse than HRTII163 and worse than GAT.157,168 Three directcomparison studies met the criteria for higherquality studies.163,166,176

The pooled estimate of the sensitivity of the testsin detecting OAG ranged from 46% (GAT) to 92%(FDT C-20-1), while specificity ranged from 75%

(FDT C-20-5) to 95% (GAT). The FDT C-20-1 testwas associated with the highest sensitivity (92%)and was one of the tests associated with the highestspecificity (94%), along with ophthalmoscopy (94%)and GAT (95%). The pooled estimate for FDT C-20-1 showed higher sensitivity and specificity thanthe pooled estimate for FDT C-20-5 and also thesingle FDT C-20 full threshold study. This isunexpected (i.e. better sensitivity of C-20-1 than C-20-5). These findings were based on only threeFDT C-20-1 studies, five FDT C-20-5 studies andone FDT C-20 full threshold study, withheterogeneity evident especially in the FDT C-20-5studies. Forest plots showing sensitivity andspecificity with 95% confidence intervals revealedstatistical heterogeneity across studies for mosttests, other than for the sensitivity of optic discphotography (number of studies, n = 6), sensitivityand specificity of HRT II (n = 3), and sensitivity ofFDT C-20-1 (n = 3). Empirically, there was noobvious single cause for the heterogeneity, butpotential contributory factors include differences inpopulations, study design, setting, prevalence andseverity of glaucoma within studies. Other factorsinclude differences in reference standard, and intests included within the same category (e.g.different types of perimetry and ophthalmoscopyhave a large number of variants, potentiallyleading to heterogeneity in discriminatory poweracross studies reporting those tests), and the extentto which studies were affected by other potentialbiases (e.g. partial and differential verification bias,incorporation bias, test and diagnostic review bias).Owing to the imprecision in the estimates from thepooled meta-analysis models for the diagnosticperformance of each test it was not possible toidentify a single test (or even a group of tests) asthe most accurate.

Based on the pairwise indirect comparisons, interms of statistically significant differences in testperformance, there was evidence that GAT had alower sensitivity than HRT II, SAP threshold andFDT C-20-1, but a higher specificity than SAPthreshold and FDT C-20-5. FDT C-20-1 alsoseemed to have a better sensitivity thanophthalmoscopy. Other differences in accuracybetween tests may well exist which could not bedetected because of the high level of uncertainty.The wide credible intervals reflected the smallnumber of studies reporting each test and thegenerally high level of heterogeneity.

Potential biasesReference standardOAG is a clinical diagnosis, based on structuralabnormalities of the optic disc and an associated


79


glaucomatous visual field defect. There is nouniversally agreed optimal reference standard forthe diagnosis of OAG, although progressivestructural optic neuropathy has been proposed asthe best possible reference standard.148,236

Variations in the reference standard used to defineOAG directly affect the estimates of testaccuracy.237,238 In addition, the different testsbecome abnormal at different stages of the diseaseand at a single time-point agreement between testsis likely to be poor owing to these differences.

In this review either of two reference standardtests was considered. The primary referencestandard was confirmed OAG on follow-up andwas considered to be the best reference standardalthough, as anticipated, few studies used it.Therefore, another reference standard, cross-sectional ophthalmologist-diagnosed OAG, wasalso considered. The diagnosis from this secondreference standard could be based on assessmentof the visual field and/or the optic disc withoutrequiring follow-up confirmation. Of the 40studies included in this review, seven used areference standard of follow-up confirmation ofglaucoma.22,106,166,171,174,178,189 However, there wasno obvious pattern in terms of the sensitivity andspecificity of the tests reported by studies using areference standard of follow-up confirmation ofglaucoma compared with those studies using areference standard of ophthalmologist-diagnosedglaucoma.

Severity of the diseaseThe majority of the studies did not stratify testaccuracy on the basis of disease severity. Ingeneral, tests become more sensitive as the diseasebecomes more severe. Hence, a study includingparticipants with advanced disease should reportbetter sensitivity. However, unless the distributionof disease severity in the examined population isexplicitly reported in primary studies, it is notpossible to evaluate the impact of any spectrumbias that might have occurred. In addition, if anadequate sample size for subgroups is notachieved, within-study comparisons of testperformance may result in a loss of power todetect significant differences.239 Seven studiesreporting test accuracy in different stages ofglaucoma were included in thisreview.158,181,182,184,186,190,191 However, noconsistent pattern of sensitivities and specificitiesfor different stages of glaucoma emerged from thestudies. One reason for this was that the studiesmostly reported different tests. Of those reportingthe same tests for different stages of glaucoma,Ieong and colleagues186 reported a sensitivity of

72% for SAP suprathreshold for early-stageglaucoma, while Enger and Sommer181 and Katzand colleagues158 both reported a sensitivity of97% for early/moderate-stage glaucoma. It is notunexpected that a visual field test such as SAPwould increase in sensitivity as the diseaseprogresses. Variations in the results between otherstudies can be explained by the use of non-uniform and non-standardised definitions forvarious stages of glaucoma. Some studies usedstructural damage to define these stages (early,moderate, severe), while others used functionaldamage. However, it could be argued that oncefunctional damage is detectable on standardperimetry, then by definition the disease hasprogressed beyond early stage.229,240,241

Incorporation biasIn glaucoma diagnosis the concept of incorporationbias is complex. For example, it has beensuggested that inclusion of any optic disc criteriain the reference standard when evaluating anotheroptic disc test (e.g. HRT) introduces incorporationbias.242 In such studies it may seem logical to useonly visual field examination as a referencestandard test. This, however, assumes thatstructural (e.g. optic disc) and functional (e.g.visual field) damage occur simultaneously inglaucoma pathogenesis, whereas there is evidencethat disc damage precedes manifest visual fieldloss.229,240,241 Up to 30% of optic nerve fibredamage occurs before visual field damage becomesdetectable. Hence, using visual field assessmentalone as a reference standard may report anunfairly low accuracy of an imaging test, especiallyif more people with early glaucoma are includedin the study. For example, if visual field damagealone is used as a reference standard and a study isconducted at time-point A (Figure 38) to evaluatean imaging test, it will report many false positives,as detectable visual field damage has not yetoccurred. However, if a similar study is performedat time-point B, there will be greater agreementbetween reference standard and index test andhence the test accuracy will be much higher.

Hospital-based studies (including case–controlstudies)Twenty of the 40 studies included in this reviewwere hospital based. A hospital population is, bynature, an enriched population and theprevalence of the disease will be higher than thatin the community. This population may alsoinclude a disproportionate number of patientswith high IOP and a disproportionately smallnumber of patients with small optic discs,potentially leading to overoptimistic performance


80

estimates. In addition, hospital-based studiesgenerally recruit participants from glaucomaclinics who have previous experience of tests andtherefore these studies cannot account for thelearning effect in those unfamiliar with such tests,unlike the case in a screening situation.243–246

However, only hospital-based studies whoseparticipants were considered to be representativeof those referred from primary care were includedin the review.

Diagnostic case–control studies are useful at theinitial stages of validating a test. To test theapplicability of a new test it should be applieddirectly to the population of its intended use.Case–control studies recruit participants with aclear disease status, that is, either with or withoutthe target disease. Indeterminate andintermediate results are common, and oftencoexisting disease produces a positive test result.The majority of the case–control studies identifiedapplied stringent criteria for inclusion such asvisual acuity of 6/9, or no other ocular disease.Rutjes and colleagues247 evaluated variouspotential sources of bias in diagnostic studies. Thefactor with the highest impact on estimates of testaccuracy was a case–control study design withseverely diseased cases and healthy controls. Fifty-seven case–control studies where the participantswere considered unrepresentative of a case-mixfound in a general population where OAGscreening would be carried out were excludedfrom the review (see Appendix 10).

Prevalence of the diseaseThe accuracy of a test may vary according to thepopulation in which it is performed. Althoughabsolute sensitivity and specificity of a diagnostictest are independent of the prevalence of adisease, a diverse spectrum of the disease isencountered in different prevalence levels. Withincreasing prevalence more cases of moderate tosevere disease are expected, and since it is easierto differentiate between severely diseased andnon-diseased people, a test would be expected toreport improved (apparent) sensitivity andspecificity. Therefore, studies with a significantlyhigher prevalence than the UK estimates shouldbe interpreted with this limitation inmind.156,161–163,168,170 These studies tended torecruit their participants through mediaadvertising rather than contacting individuals in apredefined population. These studies, includingtwo that met the criteria for higher qualitystudies,163,170 may be considered to be morerepresentative of screening in higher riskpopulations.

Higher quality studiesOnly eight studies met the criteria specified forhigher quality studies, of which six werepopulation based155,156,163,166,169,170 and two werecohort studies.175,176 For FDT C-20-5 and SAPthreshold, the higher quality studies reportedlower values for both sensitivity and specificitycompared with all studies, while two studies notmeeting the criteria for higher quality173,187


81


A B

Time

Gla

ucom

a da

mag

e

Detectable disc damage Detectable visual field damage

FIGURE 38 Structural versus functional damage and effect on cross-sectional diagnostic studies

reported very high sensitivity values. For optic discphotography, compared with all studies, thehigher quality studies reported similar sensitivity,with slightly lower specificity. For HRT II,compared with all studies, the higher qualitystudies reported higher sensitivity but slightlylower specificity.

Issues relevant to screeningUptake and time taken to perform the testIn addition to the sensitivity and specificity of thetest(s), other factors may impact on the success ofa screening programme, including the percentageof people invited who attend for screening(uptake), the percentage of those taking part whoprovide interpretable test results and the timetaken to perform the test. Uptake levels rangedfrom 28.3163 to 99.5%,154 with a median rateacross studies of 82.8%. The difference may beexplained at least in part by differences in the wayin which the studies made their targeted audienceaware of the screening programme. For example,Robin and colleagues163 advertised theirprogramme through the media, while otherstudies with greater uptake adopted a moreproactive approach in identifying their targetpopulation and inviting them to attend forscreening.21,99 The percentage of participantsproviding interpretable test results ranged from79.5% for RNFL photography to 99.1% for GAT,with ophthalmoscopy (97.8%), OKP (96.9%), SAPthreshold (98.9%), FDT C-20-1 (96.7%) and NCT(97.2%) all reporting rates of interpretable testresults greater than 95%.

Few included studies gave details of the time takento perform the test (see Table 21). None of theincluded studies of ophthalmoscopy, RNFLphotography, HRT II or GAT reported the timetaken to perform the test. One study reported thisinformation for optic disc photography,197 threefor OKP,154,170,212 four for SAPsuprathreshold,159,162,164,174 four for SAPthreshold, all of which used SITA standard orSITA fast,176,195,198,206 four for FDT C-20-1,170,185,187,214 two for FDT C-20-5155,187 andone for NCT.164 The information provided ontime taken to perform the test should beinterpreted with this limitation in mind.

What stage of glaucoma should be targeted forscreening?It is important to determine the severity ofglaucoma that screening should detect. This isimportant as tests that perform better in moderateto severe disease but have low diagnostic yield inearly glaucoma could have an overall superior

diagnostic utility as screening tests. Identifyinglarge numbers of people with early disease thatmay never progress to significant visualimpairment or reduction in quality of life mayresult in greater harm than benefit fromscreening.

Damage caused by OAG typically occurs slowlyand over a long period. Many people diagnosedwith glaucoma will never develop a significantvisual impairment during their lifetime. Currentcase detection identifies only around half thenumber of people with OAG and thus preventsonly a limited number from progressing tosignificant visual impairment. Introducing OAGscreening with a test that is sensitive for moderatedisease will prevent significant visual impairmentin an additional number of people but will stillmiss some cases. Using a highly sensitive test forOAG will identify all those who are at risk ofdeveloping significant visual field loss andblindness; however, it will also identify a largeproportion of people who are not at risk ofdeveloping severe glaucoma during their lifetime.Treating these otherwise asymptomatic individualscould result in the unnecessary use of limitedhealthcare resources. In addition, labellingasymptomatic individuals as ‘diseased’ may wellcause unnecessary anxiety.

Most of the visual disability in glaucoma is relatedto visual field loss. Therefore, it is reasonable totarget glaucoma with early visual field loss (i.e.perimetric glaucoma) in OAG screening. It isworth noting that this does not rule out structuraltests from glaucoma screening. A structural testsuch as HRT may have a better diagnosticperformance than a functional test such as SAP inthe perimetric stage of glaucoma because, in thisstage, the disc damage would have progressedbeyond early stage and would therefore be easierto detect.

Strengths and limitations of the reviewThe field of systematic reviews of diagnostic testsis a nascent one and the methodology for thesecomplex reviews is currently still evolving. Bearing these limitations in mind, this review isone of the largest systematic reviews of screeningand diagnostic tests in glaucoma. Several levels of analyses were undertaken, includingHSROC analysis on all studies and higher qualitystudies, analysis of studies reporting combinationsof tests, studies reporting accuracy of tests fordetecting stages of glaucoma and studies directlycomparing two or more tests. In addition, all thetests were modelled simultaneously (in one model)


82

using a Bayesian approach. This allowed directestimates of differences in sensitivities andspecificities to be calculated. To be included,studies had to meet specific inclusion criteria. Thevalidity of indirect comparisons does depend onassumptions regarding the characteristics of theincluded studies; however, the indirect method isformally performing the comparison that users ofthe report are likely to make when assessing thepooled results for the individual tests. As such, thismethod of indirect comparisons serves animportant purpose and reaffirms the lack ofcertainty about which test is indeed the best.

In terms of limitations, relatively few studies wereidentified for each test and it was not possible toperform sensitivity analysis based on study design.Owing to the small number of studies for eachtest, different study designs (population-basedstudies and studies including an already suspectpopulation) were pooled together in the HSROCmeta-analysis models. Only six of the 40 studiesdirectly compared two or more of the tests thatwere considered to be potentially feasible for usein a screening programme. There were too fewstudies on the individual tests for the indirectcomparison to identify what was the best test. Onlyeight studies met the criteria for higher qualitystudies. The studies were lacking in evidence oftest accuracy in high-risk groups and those mostlikely to be targeted for OAG screening. There is alack of a generally agreed reference standard testfor OAG against which other tests can beevaluated. Studies not providing sufficientinformation to allow the calculation of 2 × 2 tableswere excluded, although they may havecontributed information in terms of sensitivity andspecificity. Case–control studies where theparticipants were not considered representative ofa screening population were also excluded, even ifthe same inclusion and exclusion criteria wereapplied to both cases and controls, although theymay have contributed information on test accuracyin a clinic situation.

ConclusionsImplications for practiceFor a low-prevalence disease a screening test needsto be highly specific. In the meta-analysis modelsthe following tests provided a specificity of 85% orhigher: ophthalmoscopy (94%), optic discphotography (89%), RNFL photography (88%),HRT II (89%), FDT C-20-1 (94%), OKP (90%),SAP suprathreshold (85%) and GAT (95%). In thisreview the FDT C-20-1 test was associated with the

highest combination of sensitivity and specificityfor detecting OAG. As pointed out earlier, therewas a wide variation in the reference standardsamong included studies. Variations in the referencestandards may partly account for varied diagnosticaccuracies: a stricter reference standard within astudy will lead to a higher specificity and vice versa.However, owing to the strongly heterogeneousnature of the data overall and the relatively smallnumber of studies, it was not possible to concludewith certainty whether any one test was definitelysuperior in terms of accuracy.

Implications for future researchFuture research should focus on a consensus OAGdefinition and reference standard. As a significantproportion of visual morbidity in glaucoma isdirectly related to visual field loss, a definitionwith emphasis on visual field damage may bemore appropriate. The possibility of a consensusreference standard test should also be explored.The definition of different severities of glaucomais important, and the stage of glaucoma that isimportant to be detected by screening should beagreed. There is a need for high-quality primarystudies comparing candidate screening tests in anappropriate population.

The accuracy of the various screening tests shouldbe evaluated in a sufficiently large population-based study. Initially, a cross-sectional study toevaluate the relative accuracies of comparator testswould be preferable. The main advantage of across-sectional study is a quick outcome. Adiagnostic cross-sectional study could be an RCTwhere patients are randomised to one or the othertest(s), or it may be a paired study where eachpatient receives both (several/all) tests. Theadvantage of a paired study is that a smallersample size is required. However, for logisticalreasons, it may not be practical for everyparticipant to receive all tests. The study shouldhave a predetermined sample size for assessmentof test accuracies in high-risk subgroups and forpopulations in whom glaucoma screening isthought to be cost-effective. Different combinationalgorithms combining structural and functionaltests need further exploration. In this review thecommon cut-off chosen for each test was the onemost frequently reported by the studies, whichmay not necessarily be the most appropriate. Forexample, IOP testing was considered an integralpart of a screening strategy, but studies generallyreported data only for a cut-off of above21 mmHg, although also providing data for other,additional, cut-offs would have been moreinformative.


83


Screening for prevention of opticnerve damage due to OAGIntroductionA Cochrane systematic review of screening forOAG, led by the Cochrane Eyes and Vision group,is in the final stages of completion248 (andCochrane Collaboration Eyes and Vision Group:personal communication, 2006). A summary isprovided in this section.

The aim of this review was to determine theimpact of screening, in terms of benefits andharms, compared with opportunistic case finding.Effectiveness of screening can be assessed by theprevalence of and degree of optic nerve damagedue to OAG in screened and unscreenedpopulations, assuming that successful detectionand subsequent treatment of OAG lead to lowerprevalence of advanced optic nerve damage inscreened versus unscreened populations.

MethodsInclusion and exclusion criteriaRCTs of screening versus no screening for OAG were eligible for inclusion. The referencestrategy of no screening included case finding;that is, opportunistic detection. Trials comparingdifferent screening strategies were not included.Any method of randomisation was considered,including that in which individuals, locations orpractices were randomised, and differences instudy quality were taken into account in theanalysis. Ideally, trials should have analysed dataon an intention-to-treat (ITT) basis. It wasplanned to include other types of analysisprovided all randomised patients were accounted for and to use an available case-basedanalysis.

Types of participantStudies from any population were considered, butmajor differences in the populations studied suchas age at screen and race would be reported whenanalysing the results. People already known tohave glaucoma or already under the care of an eyespecialist, or known to be visually impaired forother reasons were not expected to be included inroutine screening. Screening is likely to detectother degenerative eye conditions and other forms

of glaucoma, although these were not included asthe primary outcome of the review.

Types of interventionStudies of any screening modality for OAG wereeligible.

Types of outcome measurePrimary outcomesAny or all of the following three primary outcomeswere considered for this review:

● Prevalence of any degree of characteristic visualfield loss in screened and non-screenedpopulations as diagnosed by any method ofvisual field assessment (excludingconfrontation). The proportion of people with apredetermined severity of field loss (attributableto glaucoma) was to be compared in thescreened and unscreened populations.

● Prevalence of optic nerve damage in screenedand non-screened populations as diagnosed by any method of imaging. The difference inthe prevalence of a prespecified degree ofstructural optic nerve damage would have beenexamined in screened and unscreenedpopulations.

● Prevalence of visual impairment in screenedand non-screened populations as defined bynumber of subjects certified or registeredaccording to national or regional standards(where the study was conducted) as:– blind – partially sighted– vision below standard for driving.

Secondary outcomesScreening may lead to more treatment andsubsequently a lower mean IOP in screened thanin unscreened populations. IOP is a surrogateoutcome but, nevertheless, indirect evidence ofeffectiveness of screening might be derived fromthe reduction in the severity of the most well-established and modifiable risk factor. Reportingof any differences in mean IOP in screened andunscreened populations was planned.

Adverse effectsFalse negatives are people with glaucoma who pass screening and go on to lose vision. False


85


Chapter 7

Evidence of effectiveness

positives are people without glaucoma who failscreening and are referred for furtherinvestigation but who do not undergo anytreatment. Referral causes excess burden on healthservices and unnecessary inconvenience andanxiety for the patient.

Quality of life measuresReporting of any measures of quality of life orhealth status attributable to the screening or OAGwas planned.

Economic dataReporting of any economic data on the costs andcost-effectiveness of programme implementation,cost per case identified or other costs relating tothe screening programme was planned.

Other outcomesThe technical differences between the screeningand control interventions, the quality of theintervention including any quality controlmeasures, rates of participation, contaminationand follow-up were measured among screeningand control arms.

Follow-upA minimum follow-up of 1 year postscreening wasrequired for all studies.

Search strategy for identification of studiesAny RCTs evaluating population-based screeningprogrammes for OAG with a minimum 1-yearfollow-up were included.

Electronic searchesThe searches outlined in Chapter 4 were used;however, for this review no language or daterestrictions were applied, according to Cochranemethodology. No manual searches wereundertaken for this review.

ResultsThe search generated 1191 records of studiesrelevant to the search criteria, but none was anRCT of screening and hence no data extraction oranalysis was conducted.

DiscussionNo RCTS were identified, the applied searchstrategy (detailed in Appendix 2) wascomprehensive, with in this case no languagerestrictions, and as such it is very unlikely to havemissed any existing trials. Two major sources ofbias that will otherwise distort the findings ofobservational studies can only be dealt with byrandomised trials of screening.

Lead-time bias occurs when the condition isdetected at an earlier stage through screening,although no influence on ultimate outcome isachieved as a result of that earlier detection. Thesurvival is apparently greater because thecondition is known about for longer, but anotherwise similar unscreened individual goes blindat the same rate, although spending less timebeing aware of the problem. In such acircumstance, it is fair to conclude that screeninghas done harm.

Length bias occurs because interval screening ismore likely to detect slowly progressive andindolent disease than aggressive, rapidlyprogressing glaucoma. Apparently, screening hasled to more people with early-stage disease beingidentified who are at much lower risk of blindness.This apparent benefit may actually be harmful ifthe risk of the adverse effects of disease in thesemild cases is very low, and the number of peoplewith aggressive, blinding glaucoma may remainthe same and the blindness rates unchanged.

Hence, this review specifically searched for RCTs ofscreening in that it is the only study design that canadequately deal with these two sources of bias.However, the organisation and conduct of suchstudies is demanding and long-term follow-up isrequired on large numbers of people if there is tobe any likelihood of detecting an effect. It isperhaps not surprising that no such trials wereidentified. Justification for such a study will dependon refinement of screening test strategies andeconomic modelling of potential benefit and cost.

ConclusionsEffectiveness of screening for OAG can only beestablished by high-quality randomised trials.Some preliminary issues need to be dealt withbefore such trials can be undertaken. A betterunderstanding of testing technologies is neededand high-quality studies in different populationsare required to delineate optimum screeningstrategies in terms of individuals, tests,combinations of tests and test frequency. It isrecognised that 1-year follow-up, included as aminimum in this review, is extremely short in thecourse of glaucoma. Ideally, much longer follow-up is required; however, surrogate outcomes suchas IOP at 1 year can be indicators of prognosis.Modelling alongside a trial can be used to predictlong-term costs and benefits. Better monitoring ofhealth outcomes in large populations usingregisters of blindness by cause can providesurveillance for the observation of the impact ofprevention strategies over time.


86

Effectiveness of glaucomatreatmentIntroductionTreatment aims to prevent visual disability andpreserve overall wellbeing for patients withglaucoma. The visual loss in glaucoma is due tothe death of retinal ganglion cells. Vascular and/ormechanical factors at the optic nerve head mayprecipitate cell death and IOP may be implicatedin either or both of these mechanisms.249

Currently, IOP is the only risk factor that can betreated.

Medical treatment, to lower IOP, is administeredtopically as eye drops. These treatments arecommonly topical �-blockers, and more recentlynewer topical agents including carbonic anhydraseinhibitors, �2-agonists and prostaglandinanalogues have been introduced. �-Blockers andprostaglandin analogues are the most commonlyused medications. Reduced rates of surgery forglaucoma are felt to be a consequence of theintroduction of these new eye drops.250 Analternative or additive treatment to the use ofmedications is laser trabeculoplasty with discretelaser ablation to the trabecular meshwork of thedrainage angle. The effectiveness of alternativemedical interventions for OAG and of lasertrabeculoplasty is being assessed in two Cochranereviews that are currently in progress.30,31

Glaucoma drainage surgery aims to lower the IOPby creating an alternative route for aqueoushumour outflow. Trabeculectomy is the mostcommon glaucoma surgical procedure. In aCochrane review of medical versus surgicalinterventions for OAG, evidence from one trialsuggests, for mild OAG, that visual fielddeterioration up to 5 years is not significantlydifferent whether treatment is initiated withmedication or trabeculectomy. There was noevidence to determine the effectiveness ofcontemporary medication (prostaglandinanalogues, �2-agonists and topical carbonicanhydrase inhibitors) compared with surgery insevere OAG.29

The aim of this part of the project was toundertake a systematic review to determine theeffectiveness of any IOP-lowering treatment(medical, laser or surgery or any combinationthereof), compared with no treatment inpreventing glaucoma progression in terms ofreduced visual field loss and progressive opticnerve damage (a surrogate outcome for visualfield loss), and on patient-reported health status.

MethodsInclusion and exclusion criteriaSystematic reviews and RCTs of treatment versusno treatment for participants with OAG wereincluded. Studies where the participants hadocular hypertension (i.e. raised IOP but noevidence of glaucoma damage) were excluded.

Data extractionOne reviewer screened the titles and abstracts ofthe identified reports.

Quality assessmentA previously validated ten-item checklistdeveloped by Oxman was used to assess themethodological quality of systematic reviewsmeeting the inclusion criteria.251,252 The checklistcontains nine criteria, scored as ‘Yes’, ‘Partially’ or‘No’, depending on the extent to which they aremet. The checklist also provides one summarycriterion for overall scientific quality, scored on aseven-point scale, where 1 indicates ‘extensiveflaws’ and 7 indicates ‘minimal flaws’.

ResultsNumber and type of studies includedIn total, 323 reports were identified, and 15 full-text papers were selected for assessment. Onesystematic review of RCTs of treatment versus notreatment for ocular hypertension and OAG wasidentified.19 No further RCTs of treatmenteffectiveness for OAG: other than those includedin the systematic review and also separatelyidentified by the search strategy, were identified.One additional RCT253 was identified whereparticipants had ocular hypertension, but this didnot meet the inclusion criteria of this specificreview and was excluded.

Characteristics of included study The systematic review by Maier and colleagues19

included seven studies; however, five of theserelated to the treatment of ocular hypertensionand therefore are not relevant to this review. Thus,this review reports the results of the two includedtrials of treatment versus no treatment forparticipants with OAG: the Early ManifestGlaucoma Trial (EMGT),27 where participants hadbeen identified as having manifest OAG with orwithout raised IOP, and the Collaborative NormalTension Glaucoma Study (CNTGS),254 whereparticipants had OAG but the IOP had not beenrecorded as over 24 mmHg in either eye.

The CNTGS was a 5-year study in the 1990s across24 centres in the USA, Canada, The Netherlandsand Finland. One eye of 145 participants with


87


progressive NTG was randomised to treatment orno treatment. In the treatment arm, treatmentcould be medical or surgical and aimed for a 30%reduction in IOP. The end-point of the study wasdocumented progression either in terms of visualfield or optic disc changes compatible withprogression. The rate of development of cataractsin the untreated participants was significantlylower than in the surgically treated group. In asurvival analysis there was no significant differencein the risk of progression between the two groups;however, after censoring for cataract developmentthe treated group had a significantly lower risk ofprogression. The mean survival time toprogression in the treated arm was 6 years, and5 years in the no-treatment arm.

The EMGT had a different spectrum ofparticipants from CNTGS, recruiting newlydetected OAG cases identified from a population-screening programme with 255 participantsrandomised to treatment or no treatment.Participants with very high IOPs (mean IOP >30 mmHg) were excluded. All eyes randomisedto treatment received a full 360-degreetrabeculoplasty plus a selective �-blocker eye drop(Betaxalol). Additional therapy was added if theIOP exceeded 25 mmHg on two consecutiveoccasions. At the final analysis (median follow-upof 6 years), 78 (62%) of the 126 control eyes versus58 (45%) of the 129 treated eyes progressed (log-rank p = 0.007). The median time to progressionwas 5.5 years in the treated patients and 4 years inthe no-treatment group. More patients in thetreatment arm developed cataract than in the no-treatment group (p = 0.004). Health-relatedquality of life (HRQoL) was measured using aSwedish translation of the 25-item National EyeInstitute Visual Function Questionnaire (NEI VFQ-25), but was not measured at baseline, as thequestionnaire was not available at that time. Therewas no significant difference in composite scoresbetween the treated and untreated group at 6-yearfollow-up. The results of this study thereforesuggest that treatment, whether by randomisationor received during follow-up, was not related tovision-targeted HRQoL. However, the analysis ofthe HRQoL data was not an ITT analysis.

Quality assessmentThe systematic review was assessed as having onlyminor flaws, in that the criteria used to assess themethodological quality of the included trials werenot stated, the search strategy was deemed to bereasonably comprehensive in that there were nolanguage restrictions, reference lists were searchedand authors were contacted for further details if

required, but there was no handsearching (seeAppendix 14 for the detailed results of the qualityassessment of the systematic review). As thesystematic review had not assessed themethodological quality of the included trials, thequality of the two included RCTs was assessedaccording to criteria developed by the CochraneCollaboration Eyes and Vision Group. Thesecriteria assess quality in terms of likelihood ofselection, performance, detection and attritionbias. In CNTGS it was unclear whether allocationwas adequately concealed, participants andclinicians were not masked to treatmentassignment, the person assessing outcomes wasunaware of the assigned treatment, it was unclearwhether follow-up rates were similar incomparison groups, and the analysis was ITT.Thus, this study can be considered as potentiallyprone to selection, performance and possiblyattrition bias. EMGT was graded as low risk of biasfor selection, detection and attrition bias (exceptfor the HRQoL outcome), but there was apossibility of performance bias in that cliniciansand participants were not masked to treatmentallocation. The nature of the study was such thatclinicians needed to be aware of treatmentallocation to decide on clinical managementduring the study.

Assessment of effectivenessThe analysis by Maier and colleagues19 combinedthe results of these two studies using a DeSimonianand Laird random effects model and showed asignificant pooled treatment effect of loweringIOP to prevent glaucoma progression (hazardratio 0.65, 95% CI 0.49 to 0.87, p = 0.003). Therewas no significant statistical heterogeneity betweenthe studies (�2 = 0.13, p = 0.72).

DiscussionIn both studies the definition of glaucomaprogression was based on either or both ofprogressive glaucomomatous optic disc changes orprogressive visual field loss and progression wasdetermined by a reading committee masked to theintervention. The criteria defining progression ofvisual field loss and optic disc changes differedbetween studies but in both studies there was astrict definition of progression, visual fieldassessment was on automated perimetry and inboth studies visual field loss had to be confirmedon repeat testing. In both studies, of thoseparticipants progressing, the majority were basedon progressive visual field loss with all bar oneparticipant in the EMGT, and three participants inthe CNTGS, progressing on optic disc criteriaalone.


88

The results suggest a beneficial treatment effect;however, neither study was graded as high qualityon all criteria, and as such the effects may besubject to bias, and the results should beinterpreted with this in mind.

Conclusions Evidence from the included, good-quality,systematic review suggests that treatment iseffective at slowing the rate of progression ofOAG. It is less certain as to how this translates intothe effectiveness of treatment on reducing long-term visual impairment and maintaining quality of life.

Probability of glaucomadeterioration from mild disease tovisual impairmentIntroductionAs described in the previous section, OAG istypically a slowly progressive disease. The purposeof this section is not systematically to describe allissues and studies that have investigatedprogression per se, but to describe specifically forthe purposes of the economic modelling theapproximate probability of progressing from milddisease to visual impairment. OAG was definedusing a visual field glaucoma staging system thathad four stages: mild, moderate, severe andvisually impaired (partial sight and blind). Thedetails are described below. Progression wasassumed to follow a linear course, implying that anewly diagnosed glaucoma patient would startwith mild disease and progress through everystage until visually impaired.

The aim of this component of the study was toestimate the yearly probability of progressing frommild to moderate, moderate to severe and severeto visually impaired.

Grading of disease severityThere is no accepted scale of glaucoma severity.Automated threshold perimetry is a widelyaccepted method of assessing uniocular glaucomaseverity and for monitoring progression in eacheye, but there is no standardised definition ofseverity and progression on automated perimetry.There is also limited evidence on the correlationbetween the severity of visual field loss andpatient-reported visual disability and quality of life.

RCTs for OAG27,255,256 each developed differentscoring systems for defining severity and

progression. These scoring systems were eventbased, in that progression was confirmed when apreset threshold was exceeded. When each ofthese scales was applied to the same cohort ofpatients the rates of apparent progression variedaccording to which scoring scale and definition ofprogression were used.257,258

A modified version of the glaucoma severity scaleused by a study group examining the costs ofglaucoma treatment by stage in Europe and theUSA was used for this study259,260 (Table 27). Thisscale itself was a modification of theHodapp–Anderson–Parrish scale.261 For thepurposes of this study a commonly reportedmeasure of the depth of the glaucomatous visualfield defect was used; this was the mean defect ormean deviation (MD) on standard automatedperimetry. The MD refers to the average deviationin decibels (dB) of the measured threshold valuesfrom the age-corrected normal value. Oneproblem with using the MD alone to classifyseverity is that other non-glaucomatous disease,mainly the presence of cataract, affects the MD.Other glaucoma severity scales are based on theMD, but also take into account othercharacteristics of visual field loss such as thelocation and clustering of the defect, the patterndeviation and the corrected pattern standarddeviation to categorise the extent of the focal lossof visual field (i.e. correcting for diffuse loss thatmay be caused by the presence of cataract). Afterpreliminary searching of the literature, it becameclear that the pattern deviation and the correctedpattern standard deviation could not beincorporated into the severity scale used, sincestudies rarely reported these items in detail.

MethodsTo estimate the rate of glaucoma progression, astudy would require a random sample of peoplewith glaucoma, and who have not been treated.This sample would be prospectively followed upwithout treatment for many years and visual fieldtested at regular intervals. Recognising that suchan approach is ethically and practically difficult, it


89


TABLE 27 Visual field-based glaucoma staging system common cut-off for studies directly comparing tests

MD score (dB)

Mild glaucoma –0.01 to –6.00 Moderate glaucoma –6.01 to –12.00Severe glaucoma –12.01 to –20.00Visual impairment (partial sight/blind) –20.01 or worse

was decided to use two complementary approachesto estimating progression:

● Approach 1: systematically identify RCTs of OAG treatment versus control and predict yearly progression rates (by stage ofOAG) beyond the current trial follow-up period.

● Approach 2: partially validate approach 1estimates and systematically identify any studiesthat provide yearly estimates of progressing toeach of the defined stages of OAG for treatedpatients.

Inclusion and exclusion criteriaTypes of studyThe following types of study were included:

● Approach 1: RCTs in which people diagnosedwith OAG are randomised to either treatmentor no-treatment control groups.

● Approach 2: any comparative or observationalstudies, including cohort studies, with analysisdata on at least 100 participants.

To be considered for inclusion in approach 1, thestudy had to report the group average baselineMD and follow-up MD measure for treatedpatients, or to have categorised progression interms of the present grading system. For approach2, the study should have categorised progressionin terms of the grading system used in this study(or provided enough information to becategorised into the grading system).

Target conditionThe target condition was OAG (mild, moderate orsevere).

ParticipantsPeople over 40 years of age were included.

OutcomesStudies reporting relevant and interpretable dataon the following outcomes were considered:

● average MD in decibels at study entry● average MD in decibels at follow-up● average yearly MD reduction● probability of progressing from mild to

moderate disease● probability of progressing from moderate to

severe disease● probability of progressing from severe disease to

visual impairment● probability of progressing to unilateral

blindness.

Data extraction strategyTwo reviewers screened the titles (and abstracts ifavailable) of all reports identified by the searchstrategy. Full-text copies of all studies deemed tobe potentially relevant were obtained and onereviewer assessed them for inclusion. One reviewerextracted details of study design, participants andoutcome data. In the event of any uncertainty, asecond reviewer provided advice and validated thedata extraction. A list of the included studies isgiven in Appendix 15.

Data analysisApproach 1The baseline MD score was used to categorisestudy participants into mild, moderate or severedisease. The reduction in MD score at follow-upwas used to approximate a yearly rate ofreduction. The yearly reduction was applied toeach follow-up year. At each follow-up year, thecurrent stage of glaucoma was determined by theMD score as given in the present grading system.The probability of progression per year wasestimated by 1 divided by the number of years inthe same grade of OAG. For example, if baselineaverage MD score was –4.0 dB the group would beconsidered mild disease. If the group were toprogress at –0.5 dB per year, it would take 5 yearsfor the group to progress to moderate disease(<–6.0 dB). The probability of yearly progressionfrom mild to moderate disease would be 1/5 = 0.2for this cohort of patients. The average MD atdiagnosis was assumed to be –4.0 dB in theprojections.

Approach 2Study participants were categorised into mild,moderate or severe disease according to eitherbaseline MD scores or study reported severity. Thepercentage of people progressing was convertedinto an approximate yearly probability ofprogressing by dividing the percentage by theaverage length of follow-up.

ResultsApproach 1As described in the section ‘Effectiveness ofglaucoma treatment’ (p. 87), two randomised trialswere identified that compared a treated groupwith a no-treatment control group.27,254 Table 28describes the type of participants in each group,progression in terms of MD changes andpercentage who progressed according to eachstudy definition of progression. Further details canbe found in Appendix 16. The results from theEMGT suggested that the average rate (treatedand untreated) of progression was approximately


90

–0.4 dB per year (12 × –0.03 dB per month) formild OAG patients and the CNTGS suggested thatthe average rate in moderate OAG patients mightbe –0.45 dB per year (average of two groups).

There were no included studies within a severedisease OAG population, therefore it was assumedthat the rate of MD progression in a severepopulation was –0.5 dB year (a linear projectionfrom the mild and moderate estimates). The threeestimates of MD progression per year for treatedpatients were used to derive a probability ofprogressing between mild to moderate, moderateto severe and severe to visual impairment usingmethods described previously (Table 29).

InterpretationThe average treated patient population wouldprogress from mild OAG disease to moderatedisease in 5 years, resulting in a yearly probabilityof progression of 0.2. The population would bemoderate OAG for 14 years and remain withsevere disease for a further 16 years, resulting in acumulative time to become visually impaired of35 years.

Reflecting the uncertainty in these estimates, for the economic modelling, a triangulardistribution was used and assumes the rate ofprogression may be half this rate or as much astriple this rate.

Approach 2Two additional randomised trials255,262 and sevencohort studies259,263–268 met the inclusion criteriaand were included. Table 30 describes the type ofparticipants in each group, and progressionpercentage who progressed according to eachstudy definition of progression. Further details canbe found in Appendix 17.

From the results presented in Table 30, it waspossible to estimate the yearly probability ofprogressing from the various OAG stages.

● the yearly probability of progressing from mildto moderate disease from five studies was0.028,255 0.05,268 0.066,265 0.10266 and 0.11263

(median = 0.066)● the yearly probability of progressing from

moderate to severe disease from six studies was


91


TABLE 28 Studies included in approach 1

Study Treatment Visual field at baseline Length of Visual field at follow-up (dB)(dB) follow-up

CNTGS254 Treated (n = 61) Mean (SD): –8.38 (5.26) 5 years Mean defects, mean (SD) (slope per year): Control (n = 79) Mean (SD): –7.54 (4.31) –0.4992 (1.97)

(moderate) –0.4018 (3.65)

Progressed at end of follow-up22 (33%) = 6.6% per year31 (39%) = 7.8% per year

EMGT27 Treated (n = 129) Mean (SD): –5.0 (3.7) 6 years Mean defects, mean (SD) (dB change Control (n = 126) Mean (SD): –4.4 (3.3) per month):

(mild) –0.03 (0.05)–0.05 (0.07)

Progressed at end of follow-up58 (45%) = 7.5% per year78 (62%) = 10.3% per year

TABLE 29 Estimates of probability of progressing per year for treated and untreated patients

No. of years Probability progressing No. of years Probability progressing (treated) per year (treated) (untreated) per year (untreated)

Mild to moderate 5 0.2 4 0.25

Moderate to severe 14 0.07 9 0.11

Severe to visually impaired 16 0.06 10 0.10

Total number of years from 35 23diagnosis to visual impairment


92

TABLE 30 Studies included in approach 2


CIGTS255 Medicine (n = 307) Mean (SD): 4.6 (4.2) 5 years Mean: 5.0 (SE 0.4)Surgery (n = 300) Mean (SD): 5 (4.3) Mean: 5.2 (SE 0.4)

Visual field scoring scale 63% had Visual field scoring scale(mild) data at

Progressed at end of follow-up (visits not 5 yearspatients):314 (10.7%) = 2.1% per year372 (13.5%) = 2.8% per year

Nouri- AGIS study subset AGIS study patients had Mean = –2.07 (SD 0.86) dB per year in those that Mahdavi, (n = 591, mean of 9 on VF scale 7.4 years progressed only (conservatively assuming 2005 eyes = 789) with (moderate) (SD 1.7) that all non-progressed patients had 0-dB (AGIS)262 a number of per year slopes, the population

different types of mean = –0.6 dB per year)progression criteria Progressed at end of follow-up compared 30% = 4% per year

Sponsel, Beaver Dam Study; (Moderate) 5 years Mild/moderate and no progression: 11/1202001267 120 treated Progressed a category: 44/120

patients Improved a category: 22/120Severe and stayed severe: 43/120

Progressed at end of follow-up44 (37%) = 7.5% per year

Eid, 2003263 102 treated patients Stage at presentation Mild to Stable: 19/102Grade I: 45 moderate: �1 stage loss: 83Grade II: 31 7 years �2 stages lost: 39Grade III: 17 Moderate 3 stages lost: 9Grade IV: 9 to severe: Mild to moderate: (36/45): 11% per year(mild/moderate) 6 years Moderate to severe: (32/48): 11% per year

Severe to Severe to visually impaired: (4/9): 3% per visually yearimpaired: 14 years

Hattenhauer, Olmsted county (Mild/moderate) 15 years Taking only ‘classic’ glaucoma patients1998264 Study: (SD 8) Bilateral blindness: 22% (8–38%)

114 ‘classic’ Unilateral blindness: 54% (42–72%)glaucoma cases

Quigley, 151 patients from (Mild/moderate) Progression was 0.23 of a grading scale 1996266 the Baltimore Eye per year 95% CI (0.04 to 0.50) (i.e. two

Study used to grades progressed in 10 years)develop a model Using the present criteria the probability ofof progression progressing would be 10% per year for

each stage

Traverso, 194 patients across Stage 0: 33/194 5 years 29.6% progressed at least one stage = 6% 2005259 Europe Stage 1: 32/194 per year

Stage 2: 34/194Stage 3: 33/194Stage 4: 31/194Stage 5: 31/194(moderate)

continued

0.04,262 0.06,259 0.075,267 0.10,266 0.11263 and0.12265 (median = 0.087)

● the yearly probability of progressing from severeto visually impaired disease from three studieswas 0.03,263 0.10266 and 0.16265 (median = 0.10).

The Olmsted County study264 suggested thatunilateral blindness in a treated population at 15-year follow-up was 54%. Applying a simplelinear progression assumption, it would take28 years (15/0.54, 95% CI 21 to 36 years) for theentire population to progress to blindness.

InterpretationThere was significant heterogeneity between studyprobabilities. The study-estimated probabilities ofyearly progression for moderate to severe and forsevere to visually impaired provided no evidencethat approach 1 estimates were clearly wrong.Indeed, the median estimates were within 0.02.The approach 1 estimated probability for mild tomoderate progression was significantly higherthan for approach 2. This difference may be partlyexplained by the assumption of severity of milddisease at diagnosis. On the grading scale used inthis review, assuming a baseline MD of –4 dBimplied that the eye needed to progress by –2 dBto become moderate. Clearly, if more mild diseasewere diagnosed, the probability of progression tomoderate disease would decrease (e.g. –3 dB woulddecrease the probability of progression to 12%).

DiscussionApproximate estimates for the probability ofprogression from mild to moderate, moderate tosevere and severe to visually impaired werederived. Approach 1 used a simple linearextrapolation of the results from the CNTGS andEMGT studies. The model suggested that it would

take 35 years for a treated population to progressto unilateral blindness. Such an estimate isplausible if the Olmsted County study isextrapolated to the entire population264 (35 yearsis contained within the Olmsted County study 95%confidence interval) and is similar to the estimatederived by Quigley and colleagues,266 whichsuggested that progression to blindness would takeapproximately 40 years.

Strengths and limitationsExtrapolating trial outcomes from short-termfollow-up to longer term outcome risks seriousunderestimation or overestimation if theassumption of linear progression is incorrect.Using two complementary approaches enabledpartial validation of the extrapolation in this study.There is, therefore, some confidence that theestimated probabilities of progression betweenstages for the entire population of glaucomapatients are approximately correct. The risk ofblindness is based on risk estimates for one eye,driven by the available primary data, and istherefore not necessarily representative of the riskof bilateral blindness.

A ‘black box’ approach was taken to estimateprogression. That is, a ‘precise’ treatment path wasnot formulated for different stages of glaucoma anddiffering presenting prognostic factors. Therefore,it is recognised that there may be some inaccuracyin the estimates for specific subgroups of glaucomapatients. This imprecision has been partially takeninto account in the economic modelling byassuming that the rate of progression may be aslittle as half the estimated rates or as much as triplethis rate. Using these assumptions, the modellingconsidered probabilities of progression that werebigger and smaller than any published estimates.


93


TABLE 30 Studies included in approach 2 (cont’d)


Spry, 2005268 108 patients AGIS score = 3.3 3.6 years 19% progressed = 5% per year(mild cases) (SD 1.3)

Olivius, 160 eyes Grade I: 27 5 years Mild to moderate (20/61 = 6.6% per year)1978265 (119 patients) Grade II: 34 Moderate to severe (19/31 = 12% per

Grade III: 39 year)Grade IV: 24 Severe to blindGrade V: 16 (13/16 = 16% per year)Grade VI: 5Grade VII: 12Grade VIII: 3(mild/moderate)

Some studies269–272 have tried to predictprogression using various prognostic factors.There is some evidence that rate of progressionincreases with age (e.g. an odds ratio of 1.3 hasbeen suggested for every 5-year increase inage),270 but it is conflicting and some prospectivestudies have not found such a relationship.273 Asimilar scenario has also been observed forIOP.274,275 It was decided to ignore such estimateswithin the economic model. The rationale for thiswas that one aspect of the economic modelling wasto identify which components of the economicmodel had the most significant impact on theresults before adding any further complexities tothe model.

Using MD to classify progression was not entirelysatisfactory. It is known that other non-glaucomatous disease, such as the presence ofcataract, affects the MD. MD was used in this studybecause a continuous measure of progression wasdesirable, but studies rarely reported progressionon a continuous scale. The more commonly usedstage models (event-based models) for progressionhave a major limitation: all patients within aspecific stage are considered to be at the sameseverity of disease and therefore stage models failto identify eyes that may be progressing but havenot yet reached the threshold to change a stage.The stage approach gives little information on the

rate and magnitude of change within patients.276

A better approach to estimating progression mightbe trend-based approaches where progression rateis examined on individual visual field points usingregression analysis. Some studies have suggestedthat such an approach is more sensitive thanevent-based methods.256,258,262

ConclusionsMain findings Using RCTs of treatment versus no treatment, thepooled hazard ratio of progression for treatmentversus no treatment was 0.65 (95% CI 0.49 to0.87). Extrapolating the trial results predicted thata treated person would progress from mild to atleast unilateral blindness in approximately35 years. Untreated, the time to progression isestimated as 23 years.

Future researchThe lack of consensus on an appropriatedefinition of ‘progression’ is a major impedimentto understanding the rate and magnitude ofchange in glaucoma patients and consequently thelong-term effects of various treatments. Acomparison of event-based and trend-basedscoring systems needs to be undertaken in a largeprospective cohort of glaucoma patients whorepresent the spectrum of glaucoma disease.


94

This chapter has three main sections: an outlineof the principles of economic evaluation, a

systematic review reporting economic evaluationsof OAG screening strategies and a final sectionreporting the economic evaluation, using aMarkov model, the structure of which was outlinedin the section ‘Economic model’ (p. 15), to assessthe cost-effectiveness of screening for OAG.

Principles of economic evaluationThe decision to use resources to provide onemethod of identifying OAG would mean that theopportunity to use them in other desirable ways(either to provide another method of identificationor to meet an entirely different health need) isgiven up. The cost of this decision is the benefits(health gains, etc.) that could have been obtainedhad the resources been used another desirable way.This is the economic notion of ‘opportunity cost’.Strictly speaking, the opportunity cost of a decisionto use resources in one way is equivalent to thebenefits forgone in the next best alternative use ofthese resources. Economic evaluation is a methodof providing decision-makers with informationabout the opportunity cost of the decisions thatcould be made. It is the comparative analysis ofalternative courses of action in terms of both theircosts (resource use) and effectiveness (healtheffects).277 An economic evaluation, in this context,would involve assessing the relative costs andbenefits associated with alternative identificationstrategies, including screening, for OAG. Theobjective of such an economic evaluation would beto provide information to assist decision-makers inthe allocation of the available resources so thatbenefits can be maximised. How an economicevaluation brings together information on costsand effects is illustrated in Figure 39. The verticalaxis represents the difference in costs between anexperimental (e.g. screening for OAG) and acontrol treatment (e.g. no formal screening forOAG). An evaluation of alternative strategies foridentifying OAG cost estimates might typically beexpected to include the value of the resources usedto provide the strategy as well as the resourceconsequences of that strategy (e.g. the costs oftreatment). The horizontal axis representsdifferences in effectiveness between the two

approaches. The effectiveness of the alternativestrategies might be measured in clinical terms (e.g.reductions in IOP), natural terms (e.g. cases ofvisual impairment avoided) or more economicmeasures, such as quality-adjusted life-years(QALYs). The latter combines estimates of bothquality of life and length of life. The wider thedefinition of benefit used, the more likely it is tomeasure outcomes of importance to individuals.

In the north-west and south-east quadrants ofFigure 39 a clear decision about which treatmentshould be preferred is provided because one orother treatment dominates. In the north-westquadrant the experimental treatment is morecostly and provides less benefit and therefore thecontrol treatment is more efficient (is dominant).In the south-east quadrant the opposite situationoccurs and the experimental treatment is moreefficient (is dominant) as it is less costly andprovides more benefit. The circle in the centre ofthe figure represents the possibility that nomeaningful differences in costs or benefits existbetween the treatments and for practical purposesthe two interventions are equally efficient. In thetwo remaining areas of the figure, the north-eastand south-west quadrants, a judgement is requiredas to whether the more effective treatment is worththe extra cost. To aid these judgements,information can be provided in terms of anincremental cost-effectiveness ratio (ICER). Thehigher the ICER of one intervention comparedwith another, the less likely it is that thisintervention will be considered efficient.

Systematic review of cost-effectiveness of screening for OAGAims and objectivesThe aim of this systematic review is to address thefollowing research questions. From the perspectiveof the UK NHS, is screening for OAG cost-effective and which method of screening is mostlikely to be cost-effective? These questions wereaddressed by:

● systematically identifying and quality assessingall the economic evaluations comparingalternative methods of screening for OAG


95


Chapter 8

Economic analysis

● summarising the evidence from the review ofthese studies for and against the alternativeinterventions.

MethodsInclusion and exclusion criteriaTypes of studyStudies that compare both costs and outcomes forOAG screening were included. Studies wereexcluded if they did not attempt to relate cost tooutcome data. The following types of paper werealso excluded: methodological papers, papers thatreviewed economic evaluations (although theirreference lists were checked), discursive analysis ofcosts/benefits, partial evaluation studies such ascost analyses, efficacy or effectiveness evaluationsand cost of treatment/burden of illness papers.

Study populationStudies had to be performed in adult populations.

Types of interventionAny intervention used for the screening of OAG.

Types of outcomeThe outcomes of the review were costs (regardlessof how estimated) and effects (no matter how

these had been specified). Additional, morespecific, secondary outcomes of the review were:

● incremental costs per case of visual impairment(e.g. loss of vision below driving standard)prevented

● incremental costs per year of visual impairment(e.g. loss of vision below driving standard)prevented

● incremental costs per case of blindnessprevented

● incremental costs per additional QALY gained● incremental costs per number of case of OAG

detected.

Search strategyThe search strategy used to identify relevantstudies is described in detail in Chapter 4.

Data extraction strategyOne reviewer extracted the data according to theguidelines produced by the Centre for Reviewsand Dissemination (CRD) for the critical appraisalof economic evaluations.91,278 Data extractionfocused on two key areas: the results of theeconomic evaluations in terms of estimates of costsand effects, and the methods used to derive the

Economic analysis

96

Experimental intervention more costly

Controlintervention more costly

Control intervention more effective

Experimental interventionmore effective

NW NE

SW SE

FIGURE 39 Relationship between the difference in costs and effects between a new (experimental) intervention and a standard(control) intervention

results and their interpretation. Where theeconomic evaluation had been based on amodelling exercise, additional data extraction wasperformed to describe the source of parameterestimates and the methods used to combine theseestimates in the economic model. The criteriaused were based on those developed by Philipsand colleagues.91 Where included studies hadpreviously been included in NHS EED, theseabstracts were also used to inform the review.

Examples of the type of data extracted from theincluded studies are described below.

● study characteristics– the research question– the study design– the comparison– the setting– the time-horizon of the study– the basis of costing

● characteristics of the study population– numbers receiving or randomised to each

intervention– other systematic differences in clinical

management– inclusion/exclusion criteria– dates to which data on effectiveness and costs

related● duration of follow-up for both costs and

effectiveness● results

– summary of effectiveness and costs (pointestimate and if reported range or standarddeviation)

– summary of cost-effectiveness/utility (pointestimate and if reported range or standarddeviation)

– sensitivity analysis● conclusions as reported by the authors.

To estimate the secondary outcomes describedabove, data were also extracted for eachintervention considered on:

● number of cases of visual impairment (e.g. lossof driving vision) prevented

● average number of years of visual impairment(e.g. loss of driving vision) prevented

● number of cases of blindness prevented● average total cost per person screened● number of cases of OAG● average number of QALYs.

Quality assessment strategyThe quality of the studies was assessed usingFigures 1–11 of the CRD report.278 Study quality

was summarised in terms of how the literature oneffectiveness was retrieved, how the effectivenessdata were derived from the studies, justificationprovided for the strategies assessed, how costswere determined, whether all relevant costs wereincluded, the perspective of the analysis (i.e.whose costs and benefits were consideredimportant to the decision-maker), the measuresused to determine cost-effectiveness and thenature of the sensitivity analysis performed.

Data synthesisNo attempt was made to synthesise quantitativelythe studies that were identified. Data from theincluded studies were summarised to identifycommon results, variations and weaknesses acrossstudies. If a study only reported average cost-effectiveness ratios then, where possible, the datawere reanalysed to provide estimates ofincremental cost-effectiveness. The ICERs wereobtained by calculating the difference in costs (∆C)between one non-dominated strategy and itspreceding non-dominated strategy, and dividing itby the difference in effectiveness (∆E) betweenthese two strategies. It is important to note thatthe strategies were compared only for the sameage groups. It was considered likely that theidentified studies would provide data for differentpatient groups (e.g. those aged 45 and over, thoseaged 65 and over), a range of pretesting risks (e.g.general population risk, strong pretest suspicionof OAG) and a range of screening and diagnosticinterventions. Therefore, separate summaries weredeveloped for each set of studies that consideredthe same patient group, pretesting risk anddiagnostic intervention. Where possible, the dataextracted from the included studies were used toprovide estimates of the secondary outcomesdescribed above.

ResultsNumber of studies identifiedAs described in Chapter 4, a total of 431 titles orabstracts were identified by the searches conductedfor the economic evaluation of screening (Table 2)and a further 65 titles or abstracts were identifiedfrom the general search of databases such asHealth Management Information Consortium andHTA. Sixty-seven full-text papers were retrievedfor assessment. From these, five eligible reportswere identified.279–283 One study was reported intwo separate reports279,280 and the journal versionwas used as the primary publication.280 The foureligible studies used modelling techniques ofvarying levels of complexity to arrive at estimatesof cost-effectiveness. These studies are listed in Appendix 18 and summarised in Appendix 19.


97


The following section critiques and summarisesthe included studies.

Characteristics of the included studies All four studies assessed cost-effectiveness ofscreening for primary OAG. There was one studyeach from the USA,282 and Canada280 and twostudies from the UK.281,283 The analysis byGottlieb and colleagues compared hypotheticalscreening programmes for a population of onemillion individuals aged between 40 and79 years.282 Boivin and colleagues considered theintroduction of screening programmes for thoseaged 40 and 79 years in the Province of Quebec inCanada.280 In 1991 the population of thisprovince was estimated to be 2.6 million.280

Gooder considered the implications of adoptingscreening for a 100,000 cohort of the UK generalpopulation aged 40 years or more.281 In the finalstudy, by Tuck and Crick, the screening strategies

were compared for a hypothetical cohort of 10,000Caucasians aged 40 years and above.283 In all fourstudies the screening strategies considered wouldbe implemented in a community setting. Thecharacteristics of the included studies aresummarised in Appendix 19.

Screening strategies considered in the studiesA description of the strategies considered by eachof the studies is provided in Appendix 19 andsummarised in Table 31. In only one of thesestudies was screening compared with current, noscreening, practice.281

Gottlieb and colleagues considered seven differentscreening strategies: ophthalmoscopy, tonometry(at two different thresholds of >21 mmHg and>24 mmHg), manual perimetry (using HF, MPT,Globuck or Goldmann fields) and automatedperimetry.282 Boivin and colleagues considered

Economic analysis

98

TABLE 31 Description of screening strategies considered by each of the studies

Study Strategy Screening interval

Gottlieb, 1983282 Ophthalmoscopy, with positives referred to ophthalmology Once onlyTonometry �21 mmHg, with positives referred to ophthalmology Once onlyTonometry �24 mmHg, with positives referred to ophthalmology Once onlyHF fields, with positives referred to ophthalmology Once onlyMPT fields, with positives referred to ophthalmology Once onlyGlobuck fields, with positives referred to ophthalmology Once onlyGoldmann fields, with positives referred to ophthalmology Once only

Boivin, 1996280 Tonometry (cut-off not stated), fundoscopy, with positives for either getting 1, 3 or 5 yearsgonioscopy and perimetry

Tonometry (cut-off not stated), with positives getting fundoscopy, gonioscopy 1, 3 or 5 yearsand perimetry

Gooder, 1995281 Opportunistic screening at the time of a routine eye test Once onlyTonometry Once only

Tuck, 1997283 Tonometry and Henson fields Once onlyTonometry and perimetry if IOP > 20 mmHg Once onlyTonometry and perimetry if IOP > 22 mmHg Once onlyTonometry at thresholds of IOP > 22 mmHg Once onlyOphthalmoscopy (sv) Once onlyPerimetry Once onlyOphthalmoscopy and tonometry (sv) Once onlyOphthalmoscopy and tonometry, positives referred to perimetry (sv) Once onlyOphthalmoscopy and tonometry, positives referred to perimetry (lx) Once onlyOphthalmoscopy and perimetry (sv) Once onlyOphthalmoscopy and tonometry (lx) Once onlyOphthalmoscopy and tonometry, ‘high-risk’ candidates referred to perimetry (sv) Once onlyTonometry at thresholds of IOP > 20 mmHg Once onlyOphthalmoscopy and tonometry, ‘high-risk’ candidates referred to perimetry (lx) Once onlyOphthalmoscopy and perimetry (lx) Once onlyOphthalmoscopy and tonometry and perimetry (sv) Once onlyOphthalmoscopy and tonometry and perimetry (lx) Once onlyOphthalmoscopy (lx) Once only

HF, Harrington–Flock; lx, lax referral criteria; MPT, manual perimetry technique; sv, severe referral criteria.

two main strategies.280 In the first, initialscreening was with tonometry (although the cut-offvalues were not stated) and fundoscopy, and ifthere were abnormal findings in either, individualswere then investigated with gonioscopy andperimetry. The second strategy was to screen thepopulation initially with tonometry alone followedby gonioscopy, fundoscopy and perimetry in thosewith abnormal IOP. A total of 12 scenarios wasassessed by varying the age range, participation,compliance and treatment efficacy rates for thesetwo main strategies.280 Gooder compared twoactive screening strategies with opportunisticscreening performed at the time of a routine eyetest (current standard UK practice). The firstscreening strategy considered was tonometry andthe second involved non-contact tonometry andfield tests. People testing positive were thenreferred on to hospital services.281 Tuck and Crickconsidered 18 different screening strategies.283

These strategies varied in terms of the tests used(ophthalmoscopy, tonometry and perimetry), thecut-off values used for tonometry (IOP > 20 orIOP > 22 mmHg) and the severity of referralcriteria. Referral criteria depended on IOP, visualfield defects (defined as “a failure on the 66-pointtest, suspicious zone or below, of a Hensonsuprathreshold field”), CDRs, an assessment ofrisk based on family history of glaucoma or highmyopia. Severity was defined as relatively lax orsevere. An example of severe criteria for referralwould be that patients with IOP between 26 and30 mmHg would only be referred if the CDR was>0.4 or if there was a visual field defect. Laxreferral criteria would refer all patients with anIOP between 26 and 30 mmHg regardless of theresults of the other tests.

As described in Table 31, only Boivin andcolleagues assessed cost-effectiveness based on acyclical screening mode (i.e. once every year, every3 years or every 5 years).280 The other studiesassumed that the screening was to be done onlyonce.281–283

Quality of included studiesAll studies were based on models, but nonespecified the type of model used. Two studies dealtwith cost-effectiveness of diagnosis and treatmentcombined280,282 and one study reported the resultsin terms of two different measures of cost-effectiveness as well as one measure ofcost–utility.281 The final study considered the costsand effects of diagnosis only (i.e. it excluded thecosts and effects consequent on diagnosis).283

None of the studies implicitly or explicitly justifiedthe screening strategies compared.

All the included studies derived their literature oneffectiveness from ad hoc searching, rather thanfrom a systematic review. The estimates ofeffectiveness of diagnostic and treatment measureswere arbitrarily determined in all four studies byassumptions made from data from previous studiesand on expert opinion. None of the studies clearlystated how they derived estimates of effectivenessfrom the included studies. Three studies clearlystated the sensitivities and specificities of thediagnostic tests used in their modelling,281–283

whereas one did not.280

The measures used to determine the effectivenessof the different strategies compared variedbetween studies. The measures included quality-adjusted years of vision (QAVYs) saved (withquality adjustment based on a subjectiveassessment of the number of years of vision thatsomeone would forgo to avoid the side-effects oftreatment),282 disability-adjusted life-years(DALYs),281 years of blindness prevented(although in the study by Boivin and colleagues itwas unclear how these were calculated: no valueswere reported, but number of years of blindnessappeared to be the same as the number of cases ofblindness avoided)280,281 and number of truepositives identified.281,283

All four studies reported detailed data on how thecosts were derived and the price year to whichcosts related (Table 32). One study reported costsin Canadian dollars,280 and two others reportedcosts in US dollars, one for the year 1980282 andone for 1995.283 The fourth study reported costsin 1995 UK pounds sterling.281 In the study byTuck and Crick costs were expressed in US dollarsbut were originally calculated in UK poundssterling and converted to US dollars using anexchange rate of £1 to US$1.55.283 Only Boivinand colleagues reported resource quantities andcosts separately.280

Although there were variations between thestudies, the type of resource use consideredrelevant to include in the costing was generallysimilar. However, none of the studies included thecosts of the organisation of the screeningprogramme such as personnel costs and costs forinviting the participants.

In the study by Gottlieb and colleagues, the costsfor diagnosis and treatment in this analysis wereestimated from the Massachusetts Blue Cross/BlueShields average daily hospital reimbursement ratesin Massachusetts in the year 1980.282 The averagecost of medications was estimated by doubling


99


Economic analysis

100 TA

BLE

32

Stud

y ch

arac

teris

tics

and

qual

ity

Stud

y an

d se

ttin

gPo

pula

tion

ass

esse

dYe

ar o

f cos

tsM

etho

d of

lite

ratu

re

Sour

ce o

f effe

ctiv

enes

s C

osts

incl

uded

in

Dis

coun

ting

Type

of

retr

ieva

lda

tath

e an

alys

isse

nsit

ivit

y an

alys

is

Got

tlieb

, 198

3282

1,00

0,00

019

80A

d ho

cA

vera

ge v

alue

s fr

om

Dia

gnos

tic,

Yes

One

-way

USA

Age

: 40–

79 y

ears

stud

ies

and

expe

rt o

pini

ontr

eatm

ent

and

5% p

er a

nnum

com

plic

atio

n of

tr

eatm

ent

cost

s

Boiv

in, 1

99628

02,

607,

210

Prof

essio

nal f

ees,

A

d ho

cA

vera

ge v

alue

s fr

om

Dia

gnos

tic,

Not

per

form

edO

ne-w

ayC

anad

aA

ge: 4

0–79

yea

rs19

94 p

rices

; dru

g st

udie

s an

d ex

pert

opi

nion

trea

tmen

t an

d pr

ices

,199

3; a

ids

soci

etal

cos

tsfo

r th

e bl

ind,

199

2;

disa

bilit

y pe

nsio

ns,

1993

Goo

der,

1995

281

100,

000

Age

: 19

95A

d ho

cA

vera

ge v

alue

s fr

om

Dia

gnos

tic c

osts

onl

yN

ot p

erfo

rmed

Non

eU

K�

40 y

ears

stud

ies

and

expe

rt o

pini

on

Tuck

, 199

7283

10,0

0019

95A

d ho

cA

vera

ge v

alue

s fr

om

Dia

gnos

tic c

osts

onl

yN

ot p

erfo

rmed

One

-way

UK

Age

: �40

yea

rsst

udie

s an

d ex

pert

opi

nion

their wholesale prices. The costs included those ofscreening tests, drugs, diagnostic evaluation,physician visits with and without treatment,surgery for glaucoma and surgery for cataracts as acomplication of glaucoma treatment. Indirectsocietal costs were not taken into account in theanalysis. The analysis by Boivin and colleaguesincluded costs for diagnostic tests and treatment(by both the clinician and optometrist), societalcosts for the blind in terms of aids (reading,writing and mobility) and disability pensions.280

The clinician costs were based on fees forprocedures performed in a private healthcaresetting. Societal costs for blindness were obtainedfrom the budgets for the ten rehabilitationagencies in the Quebec provinces and disabilitypension costs were obtained from the Régie desrentes du Quebec. The costs were not adjusted forinflation. Treatment costs were based on ahypothetical model of disease progression, whichwas based on data from selected studies. Gooderincluded the cost of standard optometrist cost foran eye test and assumed costs for the other testsperformed.281 The only other cost included wasthe cost of a first outpatient visit. Tuck and Crickassumed that the costs were based on screeningconducted as part of a general eye examination byan ophthalmologist or optometrist, usually inconjunction with prescribing lenses.283 The mainassumption was that the initial screening of 10,000people would be performed by a singleprofessional examiner over a 6-year period. Thecost analysis covered cost per hour of optometrist(including all overheads for premises, etc.), capitalcosts (tonometer and field screener) and cost ofsecondary examination at a clinic per patient visit(before diagnosis). The cost analysis only coveredthe costs of diagnosis and not the costs ofsubsequent treatment and monitoring. Theauthors of the economic analysis did not takeindirect (societal) costs into account.

Only two studies performed discounting,282,283

although it was relevant to all. In one study futurecosts were discounted at a rate of 5% perannum282 and in the other, reusable equipmentcosts were annualised using a 6% discountrate.282,283 Only one of the studies clearly statedthe time-horizon of the analysis.281

In all four studies the assessment of cost-effectiveness was presented from a governmentperspective. Two studies reported average cost per year of blindness avoided280,281 and one theaverage cost per true positive case found.281,283

Gottlieb and colleagues reported average andincremental cost per quality-adjusted year of

vision saved282 and Gooder reported incremental(versus current practice) cost per DALY saved.281

Three studies performed some form of sensitivityanalysis, although this was limited to simple one-way analysis (i.e. changing only one parameter ata time; such an approach ignores interactionsbetween different parameters).280,282,283 Sensitivityanalyses were performed around age, diseaseprevalence and treatment effectiveness rates. Thespecifics of the sensitivity analyses varied betweenstudies reflecting the different data, outcomemeasures and model structure used. For example,Gottlieb and colleagues assessed the impact ofvarying the prevalence of raised IOP, diseaseprogression, treatment effectiveness, variations insurgery refusal rate and proportion of patientscontrolled with primary medications or surgeryalone.282 In the study by Boivin and colleaguessensitivity analysis was performed with variationsin patient age range, frequency of screening, testsused, participation rate and the rate ofeffectiveness.280 Tuck and Crick, in their sensitivityanalysis, considered varying the prevalence ofprimary OAG, sensitivity values, predictive values,the costs of examination and the definition oftrue-positive cases.283

Summary of the results of the included studiesAs described above the included studies werebroadly similar with respect to population,screening and treatment costs and their results aresummarised in Tables 33–38 (and reported in moredetail in Appendix 20). Where necessary, theICERs presented in the tables were calculated, bythe reviewers, from data provided in the includedstudies. Nevertheless, data were not reported insufficient detail to reinterpret the results of thestudies in terms of a common outcome measure.

Tables 33 and 34 report the results of thecost–utility analysis conducted. Table 33 reports thefindings from Gottlieb and colleagues.282 In thistable the results are only presented for three of theseven age groups considered and all screeningstrategies that were dominated (i.e. less effectivethan less costly alternatives) have been omitted.Ophthalmoscopy was the least costly but leasteffective strategy for all age groups except for the70–74 year olds (Table 33). As the table shows, outof the seven strategies considered (see Table 31)only between three and four strategies were notdominated. The ordering of the interventionsvaried between age groups and this indicates thelikely importance of age on estimates of cost-effectiveness. It also indicates that the optimal


101


Economic analysis

102 TA

BLE

33

Incr

emen

tal c

ost

(IC)

per Q

AVY

save

d fro

m s

cree

ning

mod

el p

rodu

ced

by G

ottli

eb28

2a

Stra

tegy

Age

ran

ge

Tota

l cos

ts

QA

VY

Incr

emen

tal c

osts

R

elat

ive

Incr

emen

tal

Rel

ativ

e IC

ER

IC p

er

(yea

rs)

(198

0 U

S$)

(198

0 U

S$)

diffe

renc

e in

Q

AV

Ys

diffe

renc

e in

co

mpa

red

toQ

AV

Yco

st (

%)

effe

cts

(%)

Oph

thal

mos

copy

40–4

49.

3m

2,75

0To

nom

etry

>24

40–4

414

.4m

5,60

05.

1m

155

2,85

020

4O

phth

alm

osoc

opy

1,78

9To

nom

etry

>21

40–4

421

.0m

11,1

506.

6m

146

5,55

019

9To

nom

etry

>24

1,18

9O

phth

alm

osco

py60

–64

16.9

m15

,420

Glo

buck

fiel

ds60

–64

28.8

m18

,160

11.9

m17

02,

740

118

Oph

thal

mos

copy

4,34

3To

nom

etry

>21

60–6

439

.9m

24,8

0011

.1m

139

6,64

013

7G

lobu

ck fi

elds

1,67

2To

nom

etry

>24

75–7

923

.1m

10,1

20O

phth

alm

osco

py75

–79

26.1

m18

,680

3.0

m11

38,

560

185

Tono

met

ry >

2435

0G

lobu

ck fi

elds

75–7

938

.7m

21,2

3012

.6m

148

2,55

011

4O

phth

alm

osco

py4,

941

Gol

dman

n fie

lds

75–7

950

.1m

23,4

0011

.4m

129

2,17

011

0G

lobu

ck fi

elds

5,25

3

a A

ll co

sts

repo

rted

in 1

980

US

dolla

rs.

TA

BLE

34

Incr

emen

tal c

ost

per D

ALY

save

d fro

m s

cree

ning

mod

el p

rodu

ced

by G

oode

r281a

Stra

tegy

Tota

l cos

ts

DA

LYs

Incr

emen

tal c

osts

R

elat

ive

diffe

renc

e In

crem

enta

l R

elat

ive

diffe

renc

e IC

ER

IC p

er

(199

5 U

K£)

(199

5 U

K£)

in c

ost

(%)

DA

LYs

in e

ffect

s (%

)co

mpa

red

toD

ALY

Cur

rent

pra

ctic

e30

8,66

0b66

Tono

met

ry1,

905,

800

100

1,59

7,14

051

734

152

Cur

rent

pra

ctic

e46

,975

NC

T a

nd fi

elds

2,92

3,29

418

3.4

1,01

7,49

415

383

.418

3To

nom

etry

12

,200

aA

ll co

sts

repo

rted

in 1

995

UK

pou

nds

ster

ling.

b

Thi

s as

sum

es t

hat

oppo

rtun

istic

eye

tes

ts w

ould

not

be

disp

lace

d by

the

scr

eeni

ng s

trat

egy

as t

hey

are

cond

ucte

d fo

r ot

her

reas

ons,

but

tha

t co

sts

of r

efer

ral a

nd s

ubse

quen

ttr

eatm

ent

follo

win

g op

port

unist

ic c

ase

findi

ng a

re r

elev

ant

for

incl

usio

n.

choice of strategy might vary by age at screening.Gooder found that both screening strategiesconsidered were more effective but more costlythan current practice.281 However, screening withtonometry might not be considered cost-effectivewhile screening using NCT and fields might beconsidered worthwhile (the incremental cost perDALY saved compared with current practice wasestimated to be approximately £22,000).

The values reported for the cost–utility analysesare difficult to interpret because of the differentyears and countries to which the data relate as wellas differences in the technologies considered andoutcome measures used. Presenting the relativedifference in costs and effects provides morecomparative information. For example, in Gottlieband colleagues the cost of screening withtonometry with a threshold IOP of 24 mmHg is155% of the cost of ophthalmoscopy.282 Theseestimates put into context the increases in costsand effects that accrue from adopting a moreeffective but more costly screening strategy.

The results in terms of incremental cost per yearof blindness avoided are presented using the same approach as those described for thecost–utility analyses described above. Using thedata from Boivin and colleagues, the incrementalcosts per year of blindness were estimated(Table 35).280 With these data it is unclear whetherany of the more costly but effective strategies areworthwhile compared with the strategy oftonometry or tonometry and fundoscopy as initialtests followed by fundoscopy, gonioscopy andperimetry. The data from Gooder suggest lowerincremental costs per year of blindness avoided(Table 36),281 and indicate that screening is morelikely to be cost-effective compared with data fromBoivin and colleagues.280 However, the data aremore difficult to interpret because of thedifferences between the two studies, in terms ofcomparators, methods and source data. Withoutfurther information it is not possible todisentangle which factor or factors is mostimportant.

In terms of incremental cost per case detecteddata were available from two studies.281,283 Bothscreening strategies considered by Gooder wereconsiderably more effective than current practice,but also more costly (Table 37).281 Tonometry wasthe least effective and least costly of the two activestrategies considered, but as it was compared withthe relatively inexpensive current practice the costper case detected was relatively high. In contrast,the incremental cost per case detected for NCT

and field testing strategy compared withtonometry was relatively modest. The data fromTuck and Crick also suggest that tonometry wasthe least costly but also least effective screeningstrategy test (Table 38). This is because it wasassociated with a poor sensitivity (69% at an IOPcut-off of 20 mmHg).283 Screening strategiesinvolving ophthalmoscopy alone or incombination with either tonometry or perimetrywere dominated (i.e. less effective and more costly)and have not been included in Table 38, althoughthey are presented in Appendix 20. The use ofeither tonometry followed by perimetry orophthalmoscopy followed by tonometry andperimetry was more effective than tonometryalone. However, the cost rapidly increased and itwould require society to pay an additional US$18,500 per additional case detected associatedwith adopting a strategy of ophthalmoscopy,tonometry and perimetry for referral candidateswith lax referral criteria for further evaluationcompared with a screening strategy of perimetryalone.

DiscussionDespite an extensive systematic search of theliterature only four studies that assessed the cost-effectiveness of screening strategies for glaucomawere identified. The latest of the included studieswas published in 1997 and it analysed costs basedon 1995 prices.283 As a basis for decision-makingabout the desirability of adopting screening forOAG, our judgement is that this evidence base isinsufficient: the diagnostic tests and treatmentinterventions available for primary OAG havechanged since the identified studies wereconducted and the tests and treatmentinterventions used in routine clinical practice nowmay have different effects from those that wereassessed in the included studies. It is quitepossible that the cost-effectiveness of glaucomascreening, using currently available tests andtreatment options, may differ markedly from theestimates provided by the studies described in thisreview. Moreover, some of the screening tests usedin the studies, such as manual perimetrytechniques (HF, MPT and Globuck field tests), areno longer routinely used in clinical practice. Therehave been developments in diagnostic tests such asSAP, which is currently the choice for visual fieldtesting. Only Gottlieb and colleagues and Gooderincluded an automated perimetry test in theirassessment.281,282 New treatments are available,with the introduction of prostaglandin analogues,�2 agonists and topical carbonic anhydraseinhibitors. These were not treatments consideredin the reviewed studies.


103


Economic analysis

104 TA

BLE

35

Incr

emen

tal c

ost

per y

ear o

f blin

dnes

s av

oide

d fro

m s

cree

ning

mod

el p

rodu

ced

by B

oivin

and

col

leag

ues28

0a,b

Stra

tegy

In

itia

l Su

bseq

uent

Freq

uenc

yA

ge

Trea

tmen

t P

reva

lenc

e R

elat

ive

Tota

l cos

ts

Rel

ativ

e IC

ER

IC p

er y

ear

no.

test

(s)

test

s(y

ears

)ra

nge

effic

acy

redu

ctio

n di

ffere

nce

in

(Can

$)di

ffere

nce

in

com

pare

d to

of

blin

dnes

s (y

ears

)(%

)(n

o.

incr

emen

tal

incr

emen

tal

whi

ch

avoi

ded

of c

ases

)ef

fect

s (%

)co

st (

%)

stra

tegy

no.

?

1T

aF,

G, P

365

–79

5020

97,

763,

604

2T,

FG

, P3

65–7

950

287

137

12,5

74,6

2016

21

61,6

803

TF,

G, P

340

–79

5024

819

,154

,063

4T,

FG

, P5

40–7

950

354

143

28,6

79,5

2015

03

89,8

639

T, F

G, P

340

–79

7049

614

036

,385

,066

127

454

,264

aA

ll co

sts

repo

rted

in 1

994

Can

adia

n do

llars

.b

Base

d on

a c

ompl

ianc

e ra

te o

f 75%

and

a p

artic

ipat

ion

rate

of 7

5%.

F, fu

ndos

copy

; G, g

onio

scop

y; P,

per

imet

ry; T

, ton

omet

ry.

TA

BLE

36

Incr

emen

tal c

ost

per y

ear o

f blin

dnes

s av

oide

d fro

m s

cree

ning

mod

el p

rodu

ced

by G

oode

r281a

Stra

tegy

Tota

l cos

ts

Year

s of

In

crem

enta

l R

elat

ive

Incr

emen

tal y

ears

R

elat

ive

ICER

IC

per

yea

r of

(£

)bl

indn

ess

cost

s (£

)di

ffere

nce

in

of b

lindn

ess

diffe

renc

e in

co

mpa

red

tobl

indn

ess

avoi

ded

cost

(%

)av

oide

def

fect

s (%

)av

oide

d

Cur

rent

pra

ctic

e30

8,66

0b16

5To

nom

etry

1,90

5,80

025

01,

597,

140

517

3415

2C

urre

nt p

ract

ice

18,7

90N

CT

and

fiel

ds2,

923,

294

458.

51,

017,

494

153

117.

618

3To

nom

etry

4,

880

aA

ll co

sts

repo

rted

in 1

995

UK

pou

nds

ster

ling.

bT

his

assu

mes

tha

t op

port

unist

ic e

ye t

ests

wou

ld n

ot b

e di

spla

ced

by t

he s

cree

ning

str

ateg

y as

the

y ar

e co

nduc

ted

for

othe

r re

ason

s, b

ut t

hat

cost

s of

ref

erra

l and

sub

sequ

ent

trea

tmen

t fo

llow

ing

oppo

rtun

istic

cas

e fin

ding

are

rel

evan

t fo

r in

clus

ion.


105


A further limitation of the four studies is that onlyone included a ‘no-screening’ strategy.281

Unfortunately, the method of assembling data foruse in this economic evaluation was flawed as itwas not based on any systematic assembly andrelied on indirect comparisons. Therefore, none ofthe studies was able reliably to address thequestion as to whether any form of screeningwould be worthwhile.

It is also important to be aware of themethodological limitations of the included studies.First, it is unclear whether the studies used thebest available evidence for the diagnosticperformance of the tests and the effectiveness oftreatments. The methods used to derive estimatesof sensitivity and specificity of screening tests aswell as the effectiveness of treatment interventionsused in the economic model were poor. They werebased on ad hoc searching, rather than on asystematic review. Such an approach has beenrecognised to be subjective and therefore prone tobias and error.284 Hence, it is possible that theselection of evidence in the included studies mayhave been biased. This is a weakness observed ineconomic evaluations of other treatmentconditions.285 Furthermore, all the studiesconsidered different measures of effectiveness for the cost-effectiveness analysis. Again, thismakes it difficult to draw comparisons betweenstudies.

Two of the studies considered screening incountries other than the UK and differences inreimbursement strategies and costs complicate theinterpretation from a UK perspective.280,282

Current UK prices are markedly different from theprices quoted in the two included UK studies.While all four studies explained in detail how thecosts for the different strategies were derived, onlyone study presented resource use and costsseparately.280 This makes it difficult to judgewhether these data are applicable to the UK. Onlyone study considered a cyclical screening strategy(i.e. once every 3 years, etc.),280 and the failure ofthe others to consider such an approach isunrealistic as the incidence of glaucoma increaseswith age (see Chapter 5).

The effectiveness of screening is not justdependent on the sensitivity and specificity of thetest used. It also depends on a range of otherparameters, such as acceptance of screening,treatment efficacy rate and compliance. A varietyof different values was used across the studies andthese values were either implicit (e.g. assuming100% compliance with treatment) or explicit (e.g.

Boivin and colleagues assumed a 75% compliancerate with treatment).280

The uncertainty surrounding estimates of cost-effectiveness was also very poorly addressed by allfour studies. The simple one-way sensitivityanalysis used in three studies is unlikely to havefully explored the full extent of the uncertaintypresent in each evaluation.280,282,283

ConclusionsVery few economic evaluations comparingalternative screening strategies (including noscreening) for OAG are available. Those studiesthat were identified suffered from numerousweaknesses that would limit their usefulness fordecision-making in the UK at this time.Furthermore, the differences between the studiesin terms of tests, populations, assumedeffectiveness of tests and treatment as well as costsmakes it difficult to disentangle which factors arethe key determinants of cost-effectiveness. On thebasis of the data summarised in this review there isan insufficient evidence base for judging whetherscreening for OAG should take place, and if itshould take place, how it should be performed.These findings confirm that further research isrequired on the cost-effectiveness of alternativescreening strategies and such work should bebased on the systematic consideration of theevidence on acceptability, effectiveness and cost ofalternative screening strategies relevant to currentpractice. This evaluation is described in the nextsection.

Economic evaluation of screeningfor OAGThe cost-effectiveness of screening for OAG wasassessed using a Markov model. The structure ofthe model was described in the section ‘Economicmodel’ (p. 15). The interventions compared withinthe model are first briefly described, before themethods used to obtain the necessary data topopulate the model are presented. The methodsused to present estimates of cost-effectiveness forthe base-case analysis and the key areas ofuncertainty addressed by sensitivity analysis on thebase case are then described. Further sensitivityanalysis focused on situations where it is believedscreening may possibly be cost-effective is nextdescribed. The following two subsections reportthe results of the base case and its associatedsensitivity analysis, as well as the results of thefurther focused sensitivity analyses. Finally, theimplications of these results are discussed.

Economic analysis

106 TA

BLE

37

Incr

emen

tal c

ost

per c

ase

dete

cted

from

scr

eeni

ng m

odel

pro

duce

d by

Goo

der28

1a

Stra

tegy

Tota

l cos

ts

Cas

es d

etec

ted

Incr

emen

tal c

osts

R

elat

ive

Incr

emen

tal

Rel

ativ

e di

ffere

nce

ICER

IC

per

cas

e (1

995

UK

£)(1

995

UK

£)di

ffere

nce

case

s in

effe

cts

(%)

com

pare

d to

dete

cted

in c

ost

(%)

dete

cted

Cur

rent

pra

ctic

e30

8,66

0b33

0To

nom

etry

1,90

5,80

050

01,

597,

140

517

170

152

Cur

rent

pra

ctic

e9,

395

NC

T a

nd fi

elds

2,92

3,29

491

71,

017,

494

153

417

183

Tono

met

ry

2,44

0

aA

ll co

sts

repo

rted

in 1

995

UK

pou

nds

ster

ling.

b T

his

assu

mes

tha

t op

port

unist

ic e

ye t

ests

wou

ld n

ot b

e di

spla

ced

by t

he s

cree

ning

str

ateg

y as

the

y ar

e co

nduc

ted

for

othe

r re

ason

s, b

ut t

hat

cost

s of

ref

erra

l and

sub

sequ

ent

trea

tmen

t fo

llow

ing

oppo

rtun

istic

cas

e fin

ding

are

rel

evan

t fo

r in

clus

ion.

TA

BLE

38

Incr

emen

tal c

ost

per c

ase

dete

cted

from

the

scr

eeni

ng m

odel

pro

duce

d by

Tuc

k an

d Cr

ick28

3a

Stra

tegy

Scre

enin

g st

rate

gies

True

In

crem

enta

l R

elat

ive

Tota

l In

crem

enta

l R

elat

ive

ICER

com

pare

d IC

per

cas

e no

.po

siti

ves

case

s di

ffere

nce

cost

s co

sts

diffe

renc

e in

to

str

ateg

y de

tect

ed

dete

cted

in e

ffect

s ($

)($

)co

st (

%)

no.

(%)

1To

nom

etry

and

per

imet

ry if

IOP

> 2

0 m

mH

g40

30,4

002

Tono

met

ry a

nd p

erim

etry

if IO

P >

22

mm

Hg

477

118

35,9

085,

508

118

178

73

Tono

met

ry a

t th

resh

olds

of I

OP

> 2

2 m

mH

g49

210

443

,806

7,89

812

22

3,94

95

Perim

etry

556

112

57,9

7014

,164

132

32,

361

8O

phth

alm

osco

py a

nd t

onom

etry

follo

wed

by

561

102

76,5

5218

,582

132

518

,582

perim

etry

for

‘refe

rral

’ can

dida

tes

(lx)

11O

phth

alm

osco

py a

nd t

onom

etry

follo

wed

by

perim

etry

for

‘hig

h-ris

k’ c

andi

date

s (s

v)67

1112

082

,678

6,12

610

88

557

13O

phth

alm

osco

py a

nd t

onom

etry

follo

wed

by

perim

etry

for

‘hig

h-ris

k’ c

andi

date

s (lx

)70

310

495

,060

12,3

8211

511

4,12

715

Oph

thal

mos

copy

and

ton

omet

ry a

nd

perim

etry

(sv)

733

104

103,

514

8,45

410

913

2,81

716

Oph

thal

mos

copy

and

ton

omet

ry a

nd

perim

etry

(lx)

807

110

117,

520

14,0

0611

415

2,00

1

aA

ll co

sts

repo

rted

in 1

995

US

dolla

rs.

Interventions considered within themodelScreening and diagnostic interventionsThe screening and diagnostic interventions aredescribed in detail elsewhere (see the section‘Economic model’, p. 15). In brief, three strategieshave been considered: one representing currentpractice and the two alternative screeningstrategies (see Figures 5–7, pp. 14–15). Currentpractice reflects current glaucoma detection bycase finding by a community optometrist as partof a routine eye test. The two alternative screeningstrategies vary in how screening would beorganised. In one strategy individuals are invitedfor a screening examination by a glaucoma-trainedoptometrist. In the second strategy individuals areinvited for a simple test assessing either visualfield loss or structural damage, together with ameasurement of the IOP by a technician.Individuals identified as at risk or positive by thesetechnician tests would then be seen by a glaucomaoptometrist. In all three strategies any individualidentified as positive at the end of screening orcase finding would be referred to anophthalmologist for definitive diagnosis and, ifnecessary, treatment.

With respect to the actual test used in the variousstrategies it was concluded that for the purposes ofthe economic evaluation the IOP test used by thetechnician is Goldmann applanation tonometrywith disposable tips and a slit-lamp microscope.For the second assessment within the ‘technicianscreening’ strategy, there is a number of possiblescreening tests available; details of the tests andtheir performance are described in Chapters 3and 6. The model included a range of sensitivityand specificity values, rather than modelling theperformance of one test or combination of tests asnone of the candidate tests, or combinations oftests was clearly superior (Chapter 6).

The glaucoma optometrist assessment wasassumed to be the same test combination asophthalmologist diagnosis. This diagnostic test is a combination of IOP measurement by GAT, slit-lamp examination, fundoscopy and a visualfield test.

Management of glaucomaShould the ophthalmologist diagnose OAG, it hasbeen assumed that treatment would be initiated.The following treatment pathway has beenassumed in the model. Initial medical treatmentwould be with a topical treatment �-blocker orprostaglandin analogue). If that failed, this wouldbe followed by an additional drop of another class

of medications. For those patients for whom thisfails, argon laser trabeculoplasty (ALT) or surgery(trabeculectomy) is the next treatment step. Inaddition to medications, treatment would involvevisits to the ophthalmologist every 6 weeks at thebeginning of treatment and a full assessment every6 months. After surgery the patient would be seenat an ophthalmology outpatient clinic at 1, 2, 4, 8,12 and 26 weeks after surgery.

Parameter estimates used in the modelParameter estimates required to populate themodel were obtained from the systematic reviewsof test accuracy, OAG epidemiology, treatmenteffectiveness and cost-effectiveness, as well as othersystematic, focused searches of the literature. Thefollowing sections give details on the probabilities,costs and utility data used, as well as the probabilitydistributions adopted within the model.

ProbabilitiesTable 39 shows data on prevalence, incidence andprogression of glaucoma used in the model.Within the model, prevalence was not formallybased on data from the literature, as there weremany different subgroups for which screeningcould be determined. The model was run for arange of prevalence values, informed by thereview, aiming to identify those prevalences wherescreening strategies might be consideredworthwhile. Once these were determined theywere related to relevant subgroups to which theresults might apply.

The proportion of OAG subjects with each severityof disease was informed by the systematic review ofepidemiology (see Table 10, p. 32, for details).However, data were limited, as the majority ofstudies reporting severity did not report severitystatus for newly detected cases, and for themajority of participants severity status was notreported. Estimation was therefore based onexpert opinion from ophthalmologists (RW, AABand JB), and the included studies informed thedistribution around these estimates. Limited datawere obtained for incidence and progression ofglaucoma. Incidence data were obtained asdescribed in Chapter 5. Progression data, as wellas the relative rate of progression between treatedand untreated individuals, were based on a reviewof randomised and non-randomised evidencereported in Chapter 7. For the probabilisticsensitivity analysis triangular distributions werechosen for incidence and progression, and a log-normal distribution for the relative risk ofprogression for treated compared with untreatedindividuals.


107


The annual probabilities of having an eye test arepresented in Table 40. Data on these were scarce. Itis plausible, for instance, that the annualprobabilities of having an eye test differ between ageneral population and an OAG population, orbetween the same population in a screening ornon-screening strategy. Moreover, theseprobabilities might also depend on the periodbetween screening waves. The model structureallowed the incorporation of such differences.Unfortunately, data were not available at the levelof detail required. Data on eye test, gender andage were obtained from the British HouseholdPanel Survey (BHPS).286 The total sample size forthe BHPS was approximately 10,000 householdsfrom across the UK. Individuals in the includedhouseholds are interviewed yearly. A probitregression model was used to obtain theprobabilities of having an eye test. Alternative datawere retrieved from the Sight Test Volume andWorkforce Survey 2003/04 (STV&WS) and other

published studies.47,113 The results of theregression analysis of the BHPS data, consistentwith the STV&WS and published studies, wereused in the model for the probability of having aneye test (by a community optometrist) in thecurrent practice strategy. Normal probabilitydistributions were attached to the mean values forprobabilistic analysis. Screening acceptance datawere obtained from the epidemiology review(Chapter 5). Triangular distribution was attachedto this parameter with upper and lower limitsobtained from Hollows and Graham21 and Wolfsand colleagues,169 respectively.

Table 41 shows data on test performances. Sevenreports provided information on the accuracy ofreferrals by community-based optometrists forpeople with suspected glaucoma.287–293 However,no studies were identified that reported thediagnostic accuracy of the test strategy ofcommunity optometrists or glaucoma-trained

Economic analysis

108

TABLE 39 Prevalence, incidence and progression of glaucoma

Probability Value Source Distribution (values used todefine the distribution)

Cohort start age 40 Base-case assumption 60 and 75 years oldPrevalence of glaucoma 0 to 0.2Proportion of glaucoma mild 0.50 Expert opinion/Chapter 5 0.475 and 0.45 for 60 and 75 years

old, respectivelyProportion of glaucoma moderate 0.30 Expert opinion/Chapter 5Proportion of glaucoma severe 0.15 Expert opinion/Chapter 5Proportion of visual impaired 0.05 Expert opinion/Chapter 5 0.075 and 0.10 for 60 and 75 years

old, respectivelyIncidence of glaucoma Chapter 540 years old 0.0003 Chapter 5 Triangular (min. = 0.0001,

likeliest = 0.0003, max. = 0.0008)50 years old 0.0003 Chapter 5 Triangular (min. = 0.0001,



likeliest = 0.00181, max. =0.0044)

80 years old 0.00141 Chapter 5 Triangular (min. = 0.00097, likeliest = 0.00141, max. = 0.01)

Progression to glaucoma moderate 0.25 ‘Probability of glaucoma Triangular (min. = 0.125, deterioration from mild disease likeliest = 0.25, max. = 0.75)to visual impairment’ (p. 89)

Progression to glaucoma severe 0.11 ‘Probability of glaucoma Triangular (min. = 0.055, deterioration from mild disease to likeliest = 0.11, max. = 0.33)visual impairment’ (p. 89)

Progression to visual impaired 0.1 ‘Probability of glaucoma Triangular (min. = 0.05, deterioration from mild disease to likeliest = 0.1, max. = 0.30)visual impairment’ (p. 89)

RR treated–non-treated 0.65 ‘Effectiveness of glaucoma Log-normal, (mean = –0.43, treatment’ (p. 87) SD = 0.148)

Mortality Various See Appendix 21 for interim life table

optometrists, or included sufficient data toproduce a 2 × 2 table to calculate sensitivity andspecificity. Sensitivity and specificity foroptometrist testing were derived from Tuck.293

This study reported a survey conducted on behalfof the IGA involving 241 optometrists in Englandand Wales who, mainly commencing betweenNovember 1988 and February 1989, carried out275,600 sight tests over a 6-month period(equivalent to 5% of the national total). Theoptometrists referred 1505 patients for suspectedOAG. A diagnosis was confirmed and known for1048, of whom 436 (41.6%) had a diagnosis of

OAG confirmed by a consultant ophthalmologist.This allowed the calculation of true positives (n = 436), false positives (n = 612), total testingpositive (n = 1048) and total testing negative (n = 274,552). As those testing negative did notreceive confirmation of this by way of examinationby a consultant ophthalmologist, there was noinformation on those who tested negative butactually had glaucoma (false negatives) or indeeddid not have OAG (true negatives). Of the threestudies considered, this one was the mostappropriate (in terms of geographical coverage,number of patients seen and number of


109


TABLE 40 Probabilities of having an eye test in current practice and screening acceptance for screening strategies

Age group (years) Value Source Distribution (values used to define thedistribution)

40–59 0.248 Regression analysis on BHPS data Normal, (mean 0.248, SE 0.0019142)

60–75 0.3769 Regression analysis on BHPS data Normal (mean 0.3769, SE 0.0046524)

�75 0.42 Regression analysis on BHPS data Normal (mean 0.42, SE 0.0051359)

Screening acceptance; all groups 0.78 Epidemiology review. Range: min. Triangular (min. = 0.66, likeliest = 0.78,

from Wolfs 1999169 (Rotterdam max. = 0.918)Study); Max from Hollows 196621

(Rhondda Valley Study)

TABLE 41 Data on tests and test performance

Probability Value Source Distribution (values used todefine the distribution)

Optometrist test sensitivity 0.32 Tuck, 1991293 Beta (n = 1378, r = 436)

Optometrist test specificity 0.99 Tuck, 1991293 Beta (n = 274,228, r = 273,614)

Glaucoma optometrist test sensitivity 0.73 Grampian optometry study Beta (n = 33, r = 24)(Burr J: personal communication)

Glaucoma optometrist test specificity 0.96 Grampian optometry study Beta (n = 67, r = 64)(Burr J: personal communication)

Proportion of normal with IOP < 26 0.96 Sommer, 199123 (Baltimore Eye Beta (n = 5682, r = 5455)Survey, see Chapter 5)

Proportion of glaucoma with IOP � 26 0.35 Sommer, 199123 (Baltimore Eye Beta (n = 20, r = 7)Survey, see Chapter 5)

Technician further test indeterminacy 0.1 Systematic review data, Uniform (0.06–0.20)diagnostic (Chapter 6)

Technician further test sensitivity 0.8 Assumption Uniform (0.8–1)

Technician further test specificity 0.8 Assumption Uniform (0.8–1)

Ophthalmologist test sensitivity 1 Assumption None defined

Ophthalmologist test specificity 1 Assumption None defined

Ophthalmologist proportion diagnosed 0.43 Henson. Manchester Glaucoma Uniform (0.39–0.47)as ‘observation’ state Optometry scheme 2005 data

(Henson D, Aberdeen: personal communication, 2006)

participating optometrists) for estimating OAGprevalence and hence arriving at anapproximation of sensitivity and specificity. A 0.5%prevalence of undetected glaucoma was assumed(1378 patients out of the total of 275,600 seen).This allowed the calculation of false negatives (n = 942) and true negatives (n = 273,610) tocomplete a 2 x 2 table and provide an estimatedsensitivity and specificity for community-basedoptometrist referrals for OAG glaucoma of 31.6%and 99.8%, respectively.

To estimate the diagnostic accuracy of glaucoma-trained optometrists, data were used from a studyin Grampian evaluating a pilot communityoptometry glaucoma service, the GrampianOptometrist Study. The purpose of this study wasto assess the diagnostic accuracy of themanagement decision made by accreditedglaucoma optometrists. The optometrist decisionwas compared with two reference standards: anophthalmologist with a special interest in glaucoma,and management decision made in usual care inthe hospital-based new patient clinic. The studywas completed in January 2006 and a publicationis in preparation (Burr JM, Azuara-Blanco A,Thomas R, McLennan G, University of Aberdeen:personal communication, 2006). For the purposeof this analysis, disease was classified as OAG orocular hypertension requiring treatment. Thecategories normal and discharged, and suspectrequiring optometric review were classified as nodisease. The consultant ophthalmologist with aspecial interest in glaucoma was the referencestandard. The sensitivity of the glaucomaoptometrist was 0.73 (95% CI 0.56 to 0.85), with aspecificity of 0.96 (95% CI 0.88 to 0.99).

Data from the Baltimore Eye Survey were used forthe estimation of the proportion of normal orOAG patients with IOP of at least 26 mmHg.23

Details of this study can be found in Chapter 5.Estimation of the proportion of people able toperform the test (rate of indeterminancy) as partof the ‘technician’ screening strategy was obtainedfrom the systematic review of screening tests (seeChapter 6). In summary, for the tests thepercentage of interpretable results ranged from80% for RNFL photography to 99% for SAP(threshold) and GAT, with a median rate across alltests of 97%. The number of studies contributingdata for each test was very small, although therates were very similar across tests.

The model used sensitivity and specificity valuesfor the technician tests equal to or greater than0.8. For the ophthalmologist assessment an

assumption was made that this was the goldstandard and that the sensitivity and specificitywere equal to 1.

Beta distributions were used in the probabilisticsensitivity analysis for the accuracy of theoptometrist in the current practice case-findingstrategy, and for the glaucoma optometrist testsensitivities and specificities. Beta distributionswere also used for the proportion of OAGindividuals with IOP of at least 26 mmHg andproportion of normal individuals with IOP below26 mmHg. Uniform distributions were used fortechnician further test indeterminacy, and forsensitivity and specificity. Finally, a uniformdistribution was assumed for the proportion ofpeople classified as glaucoma suspects(observation state) following diagnostic assessmentby an ophthalmologist.

CostsTables 42 and 43 show the cost estimates used in themodel. All figures are reported in 2006 poundssterling. Where costs had to be adjusted into acommon price year, a 2% inflation rate wasassumed where no inflation rate indices wereavailable. Table 42 shows the costs for the currentoptometrist case-finding strategy. The cost for theoptometrist test was obtained from the NHS fee foran eye test paid to an optometrist.294 A triangulardistribution was assumed for this variable. Noinformation on ranges was available, and as aconsequence rates of 0.5 and 1.5 times the likeliestvalue were used as lower and upper limits. The costfor the ophthalmologist diagnosis was calculatedusing data from Scottish National Statistics for April2004 to March 2005 (source: www.isdscotland.org).The average reported cost for an ophthalmologistoutpatient visit was £65. This value was inflated bythe assumed 2% inflation rate for 2005/06. It wasalso assumed, based on the likely need for visualfield testing to be performed as an additionaloutpatient visit, that the ophthalmological diagnosiswould be equivalent to the cost of two standardophthalmology department outpatientconsultations. A triangular distribution was assumed for this parameter. The minimum andmaximum limits values were developed in the same way as the likeliest mean value, but with theScottish NHS Board lowest and highest averagecost for an ophthalmologist outpatient visit (i.e. £38 and £195, respectively). This cost was also used for cost of the observation state within the model where it was assumed that patientsjudged to be at risk would be seen yearly for amaximum of 5 years in this state or until OAG wasdiagnosed.

Economic analysis

110

Costs of treatment were calculated from Traversoand colleagues.259 This is a Europe-based studyand includes data for the UK by severity ofglaucoma. In this study, the authors obtainedrecords for 194 patients. Unfortunately, thesample sizes per country were not reported andthe figures might be subject to ‘small numbers’bias. The study reported costs in euros. The priceyear used was not reported in the study so it wasassumed to be 2004. Costs in the common priceyear were estimated using the average 2004exchange rate from euros into pounds sterling(e.g. 0.6787; source: http://www.oanda.com/convert/fxhistory), and a 2% annual inflation ratewas assumed. Triangular distributions wereattached to treatment costs. No additional datawere available to allow for construction of a range, so the assumption of 0.5 and 1.5 times thelikeliest value was applied. The exception to thiswas the annual cost for visual impairment. Thelikeliest value for the cost of visual impairmentused in this model was based on the mean value of

the last two disease stages reported in Traversoand colleagues, as these corresponded to thevisual impairment category used in this study. Atriangular distribution was assumed for this cost,with the minimum value being equal to the meanvalue of the less costly of the last two diseasestages from Traverso and the maximum beingequal to the mean value of the more costly ofthese stages.

Table 43 shows costs used for the screeningstrategies. Screening invitation costs were obtainedfrom Facey and colleagues.295 This was a study onthe organisation of the diabetic retinopathyscreening programme for Scotland. These figuresinclude the cost for national coordination, localhealth board coordination, screening offices andcall and recall operation, development andmaintenance of call and recall software, anddevelopment and maintenance of image capturesoftware. It also assumed around 125,000 peopleare screened. New NHS fees for optometrists in


111


TABLE 42 Current practice costs

Costs Value (£) Source Distribution (values used to define thedistribution)

Optometrist test 18.39 Department of Health294 Triangular (min. = 9.20, likeliest = 18.39, max. = 27.59)

Ophthalmologist diagnosis tests 133 Scotland National Statisticsa Triangular (min. = 77, likeliest = 133, max. = 397)

Glaucoma mild treatment 420 Traverso, 2005259 Triangular (min. = 210, likeliest = 420, max. = 630)

Glaucoma moderate treatment 473 Traverso, 2005259 Triangular (min. = 236.5, likeliest = 473, max. = 709.5)

Glaucoma severe treatment 376 Traverso, 2005259 Triangular (min. = 188, likeliest = 376, max. = 564)

Visual impairment annual cost 669 Traverso, 2005259 Triangular (min. = 585.41, likeliest = 669, max. = 752.06)

a Source: ISD Scotland (www.isdscotland.org).

TABLE 43 Screening strategy costs

Costs Value (£) Source Distribution (values used todefine the distribution)

Screening invitation 10.45 NHS Quality Improvement Scotland295 Triangular (min. = 5.23, likeliest = 10.45, max. = 15.68)

Glaucoma optometrist test 46.50 Scottish Executive296 Triangular (min. = 23.25, likeliest = 46.50, max. = 69.75)

Technician IOP tests 10.63 NHS Quality Improvement Scotland295 Triangular (min. = 5.32, likeliest = 10.63, max. = 15.95)

Technician second test 10.63 NHS Quality Improvement Scotland295 Triangular (min. = 5.32, likeliest = 10.63, max. = 15.95)

Scotland were used for glaucoma optometristassessment.296 The new Scottish eye examinationwould include a full examination of the eye, visualfield and IOP (e.g. with NCT), and supplementaryexams if clinically indicated (e.g. applanationpressures and threshold fields). For the technicianscreening strategy, the technician IOP test andsecond round test costs were obtained from theScottish Diabetic Retinopathy Screening study.295

The costs were based on the variable costs for non-mydriatic camera, hospital-based, one technicalstaff screening estimated by this study. Triangulardistributions were attached to the costs in Table 43with the assumption of 0.5 and 1.5 times thelikeliest value used to estimate minimum andmaximum values.

Data for treatment costs and ophthalmologistdiagnosis were the same as in the no-screeningstrategy.

Health state utilitiesThe primary purpose of the economic model wasto inform decision making in a UK setting. Recentguidance suggests that estimates of QALYs shouldideally be based on generic health state valuationmethods using UK population values,297 andtherefore a focused search of the literature andother relevant sources such as the Harvardcost–utility database for relevant utility data wasconducted. A number of studies reporting healthstate utilities was identified. These studies used awide variety of health state valuation techniquesand utilities were obtained from a variety ofdifferent settings and respondents. However, noneof these studies reported utilities applicable to aUK decision-making setting.

For this reason the results of an ongoing studywere used to provide relevant utility estimates.This study is attempting to develop a glaucoma-specific measure of quality of life suitable for usein economic evaluations. The study involved theadministration of a participant self-completedquestionnaire to people with glaucoma attending

the ophthalmology outpatient departments ofAberdeen Royal Infirmary and the United LeedsTeaching Hospital Trust (Leeds General Infirmary,St James’ Hospital and St George’s CommunityEye Centre). UK members of the IGA alsoparticipated. All participants were asked tocomplete a questionnaire that includedinformation on self-rating of glaucoma severity(mild, moderate or severe), a discrete choiceexperiment and the EuroQol 5 Dimensions (EQ-5D). A subsample of patients from Aberdeenunderwent an objective assessment of glaucomaseverity. This was by a grading of the binocularvisual field using the integrated visual fieldmethod as described by Crabb and colleagues (seeTable 1, p. 17).89 The responses to the EQ-5D wereconverted to health state utilities using UKpopulation tariffs and analysed according to theobjective and subjective assessment of glaucomaseverity (Kilonzo M, University of Aberdeen:personal communication, 2006). Table 44 showsthe estimates of utility for those people with anobjective assessment of their glaucoma severity.Although these data are based on a subsamplethey were chosen from the larger sample availablefrom the two hospitals and the IGA owing to therelatively poor concordance between objective andsubjective assessments of glaucoma severity(Appendix 22). Nevertheless, due to theuncertainty surrounding which data to use, theestimates provided by the whole data set (reportedin Appendix 22) have been used as part of asensitivity analysis.

The estimates used in the model, using these data,are detailed in Table 45. A value of 1 was assumedfor normal and observation states, while thecorresponding mean values of Table 44 were usedas utility weights for OAG states mild, moderateand severe. The visual impaired utility state wasdeveloped using data from Table 44 and fromGupta and colleagues.298 This study presentedutility values for categories that matched glaucomasevere and visual impaired states in the presentstudy. Then, the relative difference between these

Economic analysis

112

TABLE 44 Estimated health state utilities for the different levels of severity

Value Mild severity Moderate severity Severe severity(n = 37) (n = 14) (n = 9)

Mean 0.8015 0.7471 0.7133Median 0.7960 0.7435 0.7960SD 0.1254 0.1881 0.2549Minimum 0.29 0.20 0.09Maximum 0.92 0.90 0.92

two glaucoma states from Gupta and colleagueswas used to obtain the utility score for visualimpaired in Table 45. Beta distributions wereattached to these glaucoma utility weightparameters (Table 45). It was assumed that therewere no differences in the utility betweenundiagnosed OAG and treated OAG at each levelof severity.

Base-case and sensitivity analysisBase-case analysisThe base-case analysis was run for a cohort of 40-,60- and 75-year-old males with screeningoccurring every 3 years. The choice of these agesand a 3-year screening interval was arbitrary. Itwas felt that the age groups covered the rangeover which screening might be considered and a3-year screening interval was considered aplausible starting point for the analysis (theimpact of using other screening intervals wasconsidered). Gender-specific variables were notavailable for any of the model parameters exceptfor mortality, and a decision was made to use malemortality rates in the base-case analysis, consistentwith good modelling practice, as they are aconservative assumption for screening.

The model was run for a range of possible OAGprevalence values and for a lifetime horizon.Cycles length was set at 1 year. Costs are presentedin 2006 pounds sterling and effectiveness inQALYs. A discount rate of 3.5% for costs andbenefits was used following guidelines fortechnology assessment by the National Institutefor Health and Clinical Excellence (NICE).297

Results are presented in ICERs. This measure is aratio of the difference in costs divided by thedifference in the effectiveness between twoalternative strategies. These data can beinterpreted as how much society would have to

pay for an extra unit of effectiveness. Probabilisticanalysis results are presented for society’swillingness to pay values of £10,000, £20,000,£30,000 and £50,000. Cost-effectivenessacceptability curves (CEACs) for these analyses arepresented in Appendix 23. These plot theprobability of each strategy being the optimaldecision against a range of values for society’swillingness to pay for an extra unit ofeffectiveness. Central to the assessment of cost-effectiveness is the value that society wouldput on gaining an additional QALY. NICE states that “Below a most plausible ICER of£20,000 per QALY, judgements about theacceptability of a technology as an effective use of NHS resources are based primarily on the cost-effectiveness estimate. Above a mostplausible ICER of £20,000 per QALY, judgementsabout the acceptability of the technology as an effective use of NHS resources are more likelyto make more explicit reference to factorsincluding:

● the degree of uncertainty surrounding thecalculation of ICERs;

● the innovative nature of the technology;● the particular features of the condition and

population receiving the technology; and● where appropriate, the wider societal costs and

benefits.

Above an ICER of £30,000 per QALY, the case for supporting the technology on these factors has to be increasingly strong.”297(p. 33). In theabsence of a more definitive statement this reportfocuses on a willingness to pay of £30,000 for aQALY.

The main results of the base-case analysis arepresented in the section ‘Results of base-case


113


TABLE 45 Health state utility estimates used in the model

Quality of life Utility weight Source Distribution (values used to definethe distribution)

Normal 1 Assumption None

Glaucoma mild 0.8015 (Kilonzo M, University of Aberdeen: Beta (alpha = 8.2, beta = 2)personal communication, 2006)

Glaucoma moderate 0.7471 (Kilonzo M, University of Aberdeen: Beta (alpha = 11.4, beta = 3.5)personal communication, 2006)

Glaucoma severe 0.7133 (Kilonzo M, University of Aberdeen: Beta (alpha = 1.2, beta = 0.4)personal communication, 2006)

Visually impaired 0.5350 Developed using data from Gupta, Log-normal (u = –0.31029, 2005298 sigma = 0.16631)

analysis and sensitivity analysis on the base-case’(p. 115). Full probabilistic analyses were carriedout for the three cohort groups and rates of OAGprevalence from 0.1% and 20%.

Sensitivity analysisSensitivity analysis was carried out to exploreuncertainties within the model. As describedbelow, deterministic (one-way, two-way andmultiway) sensitivity analyses were carried out forthe main parameters within the model.Probabilistic sensitivity analyses were developed toaddress further parameter uncertainty in themodel.

Changes to the screening intervalThe effects of longer screening intervals (e.g. 5 and 10 years) were explored using one-waysensitivity analysis, as well as part of theprobabilistic sensitivity analysis.

Changes to the probability of having an eye testDeterministic analyses were conducted for theprobability of having an eye test with a community optometrist assuming low, mediumand high uptake rates. These were defined as an annual probability of an eye test of 2%, 13%and 37%. The rationale for these figures was based on discussion among the members of thestudy steering group. It was agreed that it waslikely that a part of the population would havelower utilisation (caused by either lower access or the exercise of choice) to a communityoptometrist test. Moreover, some people may have almost no access to these services. The values adopted would give approximately 10%,50% and 90% of the cohort receiving an eye test in the community setting over a 5-year period.

Changes to the sensitivity and specificity of thetechnician testsIn the base-case analysis it was assumed that thesensitivity and specificity of this test was 0.8 and0.8. In this sensitivity analysis the sensitivity andspecificity were varied between plausible ranges of0.5 to 1.0 for sensitivity and 0.8 to 1.0 forspecificity.

Further targeted sensitivity analyses forpotentially cost-effective scenariosFurther sensitivity analyses were carried out forthe combinations of the cohort, prevalence rateand screening interval that seemed to be mostlikely to be cost-effective. Specifically, the following sensitivity analyses were conducted forthe 40-year-old cohort, at a 5% (except where

otherwise stated) OAG prevalence rate and a 10-year screening interval.

Changes to the uptake of the communityoptometristIt is likely that the cohort of individuals withhigher OAG prevalence rates would have a higherprobability of going for an eye test, for examplepeople with a family history of OAG or peoplewith myopia. Conversely, ethnic minority groupsmay have a lower probability of attending for aneye test. Additional sensitivity analysis wascompleted assuming 1.5 times and twice theprobability of having an eye test for the no-screening strategy.

Changes to incidence and progression ofglaucomaAlthough considerable efforts were made toidentify the estimates for incidence andprogression, few data were available. Within thebase-case analysis distributions were defined toreflect the variability surrounding these estimates.Despite this it was felt possible that the valuesused might have been substantially lower orhigher than those used in the base case. In thefirst of these sensitivity analyses the incidence ofOAG was assumed to be equal to the maximumfor incidence reported in Table 39. A triangulardistribution was attached, where the maximum wasassumed to be twice the maximum used in thebase case (truncated if necessary at 1) and theminimum value was assumed to be equal to thelikeliest value from the base case.

For the second of these analyses the incidence ofOAG was assumed to be equal to the minimum forincidence reported in Table 39. A triangulardistribution was attached, where the maximum wasassumed to be the likeliest value from the basecase (truncated if necessary at 1) and theminimum value was assumed to be equal to zero.

With respect to progression in the ‘high’ analyses,the maximum values for the rates of progressionwere used. Likewise, in the ‘low’ analyses, theminimum values for the rates of progression wereused. A triangular distribution around the likeliestvalues used in the analyses was defined using thesame methods as described above.

Further sensitivity analysis was carried out basedon time to progression, rather than average risk of progression (Chapter 7), for untreated patientsfor each corresponding glaucoma state byapplying the treatment effect of 0.65 to thenumber of years until progression occurred. Using

Economic analysis

114

this method the progression rates for theuntreated were 0.31 for progression to glaucomamoderate, 0.11 for progression to glaucoma severeand 0.09 for progression to visually impaired.Triangular distributions were attached to theseparameters’ mean values using the samemethodology described above.

Changes to the sensitivity and specificity of thetechnician testsIn this sensitivity analysis the same methods asdescribed in the section ‘Base-case and sensitivityanalysis’ (p. 113) were used to explore how theresults changed as the sensitivity and specificity of the second test performed by the technician in the ‘technician screening’ strategy werechanged.

Sensitivity analysis on health state utilitiesIn previous analyses health state utilities werebased on objective assessment of the severity ofOAG. In this sensitivity analysis a larger data setwhere the severity of OAG was based on thesubjective assessment of severity was used. Thedata used in this analysis were described inAppendix 22. As noted in Appendix 22, objectiveand subjective assessments did not always agree.The main difference between the utility valuesbased on subjective and objective assessments wasthe difference in utility weights between states. Forexample, in the base-case analysis, a loss of around7% and 5% in quality of life would occur whenmoving from glaucoma mild to glaucomamoderate and from glaucoma moderate toglaucoma severe, respectively. These changes areapproximately 2.5% and 10%, respectively, for thisanalysis.

Sensitivity analysis on costsCosts of screening, diagnosis and treatmentAs described in ‘Parameter estimates used in themodel’ (p. 107), the data available on costs werelimited and consideration was given to variationsin the costs used in the model. In this sensitivityanalysis low and high estimates were derived. Forthe cost of diagnosis by the ophthalmologist lowand high values were developed using data fromScotland National Statistics (see Table 42). Forexample, in this situation, the high value wasalmost three times the base-case value used.

The treatment costs of the different disease stateswere also varied in a further treatment costscenario. In this scenario the costs for each disease state were assumed to be either half ortwice the costs used in the base-case analysis(Table 42).

A third scenario was also considered for sensitivityanalysis around cost estimates. In this scenario thecosts of the screening invitation and the testsperformed during screening were varied. Eachcost was assumed to be either half or twice thevalues used in the base-case analysis (Table 43).

Changes to the cost of visual impairmentThe perspective taken for the estimate of costs wasthat of the NHS. In this sensitivity analysis theeffect of widening the perspective to include othersectors of the economy such as Personal SocialServices and the patient was explored. The effectof this wider perspective was assumed to affect thecosts of visual impairment alone. This analysis wasconducted for a 40-year-old cohort undergoingscreening every 10 years, but with a prevalence ofOAG of either 1% or 5%. For both prevalencerates one-way sensitivity analysis was used toidentify threshold values for the annual cost ofvisual impairment. To interpret these thresholds itshould be borne in mind that, based on the datareported by Meads and Hyde,299 the annual costof a year of visual impairment can be calculated as£7851 for the first year of visual impairment and£7657 for subsequent years (details as to howthese estimates were derived are described inAppendix 24).

Results of base-case analysis andsensitivity analysis on the base caseEstimates of costs and QALYs for the base case Tables 46–48 report the estimated relative cost-effectiveness by screening strategy at differentlevels of prevalence of OAG for cohorts aged 40,60 and 75 years, respectively. These results arebased on a screening interval of 3 years.

In each of these analyses, as prevalence increasescost also increases and QALYs fall for all threestrategies and all age cohorts. Costs increase asprevalence increases because a larger proportionof individuals in the cohort incurs the costs ofdiagnosis and the continuing costs of treating theOAG. The mean cost per person is higher for the40-year-old cohort than the older cohorts becausethey are less likely to die during the time-horizonof the model and thus have more opportunity toincur costs. Estimated mean QALYs fall asprevalence increases. This is because a greaterproportion of the cohort experience the adversehealth effects of OAG. Estimated mean QALYs aregreater for the younger age group than the olderage groups at each prevalence level, primarilybecause members of the younger age group areless likely to die during the time-horizon of themodel.


115


In each analysis at each prevalence level and age group considered, ‘no screening’ (i.e. thecurrent strategy of opportunistic case finding bythe community optometrist) is the least costly but also the least effective of the three strategies considered. Adopting a strategy where a technician performs the initial screeningtests is more effective but more costly than a no-screening strategy, and a strategy of screeningby a glaucoma optometrist is more effective butmore costly than the ‘technician’ screeningstrategy.

Estimated cost-effectivenessFor each age group considered the incrementalcost per QALY gained from adopting ‘technician’

screening compared with ‘no screening’ falls asprevalence increases. The incremental cost perQALY gained indicates how well the extra costs ofa more expensive but more effective treatment areconverted into additional benefits. As theincremental cost per QALY gained falls the morelikely it becomes that technician screening will beconsidered cost-effective compared with noscreening. Similarly, for each age groupconsidered, the incremental cost per QALY gainedfrom adopting glaucoma optometrist screeningcompared with technician screening falls asprevalence increases. This indicates that asprevalence increases it is more likely thattechnician screening will be considered cost-effective compared with no screening.

Economic analysis

116

TABLE 46 Incremental cost-effectiveness for the 40-year-old cohort by different prevalence rates

Prevalence Strategy Cost (£) QALYs ICER

1% No screening 257.40 19.231Technician 520.36 19.233 107,938GO 617.34 19.234 398,881



6% No screening 639.82 18.906Technician 962.38 18.918 29,051GO 1,059.93 18.919 93,416

8% No screening 792.79 18.777Technician 1,139.19 18.791 23,775GO 1,236.97 18.793 71,648


12% No screening 1,098.72 18.517Technician 1,492.80 18.539 18,326GO 1,591.04 18.541 48,979





GO, ‘glaucoma optometrist’ strategy.

The base-case model suggests that for a 40-year-old cohort a technician screening strategycompared with a no-screening strategy isassociated with an incremental cost per QALY thatsociety might be willing to pay at a prevalencesomewhere between approximately 6 and 10%(Table 46). For a 60-year-old cohort a technicianscreening strategy compared with a no-screeningstrategy might be considered cost-effective at aprevalence between approximately 12 and 20%(Table 47). For a 75-year-old cohort, a no-screeningstrategy has an incremental cost per QALY gainedat any of the prevalence levels considered(Table 48). Furthermore, for no age cohort and noprevalence level is screening by the glaucomaoptometrist instead of screening by the technicianassociated with an incremental cost per QALY

gained that society might typically be willing to pay.

Tables 46–48 present mean costs, QALYs andincremental costs per QALY gained. Such data donot represent the imprecision surrounding theparameter estimates used in the model. Thisuncertainty was addressed by the probabilisticsensitivity analyses conducted. These show thelikelihood that each screening strategy would beconsidered cost-effective at different thresholdvalues for society’s willingness to pay for a QALY(Tables 49–51).

Tables 49 indicates for a 40-year-old cohort that atprevalence levels of 1% or less there is very littlelikelihood that any screening strategy would be


117










12% No screening 685.64 12.045Technician 959.47 12.055 27,361GO 1,028.44 12.057 60,456





more cost-effective than no screening. At a 5%prevalence level there is just over 40% likelihoodthat technician screening would be consideredcost-effective if society’s willingness to pay for aQALY was £30,000. This climbs to 56% when theprevalence is 10%. Screening by a glaucomaoptometrist is unlikely to be considered cost-effective at any of the prevalence levels or cost perQALY thresholds considered.

For a 60-year-old cohort there is less than a 50%chance that technician screening would beconsidered cost-effective when society’s willingnessto pay for a QALY is £30,000 (Tables 50) for allprevalences up to 20%. Again, screening by aglaucoma optometrist is unlikely to be consideredcost-effective at any of the prevalence levels or costper QALY thresholds considered.

There is only a low likelihood that any strategyother than no screening would be considered cost-effective for the 75-year-old cohort at any of theprevalence levels considered if society’s maximumwillingness to pay for a QALY is £30,000. Shouldsociety’s willingness to pay for a QALY be higherthan £30,000 then the likelihood that thetechnician or glaucoma optometrist screeningstrategy would be considered cost-effectiveincreases. Nevertheless, even at a willingness topay for a QALY of £50,000, no screening is mostlikely to be the most cost-effective strategy.

Sensitivity analysis performed around the basecaseChanges to the screening intervalThe base-case analysis has assumed that screeningwill take place every 3 years. In this analysis the

Economic analysis

118



1% No Screening 103.47 6.905Technician 210.76 6.905 200,028GO 250.74 6.905 521,062











impact of changing the screening interval to 5 or10 years has been explored (Figures 40–42). Thesedata indicate that as the screening intervalincreases the incremental cost per QALY gained

reduces. This is because it has been assumed thatOAG progresses relatively slowly and anyreduction in total QALYs is more thancompensated for by a reduction in costs.


119


TABLE 49 Probabilistic sensitivity analysis for 40-year-old cohort: probability of being the optimal strategy at different threshold levelsfor society’s willingness to pay for a QALY

Prevalence Strategy Cost (£) QALYs ICER Probability that intervention is cost-effective for different threshold values for

society’s willingness to pay for a QALY (%)

£10,000 £20,000 £30,000 £50,000

1% No Screening 257.40 19.231 100.0 98.8 93.9 78.5Technician 520.36 19.233 107,938 0.0 1.20 5.9 21.0GO 617.34 19.234 398,881 0.0 0.0 0.2 0.5

5% No screening 563.34 18.971 94.4 71.5 50.8 34.9Technician 873.97 18.981 33,153 5.4 27.9 48.0 61.3GO 971.41 18.982 110,218 0.2 0.6 1.2 3.8

10% No screening 945.76 18.647 79.6 48.6 35.0 24.2Technician 1,316.00 18.665 20,527 19.9 49.6 60.0 62.3GO 1,414.00 18.667 58,158 0.5 1.8 5.0 13.5

15% No screening 1,328.17 18.323 68.9 39.6 29.2 20.6Technician 1,758.02 18.349 16,097 30.1 55.3 59.4 56.7GO 1,856.59 18.352 39,648 1.0 5.1 11.4 22.7


See Appendix 23, Figures 53–57, for CEACs.


Prevalence Strategy Cost (£) QALYs ICER Probability that intervention is cost-effective for different threshold values for society’s

willingness to pay for a QALY (%)

£10,000 £20,000 £30,000 £50,000




15% No screening 821.60 11.928 81.3 53.2 41.2 30.3Technician 1,121.77 11.940 24,252 17.8 42.3 49.0 49.1GO 1,191.54 11.941 49,551 0.9 4.5 9.8 20.6



Economic analysis

120


Prevalence Strategy Cost (£) QALYs ICER Probability that intervention is cost-effective for different threshold values for society’s

willingness to pay for a QALY (%)

£10,000 £20,000 £30,000 £50,000






See Appendix 23, Figures 63–67 for CEACs.

0

20

40

60

80

100

Prevalence (%)

Technician, 3 yearsGO, 3 years



1 2 4 6 8 10 12 14 16 18 20

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

FIGURE 40 Incremental cost per QALY gained by prevalence rate and at 3-, 5- and 10-year screening intervals for the 40-year-oldcohort. Incremental cost per QALY for ‘technician’ strategy is for the comparison of ‘technician’ strategy with ‘no screening’ strategy.Incremental cost per QALY for ‘glaucoma optometrist’ strategy (GO) is for the comparison of ‘glaucoma optometrist’ strategy with‘technician’ strategy.


121


0

20

40

60

80

100

Prevalence (%)




1 2 4 6 8 10 12 14 16 18 20

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)


0

20

40

60

80

100

Prevalence (%)




1 2 4 6 8 10 12 14 16 18 20

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)


For the 40-year-old cohort, adopting thetechnician strategy in preference to a no-screeningstrategy would be associated with an incrementalcost per QALY that society might consideracceptable at a prevalence of approximately 4% (5-year screening interval) and just less than 4%(10-year screening interval). Furthermore, at aprevalence of approximately 12% adopting thescreening by a glaucoma optometrist would beassociated with an incremental cost per QALY thatsociety might consider acceptable. For the 60-year-old age group similar prevalences for thecost-effectiveness of technician screening are 8% (5-year screening interval) and 6% (10-yearscreening interval). Screening by a glaucomaoptometrist would be associated with anincremental cost per QALY that society mightconsider acceptable at approximately 20%

prevalence. At none of the screening intervals orprevalences considered for 75 year olds wouldeither technician screening or the screening by theglaucoma optometrist be considered cost-effective.

Figures 40–42 do not reflect the statisticalimprecision surrounding the parameter estimatesused in the calculation of the estimates of theincremental cost per QALY gained. Theprobabilistic sensitivity analyses reported inTables 52–54 show the likelihood that each of thestrategies might be considered cost-effective atdifferent threshold values for willingness to pay fora QALY at 3-, 5- and 10-year screening intervals.Table 52 shows these data when the prevalence is1%, Table 53 shows the results for a 5% prevalencelevel and Table 54 shows the results for a 10%prevalence level. As these tables show, the

Economic analysis

122

TABLE 52 Likelihood of a strategy being cost-effective for different age cohorts and screening intervals: 1% prevalence of OAG

Cohort Screening interval Strategy Probabilistic cost-effectiveness for different threshold values for society’s willingness to pay

for a QALY (%)

£10,000 £20,000 £30,000 £50,000

40 years old 3 years No screening 100.0 98.8 93.9 78.5(base case) Technician 0.0 1.2 5.9 21.0

GO 0.0 0.0 0.2 0.5

5 years No screening 100.0 97.1 88.2 69.2Technician 0.0 2.7 11.5 30.1GO 0.0 0.2 0.3 0.7



GO 0.0 0.1 0.2 0.6




GO 0.0 0.0 0.2 0.4




likelihood that either the technician or theglaucoma optometrist strategy would beconsidered cost-effective increases as prevalenceand screening interval increase for all three agecohorts. Again, the likelihood of the glaucomaoptometrist strategy being cost-effective is rarelygreater than 20%.

Changes in the probability of having an eye testwith a community optometristIt was discussed and agreed in the steering groupmeeting that part of the population would have alower attendance for a sight test by a communityoptometrist. In this analysis 2%, 13% and 37%community optometrist test uptake rates wereassumed. The rationale for these figures was thatthey would result in about 10%, 50% and 90% ofthe cohort having an eye test in 5 years’ time.

Tables 55–57 show the results for the 40-, 60- and75-year-old cohorts, respectively. As expected, thecost and QALY rise when uptake rates forattendance at a community optometrist are higher.The higher the uptake rate, the better the no-screening strategy performs. For instance, theincremental cost per QALY for a 1% prevalencerate of OAG for the comparison of the technicianwith the no-screening strategy was £107,938(Table 46), whereas the incremental cost per QALYwhen there was a low uptake rate of thecommunity optometrist was £59,191 (Table 55).Moreover, if there is a group of individuals withinthe cohort that do not access a communityoptometrist service, the screening strategiesbecome more cost-effective the bigger thedeprived group is. The assumption within themodel is that this group will attend screening.


123




for a QALY (%)

£10,000 £20,000 £30,000 £50,000


GO 0.2 0.6 1.2 3.8




GO 0.1 0.6 1.3 3.4




GO 0.0 0.3 0.9 2.2




Changes to the sensitivity and specificity of thetest following the measurement of IOP in the‘technician’ strategyOverall, the results of the analysis indicate that theincremental cost per QALY is relatively insensitiveto changes to either the specificity or sensitivity ofthis test. Figures 43–45 illustrate this. These figuresshow that as specificity increases the incrementalcost per QALY of the technician testing strategyfalls. Likewise, as sensitivity increases theincremental cost also falls. The figures alsoillustrate that changes in specificity are moreimportant than changes in sensitivity and that theimportance of changes in specificity and sensitivitydeclines as prevalence increases. The impact ofchanges in sensitivity and specificity does notappear to be greatly influenced by the age of thecohort screened.

As would be expected, as the sensitivity and the specificity of tests in the glaucoma optometrist strategy were not changed, anyincrease in the performance of tests performed as part of the technician strategy would make the glaucoma optometrist strategy less cost-effective compared with the technicianstrategy.

Results of further targeted sensitivityanalysisAs indicated above, the results of the base-caseanalysis and its associated sensitivity analysis haveindicated that the following are likely to increasethe cost-effectiveness of screening:

● starting to screen at a younger age rather thanan older age (e.g. screening at 40 is more likely

Economic analysis

124



for a QALY (%)

£10,000 £20,000 £30,000 £50,000


GO 0.5 1.8 5.0 13.5




GO 0.4 1.7 4.9 12.7




GO 0.2 1.1 2.5 9.3





125


TABLE 55 ICERs for different annual community optometrist test uptake rates: 40-year-old cohort

Low Medium High

Prevalence Strategy Cost (£) QALYs ICER Cost (£) QALYs ICER Cost (£) QALYs ICER

1% No screening 85.30 19.227 148.80 19.229 268.80 19.231Technician 419.90 19.233 59,191 453.90 19.233 75,830 527.10 19.233 121,443GO 518.60 19.233 292,714 551.90 19.233 331,257 623.90 19.234 424,490



6% No screening 379.97 18.892 492.37 18.899 666.65 18.909Technician 859.02 18.916 19,534 895.25 18.917 23,163 971.74 18.918 33,121GO 960.09 18.917 72,953 994.75 18.918 81,404 1,068.54 18.919 101,495

8% No screening 497.83 18.757 629.78 18.768 825.80 18.780Technician 1,034.65 18.789 16,738 1,071.79 18.790 19,436 1,149.60 18.792 26,882GO 1,136.68 18.791 56,533 1,171.88 18.792 62,840 1,246.40 18.793 77,815

10% No screening 615.70 18.623 767.20 18.636 984.94 18.651Technician 1,210.28 18.663 15,007 1,248.32 18.664 17,129 1,327.46 18.666 23,020GO 1,313.27 18.665 46,305 1,349.01 18.666 51,283 1,424.26 18.667 63,096

Low = 2%, medium = 13%, high = 37%.


Low Medium High








Low = 2%, medium = 13%, high = 37%.

Economic analysis

126


Low Medium High








Low = 2%, medium = 13%, high = 37%.

0

20

40

60

80

100

120

140

0.5 0.6 0.7 0.8 0.9 1.0

Sensitivity

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

Prev 1%, 0.8 Spec

Prev 1%, 0.9 Spec

Prev 1%, 1.0 Spec

Prev 5%, 0.8 Spec

Prev 5%, 0.9 Spec

Prev 5%, 1.0 Spec

Prev 10%, 0.8 Spec

Prev 10%, 0.9 Spec

Prev 10%, 1.0 Spec

FIGURE 43 Influence of changes in sensitivity and specificity (Spec) of the second test in the technician strategy in a 40-year-oldcohort by prevalence level (Prev)


127


0

20

40

60

80

100

120

140

160

180

200

0.5 0.6 0.7 0.8 0.9 1.0

Sensitivity

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

Prev 1%, 0.8 Spec

Prev 1%, 0.9 Spec

Prev 1%, 1.0 Spec

Prev 5%, 0.8 Spec

Prev 5%, 0.9 Spec

Prev 5%, 1.0 Spec

Prev 10%, 0.8 Spec

Prev 10%, 0.9 Spec

Prev 10%, 1.0 Spec

FIGURE 44 Influence of changes in sensitivity and specificity of the second test in the technician strategy in a 60-year-old cohort byprevalence level

0

50

100

150

200

250

300

0.5 0.6 0.7 0.8 0.9 1.0

Sensitivity

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

Prev 1%, 0.8 Spec

Prev 1%, 0.9 Spec

Prev 1%, 1.0 Spec

Prev 5%, 0.8 Spec

Prev 5%, 0.9 Spec

Prev 5%, 1.0 Spec

Prev 10%, 0.8 Spec

Prev 10%, 0.9 Spec

Prev 10%, 1.0 Spec

FIGURE 45 Influence of changes in sensitivity and specificity of the second test in the technician strategy in a 75-year-old cohort byprevalence level

to be cost-effective than screening at 60 years ofage)

● increasing the screening interval from 3 to10 years

● screening cohorts with a higher expectedprevalence of OAG.

In this section further sensitivity analyses wereundertaken for a specific cohort which reflectedthe above factors. In these sensitivity analyses ithas been assumed that screening will beperformed in a 40-year-old cohort with a 10-yearscreening interval and a 5% OAG prevalence rate,except where specifically stated otherwise.

The results of the comparison between thealternative screening strategies are shown inTable 58. The deterministic results indicate thatscreening with the technician strategy might be

considered worthwhile. The probabilisticsensitivity analysis shows that the considerableuncertainty around the parameter estimates whichare used within the model is important. Forexample, even though the point estimate ofincremental cost-effectiveness for the comparisonof the technician with the no-screening strategy is£20,571, there is only a 42% likelihood that thecost per QALY would be less than £20,000(Figure 75 in Appendix 23 shows the cost-effectiveness acceptability curves for this analysis).

Changes to the uptake rates of the communityoptometristIn this sensitivity analysis the probability ofreceiving an eye test in the community varied(Table 59). As the probability of receiving an eyetest in the community increased, both the costsand outcomes associated with the no-screening

Economic analysis

128

TABLE 58 Deterministic and probabilistic analysis results: base case 40-year-old cohort, 10-year screening interval, 5% OAGprevalence rate

Strategy Cost (£) QALYs ICER £10,000 £20,000 £30,000 £50,000

No screening 563.34 18.971 82.5% 54.3% 40.2% 29.6%Technician 703.24 18.978 20,571 16.7% 42.3% 51.4% 51.1%GO 744.38 18.979 42,188 0.8% 3.4% 8.4% 19.3%

TABLE 59 Changes to the chance of receiving an eye test in the community for a 40-year-old cohort and a 10-year screening intervalfor various prevalence levels

Prevalence Strategy 1.5 times the rate in base case 2 times the rate in base case

Cost (£) QALYs Incremental cost Cost (£) QALYs Incremental cost per QALY per QALY

2.0% No screening 417.15 19.167 495.70 19.168Technician 513.60 19.170 46,307 581.28 19.170 53,889GO 550.88 19.170 111,051 617.93 19.170 130,021






strategy increased. The gain in QALYs for the no-screening strategy more than compensates for theincrease in cost of this strategy. As a consequence,the incremental cost per QALY of the technicianstrategy compared with no screening increased(for comparison, for a 40-year-old cohort screenedat 10-year intervals the incremental cost per QALYwas £38,456 at a 2% prevalence level and £15,808at an 8% prevalence level; Figure 40). Theincremental cost per QALY for the comparison ofthe glaucoma optometrist strategy compared withthe technician strategy also increased (theincremental cost per QALY was £91,906 at a 2%prevalence level and £28,749 at an 8% prevalencelevel; Figure 40).

Changes to incidence and progression ofglaucomaTable 60 describes the results of the sensitivityanalyses for changes in the incidence andprogression of OAG. The likelihood of either ofthe two screening strategies being considered cost-effective did not greatly alter when either lower orhigher rates of incidence of OAG were used in theanalysis.

Sensitivity analysis was also conducted aroundchanges to the rate of progression. As the rate ofprogression increases (i.e. the ’high’ analyses), thelikelihood that either the technician or glaucomaoptometrist strategy would be considered cost-


129


TABLE 60 Likelihood of a strategy being cost-effective for different incidence and progression parameters: analysis for a 40-year-oldcohort with a 10-year screening interval and 5% prevalence of OAG

Cohort Probability Strategy Probabilistic cost-effectiveness for different thresholddistribution values for society’s willingness to pay for a QALY (%)parameters

£10,000 £20,000 £30,000 £50,000

Base case No screening 82.5 54.3 40.2 29.6Technician 16.7 42.3 51.4 51.1GO 0.8 3.4 8.4 19.3

Incidence High No screening 82.0 53.9 40.0 29.6Technician 17.0 42.4 50.7 50.0GO 1.0 3.7 9.3 20.4

Low No screening 83.6 55.7 42.6 30.6Technician 15.5 40.6 48.2 49.3GO 0.9 3.7 9.2 20.1

Progression mild High No screening 78.8 48.0 35.2 23.8Technician 20.5 48.3 55.3 54.8GO 0.7 3.7 9.5 21.4


Progression moderate High No screening 77.4 41.2 28.2 18.1Technician 21.9 55.2 62.2 59.2GO 0.7 3.6 9.6 22.7


Progression severe High No screening 75.8 46.2 32.8 22.3Technician 23.2 49.8 57.4 55.4GO 1.0 4.0 9.8 22.3


Alternative analysis: No screening 79.9 49.5 35.8 25.3time to progression Technician 19.3 46.8 54.9 53.7mean values GO 0.8 3.7 9.3 21.0

effective increases. This is as would be expected, asscreening is likely to detect more cases and hencedelay progression. In this situation the gain inQALYs resulting from earlier detection andtreatment more than offsets any increase in cost.

Changing the rate of progression from moderateto severe disease appears to have a greater impactthan changing the risk of progression from mild tomoderate or severe state to visually impaired. Thisis caused by the interplay of the effect on QALYs,cost and the number of people in the state. Usingalternative mean progression values, based onapplying the relative risk of progression followingtreatment to estimates of the time to progression,rather than to the annual risk of progression asadopted for the rest of the analysis, results in aslightly better case for screening. The CEACs arepresented in Appendix 23 (Figures 86–94).

Sensitivity and specificity of the second testperformed by the technicianIn this sensitivity analysis the sensitivity andspecificity of the second test performed by thetechnician and the screening interval were varied(Figure 46). As the screening interval increases, the‘technician’ strategy is more likely to be consideredcost-effective. The effects of changes in sensitivityand specificity are relatively modest in comparisonto the changes in the screening interval.

Changes in the sources of health state utilitiesIn this sensitivity analysis the results of theeconomic evaluation were revised using the healthstate valuations based on the subjective assessmentof disease severity rather than the objectiveassessment of disease severity used in the base-case analysis. Using these valuations both thetechnician and the glaucoma optometrist

Economic analysis

130

10

15

20

25

30

35

40

0.5 0.6 0.7 0.8 0.9 1.0

Sensitivity

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

3-year Int, 0.8 Spec









FIGURE 46 Influence of changes in sensitivity and specificity of the second test in the technician strategy in a 40-year-old cohort byscreening interval (Int)

TABLE 61 Sensitivity analyses around utilities: 40-year-old cohort, 10-year screening interval, 5% OAG prevalence rate

Strategy Cost (£) QALYs ICER £10,000 £20,000 £30,000 £50,000

No screening 563.34 19.007 74.1% 38.2% 23.8% 14.5%Technician 703.24 19.015 17,762 24.7% 55.0% 63.9% 58.2%GO 744.38 19.016 36,403 1.2% 6.8% 12.3% 27.3%

strategies are more likely to be considered cost-effective. For example, the likelihood for thetechnician strategy of being considered optimalrose from less than 50% (Table 58) to about 55%and over 60% for society’s willingness to pay foran extra QALY of £20,000 and £30,000,respectively (Table 61). The CEACs that illustratethis more fully are presented in Appendix 23(Figure 75–95).

Sensitivity analysis on costsTable 62 shows the results for sensitivity analysisperformed on the cost estimates used within the

model. Varying the cost of diagnosis by theophthalmologist did not have a great impact onthe cost-effectiveness of the technician strategy.There was rather more effect on the cost-effectiveness of the glaucoma optometrist strategy,but this was not of sufficient magnitude to changeconclusions about the cost-effectiveness of thisstrategy. The cost-effectiveness of the technicianstrategy compared with no screening was moresensitive to changes in the costs of treatment orthe costs of inviting people to be screened or theirsubsequent tests. Changes to these costs had lesseffect on the cost-effectiveness of the glaucoma


131


TABLE 62 Sensitivity analyses around costs: 40-year-old cohort, 10-year screening interval, 5% OAG prevalence rate

Low High

Strategy Cost (£) QALY ICER Cost (£) QALY ICER

Ophthalmologist diagnosis No screening 555.89 18.971 598.98 18.971Technician 693.27 18.978 20,200 750.96 18.978 23,172GO 728.73 18.979 36,369 819.25 18.979 117,457

Treatment costs No screening 478.85 18.971 732.31 18.971Technician 581.82 18.978 15,140 946.08 18.978 31,432GO 617.66 18.979 36,761 997.80 18.979 53,041

Tests and screening invitation No screening 501.88 18.971 686.33 18.971Technician 601.93 18.978 14,712 905.98 18.978 32,297GO 633.17 18.979 32,044 966.86 18.979 62,438

–150

–100

–50

0

50

100

150

200

Valu

e of

ICER

(200

6 £0

00s

per

addi

tiona

l QA

LY)

5 10 15 20 25 30 35 40

Annual cost of visual impairment (000s)

Technician vs no screening GO vs technician

Technician dominates

no screening

0

FIGURE 47 Value of ICERs for alternative visually impaired annual costs: 40-year-old cohort, 10-year screening interval, 1% OAGprevalence rate

optometrist strategy compared with the technicianstrategy for the usual values of society’s willingnessto pay for an extra QALY.

Changes to the cost of visual impairmentFigure 47 shows the results of this thresholdanalysis for the cost of visual impairment when theprevalence of OAG was 1%. In this case, thetechnician strategy dominates the no-screeningstrategy when the annual cost for visualimpairment is around £16,000. The cost of visualimpairment would need to be £8800 for theincremental cost per QALY for the techniciancompared with the no-screening strategy to be£30,000. The glaucoma optometrist strategywould dominate the technician strategy at highvalues of annual cost for visual impairment (e.g.over £59,000; not shown) and it needs the annualcost of visual impairment to be greater than£40,000 for the incremental cost per QALY to be£30,000 or less.

When the prevalence of OAG is changed to 5%and the annual costs of visual impairment areapproximately £5700 and £15,000, the technicianstrategy dominates the no-screening strategy, andglaucoma optometrist dominates the technicianstrategy, respectively (Figure 48).

DiscussionAt the beginning of this chapter, the paucity andlimitations of existing evidence on the cost-effectiveness of screening for OAG werehighlighted. Only one previous study wasidentified that attempted to compare an activescreening strategy with current practice.281 Thisstudy concluded that screening for OAG was notcost-effective. In the economic evaluation reportedin this section some evidence has been providedthat screening might be cost-effective for selectedat-risk subgroups. It is, however, supportive of theearlier study in that screening at prevalence levelslikely to be seen in the general population isunlikely to be cost-effective. The results presentedin the analysis do not address precisely for whichspecific cohorts of individuals screening might beconsidered as cost-effective; this will be consideredlater.

The evidence on cost-effectiveness should betreated cautiously. In part, this is due to theinherent problems in combining data, even whenthey have been systematically assembled, frommultiple sources. Caution must also be exercisedas it is currently unknown whether any of theparameter estimates (e.g. uptake of screening,diagnostic performance, disease progression,

Economic analysis

132

–80

–60

–40

–20

20

40

60Va

lue

of IC

ER (2

006

000s

£ pe

r ad

ditio

nal Q

ALY

)

0

0 5 10 15 20

GO dominates

technician strategy

Technician dominatesno screening

Annual cost of visual impairment (000s)

Technician vs no screening GO vs technician

FIGURE 48 Value of ICERs for alternative visually impaired annual costs: 40-year-old cohort, 10-year screening interval, 5% OAGprevalence rate

treatment effectiveness, costs or utilities) would beapplicable to any of the groups for which themodel provides some evidence that screeningmight possibly be cost-effective. Nevertheless,despite the limitations of the analysis, the resultsindicate some patient groups where theorganisation of a screening service might be givenfurther consideration. In situations where it maybe feasible to organise a service for the targetpatient group, further primary research on theeffectiveness and cost-effectiveness of screening forOAG would be required.

As described in the section ‘Results of furthertargeted sensitivity analysis’ (p. 124), aprobabilistic sensitivity analysis has beenconducted to address the statistical imprecisionsurrounding the point estimates used within themodel. In this analysis each parameter estimatehas an associated statistical distribution whichprovides information on the likelihood of theparameter estimate taking any particular value.The type of distribution for each parameter isitself a cause of some uncertainty for any economicevaluation. In this study the type of distributionvaried by parameter, but was consistent with priorexperience about which type of distribution wouldbe appropriate for the type and nature of the dataavailable.91,300 Despite these efforts, the precisedefinition of parameter distributions for somevariables was limited, as in some cases it wasdifficult to fit a distribution to the few dataavailable.

Further strengths and limitations of many of theparameter estimates have been expanded upon inthe preceding chapters. These issues do not needto be reiterated, except to emphasise that anylimitations identified in earlier chapters are equallyapplicable when these data are used for theeconomic model. An assumption of the model isthat no one in the cohorts is receiving treatmentprior to screening or opportunistic case detection.Relaxing this assumption would result in screeningbeing less likely to be considered cost-effective.This is because the number of cases of OAG whocould potentially benefit from screening would bereduced. It is also possible that screening mightidentify people for whom it is recommended thattreatment should be stopped, but who subsequentlygo on to develop glaucoma; the net effect isunclear. Two sets of variables that were not thefocus of previous chapters are costs and utilities.Only very limited data on the costs of diagnosisand treatment were available, and although effortswere made to identify the best data applicable tothe UK these are sparse. The model estimates

would be more robust if further data were tobecome available and consideration should begiven as to whether further primary research isneeded. The model also proved to be very sensitiveto the costs assumed for visual impairment. In thebase-case analysis the perspective taken for theassessment of costs was the NHS. In a thresholdanalysis the effect of considering those costs thatfall on other groups was also considered. Theinclusion of these costs improves the cost-effectiveness of the screening strategies and thethresholds identified are not dissimilar to theannual costs of visual impairment estimated byMeads and Hyde,299 whose data suggest an annualcost of visual impairment of approximately £7900for the first year of visual impairment and £7700for subsequent years (see Appendix 24 for details).

Data with respect to health state utilities were alsovery sparse. Few data reporting utilities wereavailable from the literature and none wasavailable for a UK population. This problem wasanticipated at the outset of the study and datawere collected using the EQ-5D questionnairefrom a sample of people with glaucoma as part ofanother ongoing study (Kilonzo M, University ofAberdeen: personal communication, 2006). Thesedata, however, were not specific to people withOAG and the sample included some people withother forms of glaucoma. Nevertheless, these datawere used as it was felt that the impact on qualityof life of the different types of glaucoma would besimilar. The data used to provide utilities datawere collected from respondents with a mean agebetween 69 and 70 years. It is unclear how theseutilities might vary for lower age groups. As aconsequence, it is not clear whether the results ofthe model would be influenced by utility data froma younger age group. It should also be noted thatfor the purposes of decision-making it has beenargued that utilities reflecting the preferences ofthe general population rather than a specificsubgroup (e.g. by age or presence of OAG) shouldbe used.

Of greater concern is that these utilities are basedon people receiving treatment. Utility data are notavailable for untreated glaucoma cases. In theanalysis it has been assumed that the utilityassociated with treated and untreated glaucoma isthe same. This is justifiable in the sense thattreatment does not remove the symptoms ofglaucoma. However, this approach fails to reflectany loss of utility associated with the side-effects oftreatment. Ideally, further data should be collectedin people whose glaucoma has not progressed,both before and after treatment has started. This


133


would allow the impact and importance of side-effects of treatment to be determined.

The quality and usefulness of the economic modelis dependent not only on the quality of the data,but also on the way in which the data are used.The data requirements and the use of the datawere determined by the structure adopted for themodel. The development of the economic modelwas, as described in Chapter 4, based ondiscussions with a number of key stakeholders. Itthen underwent a prolonged period of refinementduring which the care pathways were criticallyexamined and refined. The model structureapplies to a UK context, and may not be relevantto other country settings, although other strategiescould be developed and readily added to themodel. As described in Chapter 4, the modelstructure was developed so that the assumptionsmade in the base-case analysis could be exploredin future work. For example, in the base-caseanalysis it was assumed that the ophthalmologistwould make a perfect diagnosis. The modelstructure has allowed for the possibility that thiswill not be the case and that the ophthalmologistmight possibly initiate treatment when it is notrequired (a false positive) and fail to diagnosesome cases of OAG (a false negative). Nonetheless,since the test characteristics of the diagnostic testswere all based on the assumption thatophthalmologist assessment is the gold standard,the sensitivity and specificity of those tests shouldbe adjusted for the fact that they are based on animperfect gold standard. It should be mentionedthat it is not possible to do this unless there isanother gold standard to get all tests’ sensitivityand specificity (and ophthalmologist assessment)adjusted for. The model is a simplification of thecare pathways that may follow. For example, thediagnostic performance of the tests performed bythe glaucoma optometrist has been represented bya single value for sensitivity and specificity of atest. In reality, a battery of tests would beperformed, each with its own values for sensitivityand specificity. This simplification was made asthere is a plethora of tests that may be used andthe values for sensitivity and specificity used in themodel appeared to be consistent with theestimates from the literature. A secondsimplification made in the model was the relativelysmall number of stages used to reflect theprogression of this chronic condition. Thisassumption may fail to represent the subtleties ofdisease progression. Owing to limitations of theprimary data, estimates of the risk of progressionbetween health states are based on data from oneeye, and do not necessarily represent the

definition of the heath states in the model, whichis based on binocular visual field loss. This is alimitation as the second eye may not have suchadvanced disease as the study eye so may beoverestimated, but equally studies may have usedthe better eye for analysis and may underestimatethe risk of progressive binocular visual field loss.Furthermore, there were insufficient data todetermine whether many of the parameter valuesvaried between the stages of disease, for examplewhether diagnostic performance of the tests orrate of progression would vary by severity ofdisease. The model was, however, structured insuch a way that should such data become availablein the future they could be readily incorporated.

A further simplification in the model structure isthat rather than modelling the full variety oftreatments available for OAG it has been assumedthat the effect of treatment can be represented bya single relative effect size for treatment comparedwith no treatment.

Finally, when interpreting the results of theeconomic evaluation it should be borne in mindthat the estimates of cost-effectiveness relate to amale cohort. Gender-specific data were notavailable for any of the parameter estimates exceptfor annual all-cause mortality. Had the analysisbeen repeated with estimates of female all-causemortality it might be expected that, so long as theother parameters are unchanged, screening wouldbe more likely to be considered cost-effective. Thisis because, on average, females have a longer lifeexpectancy and are therefore more likely to gainthe benefits from earlier detection of OAG.

ConclusionScreening for OAG is associated with an ICER thatsociety might be willing to pay for particularcohorts of patients. A particular cohort of interestwas 40 year olds who might be expected to have aprevalence of OAG of between 6 and 10%(depending on society’s threshold willingness topay for a QALY) when screening is conducted at a3-year interval. As the screening interval increasesthe cost-effectiveness of the screening strategiesimproves.

The results should be treated with some cautionand further data are required to confirm thefindings. Such data relate to both improving theestimates available for some of the parameters inthe model, and also from a well-designed controlledstudy comparing viable screening strategies in thecohorts of patients for whom this research hasindicated that screening may be cost-effective.

Economic analysis

134

Potentially relevant target groupsfor screeningThe results of the economic evaluation reported inChapter 8 suggest that screening is most likely tobe cost-effective for people who have a familyhistory of OAG and people of black ethnicity, witha 10-year screening interval. Assuming thatscreening might commence at 40, 50 or 60 yearsof age, Table 63 shows the percentage of peoplefrom the UK population who would be in thetarget age, the prevalence of OAG and thepercentage of these who might be described by thetarget risk factors. Although people with myopiaor diabetes who fall within a similar age range areless likely to be considered cost-effective becauseof their lower prevalence of OAG, extending theinvitation to screening to them might also beconsidered. Table 63 also shows the estimatedproportions of the population with each of theserisk factors.

Estimating the numbers eligiblefor screeningThe numbers of people eligible for screening andthe proportions of cases of OAG that might beexpected to be included or excluded from thescreened populations can be estimated from thedata reported in Table 63 (details of how theseestimates were derived are provided in

Appendix 25). It could be decided that people ofblack race and/or with a family history of OAG arethe only groups where the prevalence of OAG issufficiently high to warrant screening. However,when considering just the first cycle of screening,these groups represent only an estimated 6% ofthe age cohort for screening starting at 40, 50 or60 years of age. Therefore, the majority of the agecohort would not be eligible for screening. As aconsequence, this strategy would have the chanceto detect only 21% of all the expected cases inthese age cohorts (although this could be as highas 29% when the extremes of confidence intervalsfor prevalence of risk factors and relative risks ofOAG reported in Table 63 are considered). If theeligibility criteria were extended to include otherat-risk groups (e.g. people with myopia ordiabetes) then, as myopia is common, screeningwould cover at most approximately 40% of the 40-year-old cohort (and 44% and 28% of the 50-or 60-year-old cohorts) and would have the chanceof detecting 58% (although it might be as high as85%) of all the expected cases in the 40-year-oldcohort (similar percentages are 66% and 36% forscreening at 50 and 60 years, respectively).

Although the precise way in which a screeningprogramme might be implemented is unclear,over time it might be expected that all thosepeople with the target risk factors would beeligible for screening. In Table 64 estimates areprovided on the basis that screening is limited to


135


Chapter 9

Factors relevant to the NHS, other sectors of the economy and patients

TABLE 63 Characteristics of the groups for whom screening for OAG may be cost-effective

Age % of total Prevalence of % of target population with risk factor(years) populationa OAG (95% CI)

Myopia301 Diabetes302 Black303 Family historyb

40 3.24 0.3 (0.1 to 0.5) 31 3 2 450 2.64 0.9 (0.6 to 1.3) 35 3 2 460 2.05 1.4 (0.9 to 1.8) 19 3 2 4

RR (95% CI) 1.88 (1.5 to 2.3) 2.08 (1.4 to 2.99) 3.8 (2.5 to 5.64) 3.14 (2.32 to 4.25)

a Based on a UK population aged 40 and above of 27,116,127 and the number of people of this age as reported in Table 8(p. 31).

b Assuming that each case of OAG has two blood relations in the target age group.

those aged 40 years and above of black raceand/or with a family history of OAG. Two sets ofestimates are provided in this table. The meanestimates were derived using the point estimatesof prevalence and relative risk of OAG along withthe information of the percentage of people in thepopulation with the target risk factors. The highestimates combined the upper values from the95% confidence intervals for relative risks andprevalence of OAG with information on thepercentage of people in the population with thetarget risk factors.

If the criteria for screening were extended toinclude those with myopia or diabetes thenapproximately 37% of the 100,000 total cohortwould be eligible for screening. The screeningstrategy would also have the chance to detectapproximately 80% of all the expected cases in thetotal cohort.

When considering the data presented in thissection it is essential to remember that all theestimates presented are associated withconsiderable uncertainty. Although they have beencalculated using the best available data theircalculation has required some very strongassumptions to be made. Furthermore, it shouldalso be borne in mind that although a

considerable number of cases of OAG will bemissed because they occur in people who are notpart of the eligible cohort it is still possible that atleast some of these cases will be detected withinthe community by case finding.

Consideration of screeningperformancePerformance of the strategies in termsof diagnosisThe relative performance of the screeningprogrammes considered has been estimated fromthe economic model reported in the section‘Economic evaluation of screening for OAG’ (p. 106). These estimates have been provided forthe comparison of a technician strategy withcurrent practice (no-screening strategy) for100,000 people with a prevalence of OAG of 5% at the start of screening (Table 65).

In the first year in which a screening programmewould be initiated, approximately 0.6% and 3.5%of the whole cohort would be referred to theophthalmologist with the no-screening strategyand technician strategy, respectively. This wouldenable approximately 49% of the total cases ofOAG within the 100,000 cohort of 40 year olds to


136

TABLE 64 Estimate of the number of people eligible for screening as well as the estimated number of cases in the eligible andineligible population

Overall population figures Mean High

Total cohort 100,000 100,000Eligible cohort (with a risk factor) 6,200 6,200Number eligible with glaucoma 437 437Number with glaucoma in total cohort 2,100 2,500Cases not called for screening, but may be picked up by case finding 1,663 1,772

TABLE 65 Performance of the tests in a 100,000 cohort at 5% prevalence of OAGa

Technician No screening

(1) Number of people referred to the ophthalmologist 3,535 611(2) Number of cases identified by the ophthalmologist as positive 2,456 376(3) Number of cases identified by the ophthalmologist as negative 1,079 235

(i.e. false positives of screening)(4) Of those judged as negative by the ophthalmologist in (3) above this number 464 101

will be kept under observation by the ophthalmologist(5) Number of true negativesb 93,698 94,542(6) Number of false negatives after the first yearb 2,283 4,363

a Numbers presented do not include the 485 people with each strategy who would be expected to die of natural causeswithin the first year.

b Includes people not presenting for screening or to the community optometrist.

be detected by the technician strategy comparedwith approximately 8% with the no-screeningstrategy (Table 65). It has been assumed within themodel that treatment will be initiated in all theseindividuals identified by the ophthalmologist ashaving OAG and that treatment would slow theprogression of the disease (treated cases of OAGhave a relative risk of progression of 0.65compared with untreated OAG).

In screening strategies not all those referred to theophthalmologist would have OAG. Of thosereferred to the ophthalmologist approximately38% and 30% of people would have beenincorrectly identified as positive for OAG (falsepositives) with the no-screening strategy andtechnician strategy, respectively (Table 65). This isequivalent to approximately 800 more falsepositives following technician screening. Within theeconomic evaluation the extra cost of investigatingthe false positives by the ophthalmologist has beenconsidered. What has not been considered is theanxiety that this may cause to someone who isincorrectly identified as having OAG. Themagnitude of this effect is uncertain, but in total itwill be greater for the technician strategy than forthe no-screening strategy.

Of the people referred to the ophthalmologist aspositive for OAG but for whom theophthalmologist does not make a diagnosis ofOAG (i.e. false positives), a proportion will still beconsidered as at risk and kept under furtherobservation. In the model it has been assumedthat these people will be followed up annually fora maximum of 5 years or until OAG is diagnosed(at which point treatment is commenced). Giventhe assumptions used within the model, inparticular the assumption of perfect diagnosis,none of the suspect cases actually has OAG whenthey start observation. They would, however, havea chance of developing OAG during the period ofobservation. Should this happen, the modelassumptions mean that any new cases of OAG thatdevelop will be identified (and treated). In the firstyear of screening approximately 0.4% of people inthe technician strategy arm and 0.1% of people inthe no-screening strategy arm would go into anobservation state (Table 65).

Even with the unrealistic assumption that thediagnostic performance of the ophthalmologist isperfect, these estimates illustrate the number ofpeople who would be held under observation bythe ophthalmologist with the technician strategy(further details of the numbers of people held inan observation state are reported in Appendix 26,

and further implications to both the NHS andthose people considered as suspect are consideredbelow).

The data presented above represent estimates forthe first year of screening. In the model used toderive these estimates it has been assumed thatscreening will be repeated every 10 years and thatpeople in both the technician and the no-screeningstrategy can be identified as having OAG by casefinding. Given that a high proportion of the casesof OAG is detected in the first year of screeningwith the technician strategy, the performance ofthe technician strategy would compare lessfavourably with the no-screening strategy insubsequent years because there would be fewercases of OAG to detect. Further details of theperformance of the alternative strategies over theduration of follow-up considered by the economicmodel reported in the section ‘Economicevaluation of screening for OAG’ (p. 106) areshown in Appendix 27. This appendix reports thenumber of people referred to the ophthalmologist,the number of these who are either true or falsepositives and the number of true and falsenegatives. From these data it is possible tocalculate the positive predictive value, the negativepredictive value and the sensitivity and specificityof the strategies for each year of follow-up(reported in Appendix 27). Consideration of thesedata may also help to inform a decision about themaximum age at which screening once initiatedshould continue (something that the evaluationhas not otherwise explicitly considered, but isworthy of further consideration).

Information on the diagnostic performancepredicted by the model can also be used toprovide estimates of the cost-effectiveness of thedifferent strategies in terms of incremental costper case detected. Table 66 reports the averagecost of diagnosis and probability of correctlydetecting OAG over the lifetime of a cohort of 40-year-old individuals for whom there is a 5%prevalence of OAG and for whom screening isrepeated every 10 years. Further details of thenumber of cases detected for both the technicianand the no-screening strategy are supplied inAppendix 28.

In the calculations that form the basis of the datapresented in Table 66 the cost of ophthalmologistshad been omitted. It should be noted that overthe remaining lifetime of a 40 year old there isapproximately a 17.6% chance of seeing anophthalmologist with the no-screening strategyand a 21.5% chance with the technician strategy.


137


The estimates provided in Table 66 also do notinclude cases of OAG that occur among peoplewho are held by the ophthalmologist inobservation. Given the assumptions within themodel of perfect diagnosis of OAG byophthalmologists, there is only a 6% and an 8%chance of a 40-year-old person entering anobservation state over their lifetime for the no-screening and technician strategy, respectively.The likelihood of OAG being detected in this stateis equal to the likelihood of a new case of OAGdeveloping.

Performance of the strategies in termsof visual impairmentOne indication of the importance of detectingcases of OAG is to consider both the number ofpeople who enter the state of severe OAG (i.e.losing vision to below the standard required fordriving) or visual impairment and the mean timespent in these states. Figure 49 describes thecumulative number of cases of visual impairmentthat are predicted by the model to occur over timefor both the technician and the no-screening

strategy. These estimates are based on a 40-year-old cohort which has a 5% prevalence of diseaseand is invited for screening every 10 years. Itshould be noted that it has been assumed that outof a total cohort of 100,000 a small number ofpeople will already be visually impaired. Hence, inthe figure the two curves for the number of peoplewith visual impairment cross the x-axis atapproximately 250 cases.

In addition to the estimates of the cumulativenumber of people with visual impairment it maybe important to consider how long people whohave visual impairment spend in this state(Table 67). In this table data have also been addedon the number of people with severe OAG, as thisis the stage where the OAG greatly affects activitiesof daily living (e.g. people may have to give updriving).

Fewer people develop severe OAG with thetechnician strategy, but they spend longer in thisstate compared with the no-screening strategy.This is because cases of severe OAG progress more


138

TABLE 66 Incremental cost per case detected for a 40 year old with a 5% chance of having OAG and assuming a 10-year screeninginterval

Strategy Cost (£) Incremental Average Incremental Incremental cost (£) cases detected cases detected cost per case

detected (£)

No screening 123 0.05351Technician 203 80 0.06255 0.0090 8823

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 10 20 30 40 50 60

No.

of c

ases

of v

isual

impa

irmen

t

Time since first screen (years)

No screening

Technician

FIGURE 49 Cumulative number of cases of visual impairment occurring over time for the initial cohort of 100,000

rapidly to becoming visually impaired, as isindicated by the greater number of peoplebecoming visually impaired with the no-screeningstrategy (Table 67).

A consequence of fewer and later cases of visualimpairment is that the estimated number of totalyears spent visually impaired on average is less forthe technician strategy than for the no-screeningstrategy. The average time spent visually impairedis on average also less with the technician strategy.

Implications for service provisionScreening, at least in the way in which thescreening strategies have been defined, is likely toresult in significant increases in the workload ofophthalmology departments. In part, this will bebecause more people will be correctly identified ashaving OAG. However, ophthalmologists may alsohave to deal with more people who have beenreferred to them as being potentially positive.Ophthalmologist departments may also have anincrease in their workload due to the increasednumber of people considered as suspect.

One aspect of service provision not included inthe economic model, which may also be affectedby a screening strategy, is the provision of servicesto those people who are visually impaired.Although the costs of these services may falloutside the health service (notably local authoritiesand the voluntary sector) they may be of sufficientmagnitude to change a decision about the cost-effectiveness of screening. Updating the estimatesfrom Meades and Hyde to 2006 UK pounds givesa cost of the first year of blindness of £7851 and acost for subsequent years of £7657 (the cost ofvision aids and rehabilitation were only incurredin the first year).299 As illustrated by Figure 48(p. 132), this is sufficient for the technician

strategy to be considered both less costly and moreeffective (i.e. dominant) compared with noscreening for a cohort of 40 year olds with a 5%prevalence of OAG. It is not, however, largeenough for the glaucoma optometrist strategy tobe associated with an incremental cost per QALYof less than £30,000 when compared with thetechnician strategy. It is clear that expanding theperspective of costs beyond the NHS will increasethe cost associated with visual impairment andhence improve the cost-effectiveness of screening.However, it is unclear whether improvement incost-effectiveness will be of sufficient magnitudefor society to consider screening to be worthwhilefor older age groups at risk of OAG.

A further implication for the provision of servicesnot considered by the economic model is thecapacity of screening to detect other significanteye disease. Such disease may be identified eitherby the community or glaucoma optometrists, or bythe ophthalmologist. Given the potentially largernumbers of people seen by these groups ofhealthcare professionals within the technicianstrategy, it might be expected that more cases ofother significant eye disease will be detectedcompared with the no-screening strategy. Shouldthis occur there would be a consequent increase inworkload and healthcare costs in order to managethese conditions (as well as, hopefully, animprovement in health).

Implications for patients and theirfamiliesThe economic model has not taken into account anumber of intangible benefits and disbenefitsassociated with the process of diagnosing OAG.These benefits and disbenefits may includeanxiety following either a true or a false positive,reassurance following a true negative and the


139


TABLE 67 Estimated time spent with severe OAG or visually impaired

Technician No screening Difference

Total individuals visually impaired 3,981 4,154 –173Total individuals with severe OAG 6,477 6,777 –300Total number of years visually impaired 81,690 87,652 –5,963Total number of years with severe OAG 52,043 50,780 1,263

For people who are visually impaired the average years spent as 20.5 21.1 –0.6visually impaired

For people who have severe OAG the average years spent with 8.0 7.5 0.5severe OAG

anger and despair following a false negative. With respect to anxiety following a true positive,some of this may be considered worthwhile ifdetection prevents or delays the onset of visualimpairment. However, for some people correctlydiagnosed as having OAG the anxiety may not beworthwhile. This may be because of theimportance they attach to the health consequencesof OAG or because the diagnosis of OAG will notresult in any health benefits in that person’slifetime.

In addition to the intangible benefits relating todiagnosis, earlier diagnosis may help to alleviatethe fear of becoming blind, which may beespecially acute for people with experience ofsomeone close to them becoming blind, such asthose with a family history of OAG.

There may also be an intangible effect on thoseexcluded from the screening programme. Forexample, people excluded from the targetpopulation for an active screening strategy may


140

TABLE 68 Balance sheet comparing the factors favouring screening or no screening (current practice)

For screening Comment Against screening

More cases of OAG detected resulting in: Unclear; probably, More cases of OAG detected and treated, • Better health on average on balance, favours resulting in:• Fewer cases of severe OAG and VI screening • More suffering from the side-effects of • Delay in onset of severe OAG and VI on average treatment• Fewer years of life spent with severe OAG and VI • More people experiencing the dislike of

on average continuing treatment• Lower costs to other sectors of the • Increased costs of monitoring of cases

economy of managing VI • Increased costs of treatment• Lower costs to patients and their families • Increased anxiety due to a diagnosis of

of managing VI OAG

Avoiding the false positives caused by no-screening, Favours no screening Large number of false positives identified at resulting in: as there are more every screen, resulting in:• Reduction in anxiety caused false positives with • Increase in anxiety among those• Reduction in the costs of diagnosis to the NHS screening incorrectly diagnosed as positive• Reduction in the costs of diagnosis to the patient • Increase in the costs of diagnosis

• Increase in the costs of diagnosis to thepatient

Avoidance of false negatives, resulting in: On balance, favours Avoidance of false negatives, resulting in:• Less loss of health due to untreated OAG screening • More anxiety as previously unaware of • Less regret and despair caused by late diagnosis diagnosis

• More side-effects of treatment

Screening involves the selection of at-risk groups, Unclear; probably, Screening involves the selection of at-risk resulting in: on balance, favours groups, resulting in:• Reassurance gained from knowing they have no screening • Anxiety among at-risk groups on being

access to screening informed they are at risk• Feelings of exclusion in those not eligible for

screening• Adverse health consequences and costs for

those not eligible for screening

More cases of other significant eye disease Unclear; probably, More cases of other significant eye disease detected and treated, resulting in: on balance, favours detected and treated, resulting in:• Better health on average screening • More suffering from the side-effects of • Fewer cases of VI treatment• Delay in onset of VI on average • More people experiencing the dislike of • Fewer years of life spent with VI on average continuing treatment• Lower costs to other sectors of the economy • Increased costs of monitoring of cases

of managing VI • Increased costs of treatment• Lower costs to patients and their families of • Increased anxiety due to a diagnosis of OAG

managing VI

VI, visual impairment.

have strong feelings about the fact that they areexcluded.

Further implications to patients and their familiesnot otherwise included in the analyses relate to the costs and worries (both to the individualand to the people providing informal care) ofvisual impairment. Although not measured orvalued, it would be expected that as the number of cases of visual impairment falls, the total costs and disbenefits associated with visualimpairment would fall. Furthermore, as thenumber of years spent with visual impairmentfalls, the costs and disbenefits of suffering visual impairment to the individual and carerwould also fall.

As indicated in the section ‘Implications forservice provision’ (p. 139), screening may lead tothe identification and treatment of othersignificant eye disease. Treatment of suchconditions may improve the health of theindividual (at extra cost to the health service), butit may also result in similar sorts of intangiblebenefits and disbenefits as described above.Furthermore, it may also reduce the costs andworries to both the individual and any carers forthose who may otherwise have gone on to developsome degree of visual impairment caused by other

significant eye disease that affects the activities ofdaily living.

SummaryIn this chapter an attempt has been made tohighlight the consequences of alternativescreening strategies based on selected groups. Anattempt has also been made to consider theimplications for the health service, other sectors ofthe economy and the individuals who may beconsidered eligible or ineligible for screening.Within the evaluation conducted as part of thisstudy not all of these implications have beenexplicitly measured and valued. This does notnecessarily mean that such potential effects shouldbe ignored. Table 68 summarises the implicationsfor the NHS, other sectors of the economy andthe potential recipients of screening. This hasbeen presented as a balance sheet where anattempt has been made to consider the likelydirection of effect, even if the magnitude of theeffect has not been measured and valued. In thisbalance sheet those factors not explicitly measuredor valued are shown in italic. It is a matter fordecision-makers to consider whether any or all ofthese issues are pertinent to the decisions theyhave to make.


141


The UK NSC assesses proposed new screeningprogrammes against a set of internationally

agreed criteria covering the condition, the test,the treatment options, and effectiveness andacceptability of the screening programme.Assessing programmes in this way is intended toensure that they do more good than harm at areasonable cost. This chapter assesses whetherscreening for OAG in the UK would meet the NSCcriteria based on the evidence presented in theprevious chapters.

The authors’ views on the extent to which eachcriterion is satisfied is appended after eachcriterion.

The conditionThe condition should be an importanthealth problemGlaucoma is second to age-related maculardegeneration as the most common cause ofblindness in adults in the UK. Glaucoma blindnessis particularly disabling as navigational vision isimpaired and severely restricts independentmobility and the ability to self-care.

The major risk factor for developing glaucomablindness is late presentation with advanceddisease. Currently, an estimated 67% of cases ofOAG are undetected by the current practice ofopportunistic case finding. Thus, it is likely thatimproving detection strategies for populationgroups at risk of sight-threatening OAG wouldreduce the incidence of visual impairment due toOAG. This review has addressed whether ascreening programme for OAG is effective andcost-effective in preventing severe disease andvisual impairment. Severe disease refers tosufficient visual loss such that one is not able todrive, and visual impairment means being blindor partially sighted.

Best estimates suggest that 3108–3138 peopleaged over 50 years were newly registered withvisual impairment (blind and partial sight) due to

glaucoma in England and Scotland in 2002/03. Ofthese, at least 1192 new registrations were dueto OAG as the main cause, but the true number

may be higher than this, as some OAG caseswould have been registered as glaucoma non-specified.

Criterion met? Yes.

The epidemiology and natural history ofthe condition, including developmentfrom latent to declared disease, shouldbe adequately understood and thereshould be a detectable risk factor,disease marker, latent period or earlysymptomatic stageThe systematic review of the epidemiologyidentified risk factors for developing OAG. Theseare: increasing age, higher levels of IOP, Africanethnicity, diabetes, myopia and family history in afirst-degree relative. Insufficient data were availableto estimate the prevalence of OAG in other ethnicminority groups in the UK. Further research isrequired to quantify these risks at different ages.

In early glaucoma, structural changes at the opticnerve may precede functional visual loss and thispotentially identifies a latent period beforeglaucomatous visual field loss. The visual loss inearly glaucoma is in the mid-peripheral field ofvision and individuals may not perceive a visualdifficulty or incorrectly attribute symptoms to anormal ageing process. In the late stages ofdisease the visual field loss impacts on centralvision and reduces HRQoL. Treatment at an earlystage can prevent serious visual impairment, aspresenting late with already advanced disease is amajor risk factor for blindness.

Criterion met? Yes.

All the cost-effective primaryprevention interventions should havebeen implemented as far as practicableOAG is not amenable to primary prevention. Theonly potentially modifiable risk factor is diabetesmellitus, but this is unlikely to have an impact as


143


Chapter 10

Does screening for open angle glaucoma meet the National Screening Committee criteria?

the proportion of cases in the population that areattributable to diabetes is low.

Criterion met? Yes.

If the carriers of a mutation areidentified as a result of the screening,the natural history of people with thisstatus should be understood, includingthe psychological implicationsGenetic screening is not indicated, as only a smallnumber of cases have an identifiable genemutation. Research is ongoing looking forcausative gene mutations that may be implicatedin adult-onset OAG, and also for mutations thatare a determinant of raised IOP. If a genemutation is identified that is a major determinantof adult OAG, a case for genetic screening couldbe considered.

Criterion met? Not currently relevant.

The testThere should be a simple, safe, preciseand validated screening testThere are numerous potentially suitable screeningtests for OAG. The systematic review of screeningtests found that all tests perform reasonably welland no single test (or strategy) is clearly betterthan the others. Furthermore, within the rangeobserved, the performance of the screeningprogramme (as judged by its cost-effectiveness)was not particularly sensitive to test accuracy.However, data were of limited quality and itremains unclear what the optimal testing strategyshould be.

Criterion met? No.

The distribution of test values in thetarget population should be known anda suitable cut-off level defined andagreedAppropriate cut-offs are available for standardoptic disc photography and visual field testing.There are widely used cut-offs for IOP and theappropriate choice depends on how IOP testing iscombined with other screening tests. More recenttechnologies (e.g. HRT, SLP, OCT and FDT) havethe advantage over subjective assessments in that‘machine classifiers’ have been developed todefine abnormal results, but these cut-offs may notbe appropriate for a screening situation. Furtherresearch is required to determine suitable cut-offsand test accuracy in a screening setting.

Criterion met? Partially met.

The test should be acceptable to thepopulationOverall, the tests are safe. There are potentialminor risks with some of the tests. IOP testingusing applanation may have a potential for cross-infection, but disposable tips can be used toeliminate the risk. Rarely, incorrect applanationtonometry may result in a corneal abrasion. Thiswould be unacceptable and painful, although itusually heals in 24 hours. NCT avoids these risks.Ophthalmoscopy and photography requiredilation of the pupil, which is associated with someshort-term discomfort (1–2 hours) such as lightsensitivity and glare. Rarely, pupil dilation canprecipitate angle closure glaucoma, but ifappropriately warned of the symptoms thecondition is easily treated. Objective tests ofstructural damage and functional tests do notrequire pupil dilation.

These potential concerns were discussed withrepresentatives from a patient organisation (theIGA). In the opinion of all five participants, thesewere potential risks and discomfort that ifexplained at the time of screening were acceptable.

Criterion met? Yes.

There should be an agreed policy onthe further diagnostic investigation ofindividuals with a positive test resultand on the choices available to thoseindividualsDiagnostic investigation of the positives onscreening would be best placed in a communityoptometric setting. The evaluation has evaluatedthe costs and benefits of using a care pathwaywhereby optometrists, who have received additionaltraining in glaucoma assessment, examine screenpositives, with positives from the optometristassessment referred to an ophthalmologist. Thispathway fits with current initiatives by theDepartment of Health, the Scottish Executive andthe Wales Eye Care Initiative in their reviews ofgeneral ophthalmic services.51–55,296


If the test is for mutations the criteriaused to select the subset of mutationsto be covered by screening, if allpossible mutations are not beingtested, should be clearly set out

Criterion met? Not relevant.


144

The treatmentThere should be an effective treatmentor intervention for patients identifiedthrough early detection, with evidenceof early treatment leading to betteroutcomes than late treatmentEvidence from two RCTs of treatment comparedwith no treatment suggests that treatment in earlydisease slows the rate of progression.Extrapolating from this, and assuming acceleratedprogression with advancing disease severity, it canbe estimated that, without treatment, the meantime to blindness in at least one eye is 23 years,and with treatment this is approximately 35 years.The extrapolation from medium- to long-termoutcome is supported by evidence fromretrospective, observational studies of the risk ofblindness from glaucoma, although results fromthese studies should be interpreted with caution,as selection bias is likely. Data from prospective,long-term cohort studies are required to confirmthese findings.

From the limited data available, a patient’svaluation of their health status (utility value)decreases, as expected, as glaucoma becomes moresevere. The modelling of a screening strategy andtreatment effectiveness to long-term outcomesuggests that earlier detection and treatmentimproves health status compared with noscreening. Further research is required to developvalid and reliable measures of visual disability andquality of life in glaucoma, and to determine howearly detection and treatment impact on patient-reported health outcomes.

Criterion met? Yes.

There should be agreed evidence-basedpolicies covering which individualsshould be offered treatment and theappropriate treatment to be offeredClinical guidelines for the treatment of OAGexist.3,5,7,304 Evidence-based guidelines for themanagement of OAG are in development as partof the clinical guidelines programme of NICE.305

Criterion met? Yes.

Clinical management of the conditionand patient outcomes should beoptimised in all healthcare providersprior to participation in a screeningprogrammeIn the UK, various healthcare practitioners areinvolved in the detection and management of

glaucoma: optometrists, nurse practitioners andophthalmologists. Overall responsibility rests withthe consultant ophthalmologist. There areconcerns that, with an ageing population andimproved detection of OAG, the current hospitaleye service for managing detected cases willbecome overloaded. Initiatives to define anddevelop a glaucoma clinical care pathway areunderway. These, together with a review of generalophthalmic services and a connected informationtechnology system in the NHS, provide the basisfor a standardised diagnostic and treatmentservice for glaucoma.

Criterion met? Yes, in principle.

The screening programmeThere should be evidence from high-quality randomised controlled trialsthat the screening programme iseffective in reducing mortality ormorbidityNo RCTs of the effectiveness of screening for OAGwere identified.

Criterion met? No.

There should be evidence that thecomplete screening programme (test,diagnostic procedures,treatment/intervention) is clinically,socially and ethically acceptable tohealth professionals and the publicNo studies on the social and ethical acceptabilityof screening were identified, but in view of thesafety and non-invasive nature of the tests, majorconcerns on acceptability would not beanticipated. It is likely that if screening were to beconsidered it would be targeted at higher riskgroups, such as people with a family history ofglaucoma or of African ethnicity, covering about6% of the UK population. This might beconsidered unacceptable for the majority of thepopulation not called for screening.

Currently, the only identifiable risk factor foridentifying people to attend for screening is age.It is feasible that specific age cohorts could beidentified and invited to complete a questionnaireof risk factors, and then those at risk could beinvited for screening. However, self-reporting ofrisk factors other than ethnicity is likely to beunreliable. Ethnic minority groups may be lesslikely to attend for screening, and campaigns toimprove communication and awareness of


145


glaucoma, its effect on vision and the importanceof attending for testing would be needed.

Discussion with representatives from a patientgroup (the IGA) highlighted the fact that ascreening programme would be very welcome, andno concerns were raised about harms of screening.However, this was a very small sample and theviews of this select group are likely to be in favourof screening.

Further research is required on patient preferencesfor screening compared with no screening, and apatient-based valuation on the benefits and harmsof screening.

Criterion met? No.

The benefit from the screeningprogramme should outweigh thephysical and psychological harm (causedby the test, diagnostic procedures andtreatment)Potential harms of screening include concernsregarding overdetection (i.e. identifying OAG at astage that is not likely to cause significantimpairment in a person’s lifetime), anxiety andinconvenience associated with being falselyidentified as positive, being a missed case, andadverse effects that may be associated withtreatment of a condition that is asymptomatic atdetection.

Even in higher risk groups, the prevalence of OAGis low, and this evaluation suggests that 30% of thetest positives would be falsely identified as OAG(although 43% of these would be suspect andrequire observation), and thus have the consequentanxiety and inconvenience associated with this.However, the balance of this is that screeningdetects more cases, but this may also be associatedwith more anxiety and side-effects of treatment.

No adverse effects of screening tests were reportedin the systematic review. The potentialpsychological harms of screening, being a falsepositive or a false negative, were not reported.Medical treatments for OAG can have adverseeffects; these may be local eye discomfort, orsystemic, particularly with topical �-blocker agents.Alternative medications, for example withprostaglandin analogues, have better safety andeffectiveness profiles.

Any harmful effects of screening should beconsidered as important outcomes in an RCT ofscreening for OAG compared with no screening.


The opportunity cost of the screeningprogramme (including testing, diagnosisand treatment, administration, trainingand quality assurance) shouldeconomically balance in relation toexpenditure on medical care as a whole(i.e. value for money)The economic evaluation suggests that screeningis cost-effective in a cohort of people aged 40, and possibly aged 50, if OAG prevalence is 4%with a screening interval of 10 years. At 60 yearsthe prevalence would need to be 6% to beconsidered cost-effective. The evaluation hasidentified certain target groups (black ethnicity,family history of OAG in a first-degree relative)where screening may be cost-effective. Othergroups at risk are people with myopia anddiabetes, but the prevalence is lower and it isunlikely to be cost-effective to screen these groups.

The economic evaluation has identified how ascreening service might be organised in that atechnology-based screening test for OAG is morecost-effective than a full ophthalmic assessment bya specialist optometrist. The evidence on cost-effectiveness should be treated cautiously, as theestimates used in the model are associated withconsiderable uncertainty.

Criterion met? No.

There should be a plan for managingand monitoring the screeningprogramme and an agreed set ofquality assurance standardsThis would need to be instituted.

Criterion met? Not yet.

Adequate staffing and facilities fortesting, diagnosis, treatment andprogramme management should beavailable prior to the commencementof the screening programmeThis is potentially feasible, but additionaltechnical staff would need to be trained, andtesting sites in primary care equipped andestablished. It is possible that a screeningprogramme for OAG could use the sameinfrastructure as the National ScreeningProgramme for sight-threatening diabeticretinopathy.

Criterion met? Not yet.


146

All other options for managing thecondition should have been considered(e.g. improving treatment, providingother services), to ensure that no morecost-effective intervention could beintroduced or current interventionsincreased within the resources availableIn the absence of screening, an improvedattendance rate for a sight test and an improvedperformance of the community optometrist atdetecting glaucoma would improve theeffectiveness of current case detection. However, ifthis improved performance of the communityoptometrist involved an increased cost ofproviding this eye examination, at levelsapproaching the cost of an assessment by aspecialised optometrist, then improving theperformance of current practice might not be acost-effective approach to improved casedetection. The economic modelling suggests that,although screening by a glaucoma optometrist ismore effective, it is more costly than a technicianstrategy.

Awareness campaigns, aimed at improving theuptake of sight testing and earlier detection,might be effective at preventing late presentationwith severe disease and improve health outcome.Further research is required on the effectivenessand cost-effectiveness of such an approach.

Criterion met? No.

Evidence-based information, explainingthe consequences of testing,investigation and treatment, should bemade available to potential participantsto assist them in making an informedchoiceThis evaluation provides evidence-basedinformation on the consequences of testing,investigation and treatment such that guidelinescould be produced, although more robustevidence is required on the long-term healthoutcomes and any potential harmful effects ofscreening to inform patients fully of theconsequences of screening.


Public pressure for widening theeligibility criteria for reducing thescreening interval, and for increasingthe sensitivity of the testing process,should be anticipated. Decisions aboutthese parameters should bescientifically justifiable to the publicThe economic model provides scientificallyjustifiable evidence for the optimal screeninginterval and the performance of the screeningprogramme. However, there are uncertainties inthe parameter estimates in the model, inparticular regarding the uptake of screening,disease progression, utility and costs associatedwith screening particular patient groups wherescreening may be most relevant. Further researchto improve these parameter estimates is required.

Criterion met? Yes.

If screening is for a mutation theprogramme should be acceptable topeople identified as carriers and toother family members

Criterion met? Not relevant.

SummaryScreening for OAG meets the UK NSC criteriaregarding the condition and treatment, but doesnot meet most of the criteria for the test or ascreening programme. Population screeningappears not to be cost-effective, but targetedscreening of high-risk groups may be. However, ifa societal perspective on the costs of visualimpairment is taken screening is more likely to beconsidered cost-effective. Measures to identifysystematically those at risk and quality assure theprogramme would be required. Adequate serviceprovision for the screen positives would need to beestablished.


147


Main resultsThe purpose of this evaluation was to assesswhether screening for OAG met the UK NSCcriteria for a screening programme. In the absenceof any evidence from RCTs of screening, a Markovmodelling approach was used, informed by aseries of systematic reviews, which compared theclinical and cost-effectiveness of screening forOAG with the current practice of case finding.Given the perspective of the analysis, the data onthe effectiveness and more especially the cost-effectiveness may be of limited transferability toother countries.

An evaluation against the NSC criteria was avaluable tool to identify areas where the evidencewas inadequate to make a judgement on whether ascreening programme should be initiated.Screening for OAG met the criteria regarding thecondition and the treatment, but did not meetmost of the criteria for the test or a screeningprogramme.

Screening using a strategy of inviting the at-riskcohort to a primary care setting for a measure ofIOP, and a second test for people with IOP below26 mmHg (the technician strategy), was moreeffective but more costly than a no-screeningstrategy. Screening by invitation to attend a highlytrained optometrist for an ophthalmic assessmentwas more effective but more costly than thetechnician screening strategy. The maindeterminant of cost-effectiveness was theprevalence of disease: the higher the prevalencethe more likely screening would be cost-effective.With screening, fewer people become visuallyimpaired (defined as partial sight and blind) andspend less time with visual impairment. Likewise,fewer people lose vision to below driving standard,although with screening, time spent in this severestate is longer, as progression to the state of visualimpairment is less likely to occur.

Taken at face value, the economic evaluationsuggests that general population screening forOAG is not cost-effective at any age. Theprevalence level would have to be in the region of3–4% in 40 year olds with a screening interval of10 years to approach what might be considered

cost-effective. The prevalence of OAG in a 40-year-old cohort is around 0.3%; at thisprevalence level there is very little likelihood thatany screening strategy would be considered cost-effective compared with current practice. Similarly, in a 60-year-old cohort the prevalence ofOAG would have to be about 6% to be consideredcost-effective at screening intervals of 5 or 10years: the prevalence of OAG in this age group isabout 1.4%.

An important factor in assessing cost-effectivenesswas the cost of visual impairment. The costs ofvisual impairment in the model were based ontreatment costs, from an NHS perspective. If awider societal perspective of costs is taken, then itis likely that the NHS cost of visual impairmentused within the model is an underestimate. This isbecause it does not include the costs falling onindividuals, carers and society in terms of loss ofindependence, and the need for social support.The threshold analysis conducted as part of theeconomic model suggests that, for a 40-year-oldcohort with a 1% prevalence of OAG, thetechnician strategy would be associated with anincremental cost per QALY of £30,000 comparedwith current practice should the annual costs ofvisual impairment be £8800. This isapproximately £1000 per year higher than theannual cost estimated by Meads and Hyde.299

Should the prevalence of OAG be 5%, then thetechnician strategy would be more effective andless costly than current practice if the annual costof visual impairment was £5700 per year.Recognising higher personal and societal costs ofvisual impairment makes screening considerablymore likely to be cost-effective even at lowerprevalence levels.

The results of the model indicate that even thoughthe prevalence is lower, screening younger peopleappears to be the more cost-effective option. Thisis because the risk of developing visual disabilityand reduced quality of life is more likely over alonger lifetime. Screening high-risk groups (blackethnicity and family history) might be worthwhile,but for these groups at 40 years the prevalence ofOAG is in the region of 1–2% and therefore nothigh enough to consider screening. At 50 years,the prevalence is higher, estimated as between


149


Chapter 11

Discussion

2 and 5%, and approaches levels where screeningmight be considered. The model has not explicitlyconsidered screening a 50-year-old cohort.Interpolating from the results of the model on 40-year-old and 60-year-old cohorts, one wouldpredict that screening every 10 years might be cost-effective in a 50-year-old cohort at a prevalence of4%. Targeted screening of those groups with thehighest risk of having OAG would, however, onlycover a small proportion (6%) of the populationand this might be considered unacceptable.Extending the target population to include otherhigher risk groups (myopia and diabetes) wouldgive greater population coverage (37%), but theprevalence estimates in 40–60 year olds are mostlikely to be 0.6–3.6% and, as such, not sufficientlyhigh to be considered cost-effective.

At the first screen for a cohort with a 5%prevalence of OAG, using a technician strategygave a positive predictive value of screening of52% compared with 62% for case finding. Thenegative predictive value was 98% and 96%,respectively. Screening detects more cases, but witha consequent increase in false-positive referrals,which has considerable implications for serviceprovision. Initiatives to develop glaucoma carepathways are underway in the UK,51–55,296 and theimplications of screening, if it is to be considered,would need to be incorporated into any futurereconfiguration of eye care services.

The only readily identifiable risk factor currentlyavailable for inviting people to screening is age. Itis feasible that specific age cohorts could beidentified and invited to complete a questionnaireof risk factors, and then at-risk people invited forscreening tests. However, self-reporting of riskfactors other than ethnicity is likely to be unreliable.Inviting people with a family history of OAG forscreening also poses considerable problems. Anational register of all newly diagnosed cases ofOAG would be required. This should be possible,but the initial costs of setting up this surveillancehave not been incorporated into the economicmodel. The review has identified that people ofblack ethnicity have a higher risk of OAG. Therewere insufficient data to estimate the risk of OAGin other ethnic minority groups in the UK.Restricting screening to select minority groups islikely to be socially unacceptable. Future researchshould examine prevalence according to ethnicityand the acceptability of offering glaucoma testingto only selected at-risk groups.

In the absence of screening, an improvedattendance rate for an eye test among at-risk

groups and an improved performance of thecommunity optometrist at detecting OAG wouldimprove the effectiveness of current casedetection. However, if the improved performanceof the community optometrist involved anincreased cost of providing the eye examination, atlevels approaching the cost of a glaucomaoptometrist test, then improving the performanceof current practice might not be a cost-effectiveapproach to improve case detection. The results ofthe economic modelling indicate that atechnology-based screening test, rather thanscreening by a full optometric examination, ismore likely to be cost-effective; as only those withsuspect pathology go on to a more costly buteffective full assessment, the feasibility ofintroducing automated testing into a primary caresetting merits consideration. One high-risk group,namely people with diabetes, is already includedin a screening programme for diabeticretinopathy, and this programme could bemodified to include testing for glaucoma.Similarly, myopes, another higher risk group, arelikely to be attending for eye tests andconsideration should be given to improvedawareness and case detection in these individuals.

When considering interventions to improve uptakecurrent eye care services an understanding of thebarriers to attendance for eye testing is required.Improved communication and awarenesscampaigns on the importance of attending forregular eye examinations would be required toimprove uptake. An ongoing study inBirmingham, UK,306 is assessing attitudes andbeliefs related to eye disease and factors associatedwith presenting late to the eye-care services. Thisstudy will provide insight and estimates of howlikely it is that high-risk groups would attend forscreening.

Assumptions, limitations anduncertaintiesA series of systematic reviews was undertaken anda language restriction was applied (except for thereports on effectiveness of screening). Thisrestriction is a potential source of bias; however itwas felt that studies reported in English were mostlikely to be relevant to the UK context. Despite asystematic search of the literature, data on thesensitivity and specificity of current optometricpractice were not identified and assumptions hadto be made. Data were available on the positivepredictive value of testing, but details on thenumber of false negatives were not reported or,

Discussion

150

more likely, the negatives on optometricexamination were not assessed by a referencestandard to ascertain whether they were true orfalse negatives.

The decision to use a cut-off of IOP of 26 mmHgwas based on expert opinion. Although the IOPdistribution in the population is known, thesystematic review found only two studies thatreported the risk of OAG according to IOP innewly detected cases. Although IOP does notdefine OAG, a higher risk of progressive disease athigher levels of IOP is reported,25,27 and moresevere disease at presentation is associated withhigher levels of IOP.28 In the systematic review ofscreening tests (Chapter 6), there were insufficientdata to determine what IOP cut-off would give thebest balance between sensitivity and specificity.Most studies reported a cut-off of above21 mmHg. In the economic model, results fromone population-based study in the USA were usedto estimate the proportion of people with an IOPof 26 mmHg or above who did or did not haveglaucoma, and similarly for people with an IOPbelow 26 mmHg. Data from this study were usedto create a beta distribution around this estimateto reflect its considerable imprecision, but thereare concerns that these data may not be applicableto the UK. The model only looked at two out ofmany possible screening strategies; in particularIOP measurement was used and GAT specified aspart of the technician-based screening pathway.The model structure is such that other tests ofIOP, such as NCT, could be considered, and basedon the results of the sensitivity analyses on costsand test performance the decision regarding cost-effectiveness would not be expected to change.Within the whole economic model-based analysesit was assumed that the ophthalmologistassessment was the gold standard. In terms of themodel this means that ophthalmologist assessmentsensitivity and specificity are equal to 1. In otherwords, these professionals have perfectinformation and do not make mistakes in theirpatient management decisions. While this mightnot be the case, all test characteristics werecalculated against ophthalmologist assessment.Should this perfect information assumption berelaxed, another reference standard should bechosen against which every test sensitivity andspecificity within the model, as well asophthalmologist assessment, should be tested.

The results of the deterministic economic analysispresented do not take into account theimprecision around the data used to deriveestimates of cost-effectiveness. This imprecision

was reflected in the probabilistic sensitivity analysisin the model; it was shown that the prevalence ofOAG would have to be 5% in a 40-year-old cohortfor technician-based screening to have a 55%chance of being considered cost-effective. For a60-year-old cohort and at this prevalence level themodel suggests that screening is unlikely to becost-effective.

Extensive sensitivity analyses explored the effectsof changing the parameter estimates used in themodel. The important drivers of estimates of cost-effectiveness were considered to be the attendancefor sight tests in current case finding, the rate ofglaucoma progression, the utility estimatesassociated with each stage of glaucoma and thecosts of visual impairment.

One of the findings of the economic model wasthat more frequent attendance for eye testing in ano-screening strategy may affect the cost-effectiveness results; this higher rate of attendancefor sight testing is likely to apply to people withmyopia or diabetes and those aged 50–60 years,prompted by the need for reading glasses. Thismay also apply to family members of known casesof OAG, as they are more likely to be aware of thesignificance of OAG and the risk to vision. Otherhigh-risk groups may attend less frequently forsight testing, making screening more cost-effective,although it might be expected that such groupswould also have a lower uptake of screening. In theUK, if an African-derived population were to beinvited for screening the attendance could beexpected to be as low as 40%.120 In the economicmodel an uptake of screening of 78% has beenassumed, with a minimum of 66% and a maximumof 92%. The net effect of lower uptake rates inethnic minority groups on the cost-effectiveness ofscreening is uncertain.

A sensitivity analysis around screening a 40-year-old cohort, using a technician-basedstrategy, at an OAG prevalence of 5% with arescreen every 10 years, found that, as expected,cost-effectiveness increased as the sensitivity andspecificity of the screening test used in thetechnician-based strategy increased. However, thesensitivity analysis found that the sensitivity andspecificity of the screening test over the rangesconsidered did not greatly alter the estimates ofcost-effectiveness. The specificity of the test doesaffect the impact that screening would have ondiagnostic services; a highly specific test isrequired to reduce the large numbers of false-positive referrals from any of the screeningstrategies.


151


The systematic review of the accuracy of potentialscreening tests found that no test, or combinationof tests, was clearly superior as a screening test.For the potential tests on which data wereavailable, the sensitivity was at least 50%, apartfrom IOP measurement, and all tests hadspecificity above 80%, apart from one test, FDT C-20-5, which had a specificity of 75%. There isuncertainty around all the estimates as the resultsare based on indirect comparisons and, as such,are prone to bias due to differences in thepopulations studied. In a screening situation it isimportant that the majority of people to bescreened are able to perform the test and haveresults that can be read. In general, across all thetests 80–99% of the people tested were able toperform the test adequately. For some tests thatwere considered as potential candidate tests forOAG screening, no studies met the inclusioncriteria for the accuracy review. As a result, thisresearch has not been able to provide estimates forthe test accuracy of SLP (the GDx VCC), OCT orthe RTA.

The review of treatment effectiveness suggests thatwith treatment at an early stage of disease, the riskof progressive visual loss is reduced byapproximately 35%, delaying time to blindness onaverage by 12 years. The treatment effect on long-term outcomes may be better or worse than thisaverage effect. There was insufficient evidence todetermine the rate of progression for differentstages of OAG severity or different at-risk groups,and thus the rate of progression in higher riskdisease is uncertain. A higher rate of progressionwould make screening more likely to beconsidered cost-effective.

There were limited published data for estimatingthe utility loss associated with different severities ofOAG.298,307 The populations used in these studieswere not necessarily representative of a UKpopulation, and as a result this evaluation usedutility estimates as measured by the EQ-5D, in 264people with glaucoma in whom severity was self-reported, apart from a subset (63 people) in whomdisease severity was validated based on binocularvisual field loss. This generic measure of healthstatus may not adequately capture the utility lossdue to glaucoma. However, the generic health state

utilities were estimated using the EQ-5D based onUK population tariffs and such an approach hasrecently been advocated as being a necessary partof the reference case for health technologyassessments conducted on behalf of NICE.297

The utility estimates used in the base case mayalso be imprecise as they were based on a smallsample of glaucoma patients with validated diseaseseverity. Using estimates based on the subjectiveassessment of disease severity led to both thetechnician and the glaucoma optometriststrategies being more likely to be considered cost-effective. For example, the likelihood for thetechnician strategy being considered optimal rosefrom less than 50% to about 61% and over 70%when society’s willingness to pay for a QALY was£20,000 and £30,000, respectively.

The costs of visual impairment in the model werebased on treatment costs, from an NHSperspective. If a wider perspective of costs istaken, then it is likely that the cost of visualimpairment is an underestimate, and does notrecognise the cost on individuals, carers andsociety in terms of loss of independence, and theneed for social support. Recognising higherpersonal and societal costs of visual impairmentmakes screening considerably more likely to becost-effective.

The model has not taken into account otherpotential benefits of screening for OAG, mainlythe possibility of detecting other treatable eyedisease. Both screening strategies are likely todetect other eye pathology. This is an additionalbenefit, but may be a negative consequence ofscreening in that referrals to ophthalmologyservices will be increased, and some of these willbe false-positive referrals. It is unclear what effectthe inclusion of costs and other effects of detectingother eye disease would have on the relative cost-effectiveness of screening. It might be expectedthat a glaucoma optometrist strategy would detectmore cases of other significant eye disease, butwould result in increased costs of diagnosis andtreatment. How this might affect the relative cost-effectiveness of the ‘glaucoma optometrist’strategy compared with the ‘technician’ strategy isalso uncertain.

Discussion

152

Implications for healthcareBased on the available evidence derived from the economic model, population screening of age cohorts between 40 and 75 years is notconsidered to be cost-effective. The model wasparticularly sensitive to estimates of prevalenceand costs of visual impairment. Selective screeningof groups with higher prevalence, such as thoseaged between 50 and 60 years with a familyhistory of OAG, or of people of black ethnic originmay be worthwhile. Selective screening of thesegroups covers 6% of the population cohort andtherefore would only have the chance to detect20–30% of all the expected cases in the 50- or 60-year-old cohorts. Moreover, systematicallyidentifying those at risk is not currently feasible inthe UK.

The positive predictive value of the more cost-effective screening strategy, based on a screeningtest that does not require skilled interpretation, isabout 52%, with a negative predictive value of98%, and as such detects more cases but alsoresults in a large number of false-positive referrals.This has implications for the ophthalmologyservices.

Based on the results of the model there are twostrategies that will improve current case detection,namely improving the attendance rate for eyeexamination generally, particularly in high-riskgroups, and improving the performance of currentoptometric assessment, either by refiningoptometric practice or by adding in a technology-based first assessment, the latter being the morecost-effective option. This has implications for anyfuture organisational changes in community eye-care services in that if, in the absence of screening,recommendations are made to improve casefinding, then recommendations that at-risk peoplerequire a full assessment by a specialisedoptometrist may not be the best use of healthcareresources, and the feasibility of improving casedetection by an initial automated test strategy in acommunity setting should be explored. Theeconomic evaluation suggests that the diagnosticskills of the optometrist are best utilised forpeople testing positive on an initial technology-based examination for OAG.

These recommendations that population screeningis unlikely to be cost-effective are based on theresults of an economic model; the parameterestimates are associated with considerableuncertainty and should be interpreted withcaution. In particular, if the rate of progressionand the costs of visual impairment are higher thanestimated then screening is more likely to be cost-effective. For example, the annual cost of visualimpairment would need to be £8800 for thetechnician strategy to have an incremental cost perQALY of £30,000 for a 40-year-old cohort with a1% prevalence of OAG. At a 5% prevalence levelof OAG, technician screening would be dominant(more effective and less costly) when the annualcost of visual impairment is £5700 or greater.

Priorities for further researchAn RCT of screening is considered to be theoptimal design to determine the benefits ofscreening. However, before initiating a trial,further research should aim to develop andprovide quality data to populate the economicmodel. The model only considered a limited set ofscreening and case-finding strategies, and furtherresearch is required to determine what an optimalscreening or case-finding strategy could be.

Priority 1: feasibility of screening strategiesThis research has several components and wouldinvolve input from qualitative researchers, healthpsychologists, health economists and trialists. Themain requirements are:

● to establish how the risk groups could beidentified; multiple identification strategieswould be required according to risk factor

● to determine the optimal test strategy in acommunity setting; this study should explorehow a technician strategy might beincorporated into existing visual assessments,for example, as part of the diabetic retinopathyscreening programmes

● to explore the acceptability of interventions toimprove attendance for glaucoma testing andthe acceptability of subsequent testing usingestablished models of behaviour change fromhealth psychology

● to value any potential harms and benefitsassociated with screening (or targeted case


153


Chapter 12

Conclusions

detection) by exploring the strength ofpreferences of potential users of the serviceusing established health economicsmethodology.

Priority 2: identifying weaknesses in the model,and improving parameter estimatesThere is considerable uncertainty regardingparameter estimates used in the model as theavailable data were considered to be too limitedand of too poor quality to provide reliableestimates. Prospective data collection on the costsof detection, management and costs of visualimpairment could be collected in the context ofcurrent service provision. Improved monitoring ofhealth outcomes in large populations usingregisters of blindness by cause would providesurveillance for the estimation of the impact ofprevention strategies over time. Surveillance

systems should explicitly consider how to ensurecompleteness of ascertainment. Improvedestimates of health status, both patient reportedand estimates of the risk of progressive loss ofvisual function, are required. As further data,including new information as to how a screeningstrategy might be organised, become availablethese should be used to refine the model. A value for information analysis is indicated todetermine which data have most impact on themodel results and hence where future primaryresearch should be directed to inform decision-making.

Priority 3: improving uptake of glaucoma testingAn RCT of interventions to improve the uptake ofscreening, or enhanced case detection, informedby the results of the prior feasibility studies isindicated.

Conclusions

154

We thank members of the steering committee(Augusto Azuara-Blanco, John Cairns, Jon

Deeks, Adrian Grant, Stephen McPherson,Richard Wormald, and David Wright) for adviceand support and Bronwyn Davidson for secretarialassistance. We thank Rod Taylor and NormanWaugh for advising on the development of theprotocol and commenting on drafts of the review.We thank the patient representatives from theInternational Glaucoma Association, and DavidGarway-Heath, David Henson, Anja Tuulonen andStephen Vernon for their clinical expert input intothe development of the screening pathways andeconomic model. We thank Sarah Hatt (Editor,Cochrane Eyes and Vision Group) and an authorof the Cochrane review on screening forprevention of optic nerve damage due to OAG, asummary of which is provided in Chapter 7.

This report was commissioned by the NHS R&DHealth Technology Assessment Programme. Theviews expressed in this report are those of theauthors and not necessarily those of the NHSR&D HTA Programme. Any errors are theresponsibility of the authors.

The Health Services Research Unit and the HealthEconomics Research Unit are both core funded bythe Chief Scientist Office of the Scottish ExecutiveHealth Department. The views expressed in thisreport are those of the authors and not necessarilythose of the funders.

Contribution of authorsJennifer Burr (Clinical Epidemiologist) led andcoordinated all aspects of the project, and wrotethe Executive Summary, Introduction,Background, Screening tests for glaucoma, Doesscreening for open angle glaucoma (OAG) meetthe National Screening Committee criteria?,Discussion and Conclusions chapters. JenniferBurr, Rodolfo Hernández (Research Fellow), LukeVale (Senior Research Fellow) and Cynthia Fraser(Information Officer) wrote the Methods chapter.Tania Lourenco (Research Fellow), with theassistance of Jennifer Burr, Jonathan Cook(Statistician) and Craig Ramsay (Senior

Statistician) conducted the epidemiology review.Graham Mowatt (Research Fellow) and RehmanSiddiqui (Clinical Research Fellow), with theassistance of Jennifer Burr, conducted the reviewof the accuracy of screening and diagnostic tests.The Cochrane Eyes and Vision Group, led byRichard Wormald (coordinating editor of theCochrane Eyes and Vision Group), assisted byJennifer Burr, conducted the review of screeningfor prevention of optic nerve damage due to OAG.Jennifer Burr updated systematic reviews on theeffectiveness of glaucoma treatment. Craig Ramsay(Senior Statistician) conducted the review ofprobability of progressive visual field loss.Kannaiyan Rabindranath (Clinical ResearchFellow), Rodolfo Hernández and Luke Valeconducted the review of economic evaluations ofscreening for glaucoma. Rodolfo Hernándezconducted the economic evaluation with theassistance of Luke Vale. Luke Vale wrote thesection on factors relevant to the NHS and othersectors, and the discussion on the economicevaluation. The tasks involved in conducting thevarious reviews included screening search results,assessing full-text studies for inclusion,undertaking data extraction and qualityassessment, and writing the review. Jonathan Cookprovided statistical support across the reviews andundertook the meta-analyses. Cynthia Fraserdeveloped and ran the search strategies, obtainedpapers and formatted the references.

Augusto Azuara-Blanco (ConsultantOphthalmologist) and Richard Wormald(Consultant Ophthalmologist) provided clinicalexpert opinion on all aspects of the project. JonDeeks (Professor of Health Statistics) providedmethodological support for the screening anddiagnostic accuracy review, and John Cairns(Professor of Health Economics) providedmethodological support for the economicevaluation. Stephen McPherson (Optometrist)provided information and advice, representingoptometry. Adrian Grant (Professor of Health Services Research) advised on the design of the project and commented on drafts of the report.


155


Acknowledgements

1. Quigley HA, Broman AT. The number of peoplewith glaucoma worldwide in 2010 and 2020. Br JOphthalmol 2006;90:262–7.

2. Congdon N, Wang F, Tielsch JM. Issues in theepidemiology and population-based screening ofprimary angle-closure glaucoma. Surv Ophthalmol1992;36:411–23.

3. AAOG Glaucoma Panel. Primary open-angleglaucoma: preferred practice pattern. AmericanAcademy of Ophthalmology; 2005. URL:http://www.aao.org/education/library/ppp/poag_new.cfm. Accessed April 2005.

4. Screening for glaucoma in the primary caresetting. VHA clinical practice guideline. UnitedStates Department of Veterans Affairs; 2000. URL:http://www.oqp.med.va.gov/cpg/Glaucoma/GLA_CPG/navbar.htm#. Accessed April 2005.

5. Tuulonen A, Airaksinen PJ, Erola E, Forsman E,Friberg K, Kaila M, et al. The Finnish evidence-based guideline for open-angle glaucoma. ActaOphthalmol Scand 2003;81:3–18.

6. Asia Pacific glaucoma guidelines. South East AsiaGlaucoma Interest Group; 2003. URL:http://www.seagig.org/pdf/APGGuidelinesNMview.pdf. Accessed September 2005.

7. Terminology and guidelines for glaucoma.European Glaucoma Society; 2003. URL:http://www.eugs.org/preview.asp. AccessedSeptember 2005.

8. World Health Organization. Principles and practiceof screening for disease. Public Health Paper No. 34.Geneva: WHO; 1968.

9. Criteria for appraising the viability, effectivenessand appropriateness of a screening programme.UK National Screening Committee; 2003. URL:http://libraries.nelh.nhs.uk/screening/viewResource.asp?uri=http://libraries.nelh.nhs.uk/common/resources/?id=59772. Accessed September 2005.

10. Spry PG, Sparrow JM. An evaluation of open-angle glaucoma against the NSC criteria forscreening viability, effectiveness andappropriateness. UK National ScreeningCommittee; 2005. URL: http://rms.nelh.nhs.uk/screening/viewResource.asp?categoryID=1352&dg=107&uri=http://libraries.nelh.nhs.uk/common/resources/?id=61002. Accessed September 2005.

11. UK National Screening Committee’s PolicyPositions 2005. UK National ScreeningCommittee; 2005. URL: http://rms.nelh.nhs.uk/

screening/viewResource.asp?categoryID=7773&uri=http%3A//libraries.nelh.nhs.uk/common/resources/?id=61406. Accessed September 2005.

12. Fleming C, Whitlock E, Biel T, Smit B. Primarycare screening for ocular hypertension andprimary open-angle glaucoma: Evidence SynthesisNo. 34. Agency for Healthcare Research & Quality,US Preventative Services Task Force; 2005. URL:http://www.ahrq.gov/clinic/uspstf05/glaucoma/glaucsyn.pdf. Accessed April 2005.

13. Retinal nerve fiber layer analysis for the diagnosisand management of glaucoma. TEC Assessment18(7). Blue Cross Blue Shield Association; 2003.URL: http://www.bcbs.com/tec/Vol18/18_07.pdf.Accessed April 2005.

14. American Academy of Ophthalmology. Opticnerve head and retinal nerve fiber layer analysis.Ophthalmology 1999;106:1414–24.

15. Delgado MF, Nguyen NT, Cox TA, Singh K,Lee DA, Dueker DK, et al. Automated perimetry: a report by the American Academy ofOphthalmology. Ophthalmology 2002;109:2362–74.

16. Harasymowycz P, Kamdeu FA, Papamatheakis D.Screening for primary open-angle glaucoma in thedeveloped world: are we there yet? Can JOphthalmol 2005;40:477–86.

17. Scott, A. Optical coherence tomography fordiagnosing retinal disease. Technote TN41.Alberta Heritage Foundation for MedicalResearch; 2003. URL: http://www.ahfmr.ab.ca/publications/?dept=&search=retinal&type=5&sort=date&dir=DESC. Accessed April 2005.

18. Sycha T, Vass C, Findl O, Bauer P, Groke I,Schmetterer L, et al. Interventions for normaltension glaucoma. Cochrane Database Syst Rev 2003(Issue 1). Article No.: CD002222. DOI:10.1002/14651858.CD002222.

19. Maier PC, Funk J, Schwarzer G, Antes G, Falck-Ytter YT. Treatment of ocular hypertensionand open angle glaucoma: meta-analysis ofrandomised controlled trials. BMJ 2005;331:134–6.

20. Bonomi L, Marchini G, Marraffa M, Bernardi P,de Franco I, Perfetti S, et al. Prevalence ofglaucoma and intraocular pressure distribution ina defined population: the Egna–Neumarkt study.Ophthalmology 1998;105:209–15.

21. Hollows FC, Graham PA. Intra-ocular pressureglaucoma and glaucoma suspects in a definedpopulation. Br J Ophthalmol 1966;50:570–86.


157


References

22. Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, et al. TheFramingham Eye Study monograph: anophthalmological and epidemiological study ofcataract, glaucoma, diabetic retinopathy, maculardegeneration, and visual acuity in a generalpopulation of 2631 adults, 1973–1975. SurvOphthalmol 1980;24:335–610.

23. Sommer A, Tielsch JM, Katz J, Quigley HA,Gottsch JD, Javitt J, et al. Relationship betweenintraocular pressure and primary open angleglaucoma among white and black Americans: theBaltimore Eye Survey. Arch Ophthalmol1991;109:1090–5.

24. Wensor MD, McCarty CA, Stanislavsky YL,Livingston PM, Taylor HR. The prevalence ofglaucoma in the Melbourne Visual ImpairmentProject. Ophthalmology 1998;105:733–9.

25. Kass MA, Gordon MO. Intraocular pressure andvisual field progression in open-angle glaucoma.Am J Ophthalmol 2000;130:490–1.

26. Leske MC, Heijl A, Hyman L, Bengtsson B. EarlyManifest Glaucoma Trial: design and baselinedata. Ophthalmology 1999;106:2144–53.

27. Heijl A, Leske MC, Bengtsson B, Hyman L,Bengtsson B, Hussein M, et al. Reduction ofintraocular pressure and glaucoma progression:results from the Early Manifest Glaucoma Trial.Arch Ophthalmol 2002;120:1268–79.

28. Grodum K, Heijl A, Bengtsson B. A comparison ofglaucoma patients identified through massscreening and in routine clinical practice. ActaOphthalmol Scand 2002;80:627–31.

29. Burr J, Azuara-Blanco A, Avenell A. Medicalversus surgical interventions for open angleglaucoma. Cochrane Database Syst Rev 2004 (Issue2). Article No.: CD004399. DOI:10.1002/14651858.CD004399.pub2.

30. Vass C, Findl O, Sycha T, Bauer P, Schmetterer L.Medical interventions for primary open angle glaucoma and ocular hypertension(Protocol). Cochrane Database Syst Rev 2004 (Issue 3). Article No.: CD003167.DOI:10.1002/14651858.CD003167.pub2.

31. de Rolim MC, Paranhos A. Laser trabeculoplastyfor open angle glaucoma (Protocol). CochraneDatabase Syst Rev 2002 (Issue 4). Article No.:CD003919. DOI: 10.1002/14651858.CD003919.

32. Bunce C, Wormald R. Leading causes ofcertification for blindness and partial sight inEngland & Wales. BMC Public Health 2006;6(8March).

33. Kelliher C, Kenny D, O’Brien C. Trends in blindregistration in the adult population of theRepublic of Ireland 1996–2003. Br J Ophthalmol2006;90:367–71.

34. Evans J. Causes of blindness and partial sight inEngland and Wales 1990–1991. London: Office ofPopulation Censuses and Surveys; 1995.

35. Bamashmus MA, Matlhaga B, Dutton GN. Causesof blindness and visual impairment in the West ofScotland. Eye 2004;18:257–61.

36. The National Assistance Act. London: UK Ministry ofNational Insurance; 1948.

37. Registered blind and partially sighted persons,Scotland 2003. Scottish Executive; 2003. URL: http://www.scotland.gov.uk/stats/bulletins/00292-00.asp. Accessed February 2006.

38. Registered blind and partially sighted people: yearending 31 March 2003, England. Department ofHealth; 2003. URL: http://www.dh.gov.uk/PublicationsAndStatistics/Statistics/StatisticalWorkAreas/StatisticalSocialCare/StatisticalSocialCareArticle/fs/en?CONTENT_ID=4082697&chk=NrtmK1.Accessed February 2006.

39. Personal social services statistics, Wales 2002–03.Physical and sensory disability. Local Government Data Unit; Wales. URL:http://www.dataunitwales.gov.uk/eng/Project.asp?id=SXAEAE-A77F9255&Cat=23. Accessed February2006.

40. King AJ, Reddy A, Thompson JR, Rosenthal AR.The rates of blindness and of partial sightregistration in glaucoma patients. Eye 2000;14:613–19.

41. Robinson R, Deutsch J, Jones HS, Youngson-ReillyS, Hamlin DM, Dhurjon L, et al. Unrecognisedand unregistered visual impairment. Br JOphthalmol 1994;78:726–40.

42. Sheldrick JH, Ng C, Austin DJ, Rosenthal AR. Ananalysis of referral routes and diagnostic accuracyin cases of suspected glaucoma. OphthalmicEpidemiol 1994;1:31–9.

43. Harrison RJ, Wild JM, Hobley AJ. Referralpatterns to an ophthalmic outpatient clinic bygeneral practitioners and ophthalmic opticiansand the role of these professionals in screening forocular disease. BMJ 1988;297:1162–7.

44. Pooley JE, Frost EC. Optometrists’ referrals to theHospital Eye Service. Ophthalmic Physiol Opt1999;19:S16–24.

45. College of Optometrists. Members’ handbook.London: College of Optometrists; 2005.

46. Wormald RP, Rauf A. Glaucoma screening. J MedScreen 1995;2:109–14.

47. van der Pols JC, Thompson JR, Bates CJ, PrenticeA, Finch S. Is the frequency of having an eye testassociated with socioeconomic factors? A nationalcross sectional study in British elderly. J EpidemiolCommunity Health 1999;53:737–8.

References

158

48. Banes MJ, Culham LE, Crowston JG, Bunce C,Khaw PT. An optometrist’s role of co-managementin a hospital glaucoma clinic. Ophthalmic PhysiolOpt 2000;20:351–9.

49. Gray SF, Spry PG, Brookes ST, Peters TJ, Spencer IC, Baker IA, et al. The Bristol sharedcare glaucoma study: outcome at follow up at2 years. Br J Ophthalmol 2000;84:456–63.

50. Hume J, Abbott F. Setting up a shared careglaucoma clinic. Nurs Stand 1995;10:34–6.

51. Wales Eye Care Initiative. National Assembly forWales. URL: http://new.wales.gov.uk/topics/health/healthservice/nhs/eye_care/?lang=en.Accessed April 2006.

52. First report of the National Eye Care Services SteeringGroup. London: UK Department of Health; 2004.

53. Review of eye care services in Scotland. ScottishExecutive; 2005. URL: http://www.scotland.gov.uk/Publications/2005/10/21111455/14557. AccessedFebruary 2006.

54. DOAS glaucoma: draft glaucoma clinical pathwayand dataset. Do Once & Share Programme(DOAS). URL: http://www.doasglaucoma.org/draft.asp. Accessed April 2006.

55. Review of General Ophthalmic Services. UKDepartment of Health. URL:http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4118493&chk=66ZQro. AccessedFebruary 2006.

56. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ.The definition and classification of glaucoma inprevalence surveys. Br J Ophthalmol 2002;86:238–42.

57. Goldmann H. Un nouveau tome re d’applanation.Bull Soc Ophthalmol Fr 1955;67:474–8.

58. Bandyopadhyay M, Raychaudhuri A, Lahiri SK,Schwartz EC, Myatt M, Johnson GJ. Comparisonof Goldmann applanation tonometry with theTonopen for measuring intraocular pressure in apopulation-based glaucoma survey in rural WestBengal. Ophthalmic Epidemiol 2002;9:215–24.

59. Salvi SM, Sivakumar S, Sidiki SS. Use ofdisposable prism tonometry in routine clinicalpractice. Eye 2005;19:743–6.

60. Shields MB. The non-contact tonometer: its valueand limitations. Surv Ophthalmol 1980;24:211–19.

61. Armaly MF. On the distribution of applanationpressure. Arch Ophthalmol 1965;73:11–18.

62. Davanger M, Ringvold A, Blika S, Elsas T.Frequency distribution of IOP. Analysis of amaterial using the gamma distribution. ActaOphthalmol (Copenh) 1991;69:561–4.

63. Mitchell P, Smith W, Attebo K, Healey PR.Prevalence of open-angle glaucoma in Australia:

the Blue Mountains Eye Study. Ophthalmology1996;103:1661–9.

64. Bankes JL, Perkins ES, Tsolakis S, Wright JE.Bedford Glaucoma Survey. BMJ 1968;i:791–6.

65. Klein BE, Klein R, Linton KL. Intraocularpressure in an American community – the BeaverDam Eye Study. Invest Ophthalmol Vis Sci1992;33:2224–8.

66. Leydecker W, Akiyama K, Neumann HG. Theintraocular pressure of healthy eyes. Klin MblAugenheilk 1958;133:662–70.

67. Rochtchina E, Mitchell P, Wang JJ. Relationshipbetween age and intraocular pressure: the BlueMountains Eye Study. Clin Exp Ophthalmol2002;30:173–5.

68. Davanger M, Ringvold A, Blika S. The probabilityof having glaucoma at different IOP levels. ActaOphthalmol (Copenh) 1991;69:565–8.

69. Morgan JE, Sheen NJ, North RV, Choong Y,Ansari E. Digital imaging of the optic nerve head:monoscopic and stereoscopic analysis. Br JOphthalmol 2005;89:879–84.

70. Dielemans I, Vingerling JR, Algra D, Hofman A,Grobbee DE, de Jong PT. Primary open-angleglaucoma, intraocular pressure, and systemicblood pressure in the general elderly population.The Rotterdam Study. Ophthalmology 1995;102:54–60.

71. Dielemans I, Vingerling JR, Wolfs RC, Hofman A,Grobbee DE, de Jong PT. The prevalence ofprimary open-angle glaucoma in a population-based study in The Netherlands. The RotterdamStudy. Ophthalmology 1994;101:1851–5.

72. Tielsch JM, Katz J, Singh K, Quigley HA, Gottsch JD, Javitt J, et al. A population-basedevaluation of glaucoma screening: the BaltimoreEye Survey. Am J Epidemiol 1991;134:1102–10.

73. Quigley HA. Diagnosing early glaucoma with nervefiber layer examination. New York: Igaku-Shoin;1996.

74. Wollstein G, Garway-Heath DF, Hitchings RA.Identification of early glaucoma cases with thescanning laser ophthalmoscope. Ophthalmology1998;105:1557–63.

75. Vernon SA, Hawker MJ, Ainsworth G, Hillman JG,Macnab HK, Dua HS. Laser scanning tomographyof the optic nerve head in a normal elderlypopulation: the Bridlington eye assessmentproject. Invest Ophthalmol Vis Sci 2005;46:2823–8.

76. Iester M, Mikelberg FS, Drance SM. The effect ofoptic disc size on diagnostic precision with theHeidelberg retina tomograph. Ophthalmology1997;104:545–8.

77. Medeiros FA, Zangwill LM, Bowd C, Sample PA,Weinreb RN. Influence of disease severity and


159


optic disc size on the diagnostic performance ofimaging instruments in glaucoma. InvestOphthalmol Vis Sci 2006;110:1145–50.

78. Hawker MJ, Vernon SA, Ainsworth G, Hillman JG,Macnab HK, Dua HS. Asymmetry in optic discmorphometry as measured by Heidelberg retinatomography in a normal elderly population: theBridlington Eye Assessment Project. InvestOphthalmol Vis Sci 2005;46:4153–8.

79. Scanning laser polarimetry. Primer excerpts –clinical guidance for using the GDx: the normativedatabase. Carl Zeiss Medictec. URL:http://www.meditec.zeiss.com/C1256CAB00599F5D/Contents-Frame/55A2E554EFCFC5B98825726C0001A9A7. Accessed February 2007.

80. Huang D, Swanson EA, Lin CP, Schuman JS,Stinson WG, Chang W, et al. Optical coherencetomography. Science 1991;254:1178–81.

81. Optical Coherence Tomography: Stratus OCT.Carl Zeiss Meditec. URL:http://www.meditec.zeiss.com/C125679E0051C774/search/47B36BB678C7F9218825707000835AD5?OpenDocument. Accessed February 2006.

82. Adams CW, Bullimore MA, Wall M, Fingeret M,Johnson CA. Normal aging effects for frequencydoubling technology perimetry. Optom Vis Sci1999;76:582–7.

83. Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-specificperimetry for indirect comparison of differentganglion cell populations in glaucoma. InvestOphthalmol Vis Sci 2000;41:1783–90.

84. Damato B, Groenewald C. Multifixationcampimetry on line: a perimeter for the detectionof visual field loss using the internet. Br JOphthalmol 2003;87:1296–8.

85. Visual field test. Damato MultifixationCampimeter. URL: http://www.testvision.org/.Accessed February 2006.

86. Heijl A, Lindgren G, Olsson J. A package for thestatistical analysis of visual fields. In: Greve EL,Heijl A, editors. Documenta OpthalmologicaProceedings Series 49, 7th International Visual FieldSymposium. Dordrecht: W Junk Publishers; 1987.pp. 153–168.

87. Bengtsson B, Heijl A. Inter-subject variability andnormal limits of the SITA Standard, SITA Fast,and the Humphrey Full Threshold computerizedperimetry strategies, SITA STATPAC. ActaOphthalmol Scand 1999;77:125–9.

88. Asman P, Heijl A. Glaucoma hemifield test.Automated visual field evaluation. Arch Ophthalmol1992;110:812–9.

89. Crabb DP, Fitzke FW, Hitchings RA, Viswanathan AC. A practical approach to

measuring the visual field component of fitness todrive. Br J Ophthalmol 2004;88:1191–6.

90. Crabb DP, Viswanathan AC. Integrated visualfields: a new approach to measuring the binocularfield of view and visual disability. Grafes Arch ClinExp Ophthalmol 2005;243:210–16.

91. Philips Z, Ginnelly L, Sculpher M, Claxton K,Golder S, Riemsma R, et al. Review of guidelinesfor good practice in decision-analytic modelling inhealth technology assessment. Health Technol Assess2004;8(36).

92. Wirtz MK, Samples JR, Rust K, Lie J, Nordling L,Schilling K, et al. GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. ArchOphthalmol 1999;117:237–41.

93. Stone EM, Fingert JH, Alward WL, Nguyen TD,Polansky JR, Sunden SL, et al. Identification of agene that causes primary open angle glaucoma.Science 1997;275:668–70.

94. Stoilova D, Child A, Trifan OC, Crick RP, Coakes RL, Sarfarazi M. Localization of a locus(GLC1B) for adult-onset primary open angleglaucoma to the 2cen-q13 region. Genomics1996;36:142–50.

95. Sheffield VC, Stone EM, Alward WL, Drack AV,Johnson AT, Streb LM, et al. Genetic linkage offamilial open angle glaucoma to chromosome1q21-q31. Nat Genet 1993;4:47–50.

96. Sarfarazi M, Child A, Stoilova D, Brice G, Desai T,Trifan OC, et al. Localization of the fourth locus(GLC1E) for adult-onset primary open-angleglaucoma to the 10p15-p14 region. Am J HumGenet 1998;62:641–52.

97. Fingert JH, Heon E, Liebmann JM, Yamamoto T,Craig JE, Rait J, et al. Analysis of myocilinmutations in 1703 glaucoma patients from fivedifferent populations. Hum Mol Genet1999;8:899–905.

98. DerSimonian R, Laird N. Meta-analysis in clinicaltrials. Controll Clin Trial 1986;7:177–88.

99. Anton A, Andrada MT, Mujica V, Calle MA,Portela J, Mayo A. Prevalence of primary open-angle glaucoma in a Spanish population: theSegovia Study. J Glaucoma 2004;13:371–6.

100. Bengtsson B. Findings associated withglaucomatous visual field defects. Acta Ophthalmol(Copenh) 1980;58:20–32.

101. Cooper RL, Grose GC, Constable IJ. Massscreening of the optic disc for glaucoma: a follow-up study. Aust N Z J Ophthalmol 1986;14:35–9.

102. Ellis JD, Evans JMM, Ruta DA, Baines PS, Leese G,MacDonald TM, et al. Glaucoma incidence in anunselected cohort of diabetic patients: is diabetesmellitus a risk factor for glaucoma? Br J Ophthalmol2000;84:1218–24.

References

160

103. Gibson JM, Rosenthal AR, Lavery J. A study of theprevalence of eye disease in the elderly in anEnglish community. Trans Ophthalmol Soc UK1985;104:196–203.

104. Lee PP, Feldman ZW, Ostermann J, Brown DS,Sloan FA. Longitudinal prevalence of major eyediseases. Arch Ophthalmol 2003;121:1303–10.

105. Dielemans I, de Jong PT, Stolk R, Vingerling JR,Grobbee DE, Hofman A. Primary open-angleglaucoma, intraocular pressure, and diabetesmellitus in the general elderly population. TheRotterdam Study. Ophthalmology 1996;103:1271–5.

106. Bonomi L, Marchini G, Marraffa M, Morbio R.The relationship between intraocular pressure andglaucoma in a defined population. Data from theEgna–Neumarkt Glaucoma Study. Ophthalmologica2001;215:34–8.

107. Cedrone C, Culasso F, Cesareo M, Zapelloni A,Cedrone P, Cerulli L. Prevalence of glaucoma inPonza, Italy: a comparison with other studies.Ophthalmic Epidemiol 1997;4:59–72.

108. Coffey M, Reidy A, Wormald R, Xian WX,Wright L, Courtney P. Prevalence of glaucoma inthe west of Ireland. Br J Ophthalmol 1993;77:17–21.

109. Ekstrom C. Prevalence of open-angle glaucoma incentral Sweden. The Tierp Glaucoma Survey. ActaOphthalmol Scand 1996;74:107–12.

110. Jonasson F, Damji KF, Arnarsson A, Sverrisson T,Wang L, Sasaki H, et al. Prevalence of open-angleglaucoma in Iceland: Reykjavik Eye Study. Eye2003;17:747–53.

111. Klein BE, Klein R, Sponsel WE, Franke T,Cantor LB, Martone J, et al. Prevalence ofglaucoma. The Beaver Dam Eye Study.Ophthalmology 1992;99:1499–504.

112. Kozobolis VP, Detorakis ET, Tsilimbaris M,Siganos DS, Vlachonikolis IG, Pallikaris IG. Crete,Greece glaucoma study. J Glaucoma 2000;9:143–9.

113. Reidy A, Minassian DC, Vafidis G, Joseph J,Farrow S, Wu J, et al. Prevalence of serious eyedisease and visual impairment in a north Londonpopulation: population based, cross sectionalstudy. BMJ 1998;316:1643–6.

114. Tielsch JM, Sommer A, Katz J, Royall RM,Quigley HA, Javitt J. Racial variations in theprevalence of primary open-angle glaucoma. TheBaltimore Eye Survey. JAMA 1991;266:369–74.

115. Weih LM, Nanjan M, McCarty CA, Taylor HR.Prevalence and predictors of open-angleglaucoma: results from the Visual ImpairmentProject. Ophthalmology 2001;108:1966–72.

116. Wormald RPL, Wright LA, Courtney P,Beaumont B, Haines AP. Visual problems in theelderly population and implications for services.BMJ 1992;304:1226–9.

117. Jonasson F, Thordarson K. Prevalence of oculardisease and blindness in a rural area in the easternregion of Iceland during 1980 through 1984. ActaOphthalmol Suppl 1987;182:40–3.

118. Ringvold A, Blika S, Elsas T, Guldahl J, Brevik T,Hesstvedt P, et al. The middle-Norway eye-screening study. II. Prevalence of simple andcapsular glaucoma. Acta Ophthalmol (Copenh)1991;69:273–80.

119. Schoff EO, Hattenhauer MG, Ing HH, Hodge DO,Kennedy RH, Herman DC. Estimated incidence ofopen-angle glaucoma in Olmsted County,Minnesota. Ophthalmology 2001;108:882–6.

120. Wormald RP, Basauri E, Wright LA, Evans JR. TheAfrican Caribbean Eye Survey: risk factors forglaucoma in a sample of African Caribbean peopleliving in London. Eye 1994;8:315–20.

121. Hiller R, Podgor MJ, Sperduto RD, Wilson PWF,Chew EY, D’Agostino RB. High intraocularpressure and survival: the Framingham studies.Am J Ophthalmol 1999;128:440–5.

122. Mitchell P, Smith W, Chey T, Healey PR. Open-angle glaucoma and diabetes: the Blue MountainsEye Study, Australia. Ophthalmology1997;104:712–8.

123. Podgor MJ, Leske MC, Ederer F. Incidenceestimates for lens changes, macular changes,open-angle glaucoma and diabetic retinopathy. AmJ Epidemiol 1983;118:206–12.

124. de Voogd S, Ikram MK, Wolfs RC, Jansonius NM,Hofman A, de Jong PT. Incidence of open-angleglaucoma in a general elderly population: theRotterdam Study. Ophthalmology 2005;112:1487–93.

125. Mukesh BN, McCarty CA, Rait JL, Taylor HR.Five-year incidence of open-angle glaucoma: thevisual impairment project. Ophthalmology 2002;109:1047–51.

126. Lee AJ, Wang JJ, Rochtchina E, Healey P, ChiaEM, Mitchell P. Patterns of glaucomatous visualfield defects in an older population: the BlueMountains Eye Study. Clin Exp Ophthalmol 2003;31:331–5.

127. Tielsch JM. A population-based perspective onlow-tension and classic primary open-angleglaucoma: the Baltimore Eye Survey. Chibret Int JOphthalmol 1994;10:1–5.

128. Grodum K, Heijl A, Bengtsson B. Refractive errorand glaucoma. Acta Ophthalmol Scand 2001;79:560–6.

129. Mitchell P, Hourihan F, Sandbach J, Wang JJ. Therelationship between glaucoma and myopia: theBlue Mountains Eye Study. Ophthalmology 1999;106:2010–15.

130. Weih LM, Mukesh BN, McCarty CA, Taylor HR.Association of demographic, familial, medical and


161


ocular factors with intraocular pressure. ArchOphthalmol 2001;119:875–80.

131. Wong TY, Klein BE, Klein R, Knudtson M, Lee KE.Refractive errors intraocular pressure andglaucoma in a white population. Ophthalmology2003;110:211–17.

132. Klein BE, Klein R, Jensen SC. Open-angleglaucoma and older-onset diabetes. The BeaverDam Eye Study. Ophthalmology 1994;101:1173–7.

133. Mitchell P. Bias in self-reported family history andrelationship to glaucoma. Ophthalmic Epidemiol2002;9:333–45.

134. Tielsch JM, Katz J, Sommer A, Quigley HA,Javitt JC. Family history and risk of primary openangle glaucoma: the Baltimore Eye Survey. ArchOphthalmol 1994;112:69–73.

135. Wolfs RC, Klaver CC, Ramrattan RS, Van Duijn CM, Hofman A, De Jong LA. Geneticrisk of primary open-angle glaucoma: populationbased familial aggregation study. Arch Ophthalmol1998;116:1640-5.

136. Beral V. ‘The practice of meta-analysis’: discussion.Meta-analysis of observational studies: a case studyof work in progress. J Clin Epidemiol 1995;48:165–6.

137. Dickersin K. Systematic reviews in epidemiology:why are we so far behind? Int J Epidemiol 2002;31:6–12.

138. Weed DL. Interpreting epidemiological evidence:how meta-analysis and causal inference methodsare related. Int J Epidemiol 2000;29:387–90.

139. Leske MC, Connell AM, Wu SY, Nemesure B, Li X,Schachat A, et al. The Barbados Eye StudiesGroup. Incidence of open-angle glaucoma: theBarbados Eye Studies. Arch Ophthalmol 2001;119:89–95.

140. Minassian DC, Reidy A, Coffey M, Minassian A.Utility of predictive equations for estimating theprevalence and incidence of primary open angleglaucoma in the UK. Br J Ophthalmol 2000;84:1159–61.

141. Kaimbo D, Buntinx F, Missotten L. Risk factors foropen angle glaucoma: a study in two rural areas ofthe Democratic Republic of Congo. Arch PublicHealth 2002;60:101–14.

142. Leske MC, Connell AM, Schachat AP, Hyman L.The Barbados Eye Study. Prevalence of open angleglaucoma. Arch Ophthalmol 1994;112:821–9.

143. Leske MC, Connell AM, Wu SY, Hyman LG,Schachat AP. Risk factors for open-angleglaucoma. The Barbados Eye Study. ArchOphthalmol 1995;113:918–24.

144. Murdoch IE, Cousens SN, Babalola OE, Yang YF,Abiose A, Jones BR. Glaucoma prevalence may not

be uniformly high in all ‘black’ populations. Afr JMed Med Sci 2001;30:337–9.

145. Varma R, Ying-Lai M, Francis BA, Nguyen BBT,Deneen J, Wilson MR, et al. Prevalence of open-angle glaucoma and ocular hypertension inLatinos: the Los Angeles Latino Eye Study.Ophthalmology 2004;111:1439–48.

146. Fong DS, Epstein DL, Allingham RR. Glaucomaand myopia: are they related? Int Ophthalmol Clin1990;30:215–18.

147. Bonovas S, Peponis V, Filioussi K. Diabetes mellitusas a risk factor for primary open-angle glaucoma:a meta-analysis. Diabet Med 2004;21:609–14.

148. Weinreb RN, Khaw KT. Primary open-angleglaucoma. Lancet 2004;363:1711–20.

149. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM,Kleijnen J. The development of QUADAS: a toolfor the quality assessment of studies of diagnosticaccuracy included in systematic reviews. BMC MedRes Methodol 2003;3(10 November).

150. Leemis LM, Trivedi KS. A comparison ofapproximate interval estimators for the Bernoulliparameter. Am Stat 1996;50:63–8.

151. Zamora J, Muriel A. Meta-DiSc for Windows: asoftware package for the meta-analysis of diagnostic tests.Barcelona: XI Cochrane Colloquium. URL:www.hrc.es/investigacion/metadisc_en.htm

152. Rutter CM, Gatsonis CA. A hierarchical regressionapproach to meta-analysis of diagnostic testaccuracy evaluations. Stat Med 2001;20:2865–84.

153. Spiegelhalter D, Thomas A, Best N. WinBUGS:Bayesian inference using Gibbs sampling. User manual,version 1.4. Cambridge: MRC Biostatistics Unit;2003.

154. Christoffersen T, Fors T, Waage S, Holtedahl K.Glaucoma screening with oculokinetic perimetry ingeneral practice: is its specificity acceptable? Eye1995;9:36–9.

155. Detry-Morel M, Zeyen T, Kestelyn P, Collignon J,Goethals M, Belgian Glaucoma Society. Screeningfor glaucoma in a general population with thenon-mydriatic fundus camera and the frequencydoubling perimeter. Eur J Ophthalmol2004;14:387–93.

156. Harasymowycz P, Papamatheakis D, Fansi AK,Gresset J, Lesk MR. Validity of screening forglaucomatous optic nerve damage using confocalscanning laser ophthalmoscopy (HeidelbergRetina Tomograph II) in high-risk populations: apilot study. Ophthalmology 2005;112:2164–71.

157. Ivers RQ, Optom B, Macaskill P, Cumming RG,Mitchell P. Sensitivity and specificity of tests todetect eye disease in an older population.Ophthalmology 2001;108:968–75.

References

162

158. Katz J, Sommer A, Gaasterland DE, Anderson DR.Comparison of analytic algorithms for detectingglaucomatous visual field loss. Arch Ophthalmol1991;109:1684–9.

159. Katz J, Tielsch JM, Quigley HA, Javitt J, Witt K,Sommer A. Automated suprathreshold screeningfor glaucoma: the Baltimore Eye Survey. InvestOphthalmol Vis Sci 1993;34:3271–7.

160. Katz J, Quigley HA, Sommer A. Repeatability ofthe Glaucoma Hemifield Test in automatedperimetry. Invest Ophthalmol Vis Sci 1995;36:1658–64.

161 Mansberger SL, Johnson CA, Cioffi GA, Choi D,Krishnadas SR, Srinivasan M, et al. Predictivevalue of frequency doubling technology perimetryfor detecting glaucoma in a developing country. JGlaucoma 2005;14:128–34.

162. Mundorf TK, Zimmerman TJ, Nardin GF,Kendall KS. Automated perimetry, tonometry, andquestionnaire in glaucoma screening. Am JOphthalmol 1989;108:505–8.

163. Robin TA, Muller A, Rait J, Keeffe JE, Taylor HR.Performance of community-based glaucomascreening using frequency doubling technologyand Heidelberg retinal tomography. OphthalmicEpidemiol 2005;12:167–78.

164. Vernon SA, Henry DJ, Cater L, Jones SJ.Screening for glaucoma in the community by non-ophthalmologically trained staff using semiautomated equipment. Eye 1990;4:89–97.

165. Vernon SA, Jones SJ, Henry DJ. Maximising thesensitivity and specificity of non-contact tonometryin glaucoma screening. Eye 1991;5:491–3.

166. Vitale S, Smith TD, Quigley T, Kerrigan-Baumrind TA, Pease TE, Varma R, et al.Screening performance of functional andstructural measurements of neural damage inopen-angle glaucoma: a case–control study fromthe Baltimore Eye Survey. J Glaucoma 2000;9:346–56.

167. Wang F, Quigley HA, Tielsch JM. Screening forglaucoma in a medical clinic with photographs ofthe nerve fiber layer. Arch Ophthalmol 1994;112:796–800.

168. Wang F, Tielsch JM, Ford DE, Quigley HA,Whelton PK. Evaluation of screening schemes foreye disease in a primary care setting. OphthalmicEpidemiol 1998;5:69–82.

169. Wolfs RC, Ramrattan RS, Hofman A, de Jong PT.Cup-to-disc ratio: ophthalmoscopy versusautomated measurement in a general population:the Rotterdam Study. Ophthalmology1999;106:1597–601.

170. Yamada N, Chen PP, Mills RP, Leen MM,Lieberman MF, Stamper RL, et al. Screening for

glaucoma with frequency-doubling technology andDamato campimetry. Arch Ophthalmol1999;117:1479–84.

171. Ekstrom C. Elevated intraocular pressure andpseudoexfoliation of the lens capsule as riskfactors for chronic open angle glaucoma – apopulation based 5 year follow up study. ActaOphthalmol (Copenh) 1993;71:189–95.

172. Hammond EA, Begley PK. Screening forglaucoma: a comparison of ophthalmoscopy andtonometry. Nurs Res 1979;28:371–2.

173. Khong JJ, Dimitrov PN, Rait J, McCarty CA. Can the specificity of the FDT for glaucoma beimproved by confirming abnormal results?J Glaucoma 2001;10:199–202.

174. Marraffa M, Marchini G, Albertini R, Bonomi L.Comparison of different screening methods forthe detection of visual field defects in earlyglaucoma. Int Ophthalmol 1989;13:43–5.

175. Schultz RO, Radius RL, Hartz AJ, Brown DB,Eytan ON, Ogawa GSH, et al. Screening forglaucoma with stereo disc photography. J Glaucoma1995;4:177–82.

176. Spry PGD, Hussin HM, Sparrow JM. Clinicalevaluation of frequency doubling technologyperimetry using the Humphrey Matrix 24-2threshold strategy. Br J Ophthalmol 2005;89:1031–5.

177. Theodossiades J, Murdoch I. What optic discparameters are most accurately assessed using thedirect ophthalmoscope? Eye 2001;15:283–7.

178. Airaksinen PJ, Drance SM, Douglas GR,Mawson DK, Nieminen H. Diffuse and localizednerve fiber loss in glaucoma. Am J Ophthalmol1984;98:566–71.

179. Anton A, Maquet JA, Mayo A, Tapia J, Pastor JC.Value of logistic discriminant analysis forinterpreting initial visual field defects.Ophthalmology 1997;104:525–31.

180. Damato BE, Ahmed J, Allan D, McClure E, Jay JL.The detection of glaucomatous visual field defectsby oculo-kinetic perimetry: which points are bestfor screening? Eye 1989;3:727–31.

181. Enger C, Sommer A. Recognizing glaucomatousfield loss with the Humphrey STATPAC. ArchOphthalmol 1987;105:1355–7.

182. Harper RA, Hill AR, Reeves BC. Effectiveness ofunsupervised oculokinetic perimetry for detectingglaucomatous visual field defects. OphthalmicPhysiol Opt 1994;14:199–202.

183. Heeg GP, Blanksma LJ, Hardus PL,Jansonius NM. The Groningen LongitudinalGlaucoma Study. I. Baseline sensitivity andspecificity of the frequency doubling perimeterand the GDx nerve fibre analyser. Acta OphthalmolScand 2005;83:46–52.


163


184. Heeg GP, Stoutenbeek R, Jansonius NM.Strategies for improving the diagnostic specificityof the frequency doubling perimeter. ActaOphthalmol Scand 2005;83:53–6.

185. Stoutenbeek R, Heeg GP, Jansonius NM.Frequency doubling perimetry screening modecompared to the full-threshold mode. OphthalmicPhysiol Opt 2004;24:493–7.

186. Ieong A, Murdoch I, Cousens S, Healey P,Theodossiades J. Sensitivity and specificity of twoglaucoma case-finding strategies for optometrists.Ophthalmic Physiol Opt 2003;23:341–6.

187. Johnson CA, Cioffi GA, Van Buskirk EM.Evaluation of two screening tests for frequencydoubling technology perimetry. 13th InternationalPerimetric Society Meeting, Garda, Italy, September;1999. p. 103.

188. Quigley HA, Miller NR, George T. Clinicalevaluation of nerve fiber layer atrophy as anindicator of glaucomatous optic nerve damage.Arch Ophthalmol 1980;98:1564–71.

189. Sommer A, Pollack I, Maumenee AE. Optic discparameters and onset of glaucomatous field loss.II. Static screening criteria. Arch Ophthalmol1979;97:1449–54.

190. Wollstein G, Garway-Heath DF, Fontana L,Hitchings RA. Identifying early glaucomatouschanges. Comparison between expert clinicalassessment of optic disc photographs and confocalscanning ophthalmoscopy. Ophthalmology2000;107:2272–7.

191. Wood CM. Limitations of direct ophthalmoscopyin screening for glaucoma. BMJ 1987;294:1587–8.

192. Artes PH, Iwase A, Ohno Y, Kitazawa Y,Chauhan BC. Properties of perimetric thresholdestimates from Full Threshold, SITA Standard,and SITA Fast strategies. Invest Ophthalmol Vis Sci2002;43:2654–9.

193. Atanassov MA, Konareva MI. Reproducibility andagreement between three methods of intraocularpressure measurement. Folia Medica (Plovdiv)2002;44:19–22.

194. Bengtsson B. Reliability of computerizedperimetric threshold tests as assessed by reliabilityindices and threshold reproducibility in patientswith suspect and manifest glaucoma. ActaOphthalmol Scand 2000;78:519–22.

195. Bjerre A, Grigg JR, Parry NR, Henson DB.Test–retest variability of multifocal visual evokedpotential and SITA standard perimetry inglaucoma. Invest Ophthalmol Vis Sci 2004;45:4035–40.

196. Bonomi L, Baravelli S, Cobbe C, Tomazzoli L.Evaluation of Keeler Pulsair non-contacttonometry: reliability and reproducibility. GrafesArch Clin Exp Ophthalmol 1991;229:210–12.

197. Caprioli J, Klingbeil U, Sears M, Pope B.Reproducibility of optic disc measurements withcomputerized analysis of stereoscopic videoimages. Arch Ophthalmol 1986;104:1035–9.

198. Capris P, Corallo G, Gatti G, Zingirian M. SITAand full threshold strategies in the study of theperimetric defects in glaucoma. Acta OphthalmolScand Suppl 1999;77:18–19.

199. Dielemans I, Vingerling JR, Hofman A,Grobbee DE, de Jong PT. Reliability of intraocularpressure measurement with the Goldmannapplanation tonometer in epidemiological studies.Grafes Arch Clin Exp Ophthalmol 1994;232:141–4.

200. Eiden SB, Cooper J, Olivares G, Horn D, LondonR. Interexaminer reliability of the optic cup to discratio assessment. Am J Optom Physiol Opt1986;63:753–6.

201. Gillespie BW, Musch DC, Guire KE, Mills RP,Lichter PR, Janz NK, et al. The collaborative initialglaucoma treatment study: baseline visual fieldand test–retest variability. Invest Ophthalmol Vis Sci2003;44:2613–20.

202. Harper R, Radi N, Reeves BC, Fenerty C,Spencer AF, Batterbury M. Agreement betweenophthalmologists and optometrists in optic discassessment: training implications for glaucoma co-management. Grafes Arch Clin Exp Ophthalmol2001;239:342–50.

203. Kocak I, Orgul S, Saruhan A, Haefliger I,Hendrickson P, Flammer J. Measurement ofintraocular pressure with a modern noncontacttonometer. Ophthalmologica 1998;212:81–7.

204. Lotti R, Frau B, Cerruti S, Trillo C, Traverso CE.Reliability of applanation tonometry readingsobtained with a disposable latex cap.Ophthalmologica 1999;213:277–80.

205. Phelps CD, Phelps GK. Measurement ofintraocular pressure: a study of its reproducibility.Grafes Arch Clin Exp Ophthalmol 1976;198:39–43.

206. Sekhar GC, Naduvilath TJ, Lakkai M,Jayakumar AJ, Pandi GT, Mandal AK, et al.Sensitivity of Swedish interactive thresholdalgorithm compared with standard full thresholdalgorithm in Humphrey visual field testing.Ophthalmology 2000;107:1303–8.

207. Shuttleworth GN, Khong CH, Diamond JP. A newdigital optic disc stereo camera: intraobserver andinterobserver repeatability of optic discmeasurements. Br J Ophthalmol 2000;84:403–7.

208. Spry PG, Henson DB, Sparrow JM, North RV.Quantitative comparison of static perimetricstrategies in early glaucoma: test–retest variability.J Glaucoma 2000;9:247–53.

209. Sturmer J, Poinoosawmy D, Broadway DC,Hitchings RA. Intra- and inter-observer variation

References

164

of optic nerve head measurements in glaucomasuspects using disc-data. Int Ophthalmol 1992;16:227–33.

210. Tatemichi M, Nakano T, Tanaka K, Hayashi T,Nawa T, Miyamoto T, et al. Performance ofglaucoma mass screening with only a visual fieldtest using frequency-doubling technologyperimetry. Am J Ophthalmol 2002;134:529–37.

211. Tonnu PA, Ho T, Sharma K, White E, Bunce C,Garway-Heath D. A comparison of four methodsof tonometry: method agreement andinterobserver variability. Br J Ophthalmol2005;89:847–50.

212. Westling AK, Newland HS. Interrater agreementin oculo-kinetic perimetry – a screening test forglaucoma. Aust N Z J Ophthalmol 1995;23:125–8.

213. Azuara-Blanco A, Katz LJ, Spaeth GL, Nicholl J,Lanzl IM. Detection of changes of the optic disc inglaucomatous eyes: clinical examination andimage analysis with the Topcon Imagenet system.Acta Ophthalmol Scand 2000;78:647–50.

214. Brush MB, Chen PP. Test–retest variability inglaucoma patients tested with C-20-1 screening-mode frequency doubling technology perimetry.J Glaucoma 2004;13:273–7.

215. Carpineto P, Ciancaglini M, Zuppardi E,Falconio G, Doronzo E, Mastropasqua L.Reliability of nerve fiber layer thicknessmeasurements using optical coherencetomography in normal and glaucomatous eyes.Ophthalmology 2003;110:190–5.

216. Ciancaglini M, Sebastiani A, Carpineto P,Costagliola C, Ciafre M, Parmegiani F, et al.Reproducibility of retinal thickness measurementswith retinal thickness analyser in healthy andglaucomatous subjects. Acta Ophthalmol Scand Suppl2002;80:43–4.

217. Eikelboom RH, Barry CJ, Jitskaia L, Voon AS,Yogesan K. Neuroretinal rim measurement errorusing PC-based stereo software. Clin ExpOphthalmol 2000;28:178–80.

218. Frenkel S, Slonim E, Horani A, Molcho M,Barzel I, Blumenthal EZ. Operator learning effectand interoperator reproducibility of the scanninglaser polarimeter with variable cornealcompensation. Ophthalmology 2005;112:257–61.

219. Garway-Heath DF, Poinoosawmy D, Wollstein G,Viswanathan A, Kamal D, Fontana L, et al. Inter-and intraobserver variation in the analysis of opticdisc images: comparison of the Heidelberg retinatomograph and computer assisted planimetry. Br JOphthalmol 1999;83:664–9.

220. Harper R, Reeves B, Smith G. Observer variabilityin optic disc assessment: implications for glaucomashared care. Ophthalmic Physiol Opt 2000;20:265–73.

221. Hatch WV, Trope GE, Buys YM, Macken P,Etchells EE, Flanagan JG. Agreement in assessingglaucomatous discs in a clinical teaching settingwith stereoscopic disc photographs, planimetry,and laser scanning tomography. J Glaucoma1999;8:99–104.

222. Heeg GP, Ponsioen TL, Jansonius NM. Learningeffect, normal range, and test-retest variability ofFrequency Doubling Perimetry as a function ofage, perimetric experience, and the presence orabsence of glaucoma. Ophthalmic Physiol Opt2003;23:535–40.

223. Hollo G, Follmann P, Pap G. A clinical evaluationof XPERT NCT (Reichert) for glaucoma screeningby optometrists. Int Ophthalmol 1992;16:291–3.

224. Hollo G, Suveges I, Nagymihaly A, Vargha P.Scanning laser polarimetry of the retinal nervefibre layer in primary open angle and capsularglaucoma. Br J Ophthalmol 1997;81:857–61.

225. Liu X, Ling Y, Luo R, Ge J, Zheng X. Opticalcoherence tomography in measuring retinal nervefiber layer thickness in normal subjects andpatients with open-angle glaucoma. Chin Med J(Engl) 2001;114:524–9.

226. Mok KH, Lee VW, So KF. Increasing scans perexamination improves the reproducibility onretinal nerve fiber layer measurements by opticalcoherence tomography. Optom Vis Sci 2004;81:268–71.

227. Sanchez-Galeana C, Bowd C, Blumenthal EZ,Gokhale PA, Zangwill LM, Weinreb RN. Usingoptical imaging summary data to detect glaucoma.Ophthalmology 2001;108:1812–18.

228. Sommer A, Quigley HA, Robin AL, Miller NR,Katz J, Arkell S. Evaluation of nerve fiber layerassessment. Arch Ophthalmol 1984;102:1766–71.

229. Sommer A, Katz J, Quigley HA, Miller NR,Robin AL, Richter RC, et al. Clinically detectablenerve fiber atrophy precedes the onset ofglaucomatous field loss. Arch Ophthalmol1991;109:77–83.

230. Spalding JM, Litwak AB, Shufelt CL. Optic nerveevaluation among optometrists. Optom Vis Sci2000;77:446–52.

231. Strouthidis NG, White ET, Owen VMF, Ho TA,Hammond CJ, Garway-Heath DF. Factors affectingthe test–retest variability of Heidelberg retinatomograph and Heidelberg retina tomograph IImeasurements. Br J Ophthalmol 2005;89:1427–32.

232. Takamoto T, Schwartz B. Reproducibility ofphotogrammetric optic disc cup measurements.Invest Ophthalmol Vis Sci 1985;26:814–17.

233. Varma R, Steinmann WC, Scott IU. Expertagreement in evaluating the optic disc forglaucoma. Ophthalmology 1992;99:215–21.


165


234. Watkins RJ, Broadway DC. Intraobserver andinterobserver reliability indices for drawingscanning laser ophthalmoscope optic disc contourlines with and without the aid of optic discphotographs. J Glaucoma 2005;14:351–7.

235. Tielsch JM, Sommer A, Witt K, Katz J, Royall RM.Blindness and visual impairment in an Americanurban population. The Baltimore Eye Survey. ArchOphthalmol 1990;108:286–90.

236. Medeiros FA, Zangwill LM, Bowd C, Sample PA,Weinreb RN. Use of progressive glaucomatousoptic disk change as the reference standard forevaluation of diagnostic tests in glaucoma. Am JOphthalmol 2005;139:1010–18.

237. Ellish NJ, Higginbotham EJ. Evaluating a visualfield screening test for glaucoma: how the choiceof the gold standard affects the validity of the test.Ophthalmic Epidemiol 2001;8:297–307.

238. Miglior S, Guareschi M, Romanazzi F, Albe E,Torri V, Orzalesi N. The impact of definition ofprimary open-angle glaucoma on the cross-sectional assessment of diagnostic validity ofHeidelberg retinal tomography. Am J Ophthalmol2005;139:878–87.

239. Streiner DL. Breaking up is hard to do: theheartbreak of dichotomizing continuous data. CanJ Psychiatry 2002;47:262–6.

240. Caprioli J. Clinical evaluation of the optic nerve inglaucoma. Trans Am Ophthalmol Soc 1994;92:589–641.

241. Quigley HA, Addicks EM, Green WR. Optic nervedamage in human glaucoma. III. Quantitativecorrelation of nerve fiber loss and visual fielddefect in glaucoma, ischemic neuropathy,papilledema, and toxic neuropathy. ArchOphthalmol 1982;100:135–46.

242. Garway-Heath D, Hitchings R. Sources of bias instudies of optic disc and retinal nerve fibre layermorphology. Br J Ophthalmol 1998;82:986.

243. Wild JM, Kim LS, Pacey IE, Cunliffe IA. Evidencefor a learning effect in short-wavelengthautomated perimetry. Ophthalmology 2006;113:206–15.

244. Yenice O, Temel A. Evaluation of two Humphreyperimetry programs: full threshold and SITAstandard testing strategy for learning effect. Eur JOphthalmol 2005;15:209–12.

245. Matsuo H, Tomita G, Suzuki Y, Araie M. Learningeffect and measurement variability in frequency-doubling technology perimetry in chronic open-angle glaucoma. J Glaucoma 2002;11:467–73.

246. Joson PJ, Kamantigue ME, Chen PP. Learningeffects among perimetric novices in frequencydoubling technology perimetry. Ophthalmology2002;109:757–60.

247. Rutjes AW, Reitsma JB, Di Nisio M, Smidt N,van Rijn JC, Bossuyt PM. Evidence of bias andvariation in diagnostic accuracy studies. CMAJ2006;174:469–76.

248. Hatt S, Wormald R, Burr J. Screening forprevention of optic nerve damage due to chronicopen angle glaucoma (Protocol). Cochrane DatabaseSyst Rev 2006 (Issue 3). Article No.: CD006129.DOI: 10.1002/14651858.CD006129.

249. Fechtner RD, Weinreb RN. Mechanisms of opticnerve damage in primary open angle glaucoma.Surv Ophthalmol 1994;39:23–42.

250. Bateman DN, Clark R, Azuara-Blanco A, Bain M,Forrest J. The effects of new topical treatments onmanagement of glaucoma in Scotland: anexamination of ophthalmological health care. Br JOphthalmol 2002;86:551–4.

251. Oxman AD. Checklists for review articles. BMJ1994;309:648–51.

252. Oxman AD, Guyatt GH. The science of reviewingresearch. Ann N Y Acad Sci 1993;703:125–33.

253. Miglior S, Zeyen T, Pfeiffer N, Cunha-Vaz J,Torri V, Adamsons I, et al. Results of the EuropeanGlaucoma Prevention Study. Ophthalmology2005;112:366–75.

254. Schulzer M, Alward WL, Feldman F, Cashwell LF,Wilensky J, Geijssen HC, et al. Comparison ofglaucomatous progression between untreatedpatients with normal-tension glaucoma andpatients with therapeutically reduced intraocularpressures. Am J Ophthalmol 1998;126:487–97.

255. Lichter PR, Musch DC, Gillespie BW, Guire KE,Janz NK, Wren PA, et al. Interim clinical outcomesin the Collaborative Initial Glaucoma TreatmentStudy comparing initial treatment randomized tomedications or surgery. Ophthalmology2001;108:1943–53.

256. Advanced Glaucoma Intervention Study. 2. Visualfield test scoring and reliability. Ophthalmology1994;101:1445–55.

257. Katz J, Congdon N, Friedman DS. Methodologicalvariations in estimating apparent progressivevisual field loss in clinical trials of glaucomatreatment. Arch Ophthalmol 1999;117:1137–42.

258. Vesti E, Johnson CA, Chauhan BC. Comparison ofdifferent methods for detecting glaucomatousvisual field progression. Invest Ophthalmol Vis Sci2003;44:3873–9.

259. Traverso CE, Walt JG, Kelly SP, Hommer AH,Bron AM, Denis P, et al. Direct costs of glaucomaand severity of the disease: a multinational longterm study of resource utilisation in Europe. Br JOphthalmol 2005;89:1245–9.

260. Lee PP, Walt JG, Doyle JJ, Kotak SV, Evans SJ,Budenz DL, et al. A multicenter, retrospective pilot

References

166

study of resource use and costs associated withseverity of disease in glaucoma. Arch Ophthalmol2006;124:12–19.

261. Hodapp E, Parrish RK, Anderson DR. Clinicaldecision in glaucoma. St Louis, MO: Mosby; 1993.

262. Nouri-Mahdavi K, Caprioli J, Coleman AL,Hoffman D, Gaasterland D. Pointwise linearregression for evaluation of visual field outcomesand comparison with the advanced glaucomaintervention study methods. Arch Ophthalmol2005;123:193–9.

263. Eid TM, Spaeth GL, Bitterman A, Steinmann WC.Rate and amount of visual loss in 102 patients withopen-angle glaucoma followed up for at least 15years. Ophthalmology 2003;110:900–7.

264. Hattenhauer MG, Johnson DH, Ing HH,Herman DC, Hodge DO, Yawn BP, et al. Theprobability of blindness from open-angleglaucoma. Ophthalmology 1998;105:2099–104.

265. Olivius E, Thorburn W. Prognosis of glaucomasimplex and glaucoma capsulare. A comparativestudy. Acta Ophthalmol (Copenh) 1978;56:921–34.

266. Quigley HA, Tielsch JM, Katz J, Sommer A. Rateof progression in open-angle glaucoma estimatedfrom cross-sectional prevalence of visual fielddamage. Am J Ophthalmol 1996;122:355–63.

267. Sponsel WE. Frequency of sustainedglaucomatous-type visual field loss and associatedoptic nerve cupping in Beaver Dam Wisconsin.Clin Exp Ophthalmol 2001;29:352–8.

268. Spry PG, Sparrow JM, Diamond JP, Harris HS.Risk factors for progressive visual field loss inprimary open angle glaucoma. Eye 2005;9:643–51.

269. Jonas JB, Martus P, Budde WM, Junemann A,Hayler J. Small neuroretinal rim and largeparapapillary atrophy as predictive factors forprogression of glaucomatous optic neuropathy.Ophthalmology 2002;109:1561–7.

270. Nouri-Mahdavi K, Hoffman D, Coleman AL,Liu G, Li G, Gaasterland D, et al. Predictive factorsfor glaucomatous visual field progression in theAdvanced Glaucoma Intervention Study.Ophthalmology 2004;111:1627–35.

271. Suzuki Y, Shirato S, Adachi M, Hamada C. Riskfactors for the progression of treated primaryopen-angle glaucoma: a multivariate life-tableanalysis. Grafes Arch Clin Exp Ophthalmol1999;237:463–7.

272. Tattersall CL, Vernon SA, Negi A. Is poor lifeexpectancy a predictive factor in the progressionof primary open angle glaucoma? Eye 2005;19:387–91.

273. Drance S, Anderson DR, Schulzer M. Risk factorsfor progression of visual field abnormalities innormal-tension glaucoma. Am J Ophthalmol2001;131:699–708.

274. Oliver JE, Hattenhauer MG, Herman D,Hodge DO, Kennedy R, Fang-Yen M, et al.Blindness and glaucoma: a comparison of patientsprogressing to blindness from glaucoma withpatients maintaining vision. Am J Ophthalmol2002;133:764–72.

275. Palmberg P. Risk factors for glaucoma progression:where does intraocular pressure fit in? ArchOphthalmol 2001;119:897–8.

276. Garway-Heath T. Measurement of rate ofprogression. Int Glaucoma Rev 2006;7:9–11.

277. Drummond MF, Sculpher MJ, Torrance GW,O'Brien BJ, Stoddart GL. Methods for the economicevaluation of health care programmes. 3rd ed. Oxford:Oxford University Press; 2005.

278. Improving access to cost-effectiveness information forhealth care decision making: the NHS EconomicEvaluation Database. CRD Report No. 6. York: NHSCentre for Reviews and Dissemination; 2001.

279. Boivin J, McGregor M. The screening of primaryopen-angle glaucoma – systematic review. Montreal:Conseil d’Evaluation des Technologies de la Santedu Quebec; 1995.

280. Boivin JF, McGregor M, Archer C. Costeffectiveness of screening for primary open angleglaucoma. J Med Screen 1996;3:154–63.

281. Gooder P. Screening for glaucoma. Development andEvaluation Committee (DEC) Report No. 38.Bristol: Research & Development DirectorateSouth and West; 1995.

282. Gottlieb LK, Schwartz B, Pauker SG. Glaucomascreening. A cost-effectiveness analysis. SurvOphthalmol 1983;28:206–26.

283. Tuck MW, Crick RP. The cost-effectiveness ofvarious modes of screening for primary openangle glaucoma. Ophthalmic Epidemiol 1997;4:3–17.

284. Teagarden JR. Meta-analysis: whither narrativereview? Pharmacotherapy 1989;9:274–81.

285. Demichelli V, Jefferson T, Vale L. Effectivenessestimates in economic evaluation. In: DonaldsonC, Mugford M, Vale L, editors. From effectiveness toefficiency – health economics and systematic review.London: BMJ Books; 2002.

286. British Household Panel Survey (BHPS). Institutefor Social & Economic Research, University ofEssex. URL: http://www.iser.essex.ac.uk/ulsc/bhps/.Accessed April 2006.

287. Theodossiades J, Murdoch I. Positive predictivevalue of optometrist-initiated referrals forglaucoma. Ophthalmic Physiol Opt 1999;19:62–7.

288. Tuck M, Crick R. Glaucoma screening byoptometrists: ten years on. Health Trends1998;30:130–4.

289. Vernon SA, Ghosh G. Do locally agreed guidelinesfor optometrists concerning the referral of


167


glaucoma suspects influence referral practice? Eye2001;15:458–63.

290. Bowling B, Chen SD, Salmon JF. Outcomes ofreferrals by community optometrists to a hospitalglaucoma service. Br J Ophthalmol 2005;89:1102–4.

291. Henson DB, Spencer AF, Harper R, Cadman EJ.Community refinement of glaucoma referrals. Eye2003;17:21–6.

292. Brittain GPH, Austin DJ, Kelly SP. A prospectivesurvey to determine sources and diagnosticaccuracy of glaucoma referrals. Health Trends1988;20:43–4.

293. Tuck MW. Referrals for suspected glaucoma: anInternational Glaucoma Association survey.Ophthalmic Physiol Opt 1991;11:22–6.

294. Busby, D. General ophthalmic services: increases toNHS sight test fee and NHS optical voucher valuesand tax credit limits from April 2005. Departmentof Health. URL: http://www.dh.gov.uk/assetRoot/04/10/70/47/04107047.pdf. Accessed April 2006.

295. Facey K, Cummins E, Macpherson K, Morris A,Reay L, Slattery J. Organisation of services for diabeticretinopathy screening. HTA Report 1. Glasgow: NHS Quality Improvement Scotland [HealthTechnology Board for Scotland (HTBS)]; 2002.

296. General ophthalmic services. Primary CareCircular PCA(O)(2005)03. Scottish Executive.URL: http://www.show.scot.nhs.uk/sehd/pca/PCA2005(O)03.pdf. Accessed February 2006.

297. Guide to the methods of technology appraisal.National Institute for Clinical Excellence. URL:http://www.nice.org.uk/page.aspx?o=201974.Accessed September 2005.

298. Gupta V, Srinivasan G, Mei SS, Gazzard G,Sihota R, Kapoor KS. Utility values amongglaucoma patients: an impact on the quality of life.Br J Ophthalmol 2005;89:1241–4.

299. Meads C, Hyde C. How much is the cost of visualimpairment: caveat emptor. Pharmacoeconomics2006;24:207–9.

300. Iversen GR. Bayesian statistical inference. ThousandOaks, CA: Sage; 1984.

301. Mutti DO, Zadnik K. Age-related decreases in theprevalence of myopia: longitudinal change orcohort effect? Invest Ophthalmol Vis Sci2000;41:2103–7.

302. Diabetes population prevalence model. DiabetesUK. URL: http://www.diabetes.org.uk/infocentre/reports/prevalencemodel.doc. Accessed February2006.

303. The UK population: by ethnic group. UnitedKingdom Census 2001. National Statistics. URL:http://www.statistics.gov.uk/CCI/nugget.asp?ID=273&Pos=4&ColRank=2&Rank=1000. AccessedFebruary 2006.

304. Guidelines for the management of open angle glaucoma and ocular hypertension. Royal College of Ophthalmologists. URL:http://www.rcophth.ac.uk/docs/publications/glaucoma2004.pdf. Accessed February 2006.

305. Glaucoma. Clinical guideline in development.National Institute for Health and ClinicalExcellence. URL: http://www.nice.org.uk/page.aspx?o=292041. Accessed February 2006.

306. Shah P, Cross V. ReGAE 1: using the Shah–Crossmodel as an orientating framework inAfrican–Caribbean glaucoma research. Eye [serialon the Internet] 2006;doi: 10.1038/sj.eye.6702130.

307. Saw SM, Gazzard G, Eong KG, Oen F, Seah S.Utility values in Singapore Chinese adults withprimary open-angle and primary angle-closureglaucoma. J Glaucoma 2005;14:455–62.

308. Perkins ES. The Bedford Glaucoma Survey. I.Long-term follow-up of borderline cases. Br JOphthalmol 1973;57:179–85.

309. Bengtsson B. Manifest glaucoma in the aged. I:Occurrence nine years after a population survey.Acta Ophthalmol (Copenh) 1981;59:321–31.

310. Bengtsson BO. Incidence of manifest glaucoma.Br J Ophthalmol 1989;73:483–7.

311. Bonomi L, Marchine G, Marraffa M, Bernardi P,Morbio R, Varotto A, et al. Vascular risk factors forprimary open-angle glaucoma. Ophthalmology2001;107:1287–93.

312. Borger PH, van Leeuwen R, Hulsman CA,Wolfs RC, van der Kuip DA, Hofman A, et al. Isthere a direct association between age-related eyediseases and mortality? The Rotterdam Study.Ophthalmology 2003;110:1292–6.

313. Ramrattan RS, Wolfs RC, Jonas JB, Hofman A,de Jong PT. Determinants of optic disccharacteristics in a general population: TheRotterdam Study. Ophthalmology 1999;106:1588–96.

314. Ramrattan RS, Wolfs RCW, Panda-Jonas S, JonasJB, Bakker D, Pols HA, et al. Prevalence and causesof visual field loss in the elderly and associationswith impairment in daily functioning: theRotterdam Study. Arch Ophthalmol2001;119:1788–94.

315. Grodum K. Glaucoma characteristics and risk factors:results from Malmo Eye Survey. Copenhagen:Blackwell Munksgaard; 2004.

316. Grodum K, Heijl A, Bengtsson B. Risk ofglaucoma in ocular hypertension with and withoutpseudoexfoliation. Ophthalmology 2005;112:386–90.

317. Kahn HA, Leibowitz HM, Ganley JP, Kini MM,Colton T, Nickerson RS, et al. The FraminghamEye Study. I. Outline and major prevalencefindings. Am J Epidemiol 1977;106:17–32.

References

168

318. Kahn HA, Milton RC. Revised Framingham eyestudy prevalence of glaucoma and diabeticretinopathy. Am J Epidemiol 1980;111:769–76.

319. Kini MM, Leibowitz HM, Colton T, Nickerson RJ,Ganley J, Dawber TR. Prevalence of senilecataract, diabetic retinopathy, senile maculardegeneration, and open-angle glaucoma in theFramingham eye study. Am J Ophthalmol1978;85:28–34.

320. Graham PA. Prevalence of glaucoma. Populationsurveys. Trans Ophthalmol Soc UK 1978;98:288–9.

321. Duggal P, Klein AP, Lee KE, Iyengar SK, Klein R,Bailey-Wilson JE, et al. A genetic contribution tointraocular pressure: the Beaver Dam Eye Study.Invest Ophthalmol Vis Sci 2005;46:555–60.

322. Klein BE, Klein R, Ritter LL. Relationship ofdrinking alcohol and smoking to prevalence ofopen-angle glaucoma: the Beaver Dam Eye Study.Ophthalmology 1993;100:1609–13.

323. Klein BE, Klein R, Lee KE. Heritability of riskfactors for primary open-angle glaucoma: theBeaver Dam Eye Study. Invest Ophthalmol Vis Sci2004;45:59–62.

324. Klein BEK, Klein R, Knudtson MD. Intraocularpressure and systemic blood pressure: longitudinalperspective: The Beaver Dam Eye Study. Br JOphthalmol 2005;89:284–7.

325. Klein R, Klein BEK, Moss SE. Age-related eyedisease and survival: the Beaver Dam Eye Study.Arch Ophthalmol 1995;113:333–9.

326. Klein R, Klein BE, Tomany SC, Wong TY. Therelation of retinal microvascular characteristics toage-related eye disease: the Beaver Dam EyeStudy. Am J Ophthalmol 2004;137:435–44.

327. Viswanathan AC, Hitchings RA, Indar A,Mitchell P, Healey PR, McGuffin P, et al.Commingling analysis of intraocular pressure andglaucoma in an older Australian population. AnnHum Genet 2004;68:489–97.

328. Lee AJ, Mitchell P, Rochtchina E, Healey PR, BlueMountains Eye Study. Female reproductive factorsand open angle glaucoma: the Blue MountainsEye Study. Br J Ophthalmol 2003;87:1324–8.

329. Mitchell P, Cumming RG, Mackey DA. Inhaledcorticosteroids, family history and risk ofglaucoma. Ophthalmology 1999;106:2301–6.

330. Lee AJ, Rochtchina E, Mitchell P. Intraocularpressure asymmetry and undiagnosed open-angleglaucoma in an older population. Am J Ophthalmol2004;137:380–2.

331. Wang JJ, Mitchell P, Smith W. Is there anassociation between migraine headache and open-angle glaucoma? Findings from the BlueMountains Eye Study. Ophthalmology 1997;104:1714-19.

332. Younan C, Mitchell P, Cumming RG,Rochtchina E, Wang JJ. Myopia and incidentcataract and cataract surgery: the Blue MountainsEye Study. Invest Ophthalmol Vis Sci 2002;43:3625–32.

333. Lee AJ, Rochtchina E, Wang JJ, Healey PR,Mitchell P. Open-angle glaucoma and systemicthyroid disease in an older population: the BlueMountains Eye Study. Eye 2004;18:600–8.

334. Mitchell P, Lee AJ, Rochtchina E, Wang JJ. Open-angle glaucoma and systemic hypertension: theBlue Mountains Eye Study. J Glaucoma2004;13:319–26.

335. Attebo K, Ivers RQ, Mitchell P. Refractive errors inan older population – the Blue Mountains EyeStudy. Ophthalmology 1999;106:1066–72.

336. Mitchell P, Leung H, Wang JJ, Rochtchina E,Lee AJ, Wong TY. Retinal vessel diameter andopen-angle glaucoma: the Blue Mountains EyeStudy. Ophthalmology 2005;112:245–50.

337. Mitchell P, Wang JJ, Hourihan F. The relationshipbetween glaucoma and pseudoexfoliation. ArchOphthalmol 1999;117:1319–24.

338. Rahmani B, Tielsch JM, Katz J, Gottsch J,Quigley H, Javitt J, et al. The cause-specificprevalence of visual impairment in an urbanpopulation. The Baltimore Eye Survey.Ophthalmology 1996;103:1721–6.

339. Sommer A, Tielsch JM, Katz J, Quigley HA,Gottsch JD, Javitt JC, et al. Racial differences inthe cause-specific prevalence of blindness in eastBaltimore. N Engl J Med 1991;325:1412–17.

340. Sommer A. Glaucoma risk factors observed in theBaltimore Eye Survey. Curr Opin Ophthalmol1996;7:93–8.

341. Tielsch JM, Katz J, Sommer A, Quigley HA,Javitt JC. Hypertension, perfusion pressure, andprimary open-angle glaucoma: a population-basedassessment. Arch Ophthalmol 1995;113:216–21.

342. Tielsch JM, Katz J, Quigley HA, Javitt JC,Sommer A. Diabetes, intraocular pressure, andprimary open-angle glaucoma in the BaltimoreEye Survey. Ophthalmology 1995;102:48–53.

343. Varma R, Hilton SC, Tielsch JM, Katz J,Quigley HA, Sommer A. Neural rim area declineswith increased intraocular pressure in urbanAmericans. Arch Ophthalmol 1995;113:1001–5.

344. Le A, Mukesh BN, McCarty CA, Taylor HR. Riskfactors associated with the incidence of open-angleglaucoma: the Visual Impairment Project. InvestOphthalmol Vis Sci 2003;44:3783–9.

345. Van Newkirk MR, Weih L, McCarty CA, TaylorHR. Cause-specific prevalence of bilateral visualimpairment in Victoria, Australia: the VisualImpairment Project. Ophthalmology2001;108:960–7.


169


346. Wensor M, McCarty C, Taylor H. Prevalence andrisk factors of myopia in Victoria, Melbourne. ArchOphthalmol 1999;117:658–63.

347. Wong EY, Keeffe JE, Rait JL, Vu HT, Le A,McCarty C, et al. Detection of undiagnosedglaucoma by eye health professionals.Ophthalmology 2004;111:1508–14.

References

170

This version of HTA monograph volume 11, number 41 does not include the 176 pages of appendices. This is to save download time from the HTA website. The printed version of this monograph also excludes the appendices. View/download the appendices (2671 kbytes).


343


Volume 1, 1997

No. 1Home parenteral nutrition: a systematicreview.

By Richards DM, Deeks JJ, SheldonTA, Shaffer JL.

No. 2Diagnosis, management and screeningof early localised prostate cancer.

A review by Selley S, Donovan J,Faulkner A, Coast J, Gillatt D.

No. 3The diagnosis, management, treatmentand costs of prostate cancer in Englandand Wales.

A review by Chamberlain J, Melia J,Moss S, Brown J.

No. 4Screening for fragile X syndrome.

A review by Murray J, Cuckle H,Taylor G, Hewison J.

No. 5A review of near patient testing inprimary care.

By Hobbs FDR, Delaney BC,Fitzmaurice DA, Wilson S, Hyde CJ,Thorpe GH, et al.

No. 6Systematic review of outpatient servicesfor chronic pain control.

By McQuay HJ, Moore RA, EcclestonC, Morley S, de C Williams AC.

No. 7Neonatal screening for inborn errors ofmetabolism: cost, yield and outcome.

A review by Pollitt RJ, Green A,McCabe CJ, Booth A, Cooper NJ,Leonard JV, et al.

No. 8Preschool vision screening.

A review by Snowdon SK, Stewart-Brown SL.

No. 9Implications of socio-cultural contextsfor the ethics of clinical trials.

A review by Ashcroft RE, ChadwickDW, Clark SRL, Edwards RHT, Frith L,Hutton JL.

No. 10A critical review of the role of neonatalhearing screening in the detection ofcongenital hearing impairment.

By Davis A, Bamford J, Wilson I,Ramkalawan T, Forshaw M, Wright S.

No. 11Newborn screening for inborn errors ofmetabolism: a systematic review.

By Seymour CA, Thomason MJ,Chalmers RA, Addison GM, Bain MD,Cockburn F, et al.

No. 12Routine preoperative testing: a systematic review of the evidence.

By Munro J, Booth A, Nicholl J.

No. 13Systematic review of the effectiveness of laxatives in the elderly.

By Petticrew M, Watt I, Sheldon T.

No. 14When and how to assess fast-changingtechnologies: a comparative study ofmedical applications of four generictechnologies.

A review by Mowatt G, Bower DJ,Brebner JA, Cairns JA, Grant AM,McKee L.

Volume 2, 1998

No. 1Antenatal screening for Down’ssyndrome.

A review by Wald NJ, Kennard A,Hackshaw A, McGuire A.

No. 2Screening for ovarian cancer: a systematic review.

By Bell R, Petticrew M, Luengo S,Sheldon TA.

No. 3Consensus development methods, andtheir use in clinical guidelinedevelopment.

A review by Murphy MK, Black NA,Lamping DL, McKee CM, SandersonCFB, Askham J, et al.

No. 4A cost–utility analysis of interferon beta for multiple sclerosis.

By Parkin D, McNamee P, Jacoby A,Miller P, Thomas S, Bates D.

No. 5Effectiveness and efficiency of methodsof dialysis therapy for end-stage renaldisease: systematic reviews.

By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M,Daly C, et al.

No. 6Effectiveness of hip prostheses inprimary total hip replacement: a criticalreview of evidence and an economicmodel.

By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M,Bevan G.

No. 7Antimicrobial prophylaxis in colorectalsurgery: a systematic review ofrandomised controlled trials.

By Song F, Glenny AM.

No. 8Bone marrow and peripheral bloodstem cell transplantation for malignancy.

A review by Johnson PWM, Simnett SJ,Sweetenham JW, Morgan GJ, Stewart LA.

No. 9Screening for speech and languagedelay: a systematic review of theliterature.

By Law J, Boyle J, Harris F, HarknessA, Nye C.

No. 10Resource allocation for chronic stableangina: a systematic review ofeffectiveness, costs and cost-effectiveness of alternativeinterventions.

By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR,Buxton MJ.

No. 11Detection, adherence and control ofhypertension for the prevention ofstroke: a systematic review.

By Ebrahim S.

No. 12Postoperative analgesia and vomiting,with special reference to day-casesurgery: a systematic review.

By McQuay HJ, Moore RA.

No. 13Choosing between randomised andnonrandomised studies: a systematicreview.

By Britton A, McKee M, Black N,McPherson K, Sanderson C, Bain C.

No. 14Evaluating patient-based outcomemeasures for use in clinical trials.

A review by Fitzpatrick R, Davey C,Buxton MJ, Jones DR.

Health Technology Assessment reports published to date

No. 15Ethical issues in the design and conductof randomised controlled trials.

A review by Edwards SJL, Lilford RJ,Braunholtz DA, Jackson JC, Hewison J,Thornton J.

No. 16Qualitative research methods in healthtechnology assessment: a review of theliterature.

By Murphy E, Dingwall R, GreatbatchD, Parker S, Watson P.

No. 17The costs and benefits of paramedicskills in pre-hospital trauma care.

By Nicholl J, Hughes S, Dixon S,Turner J, Yates D.

No. 18Systematic review of endoscopicultrasound in gastro-oesophagealcancer.

By Harris KM, Kelly S, Berry E,Hutton J, Roderick P, Cullingworth J, et al.

No. 19Systematic reviews of trials and otherstudies.

By Sutton AJ, Abrams KR, Jones DR,Sheldon TA, Song F.

No. 20Primary total hip replacement surgery: a systematic review of outcomes andmodelling of cost-effectivenessassociated with different prostheses.

A review by Fitzpatrick R, Shortall E,Sculpher M, Murray D, Morris R, LodgeM, et al.

Volume 3, 1999

No. 1Informed decision making: an annotatedbibliography and systematic review.

By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J,Robinson MB, et al.

No. 2Handling uncertainty when performingeconomic evaluation of healthcareinterventions.

A review by Briggs AH, Gray AM.

No. 3The role of expectancies in the placeboeffect and their use in the delivery ofhealth care: a systematic review.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Thomas H.

No. 4A randomised controlled trial ofdifferent approaches to universalantenatal HIV testing: uptake andacceptability. Annex: Antenatal HIVtesting – assessment of a routinevoluntary approach.

By Simpson WM, Johnstone FD, BoydFM, Goldberg DJ, Hart GJ, GormleySM, et al.

No. 5Methods for evaluating area-wide andorganisation-based interventions inhealth and health care: a systematicreview.

By Ukoumunne OC, Gulliford MC,Chinn S, Sterne JAC, Burney PGJ.

No. 6Assessing the costs of healthcaretechnologies in clinical trials.

A review by Johnston K, Buxton MJ,Jones DR, Fitzpatrick R.

No. 7Cooperatives and their primary careemergency centres: organisation andimpact.

By Hallam L, Henthorne K.

No. 8Screening for cystic fibrosis.

A review by Murray J, Cuckle H,Taylor G, Littlewood J, Hewison J.

No. 9A review of the use of health statusmeasures in economic evaluation.

By Brazier J, Deverill M, Green C,Harper R, Booth A.

No. 10Methods for the analysis of quality-of-life and survival data in healthtechnology assessment.

A review by Billingham LJ, AbramsKR, Jones DR.

No. 11Antenatal and neonatalhaemoglobinopathy screening in theUK: review and economic analysis.

By Zeuner D, Ades AE, Karnon J,Brown J, Dezateux C, Anionwu EN.

No. 12Assessing the quality of reports ofrandomised trials: implications for theconduct of meta-analyses.

A review by Moher D, Cook DJ, JadadAR, Tugwell P, Moher M, Jones A, et al.

No. 13‘Early warning systems’ for identifyingnew healthcare technologies.

By Robert G, Stevens A, Gabbay J.

No. 14A systematic review of the role of humanpapillomavirus testing within a cervicalscreening programme.

By Cuzick J, Sasieni P, Davies P,Adams J, Normand C, Frater A, et al.

No. 15Near patient testing in diabetes clinics:appraising the costs and outcomes.

By Grieve R, Beech R, Vincent J,Mazurkiewicz J.

No. 16Positron emission tomography:establishing priorities for healthtechnology assessment.

A review by Robert G, Milne R.

No. 17 (Pt 1)The debridement of chronic wounds: a systematic review.

By Bradley M, Cullum N, Sheldon T.

No. 17 (Pt 2)Systematic reviews of wound caremanagement: (2) Dressings and topicalagents used in the healing of chronicwounds.

By Bradley M, Cullum N, Nelson EA,Petticrew M, Sheldon T, Torgerson D.

No. 18A systematic literature review of spiraland electron beam computedtomography: with particular reference toclinical applications in hepatic lesions,pulmonary embolus and coronary arterydisease.

By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

No. 19What role for statins? A review andeconomic model.

By Ebrahim S, Davey Smith G,McCabe C, Payne N, Pickin M, SheldonTA, et al.

No. 20Factors that limit the quality, numberand progress of randomised controlledtrials.

A review by Prescott RJ, Counsell CE,Gillespie WJ, Grant AM, Russell IT,Kiauka S, et al.

No. 21Antimicrobial prophylaxis in total hipreplacement: a systematic review.

By Glenny AM, Song F.

No. 22Health promoting schools and healthpromotion in schools: two systematicreviews.

By Lister-Sharp D, Chapman S,Stewart-Brown S, Sowden A.

No. 23Economic evaluation of a primary care-based education programme for patientswith osteoarthritis of the knee.

A review by Lord J, Victor C,Littlejohns P, Ross FM, Axford JS.

Volume 4, 2000

No. 1The estimation of marginal timepreference in a UK-wide sample(TEMPUS) project.

A review by Cairns JA, van der PolMM.

No. 2Geriatric rehabilitation followingfractures in older people: a systematicreview.

By Cameron I, Crotty M, Currie C,Finnegan T, Gillespie L, Gillespie W, et al.


344

No. 3Screening for sickle cell disease andthalassaemia: a systematic review withsupplementary research.

By Davies SC, Cronin E, Gill M,Greengross P, Hickman M, Normand C.

No. 4Community provision of hearing aidsand related audiology services.

A review by Reeves DJ, Alborz A,Hickson FS, Bamford JM.

No. 5False-negative results in screeningprogrammes: systematic review ofimpact and implications.

By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

No. 6Costs and benefits of communitypostnatal support workers: arandomised controlled trial.

By Morrell CJ, Spiby H, Stewart P,Walters S, Morgan A.

No. 7Implantable contraceptives (subdermalimplants and hormonally impregnatedintrauterine systems) versus other formsof reversible contraceptives: twosystematic reviews to assess relativeeffectiveness, acceptability, tolerabilityand cost-effectiveness.

By French RS, Cowan FM, MansourDJA, Morris S, Procter T, Hughes D, et al.

No. 8An introduction to statistical methodsfor health technology assessment.

A review by White SJ, Ashby D, Brown PJ.

No. 9Disease-modifying drugs for multiplesclerosis: a rapid and systematic review.

By Clegg A, Bryant J, Milne R.

No. 10Publication and related biases.

A review by Song F, Eastwood AJ,Gilbody S, Duley L, Sutton AJ.

No. 11Cost and outcome implications of theorganisation of vascular services.

By Michaels J, Brazier J, PalfreymanS, Shackley P, Slack R.

No. 12Monitoring blood glucose control indiabetes mellitus: a systematic review.

By Coster S, Gulliford MC, Seed PT,Powrie JK, Swaminathan R.

No. 13The effectiveness of domiciliary healthvisiting: a systematic review ofinternational studies and a selective review of the Britishliterature.

By Elkan R, Kendrick D, Hewitt M,Robinson JJA, Tolley K, Blair M, et al.

No. 14The determinants of screening uptakeand interventions for increasing uptake:a systematic review.

By Jepson R, Clegg A, Forbes C,Lewis R, Sowden A, Kleijnen J.

No. 15The effectiveness and cost-effectivenessof prophylactic removal of wisdomteeth.

A rapid review by Song F, O’Meara S,Wilson P, Golder S, Kleijnen J.

No. 16Ultrasound screening in pregnancy: asystematic review of the clinicaleffectiveness, cost-effectiveness andwomen’s views.

By Bricker L, Garcia J, Henderson J,Mugford M, Neilson J, Roberts T, et al.

No. 17A rapid and systematic review of theeffectiveness and cost-effectiveness ofthe taxanes used in the treatment ofadvanced breast and ovarian cancer.

By Lister-Sharp D, McDonagh MS,Khan KS, Kleijnen J.

No. 18Liquid-based cytology in cervicalscreening: a rapid and systematic review.

By Payne N, Chilcott J, McGoogan E.

No. 19Randomised controlled trial of non-directive counselling,cognitive–behaviour therapy and usualgeneral practitioner care in themanagement of depression as well asmixed anxiety and depression inprimary care.

By King M, Sibbald B, Ward E, BowerP, Lloyd M, Gabbay M, et al.

No. 20Routine referral for radiography ofpatients presenting with low back pain:is patients’ outcome influenced by GPs’referral for plain radiography?

By Kerry S, Hilton S, Patel S, DundasD, Rink E, Lord J.

No. 21Systematic reviews of wound caremanagement: (3) antimicrobial agentsfor chronic wounds; (4) diabetic footulceration.

By O’Meara S, Cullum N, Majid M,Sheldon T.

No. 22Using routine data to complement andenhance the results of randomisedcontrolled trials.

By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

No. 23Coronary artery stents in the treatmentof ischaemic heart disease: a rapid andsystematic review.

By Meads C, Cummins C, Jolly K,Stevens A, Burls A, Hyde C.

No. 24Outcome measures for adult criticalcare: a systematic review.

By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM,Daly K, et al.

No. 25A systematic review to evaluate theeffectiveness of interventions to promote the initiation of breastfeeding.

By Fairbank L, O’Meara S, RenfrewMJ, Woolridge M, Sowden AJ, Lister-Sharp D.

No. 26Implantable cardioverter defibrillators:arrhythmias. A rapid and systematicreview.

By Parkes J, Bryant J, Milne R.

No. 27Treatments for fatigue in multiplesclerosis: a rapid and systematic review.

By Brañas P, Jordan R, Fry-Smith A,Burls A, Hyde C.

No. 28Early asthma prophylaxis, naturalhistory, skeletal development andeconomy (EASE): a pilot randomisedcontrolled trial.

By Baxter-Jones ADG, Helms PJ,Russell G, Grant A, Ross S, Cairns JA, et al.

No. 29Screening for hypercholesterolaemiaversus case finding for familialhypercholesterolaemia: a systematicreview and cost-effectiveness analysis.

By Marks D, Wonderling D,Thorogood M, Lambert H, HumphriesSE, Neil HAW.

No. 30A rapid and systematic review of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists in the medical managementof unstable angina.

By McDonagh MS, Bachmann LM,Golder S, Kleijnen J, ter Riet G.

No. 31A randomised controlled trial ofprehospital intravenous fluidreplacement therapy in serious trauma.

By Turner J, Nicholl J, Webber L,Cox H, Dixon S, Yates D.

No. 32Intrathecal pumps for giving opioids inchronic pain: a systematic review.

By Williams JE, Louw G, Towlerton G.

No. 33Combination therapy (interferon alfaand ribavirin) in the treatment ofchronic hepatitis C: a rapid andsystematic review.

By Shepherd J, Waugh N, Hewitson P.


345


No. 34A systematic review of comparisons ofeffect sizes derived from randomisedand non-randomised studies.

By MacLehose RR, Reeves BC,Harvey IM, Sheldon TA, Russell IT,Black AMS.

No. 35Intravascular ultrasound-guidedinterventions in coronary artery disease:a systematic literature review, withdecision-analytic modelling, of outcomesand cost-effectiveness.

By Berry E, Kelly S, Hutton J,Lindsay HSJ, Blaxill JM, Evans JA, et al.

No. 36A randomised controlled trial toevaluate the effectiveness and cost-effectiveness of counselling patients withchronic depression.

By Simpson S, Corney R, Fitzgerald P,Beecham J.

No. 37Systematic review of treatments foratopic eczema.

By Hoare C, Li Wan Po A, Williams H.

No. 38Bayesian methods in health technologyassessment: a review.

By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

No. 39The management of dyspepsia: asystematic review.

By Delaney B, Moayyedi P, Deeks J,Innes M, Soo S, Barton P, et al.

No. 40A systematic review of treatments forsevere psoriasis.

By Griffiths CEM, Clark CM, ChalmersRJG, Li Wan Po A, Williams HC.

Volume 5, 2001

No. 1Clinical and cost-effectiveness ofdonepezil, rivastigmine andgalantamine for Alzheimer’s disease: arapid and systematic review.

By Clegg A, Bryant J, Nicholson T,McIntyre L, De Broe S, Gerard K, et al.

No. 2The clinical effectiveness and cost-effectiveness of riluzole for motorneurone disease: a rapid and systematicreview.

By Stewart A, Sandercock J, Bryan S,Hyde C, Barton PM, Fry-Smith A, et al.

No. 3Equity and the economic evaluation ofhealthcare.

By Sassi F, Archard L, Le Grand J.

No. 4Quality-of-life measures in chronicdiseases of childhood.

By Eiser C, Morse R.

No. 5Eliciting public preferences forhealthcare: a systematic review oftechniques.

By Ryan M, Scott DA, Reeves C, BateA, van Teijlingen ER, Russell EM, et al.

No. 6General health status measures forpeople with cognitive impairment:learning disability and acquired braininjury.

By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

No. 7An assessment of screening strategies forfragile X syndrome in the UK.

By Pembrey ME, Barnicoat AJ,Carmichael B, Bobrow M, Turner G.

No. 8Issues in methodological research:perspectives from researchers andcommissioners.

By Lilford RJ, Richardson A, StevensA, Fitzpatrick R, Edwards S, Rock F, et al.

No. 9Systematic reviews of wound caremanagement: (5) beds; (6) compression;(7) laser therapy, therapeuticultrasound, electrotherapy andelectromagnetic therapy.

By Cullum N, Nelson EA, FlemmingK, Sheldon T.

No. 10Effects of educational and psychosocialinterventions for adolescents withdiabetes mellitus: a systematic review.

By Hampson SE, Skinner TC, Hart J,Storey L, Gage H, Foxcroft D, et al.

No. 11Effectiveness of autologous chondrocytetransplantation for hyaline cartilagedefects in knees: a rapid and systematicreview.

By Jobanputra P, Parry D, Fry-SmithA, Burls A.

No. 12Statistical assessment of the learningcurves of health technologies.

By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF,Russell IT.

No. 13The effectiveness and cost-effectivenessof temozolomide for the treatment ofrecurrent malignant glioma: a rapid andsystematic review.

By Dinnes J, Cave C, Huang S, Major K, Milne R.

No. 14A rapid and systematic review of theclinical effectiveness and cost-effectiveness of debriding agents intreating surgical wounds healing bysecondary intention.

By Lewis R, Whiting P, ter Riet G,O’Meara S, Glanville J.

No. 15Home treatment for mental healthproblems: a systematic review.

By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

No. 16How to develop cost-consciousguidelines.

By Eccles M, Mason J.

No. 17The role of specialist nurses in multiplesclerosis: a rapid and systematic review.

By De Broe S, Christopher F, Waugh N.

No. 18A rapid and systematic review of theclinical effectiveness and cost-effectiveness of orlistat in themanagement of obesity.

By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

No. 19The clinical effectiveness and cost-effectiveness of pioglitazone for type 2diabetes mellitus: a rapid and systematicreview.

By Chilcott J, Wight J, Lloyd JonesM, Tappenden P.

No. 20Extended scope of nursing practice: amulticentre randomised controlled trialof appropriately trained nurses andpreregistration house officers in pre-operative assessment in elective generalsurgery.

By Kinley H, Czoski-Murray C,George S, McCabe C, Primrose J, Reilly C, et al.

No. 21Systematic reviews of the effectiveness ofday care for people with severe mentaldisorders: (1) Acute day hospital versusadmission; (2) Vocational rehabilitation;(3) Day hospital versus outpatient care.

By Marshall M, Crowther R, Almaraz-Serrano A, Creed F, Sledge W, Kluiter H, et al.

No. 22The measurement and monitoring ofsurgical adverse events.

By Bruce J, Russell EM, Mollison J,Krukowski ZH.

No. 23Action research: a systematic review andguidance for assessment.

By Waterman H, Tillen D, Dickson R,de Koning K.

No. 24A rapid and systematic review of theclinical effectiveness and cost-effectiveness of gemcitabine for thetreatment of pancreatic cancer.

By Ward S, Morris E, Bansback N,Calvert N, Crellin A, Forman D, et al.


346

No. 25A rapid and systematic review of theevidence for the clinical effectivenessand cost-effectiveness of irinotecan,oxaliplatin and raltitrexed for thetreatment of advanced colorectal cancer.

By Lloyd Jones M, Hummel S,Bansback N, Orr B, Seymour M.

No. 26Comparison of the effectiveness ofinhaler devices in asthma and chronicobstructive airways disease: a systematicreview of the literature.

By Brocklebank D, Ram F, Wright J,Barry P, Cates C, Davies L, et al.

No. 27The cost-effectiveness of magneticresonance imaging for investigation ofthe knee joint.

By Bryan S, Weatherburn G, BungayH, Hatrick C, Salas C, Parry D, et al.

No. 28A rapid and systematic review of theclinical effectiveness and cost-effectiveness of topotecan for ovariancancer.

By Forbes C, Shirran L, Bagnall A-M,Duffy S, ter Riet G.

No. 29Superseded by a report published in alater volume.

No. 30The role of radiography in primary carepatients with low back pain of at least 6weeks duration: a randomised(unblinded) controlled trial.

By Kendrick D, Fielding K, Bentley E,Miller P, Kerslake R, Pringle M.

No. 31Design and use of questionnaires: areview of best practice applicable tosurveys of health service staff andpatients.

By McColl E, Jacoby A, Thomas L,Soutter J, Bamford C, Steen N, et al.

No. 32A rapid and systematic review of theclinical effectiveness and cost-effectiveness of paclitaxel, docetaxel,gemcitabine and vinorelbine in non-small-cell lung cancer.

By Clegg A, Scott DA, Sidhu M,Hewitson P, Waugh N.

No. 33Subgroup analyses in randomisedcontrolled trials: quantifying the risks offalse-positives and false-negatives.

By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M,Davey Smith G.

No. 34Depot antipsychotic medication in thetreatment of patients with schizophrenia:(1) Meta-review; (2) Patient and nurseattitudes.

By David AS, Adams C.

No. 35A systematic review of controlled trialsof the effectiveness and cost-effectiveness of brief psychologicaltreatments for depression.

By Churchill R, Hunot V, Corney R,Knapp M, McGuire H, Tylee A, et al.

No. 36Cost analysis of child healthsurveillance.

By Sanderson D, Wright D, Acton C,Duree D.

Volume 6, 2002

No. 1A study of the methods used to selectreview criteria for clinical audit.

By Hearnshaw H, Harker R, CheaterF, Baker R, Grimshaw G.

No. 2Fludarabine as second-line therapy forB cell chronic lymphocytic leukaemia: a technology assessment.

By Hyde C, Wake B, Bryan S, BartonP, Fry-Smith A, Davenport C, et al.

No. 3Rituximab as third-line treatment forrefractory or recurrent Stage III or IVfollicular non-Hodgkin’s lymphoma: asystematic review and economicevaluation.

By Wake B, Hyde C, Bryan S, BartonP, Song F, Fry-Smith A, et al.

No. 4A systematic review of dischargearrangements for older people.

By Parker SG, Peet SM, McPherson A,Cannaby AM, Baker R, Wilson A, et al.

No. 5The clinical effectiveness and cost-effectiveness of inhaler devices used inthe routine management of chronicasthma in older children: a systematicreview and economic evaluation.

By Peters J, Stevenson M, Beverley C,Lim J, Smith S.

No. 6The clinical effectiveness and cost-effectiveness of sibutramine in themanagement of obesity: a technologyassessment.

By O’Meara S, Riemsma R, ShirranL, Mather L, ter Riet G.

No. 7The cost-effectiveness of magneticresonance angiography for carotidartery stenosis and peripheral vasculardisease: a systematic review.

By Berry E, Kelly S, Westwood ME,Davies LM, Gough MJ, Bamford JM,et al.

No. 8Promoting physical activity in SouthAsian Muslim women through ‘exerciseon prescription’.

By Carroll B, Ali N, Azam N.

No. 9Zanamivir for the treatment of influenzain adults: a systematic review andeconomic evaluation.

By Burls A, Clark W, Stewart T,Preston C, Bryan S, Jefferson T, et al.

No. 10A review of the natural history andepidemiology of multiple sclerosis:implications for resource allocation andhealth economic models.

By Richards RG, Sampson FC, Beard SM, Tappenden P.

No. 11Screening for gestational diabetes: asystematic review and economicevaluation.

By Scott DA, Loveman E, McIntyre L,Waugh N.

No. 12The clinical effectiveness and cost-effectiveness of surgery for people withmorbid obesity: a systematic review andeconomic evaluation.

By Clegg AJ, Colquitt J, Sidhu MK,Royle P, Loveman E, Walker A.

No. 13The clinical effectiveness of trastuzumabfor breast cancer: a systematic review.

By Lewis R, Bagnall A-M, Forbes C,Shirran E, Duffy S, Kleijnen J, et al.

No. 14The clinical effectiveness and cost-effectiveness of vinorelbine for breastcancer: a systematic review andeconomic evaluation.

By Lewis R, Bagnall A-M, King S,Woolacott N, Forbes C, Shirran L, et al.

No. 15A systematic review of the effectivenessand cost-effectiveness of metal-on-metalhip resurfacing arthroplasty fortreatment of hip disease.

By Vale L, Wyness L, McCormack K,McKenzie L, Brazzelli M, Stearns SC.

No. 16The clinical effectiveness and cost-effectiveness of bupropion and nicotinereplacement therapy for smokingcessation: a systematic review andeconomic evaluation.

By Woolacott NF, Jones L, Forbes CA,Mather LC, Sowden AJ, Song FJ, et al.

No. 17A systematic review of effectiveness andeconomic evaluation of new drugtreatments for juvenile idiopathicarthritis: etanercept.

By Cummins C, Connock M, Fry-Smith A, Burls A.

No. 18Clinical effectiveness and cost-effectiveness of growth hormone inchildren: a systematic review andeconomic evaluation.

By Bryant J, Cave C, Mihaylova B,Chase D, McIntyre L, Gerard K, et al.


347


No. 19Clinical effectiveness and cost-effectiveness of growth hormone inadults in relation to impact on quality oflife: a systematic review and economicevaluation.

By Bryant J, Loveman E, Chase D,Mihaylova B, Cave C, Gerard K, et al.

No. 20Clinical medication review by apharmacist of patients on repeatprescriptions in general practice: arandomised controlled trial.

By Zermansky AG, Petty DR, RaynorDK, Lowe CJ, Freementle N, Vail A.

No. 21The effectiveness of infliximab andetanercept for the treatment ofrheumatoid arthritis: a systematic reviewand economic evaluation.

By Jobanputra P, Barton P, Bryan S,Burls A.

No. 22A systematic review and economicevaluation of computerised cognitivebehaviour therapy for depression andanxiety.

By Kaltenthaler E, Shackley P, StevensK, Beverley C, Parry G, Chilcott J.

No. 23A systematic review and economicevaluation of pegylated liposomaldoxorubicin hydrochloride for ovariancancer.

By Forbes C, Wilby J, Richardson G,Sculpher M, Mather L, Reimsma R.

No. 24A systematic review of the effectivenessof interventions based on a stages-of-change approach to promote individualbehaviour change.

By Riemsma RP, Pattenden J, Bridle C,Sowden AJ, Mather L, Watt IS, et al.

No. 25A systematic review update of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists.

By Robinson M, Ginnelly L, SculpherM, Jones L, Riemsma R, Palmer S, et al.

No. 26A systematic review of the effectiveness,cost-effectiveness and barriers toimplementation of thrombolytic andneuroprotective therapy for acuteischaemic stroke in the NHS.

By Sandercock P, Berge E, Dennis M,Forbes J, Hand P, Kwan J, et al.

No. 27A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in abronchiectasis clinic.

By Caine N, Sharples LD,Hollingworth W, French J, Keogan M,Exley A, et al.

No. 28Clinical effectiveness and cost –consequences of selective serotoninreuptake inhibitors in the treatment ofsex offenders.

By Adi Y, Ashcroft D, Browne K,Beech A, Fry-Smith A, Hyde C.

No. 29Treatment of established osteoporosis: a systematic review and cost–utilityanalysis.

By Kanis JA, Brazier JE, Stevenson M,Calvert NW, Lloyd Jones M.

No. 30Which anaesthetic agents are cost-effective in day surgery? Literaturereview, national survey of practice andrandomised controlled trial.

By Elliott RA Payne K, Moore JK,Davies LM, Harper NJN, St Leger AS,et al.

No. 31Screening for hepatitis C amonginjecting drug users and ingenitourinary medicine clinics:systematic reviews of effectiveness,modelling study and national survey ofcurrent practice.

By Stein K, Dalziel K, Walker A,McIntyre L, Jenkins B, Horne J, et al.

No. 32The measurement of satisfaction withhealthcare: implications for practicefrom a systematic review of theliterature.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Storey L, et al.

No. 33The effectiveness and cost-effectivenessof imatinib in chronic myeloidleukaemia: a systematic review.

By Garside R, Round A, Dalziel K,Stein K, Royle R.

No. 34A comparative study of hypertonicsaline, daily and alternate-day rhDNase in children with cystic fibrosis.

By Suri R, Wallis C, Bush A,Thompson S, Normand C, Flather M, et al.

No. 35A systematic review of the costs andeffectiveness of different models ofpaediatric home care.

By Parker G, Bhakta P, Lovett CA,Paisley S, Olsen R, Turner D, et al.

Volume 7, 2003

No. 1How important are comprehensiveliterature searches and the assessment oftrial quality in systematic reviews?Empirical study.

By Egger M, Jüni P, Bartlett C,Holenstein F, Sterne J.

No. 2Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of home versus hospital orsatellite unit haemodialysis for peoplewith end-stage renal failure.

By Mowatt G, Vale L, Perez J, WynessL, Fraser C, MacLeod A, et al.

No. 3Systematic review and economicevaluation of the effectiveness ofinfliximab for the treatment of Crohn’sdisease.

By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

No. 4A review of the clinical effectiveness andcost-effectiveness of routine anti-Dprophylaxis for pregnant women whoare rhesus negative.

By Chilcott J, Lloyd Jones M, WightJ, Forman K, Wray J, Beverley C, et al.

No. 5Systematic review and evaluation of theuse of tumour markers in paediatriconcology: Ewing’s sarcoma andneuroblastoma.

By Riley RD, Burchill SA, Abrams KR,Heney D, Lambert PC, Jones DR, et al.

No. 6The cost-effectiveness of screening forHelicobacter pylori to reduce mortalityand morbidity from gastric cancer andpeptic ulcer disease: a discrete-eventsimulation model.

By Roderick P, Davies R, Raftery J,Crabbe D, Pearce R, Bhandari P, et al.

No. 7The clinical effectiveness and cost-effectiveness of routine dental checks: asystematic review and economicevaluation.

By Davenport C, Elley K, Salas C,Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

No. 8A multicentre randomised controlledtrial assessing the costs and benefits ofusing structured information andanalysis of women’s preferences in themanagement of menorrhagia.

By Kennedy ADM, Sculpher MJ,Coulter A, Dwyer N, Rees M, Horsley S, et al.

No. 9Clinical effectiveness and cost–utility ofphotodynamic therapy for wet age-relatedmacular degeneration: a systematic reviewand economic evaluation.

By Meads C, Salas C, Roberts T,Moore D, Fry-Smith A, Hyde C.

No. 10Evaluation of molecular tests forprenatal diagnosis of chromosomeabnormalities.

By Grimshaw GM, Szczepura A,Hultén M, MacDonald F, Nevin NC,Sutton F, et al.


348

No. 11First and second trimester antenatalscreening for Down’s syndrome: theresults of the Serum, Urine andUltrasound Screening Study (SURUSS).

By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L,Mackinson AM.

No. 12The effectiveness and cost-effectivenessof ultrasound locating devices forcentral venous access: a systematicreview and economic evaluation.

By Calvert N, Hind D, McWilliamsRG, Thomas SM, Beverley C, Davidson A.

No. 13A systematic review of atypicalantipsychotics in schizophrenia.

By Bagnall A-M, Jones L, Lewis R,Ginnelly L, Glanville J, Torgerson D, et al.

No. 14Prostate Testing for Cancer andTreatment (ProtecT) feasibility study.

By Donovan J, Hamdy F, Neal D,Peters T, Oliver S, Brindle L, et al.

No. 15Early thrombolysis for the treatment of acute myocardial infarction: asystematic review and economicevaluation.

By Boland A, Dundar Y, Bagust A,Haycox A, Hill R, Mujica Mota R,et al.

No. 16Screening for fragile X syndrome: a literature review and modelling.

By Song FJ, Barton P, Sleightholme V,Yao GL, Fry-Smith A.

No. 17Systematic review of endoscopic sinussurgery for nasal polyps.

By Dalziel K, Stein K, Round A,Garside R, Royle P.

No. 18Towards efficient guidelines: how tomonitor guideline use in primary care.

By Hutchinson A, McIntosh A, Cox S,Gilbert C.

No. 19Effectiveness and cost-effectiveness ofacute hospital-based spinal cord injuriesservices: systematic review.

By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

No. 20Prioritisation of health technologyassessment. The PATHS model:methods and case studies.

By Townsend J, Buxton M, Harper G.

No. 21Systematic review of the clinicaleffectiveness and cost-effectiveness of tension-free vaginal tape fortreatment of urinary stress incontinence.

By Cody J, Wyness L, Wallace S,Glazener C, Kilonzo M, Stearns S,et al.

No. 22The clinical and cost-effectiveness ofpatient education models for diabetes: a systematic review and economicevaluation.

By Loveman E, Cave C, Green C,Royle P, Dunn N, Waugh N.

No. 23The role of modelling in prioritisingand planning clinical trials.

By Chilcott J, Brennan A, Booth A,Karnon J, Tappenden P.

No. 24Cost–benefit evaluation of routineinfluenza immunisation in people 65–74years of age.

By Allsup S, Gosney M, Haycox A,Regan M.

No. 25The clinical and cost-effectiveness ofpulsatile machine perfusion versus coldstorage of kidneys for transplantationretrieved from heart-beating and non-heart-beating donors.

By Wight J, Chilcott J, Holmes M,Brewer N.

No. 26Can randomised trials rely on existingelectronic data? A feasibility study toexplore the value of routine data inhealth technology assessment.

By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

No. 27Evaluating non-randomised interventionstudies.

By Deeks JJ, Dinnes J, D’Amico R,Sowden AJ, Sakarovitch C, Song F, et al.

No. 28A randomised controlled trial to assessthe impact of a package comprising apatient-orientated, evidence-based self-help guidebook and patient-centredconsultations on disease managementand satisfaction in inflammatory boweldisease.

By Kennedy A, Nelson E, Reeves D,Richardson G, Roberts C, Robinson A,et al.

No. 29The effectiveness of diagnostic tests forthe assessment of shoulder pain due tosoft tissue disorders: a systematic review.

By Dinnes J, Loveman E, McIntyre L,Waugh N.

No. 30The value of digital imaging in diabeticretinopathy.

By Sharp PF, Olson J, Strachan F,Hipwell J, Ludbrook A, O’Donnell M, et al.

No. 31Lowering blood pressure to preventmyocardial infarction and stroke: a new preventive strategy.

By Law M, Wald N, Morris J.

No. 32Clinical and cost-effectiveness ofcapecitabine and tegafur with uracil forthe treatment of metastatic colorectalcancer: systematic review and economicevaluation.

By Ward S, Kaltenthaler E, Cowan J,Brewer N.

No. 33Clinical and cost-effectiveness of new and emerging technologies for earlylocalised prostate cancer: a systematicreview.

By Hummel S, Paisley S, Morgan A,Currie E, Brewer N.

No. 34Literature searching for clinical andcost-effectiveness studies used in healthtechnology assessment reports carriedout for the National Institute forClinical Excellence appraisal system.

By Royle P, Waugh N.

No. 35Systematic review and economicdecision modelling for the preventionand treatment of influenza A and B.

By Turner D, Wailoo A, Nicholson K,Cooper N, Sutton A, Abrams K.

No. 36A randomised controlled trial toevaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients bynurses.

By Boland A, Haycox A, Bagust A,Fitzsimmons L.

No. 37Redesigning postnatal care: arandomised controlled trial of protocol-based midwifery-led carefocused on individual women’s physical and psychological health needs.

By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ,Knowles H, et al.

No. 38Estimating implied rates of discount inhealthcare decision-making.

By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.


349


No. 39Systematic review of isolation policies inthe hospital management of methicillin-resistant Staphylococcus aureus: a review ofthe literature with epidemiological andeconomic modelling.

By Cooper BS, Stone SP, Kibbler CC,Cookson BD, Roberts JA, Medley GF, et al.

No. 40Treatments for spasticity and pain inmultiple sclerosis: a systematic review.

By Beard S, Hunn A, Wight J.

No. 41The inclusion of reports of randomisedtrials published in languages other thanEnglish in systematic reviews.

By Moher D, Pham B, Lawson ML,Klassen TP.

No. 42The impact of screening on futurehealth-promoting behaviours and healthbeliefs: a systematic review.

By Bankhead CR, Brett J, Bukach C,Webster P, Stewart-Brown S, Munafo M,et al.

Volume 8, 2004

No. 1What is the best imaging strategy foracute stroke?

By Wardlaw JM, Keir SL, Seymour J,Lewis S, Sandercock PAG, Dennis MS, et al.

No. 2Systematic review and modelling of theinvestigation of acute and chronic chestpain presenting in primary care.

By Mant J, McManus RJ, Oakes RAL,Delaney BC, Barton PM, Deeks JJ, et al.

No. 3The effectiveness and cost-effectivenessof microwave and thermal balloonendometrial ablation for heavymenstrual bleeding: a systematic reviewand economic modelling.

By Garside R, Stein K, Wyatt K,Round A, Price A.

No. 4A systematic review of the role ofbisphosphonates in metastatic disease.

By Ross JR, Saunders Y, Edmonds PM,Patel S, Wonderling D, Normand C, et al.

No. 5Systematic review of the clinicaleffectiveness and cost-effectiveness ofcapecitabine (Xeloda®) for locallyadvanced and/or metastatic breast cancer.

By Jones L, Hawkins N, Westwood M,Wright K, Richardson G, Riemsma R.

No. 6Effectiveness and efficiency of guidelinedissemination and implementationstrategies.

By Grimshaw JM, Thomas RE,MacLennan G, Fraser C, Ramsay CR,Vale L, et al.

No. 7Clinical effectiveness and costs of theSugarbaker procedure for the treatmentof pseudomyxoma peritonei.

By Bryant J, Clegg AJ, Sidhu MK,Brodin H, Royle P, Davidson P.

No. 8Psychological treatment for insomnia inthe regulation of long-term hypnoticdrug use.

By Morgan K, Dixon S, Mathers N,Thompson J, Tomeny M.

No. 9Improving the evaluation of therapeuticinterventions in multiple sclerosis:development of a patient-based measureof outcome.

By Hobart JC, Riazi A, Lamping DL,Fitzpatrick R, Thompson AJ.

No. 10A systematic review and economicevaluation of magnetic resonancecholangiopancreatography comparedwith diagnostic endoscopic retrogradecholangiopancreatography.

By Kaltenthaler E, Bravo Vergel Y,Chilcott J, Thomas S, Blakeborough T,Walters SJ, et al.

No. 11The use of modelling to evaluate newdrugs for patients with a chroniccondition: the case of antibodies againsttumour necrosis factor in rheumatoidarthritis.

By Barton P, Jobanputra P, Wilson J,Bryan S, Burls A.

No. 12Clinical effectiveness and cost-effectiveness of neonatal screening forinborn errors of metabolism usingtandem mass spectrometry: a systematicreview.

By Pandor A, Eastham J, Beverley C,Chilcott J, Paisley S.

No. 13Clinical effectiveness and cost-effectiveness of pioglitazone androsiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

By Czoski-Murray C, Warren E,Chilcott J, Beverley C, Psyllaki MA,Cowan J.

No. 14Routine examination of the newborn:the EMREN study. Evaluation of anextension of the midwife role including a randomised controlled trial of appropriately trained midwivesand paediatric senior house officers.

By Townsend J, Wolke D, Hayes J,Davé S, Rogers C, Bloomfield L, et al.

No. 15Involving consumers in research anddevelopment agenda setting for theNHS: developing an evidence-basedapproach.

By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

No. 16A multi-centre randomised controlledtrial of minimally invasive directcoronary bypass grafting versuspercutaneous transluminal coronaryangioplasty with stenting for proximalstenosis of the left anterior descendingcoronary artery.

By Reeves BC, Angelini GD, BryanAJ, Taylor FC, Cripps T, Spyt TJ, et al.

No. 17Does early magnetic resonance imaginginfluence management or improveoutcome in patients referred tosecondary care with low back pain? A pragmatic randomised controlledtrial.

By Gilbert FJ, Grant AM, GillanMGC, Vale L, Scott NW, Campbell MK,et al.

No. 18The clinical and cost-effectiveness ofanakinra for the treatment ofrheumatoid arthritis in adults: asystematic review and economic analysis.

By Clark W, Jobanputra P, Barton P,Burls A.

No. 19A rapid and systematic review andeconomic evaluation of the clinical andcost-effectiveness of newer drugs fortreatment of mania associated withbipolar affective disorder.

By Bridle C, Palmer S, Bagnall A-M,Darba J, Duffy S, Sculpher M, et al.

No. 20Liquid-based cytology in cervicalscreening: an updated rapid andsystematic review and economic analysis.

By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

No. 21Systematic review of the long-termeffects and economic consequences oftreatments for obesity and implicationsfor health improvement.

By Avenell A, Broom J, Brown TJ,Poobalan A, Aucott L, Stearns SC, et al.

No. 22Autoantibody testing in children withnewly diagnosed type 1 diabetesmellitus.

By Dretzke J, Cummins C,Sandercock J, Fry-Smith A, Barrett T,Burls A.


350

No. 23Clinical effectiveness and cost-effectiveness of prehospital intravenousfluids in trauma patients.

By Dretzke J, Sandercock J, Bayliss S,Burls A.

No. 24Newer hypnotic drugs for the short-term management of insomnia: asystematic review and economicevaluation.

By Dündar Y, Boland A, Strobl J,Dodd S, Haycox A, Bagust A, et al.

No. 25Development and validation of methodsfor assessing the quality of diagnosticaccuracy studies.

By Whiting P, Rutjes AWS, Dinnes J,Reitsma JB, Bossuyt PMM, Kleijnen J.

No. 26EVALUATE hysterectomy trial: amulticentre randomised trial comparingabdominal, vaginal and laparoscopicmethods of hysterectomy.

By Garry R, Fountain J, Brown J,Manca A, Mason S, Sculpher M, et al.

No. 27Methods for expected value ofinformation analysis in complex healtheconomic models: developments on thehealth economics of interferon-� andglatiramer acetate for multiple sclerosis.

By Tappenden P, Chilcott JB,Eggington S, Oakley J, McCabe C.

No. 28Effectiveness and cost-effectiveness ofimatinib for first-line treatment ofchronic myeloid leukaemia in chronicphase: a systematic review and economicanalysis.

By Dalziel K, Round A, Stein K,Garside R, Price A.

No. 29VenUS I: a randomised controlled trialof two types of bandage for treatingvenous leg ulcers.

By Iglesias C, Nelson EA, Cullum NA,Torgerson DJ on behalf of the VenUSTeam.

No. 30Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of myocardial perfusionscintigraphy for the diagnosis andmanagement of angina and myocardialinfarction.

By Mowatt G, Vale L, Brazzelli M,Hernandez R, Murray A, Scott N, et al.

No. 31A pilot study on the use of decisiontheory and value of information analysisas part of the NHS Health TechnologyAssessment programme.

By Claxton Kon K, Ginnelly L, SculpherM, Philips Z, Palmer S.

No. 32The Social Support and Family HealthStudy: a randomised controlled trial andeconomic evaluation of two alternativeforms of postnatal support for mothersliving in disadvantaged inner-city areas.

By Wiggins M, Oakley A, Roberts I,Turner H, Rajan L, Austerberry H, et al.

No. 33Psychosocial aspects of genetic screeningof pregnant women and newborns: a systematic review.

By Green JM, Hewison J, Bekker HL,Bryant, Cuckle HS.

No. 34Evaluation of abnormal uterinebleeding: comparison of threeoutpatient procedures within cohortsdefined by age and menopausal status.

By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

No. 35Coronary artery stents: a rapid systematicreview and economic evaluation.

By Hill R, Bagust A, Bakhai A,Dickson R, Dündar Y, Haycox A, et al.

No. 36Review of guidelines for good practicein decision-analytic modelling in healthtechnology assessment.

By Philips Z, Ginnelly L, Sculpher M,Claxton K, Golder S, Riemsma R, et al.

No. 37Rituximab (MabThera®) for aggressivenon-Hodgkin’s lymphoma: systematicreview and economic evaluation.

By Knight C, Hind D, Brewer N,Abbott V.

No. 38Clinical effectiveness and cost-effectiveness of clopidogrel andmodified-release dipyridamole in thesecondary prevention of occlusivevascular events: a systematic review andeconomic evaluation.

By Jones L, Griffin S, Palmer S, MainC, Orton V, Sculpher M, et al.

No. 39Pegylated interferon �-2a and -2b incombination with ribavirin in thetreatment of chronic hepatitis C: asystematic review and economicevaluation.

By Shepherd J, Brodin H, Cave C,Waugh N, Price A, Gabbay J.

No. 40Clopidogrel used in combination withaspirin compared with aspirin alone inthe treatment of non-ST-segment-elevation acute coronary syndromes: asystematic review and economicevaluation.

By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

No. 41Provision, uptake and cost of cardiacrehabilitation programmes: improvingservices to under-represented groups.

By Beswick AD, Rees K, Griebsch I,Taylor FC, Burke M, West RR, et al.

No. 42Involving South Asian patients inclinical trials.

By Hussain-Gambles M, Leese B,Atkin K, Brown J, Mason S, Tovey P.

No. 43Clinical and cost-effectiveness ofcontinuous subcutaneous insulininfusion for diabetes.

By Colquitt JL, Green C, Sidhu MK,Hartwell D, Waugh N.

No. 44Identification and assessment ofongoing trials in health technologyassessment reviews.

By Song FJ, Fry-Smith A, DavenportC, Bayliss S, Adi Y, Wilson JS, et al.

No. 45Systematic review and economicevaluation of a long-acting insulinanalogue, insulin glargine

By Warren E, Weatherley-Jones E,Chilcott J, Beverley C.

No. 46Supplementation of a home-basedexercise programme with a class-basedprogramme for people with osteoarthritisof the knees: a randomised controlledtrial and health economic analysis.

By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N,Roberts CR, et al.

No. 47Clinical and cost-effectiveness of once-daily versus more frequent use of samepotency topical corticosteroids for atopiceczema: a systematic review andeconomic evaluation.

By Green C, Colquitt JL, Kirby J,Davidson P, Payne E.

No. 48Acupuncture of chronic headachedisorders in primary care: randomisedcontrolled trial and economic analysis.

By Vickers AJ, Rees RW, Zollman CE,McCarney R, Smith CM, Ellis N, et al.

No. 49Generalisability in economic evaluationstudies in healthcare: a review and casestudies.

By Sculpher MJ, Pang FS, Manca A,Drummond MF, Golder S, Urdahl H, et al.

No. 50Virtual outreach: a randomisedcontrolled trial and economic evaluationof joint teleconferenced medicalconsultations.

By Wallace P, Barber J, Clayton W,Currell R, Fleming K, Garner P, et al.


351


Volume 9, 2005

No. 1Randomised controlled multipletreatment comparison to provide a cost-effectiveness rationale for theselection of antimicrobial therapy inacne.

By Ozolins M, Eady EA, Avery A,Cunliffe WJ, O’Neill C, Simpson NB, et al.

No. 2Do the findings of case series studiesvary significantly according tomethodological characteristics?

By Dalziel K, Round A, Stein K,Garside R, Castelnuovo E, Payne L.

No. 3Improving the referral process forfamilial breast cancer geneticcounselling: findings of threerandomised controlled trials of twointerventions.

By Wilson BJ, Torrance N, Mollison J,Wordsworth S, Gray JR, Haites NE, et al.

No. 4Randomised evaluation of alternativeelectrosurgical modalities to treatbladder outflow obstruction in men withbenign prostatic hyperplasia.

By Fowler C, McAllister W, Plail R,Karim O, Yang Q.

No. 5A pragmatic randomised controlled trialof the cost-effectiveness of palliativetherapies for patients with inoperableoesophageal cancer.

By Shenfine J, McNamee P, Steen N,Bond J, Griffin SM.

No. 6Impact of computer-aided detectionprompts on the sensitivity and specificityof screening mammography.

By Taylor P, Champness J, Given-Wilson R, Johnston K, Potts H.

No. 7Issues in data monitoring and interimanalysis of trials.

By Grant AM, Altman DG, BabikerAB, Campbell MK, Clemens FJ,Darbyshire JH, et al.

No. 8Lay public’s understanding of equipoiseand randomisation in randomisedcontrolled trials.

By Robinson EJ, Kerr CEP, StevensAJ, Lilford RJ, Braunholtz DA, EdwardsSJ, et al.

No. 9Clinical and cost-effectiveness ofelectroconvulsive therapy for depressiveillness, schizophrenia, catatonia andmania: systematic reviews and economicmodelling studies.

By Greenhalgh J, Knight C, Hind D,Beverley C, Walters S.

No. 10Measurement of health-related qualityof life for people with dementia:development of a new instrument(DEMQOL) and an evaluation ofcurrent methodology.

By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

No. 11Clinical effectiveness and cost-effectiveness of drotrecogin alfa(activated) (Xigris®) for the treatment ofsevere sepsis in adults: a systematicreview and economic evaluation.

By Green C, Dinnes J, Takeda A,Shepherd J, Hartwell D, Cave C, et al.

No. 12A methodological review of howheterogeneity has been examined insystematic reviews of diagnostic testaccuracy.

By Dinnes J, Deeks J, Kirby J,Roderick P.

No. 13Cervical screening programmes: canautomation help? Evidence fromsystematic reviews, an economic analysisand a simulation modelling exerciseapplied to the UK.

By Willis BH, Barton P, Pearmain P,Bryan S, Hyde C.

No. 14Laparoscopic surgery for inguinalhernia repair: systematic review ofeffectiveness and economic evaluation.

By McCormack K, Wake B, Perez J,Fraser C, Cook J, McIntosh E, et al.

No. 15Clinical effectiveness, tolerability andcost-effectiveness of newer drugs forepilepsy in adults: a systematic reviewand economic evaluation.

By Wilby J, Kainth A, Hawkins N,Epstein D, McIntosh H, McDaid C, et al.

No. 16A randomised controlled trial tocompare the cost-effectiveness oftricyclic antidepressants, selectiveserotonin reuptake inhibitors andlofepramine.

By Peveler R, Kendrick T, Buxton M,Longworth L, Baldwin D, Moore M, et al.

No. 17Clinical effectiveness and cost-effectiveness of immediate angioplastyfor acute myocardial infarction:systematic review and economicevaluation.

By Hartwell D, Colquitt J, LovemanE, Clegg AJ, Brodin H, Waugh N, et al.

No. 18A randomised controlled comparison ofalternative strategies in stroke care.

By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

No. 19The investigation and analysis of criticalincidents and adverse events inhealthcare.

By Woloshynowych M, Rogers S,Taylor-Adams S, Vincent C.

No. 20Potential use of routine databases inhealth technology assessment.

By Raftery J, Roderick P, Stevens A.

No. 21Clinical and cost-effectiveness of newerimmunosuppressive regimens in renaltransplantation: a systematic review andmodelling study.

By Woodroffe R, Yao GL, Meads C,Bayliss S, Ready A, Raftery J, et al.

No. 22A systematic review and economicevaluation of alendronate, etidronate,risedronate, raloxifene and teriparatidefor the prevention and treatment ofpostmenopausal osteoporosis.

By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

No. 23A systematic review to examine theimpact of psycho-educationalinterventions on health outcomes andcosts in adults and children with difficultasthma.

By Smith JR, Mugford M, Holland R,Candy B, Noble MJ, Harrison BDW, et al.

No. 24An evaluation of the costs, effectivenessand quality of renal replacementtherapy provision in renal satellite unitsin England and Wales.

By Roderick P, Nicholson T, ArmitageA, Mehta R, Mullee M, Gerard K, et al.

No. 25Imatinib for the treatment of patientswith unresectable and/or metastaticgastrointestinal stromal tumours:systematic review and economicevaluation.

By Wilson J, Connock M, Song F, YaoG, Fry-Smith A, Raftery J, et al.

No. 26Indirect comparisons of competinginterventions.

By Glenny AM, Altman DG, Song F,Sakarovitch C, Deeks JJ, D’Amico R, et al.

No. 27Cost-effectiveness of alternativestrategies for the initial medicalmanagement of non-ST elevation acutecoronary syndrome: systematic reviewand decision-analytical modelling.

By Robinson M, Palmer S, SculpherM, Philips Z, Ginnelly L, Bowens A, et al.


352

No. 28Outcomes of electrically stimulatedgracilis neosphincter surgery.

By Tillin T, Chambers M, Feldman R.

No. 29The effectiveness and cost-effectivenessof pimecrolimus and tacrolimus foratopic eczema: a systematic review andeconomic evaluation.

By Garside R, Stein K, Castelnuovo E,Pitt M, Ashcroft D, Dimmock P, et al.

No. 30Systematic review on urine albumintesting for early detection of diabeticcomplications.

By Newman DJ, Mattock MB, DawnayABS, Kerry S, McGuire A, Yaqoob M, et al.

No. 31Randomised controlled trial of the cost-effectiveness of water-based therapy forlower limb osteoarthritis.

By Cochrane T, Davey RC, Matthes Edwards SM.

No. 32Longer term clinical and economicbenefits of offering acupuncture care topatients with chronic low back pain.

By Thomas KJ, MacPherson H,Ratcliffe J, Thorpe L, Brazier J,Campbell M, et al.

No. 33Cost-effectiveness and safety of epiduralsteroids in the management of sciatica.

By Price C, Arden N, Coglan L,Rogers P.

No. 34The British Rheumatoid Outcome StudyGroup (BROSG) randomised controlledtrial to compare the effectiveness andcost-effectiveness of aggressive versussymptomatic therapy in establishedrheumatoid arthritis.

By Symmons D, Tricker K, Roberts C,Davies L, Dawes P, Scott DL.

No. 35Conceptual framework and systematicreview of the effects of participants’ andprofessionals’ preferences in randomisedcontrolled trials.

By King M, Nazareth I, Lampe F,Bower P, Chandler M, Morou M, et al.

No. 36The clinical and cost-effectiveness ofimplantable cardioverter defibrillators: a systematic review.

By Bryant J, Brodin H, Loveman E,Payne E, Clegg A.

No. 37A trial of problem-solving by communitymental health nurses for anxiety,depression and life difficulties amonggeneral practice patients. The CPN-GPstudy.

By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J,Pickering R, et al.

No. 38The causes and effects of socio-demographic exclusions from clinicaltrials.

By Bartlett C, Doyal L, Ebrahim S,Davey P, Bachmann M, Egger M, et al.

No. 39Is hydrotherapy cost-effective? Arandomised controlled trial of combinedhydrotherapy programmes comparedwith physiotherapy land techniques inchildren with juvenile idiopathicarthritis.

By Epps H, Ginnelly L, Utley M,Southwood T, Gallivan S, Sculpher M, et al.

No. 40A randomised controlled trial and cost-effectiveness study of systematicscreening (targeted and total populationscreening) versus routine practice forthe detection of atrial fibrillation inpeople aged 65 and over. The SAFEstudy.

By Hobbs FDR, Fitzmaurice DA,Mant J, Murray E, Jowett S, Bryan S, et al.

No. 41Displaced intracapsular hip fractures in fit, older people: a randomisedcomparison of reduction and fixation,bipolar hemiarthroplasty and total hiparthroplasty.

By Keating JF, Grant A, Masson M,Scott NW, Forbes JF.

No. 42Long-term outcome of cognitivebehaviour therapy clinical trials incentral Scotland.

By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR,Major KA, et al.

No. 43The effectiveness and cost-effectivenessof dual-chamber pacemakers comparedwith single-chamber pacemakers forbradycardia due to atrioventricularblock or sick sinus syndrome: systematic review and economicevaluation.

By Castelnuovo E, Stein K, Pitt M,Garside R, Payne E.

No. 44Newborn screening for congenital heartdefects: a systematic review and cost-effectiveness analysis.

By Knowles R, Griebsch I, DezateuxC, Brown J, Bull C, Wren C.

No. 45The clinical and cost-effectiveness of leftventricular assist devices for end-stageheart failure: a systematic review andeconomic evaluation.

By Clegg AJ, Scott DA, Loveman E,Colquitt J, Hutchinson J, Royle P, et al.

No. 46The effectiveness of the HeidelbergRetina Tomograph and laser diagnosticglaucoma scanning system (GDx) indetecting and monitoring glaucoma.

By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

No. 47Clinical and cost-effectiveness ofautologous chondrocyte implantationfor cartilage defects in knee joints:systematic review and economicevaluation.

By Clar C, Cummins E, McIntyre L,Thomas S, Lamb J, Bain L, et al.

No. 48Systematic review of effectiveness ofdifferent treatments for childhoodretinoblastoma.

By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K,Riemsma R.

No. 49Towards evidence-based guidelines for the prevention of venousthromboembolism: systematic reviews of mechanical methods, oralanticoagulation, dextran and regionalanaesthesia as thromboprophylaxis.

By Roderick P, Ferris G, Wilson K,Halls H, Jackson D, Collins R,et al.

No. 50The effectiveness and cost-effectivenessof parent training/educationprogrammes for the treatment ofconduct disorder, including oppositionaldefiant disorder, in children.

By Dretzke J, Frew E, Davenport C,Barlow J, Stewart-Brown S, Sandercock J, et al.

Volume 10, 2006

No. 1The clinical and cost-effectiveness ofdonepezil, rivastigmine, galantamineand memantine for Alzheimer’s disease.

By Loveman E, Green C, Kirby J,Takeda A, Picot J, Payne E, et al.

No. 2FOOD: a multicentre randomised trialevaluating feeding policies in patientsadmitted to hospital with a recentstroke.

By Dennis M, Lewis S, Cranswick G,Forbes J.

No. 3The clinical effectiveness and cost-effectiveness of computed tomographyscreening for lung cancer: systematicreviews.

By Black C, Bagust A, Boland A,Walker S, McLeod C, De Verteuil R, et al.


353


No. 4A systematic review of the effectivenessand cost-effectiveness of neuroimagingassessments used to visualise the seizure focus in people with refractoryepilepsy being considered for surgery.

By Whiting P, Gupta R, Burch J,Mujica Mota RE, Wright K, Marson A, et al.

No. 5Comparison of conference abstracts and presentations with full-text articles in the health technologyassessments of rapidly evolvingtechnologies.

By Dundar Y, Dodd S, Dickson R,Walley T, Haycox A, Williamson PR.

No. 6Systematic review and evaluation ofmethods of assessing urinaryincontinence.

By Martin JL, Williams KS, AbramsKR, Turner DA, Sutton AJ, Chapple C,et al.

No. 7The clinical effectiveness and cost-effectiveness of newer drugs for childrenwith epilepsy. A systematic review.

By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

No. 8Surveillance of Barrett’s oesophagus:exploring the uncertainty throughsystematic review, expert workshop andeconomic modelling.

By Garside R, Pitt M, Somerville M,Stein K, Price A, Gilbert N.

No. 9Topotecan, pegylated liposomaldoxorubicin hydrochloride andpaclitaxel for second-line or subsequenttreatment of advanced ovarian cancer: asystematic review and economicevaluation.

By Main C, Bojke L, Griffin S,Norman G, Barbieri M, Mather L, et al.

No. 10Evaluation of molecular techniques in prediction and diagnosis ofcytomegalovirus disease inimmunocompromised patients.

By Szczepura A, Westmoreland D,Vinogradova Y, Fox J, Clark M.

No. 11Screening for thrombophilia in high-risksituations: systematic review and cost-effectiveness analysis. The Thrombosis:Risk and Economic Assessment ofThrombophilia Screening (TREATS)study.

By Wu O, Robertson L, Twaddle S,Lowe GDO, Clark P, Greaves M, et al.

No. 12A series of systematic reviews to informa decision analysis for sampling andtreating infected diabetic foot ulcers.

By Nelson EA, O’Meara S, Craig D,Iglesias C, Golder S, Dalton J, et al.

No. 13Randomised clinical trial, observationalstudy and assessment of cost-effectiveness of the treatment of varicoseveins (REACTIV trial).

By Michaels JA, Campbell WB,Brazier JE, MacIntyre JB, PalfreymanSJ, Ratcliffe J, et al.

No. 14The cost-effectiveness of screening fororal cancer in primary care.

By Speight PM, Palmer S, Moles DR,Downer MC, Smith DH, Henriksson Met al.

No. 15Measurement of the clinical and cost-effectiveness of non-invasive diagnostictesting strategies for deep veinthrombosis.

By Goodacre S, Sampson F, StevensonM, Wailoo A, Sutton A, Thomas S, et al.

No. 16Systematic review of the effectivenessand cost-effectiveness of HealOzone®

for the treatment of occlusal pit/fissurecaries and root caries.

By Brazzelli M, McKenzie L, FieldingS, Fraser C, Clarkson J, Kilonzo M, et al.

No. 17Randomised controlled trials ofconventional antipsychotic versus newatypical drugs, and new atypical drugsversus clozapine, in people withschizophrenia responding poorly to, or intolerant of, current drugtreatment.

By Lewis SW, Davies L, Jones PB,Barnes TRE, Murray RM, Kerwin R, et al.

No. 18Diagnostic tests and algorithms used inthe investigation of haematuria:systematic reviews and economicevaluation.

By Rodgers M, Nixon J, Hempel S,Aho T, Kelly J, Neal D, et al.

No. 19Cognitive behavioural therapy inaddition to antispasmodic therapy forirritable bowel syndrome in primarycare: randomised controlled trial.

By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

No. 20A systematic review of the clinicaleffectiveness and cost-effectiveness ofenzyme replacement therapies forFabry’s disease andmucopolysaccharidosis type 1.

By Connock M, Juarez-Garcia A, FrewE, Mans A, Dretzke J, Fry-Smith A, et al.

No. 21Health benefits of antiviral therapy formild chronic hepatitis C: randomisedcontrolled trial and economicevaluation.

By Wright M, Grieve R, Roberts J,Main J, Thomas HC on behalf of theUK Mild Hepatitis C Trial Investigators.

No. 22Pressure relieving support surfaces: arandomised evaluation.

By Nixon J, Nelson EA, Cranny G,Iglesias CP, Hawkins K, Cullum NA, et al.

No. 23A systematic review and economicmodel of the effectiveness and cost-effectiveness of methylphenidate,dexamfetamine and atomoxetine for thetreatment of attention deficithyperactivity disorder in children andadolescents.

By King S, Griffin S, Hodges Z,Weatherly H, Asseburg C, Richardson G,et al.

No. 24The clinical effectiveness and cost-effectiveness of enzyme replacementtherapy for Gaucher’s disease: a systematic review.

By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

No. 25Effectiveness and cost-effectiveness ofsalicylic acid and cryotherapy forcutaneous warts. An economic decisionmodel.

By Thomas KS, Keogh-Brown MR,Chalmers JR, Fordham RJ, Holland RC,Armstrong SJ, et al.

No. 26A systematic literature review of theeffectiveness of non-pharmacologicalinterventions to prevent wandering indementia and evaluation of the ethicalimplications and acceptability of theiruse.

By Robinson L, Hutchings D, CornerL, Beyer F, Dickinson H, Vanoli A, et al.

No. 27A review of the evidence on the effectsand costs of implantable cardioverterdefibrillator therapy in different patientgroups, and modelling of cost-effectiveness and cost–utility for thesegroups in a UK context.

By Buxton M, Caine N, Chase D,Connelly D, Grace A, Jackson C, et al.


354

No. 28Adefovir dipivoxil and pegylatedinterferon alfa-2a for the treatment ofchronic hepatitis B: a systematic reviewand economic evaluation.

By Shepherd J, Jones J, Takeda A,Davidson P, Price A.

No. 29An evaluation of the clinical and cost-effectiveness of pulmonary arterycatheters in patient management inintensive care: a systematic review and arandomised controlled trial.

By Harvey S, Stevens K, Harrison D,Young D, Brampton W, McCabe C, et al.

No. 30Accurate, practical and cost-effectiveassessment of carotid stenosis in the UK.

By Wardlaw JM, Chappell FM,Stevenson M, De Nigris E, Thomas S,Gillard J, et al.

No. 31Etanercept and infliximab for thetreatment of psoriatic arthritis: a systematic review and economicevaluation.

By Woolacott N, Bravo Vergel Y,Hawkins N, Kainth A, Khadjesari Z,Misso K, et al.

No. 32The cost-effectiveness of testing forhepatitis C in former injecting drugusers.

By Castelnuovo E, Thompson-Coon J,Pitt M, Cramp M, Siebert U, Price A, et al.

No. 33Computerised cognitive behaviourtherapy for depression and anxietyupdate: a systematic review andeconomic evaluation.

By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M,Beverley C, et al.

No. 34Cost-effectiveness of using prognosticinformation to select women with breast cancer for adjuvant systemic therapy.

By Williams C, Brunskill S, Altman D,Briggs A, Campbell H, Clarke M, et al.

No. 35Psychological therapies includingdialectical behaviour therapy forborderline personality disorder: a systematic review and preliminaryeconomic evaluation.

By Brazier J, Tumur I, Holmes M,Ferriter M, Parry G, Dent-Brown K, et al.

No. 36Clinical effectiveness and cost-effectiveness of tests for the diagnosisand investigation of urinary tractinfection in children: a systematic reviewand economic model.

By Whiting P, Westwood M, Bojke L,Palmer S, Richardson G, Cooper J, et al.

No. 37Cognitive behavioural therapy inchronic fatigue syndrome: a randomisedcontrolled trial of an outpatient groupprogramme.

By O’Dowd H, Gladwell P, Rogers CA,Hollinghurst S, Gregory A.

No. 38A comparison of the cost-effectiveness offive strategies for the prevention of non-steroidal anti-inflammatory drug-inducedgastrointestinal toxicity: a systematicreview with economic modelling.

By Brown TJ, Hooper L, Elliott RA,Payne K, Webb R, Roberts C, et al.

No. 39The effectiveness and cost-effectivenessof computed tomography screening forcoronary artery disease: systematicreview.

By Waugh N, Black C, Walker S,McIntyre L, Cummins E, Hillis G.

No. 40What are the clinical outcome and cost-effectiveness of endoscopy undertakenby nurses when compared with doctors?A Multi-Institution Nurse EndoscopyTrial (MINuET).

By Williams J, Russell I, Durai D,Cheung W-Y, Farrin A, Bloor K, et al.

No. 41The clinical and cost-effectiveness ofoxaliplatin and capecitabine for theadjuvant treatment of colon cancer:systematic review and economicevaluation.

By Pandor A, Eggington S, Paisley S,Tappenden P, Sutcliffe P.

No. 42A systematic review of the effectivenessof adalimumab, etanercept andinfliximab for the treatment ofrheumatoid arthritis in adults and aneconomic evaluation of their cost-effectiveness.

By Chen Y-F, Jobanputra P, Barton P,Jowett S, Bryan S, Clark W, et al.

No. 43Telemedicine in dermatology: a randomised controlled trial.

By Bowns IR, Collins K, Walters SJ,McDonagh AJG.

No. 44Cost-effectiveness of cell salvage andalternative methods of minimisingperioperative allogeneic bloodtransfusion: a systematic review andeconomic model.

By Davies L, Brown TJ, Haynes S,Payne K, Elliott RA, McCollum C.

No. 45Clinical effectiveness and cost-effectiveness of laparoscopic surgery forcolorectal cancer: systematic reviews andeconomic evaluation.

By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C,McKinley A, et al.

No. 46Etanercept and efalizumab for thetreatment of psoriasis: a systematicreview.

By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

No. 47Systematic reviews of clinical decisiontools for acute abdominal pain.

By Liu JLY, Wyatt JC, Deeks JJ,Clamp S, Keen J, Verde P, et al.

No. 48Evaluation of the ventricular assistdevice programme in the UK.

By Sharples L, Buxton M, Caine N,Cafferty F, Demiris N, Dyer M, et al.

No. 49A systematic review and economicmodel of the clinical and cost-effectiveness of immunosuppressivetherapy for renal transplantation inchildren.

By Yao G, Albon E, Adi Y, Milford D,Bayliss S, Ready A, et al.

No. 50Amniocentesis results: investigation ofanxiety. The ARIA trial.

By Hewison J, Nixon J, Fountain J,Cocks K, Jones C, Mason G, et al.

Volume 11, 2007

No. 1Pemetrexed disodium for the treatmentof malignant pleural mesothelioma: a systematic review and economicevaluation.

By Dundar Y, Bagust A, Dickson R,Dodd S, Green J, Haycox A, et al.

No. 2A systematic review and economicmodel of the clinical effectiveness andcost-effectiveness of docetaxel incombination with prednisone orprednisolone for the treatment ofhormone-refractory metastatic prostatecancer.

By Collins R, Fenwick E, Trowman R,Perard R, Norman G, Light K, et al.

No. 3A systematic review of rapid diagnostictests for the detection of tuberculosisinfection.

By Dinnes J, Deeks J, Kunst H,Gibson A, Cummins E, Waugh N, et al.

No. 4The clinical effectiveness and cost-effectiveness of strontium ranelate forthe prevention of osteoporotic fragility fractures in postmenopausalwomen.

By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.


355


No. 5A systematic review of quantitative andqualitative research on the role andeffectiveness of written informationavailable to patients about individualmedicines.

By Raynor DK, Blenkinsopp A,Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

No. 6Oral naltrexone as a treatment forrelapse prevention in formerly opioid-dependent drug users: a systematic review and economicevaluation.

By Adi Y, Juarez-Garcia A, Wang D,Jowett S, Frew E, Day E, et al.

No. 7Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

No. 8Epidemiological, social, diagnostic andeconomic evaluation of populationscreening for genital chlamydial infection.

By Low N, McCarthy A, Macleod J,Salisbury C, Campbell R, Roberts TE, et al.

No. 9Methadone and buprenorphine for themanagement of opioid dependence: a systematic review and economicevaluation.

By Connock M, Juarez-Garcia A,Jowett S, Frew E, Liu Z, Taylor RJ, et al.

No. 10Exercise Evaluation Randomised Trial(EXERT): a randomised trial comparingGP referral for leisure centre-basedexercise, community-based walking andadvice only.

By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D,Harridge SDR, et al.

No. 11Interferon alfa (pegylated and non-pegylated) and ribavirin for thetreatment of mild chronic hepatitis C: a systematic review and economicevaluation.

By Shepherd J, Jones J, Hartwell D,Davidson P, Price A, Waugh N.

No. 12Systematic review and economicevaluation of bevacizumab andcetuximab for the treatment ofmetastatic colorectal cancer.

By Tappenden P, Jones R, Paisley S,Carroll C.

No. 13A systematic review and economicevaluation of epoetin alfa, epoetin betaand darbepoetin alfa in anaemiaassociated with cancer, especially thatattributable to cancer treatment.

By Wilson J, Yao GL, Raftery J,Bohlius J, Brunskill S, Sandercock J, et al.

No. 14A systematic review and economicevaluation of statins for the preventionof coronary events.

By Ward S, Lloyd Jones M, Pandor A,Holmes M, Ara R, Ryan A, et al.

No. 15A systematic review of the effectivenessand cost-effectiveness of differentmodels of community-based respite care for frail older people and theircarers.

By Mason A, Weatherly H, SpilsburyK, Arksey H, Golder S, Adamson J, et al.

No. 16Additional therapy for young childrenwith spastic cerebral palsy: a randomised controlled trial.

By Weindling AM, Cunningham CC,Glenn SM, Edwards RT, Reeves DJ.

No. 17Screening for type 2 diabetes: literaturereview and economic modelling.

By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A,Goyder E, et al.

No. 18The effectiveness and cost-effectivenessof cinacalcet for secondaryhyperparathyroidism in end-stage renal disease patients on dialysis: asystematic review and economicevaluation.

By Garside R, Pitt M, Anderson R,Mealing S, Roome C, Snaith A, et al.

No. 19The clinical effectiveness and cost-effectiveness of gemcitabine formetastatic breast cancer: a systematicreview and economic evaluation.

By Takeda AL, Jones J, Loveman E,Tan SC, Clegg AJ.

No. 20A systematic review of duplexultrasound, magnetic resonanceangiography and computed tomographyangiography for the diagnosis and assessment of symptomatic, lowerlimb peripheral arterial disease.

By Collins R, Cranny G, Burch J,Aguiar-Ibáñez R, Craig D, Wright K, et al.

No. 21The clinical effectiveness and cost-effectiveness of treatments for childrenwith idiopathic steroid-resistantnephrotic syndrome: a systematic review.

By Colquitt JL, Kirby J, Green C,Cooper K, Trompeter RS.

No. 22A systematic review of the routinemonitoring of growth in children ofprimary school age to identify growth-related conditions.

By Fayter D, Nixon J, Hartley S,Rithalia A, Butler G, Rudolf M, et al.

No. 23Systematic review of the effectiveness ofpreventing and treating Staphylococcusaureus carriage in reducing peritonealcatheter-related infections.

By McCormack K, Rabindranath K,Kilonzo M, Vale L, Fraser C, McIntyre L,et al.

No. 24The clinical effectiveness and cost ofrepetitive transcranial magneticstimulation versus electroconvulsivetherapy in severe depression: a multicentre pragmatic randomisedcontrolled trial and economic analysis.

By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D,et al.

No. 25A randomised controlled trial andeconomic evaluation of direct versusindirect and individual versus groupmodes of speech and language therapyfor children with primary languageimpairment.

By Boyle J, McCartney E, Forbes J,O’Hare A.

No. 26Hormonal therapies for early breastcancer: systematic review and economicevaluation.

By Hind D, Ward S, De Nigris E,Simpson E, Carroll C, Wyld L.

No. 27Cardioprotection against the toxic effects of anthracyclines given tochildren with cancer: a systematic review.

By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

No. 28Adalimumab, etanercept and infliximabfor the treatment of ankylosingspondylitis: a systematic review andeconomic evaluation.

By McLeod C, Bagust A, Boland A,Dagenais P, Dickson R, Dundar Y, et al.


356

No. 29Prenatal screening and treatmentstrategies to prevent group B streptococcaland other bacterial infections in earlyinfancy: cost-effectiveness and expectedvalue of information analyses.

By Colbourn T, Asseburg C, Bojke L,Philips Z, Claxton K, Ades AE, et al.

No. 30Clinical effectiveness and cost-effectiveness of bone morphogeneticproteins in the non-healing of fracturesand spinal fusion: a systematic review.

By Garrison KR, Donell S, Ryder J,Shemilt I, Mugford M, Harvey I, et al.

No. 31A randomised controlled trial ofpostoperative radiotherapy followingbreast-conserving surgery in aminimum-risk older population. The PRIME trial.

By Prescott RJ, Kunkler IH, WilliamsLJ, King CC, Jack W, van der Pol M, et al.

No. 32Current practice, accuracy, effectivenessand cost-effectiveness of the schoolentry hearing screen.

By Bamford J, Fortnum H, Bristow K,Smith J, Vamvakas G, Davies L, et al.

No. 33The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

By Black C, Cummins E, Royle P,Philip S, Waugh N.

No. 34Surveillance of cirrhosis forhepatocellular carcinoma: systematicreview and economic analysis.

By Thompson Coon J, Rogers G,Hewson P, Wright D, Anderson R,Cramp M, et al.

No. 35The Birmingham Rehabilitation Uptake Maximisation Study (BRUM).Home-based compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

By Jolly K, Taylor R, Lip GYH,Greenfield S, Raftery J, Mant J, et al.

No. 36A systematic review of the clinical,public health and cost-effectiveness of rapid diagnostic tests for thedetection and identification of bacterial intestinal pathogens in faeces and food.

By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

No. 37A randomised controlled trialexamining the longer-term outcomes ofstandard versus new antiepileptic drugs. The SANAD trial.

By Marson AG, Appleton R, BakerGA, Chadwick DW, Doughty J, Eaton B,et al.

No. 38Clinical effectiveness and cost-effectiveness of different models of managing long-term oralanticoagulation therapy: a systematicreview and economic modelling.

By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D,Moore D, et al.

No. 39A systematic review and economicmodel of the clinical effectiveness and cost-effectiveness of interventions forpreventing relapse in people withbipolar disorder.

By Soares-Weiser K, Bravo Vergel Y,Beynon S, Dunn G, Barbieri M, Duffy S,et al.

No. 40Taxanes for the adjuvant treatment ofearly breast cancer: systematic reviewand economic evaluation.

By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

No. 41The clinical effectiveness and cost-effectiveness of screening for open angleglaucoma: a systematic review andeconomic evaluation.

By Burr JM, Mowatt G, Hernández R,Siddiqui MAR, Cook J, Lourenco T, et al.


357



359

Health Technology AssessmentProgramme

Prioritisation Strategy GroupMembers

Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital

Professor Robin E Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions,City Hospital NHS Trust,Birmingham

Dr Edmund Jessop, MedicalAdviser, National Specialist,Commissioning Advisory Group(NSCAG), Department ofHealth, London

Professor Jon Nicholl, Director,Medical Care Research Unit,University of Sheffield, School of Health and Related Research

Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Deputy Director, Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

HTA Commissioning BoardMembers

Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

Deputy Chair, Dr Andrew Farmer, University Lecturer in GeneralPractice, Department of Primary Health Care, University of Oxford

Dr Jeffrey Aronson,Reader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford

Professor Deborah Ashby,Professor of Medical Statistics,Department of Environmentaland Preventative Medicine,Queen Mary University ofLondon

Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London

Professor John Cairns, Professor of Health Economics,Public Health Policy, London School of Hygiene and Tropical Medicine, London

Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork

Professor Jon Deeks, Professor of Health Statistics,University of Birmingham

Professor Jenny Donovan,Professor of Social Medicine,Department of Social Medicine,University of Bristol

Professor Freddie Hamdy,Professor of Urology, University of Sheffield

Professor Allan House, Professor of Liaison Psychiatry,University of Leeds

Professor Sallie Lamb, Director,Warwick Clinical Trials Unit,University of Warwick

Professor Stuart Logan,Director of Health & SocialCare Research, The PeninsulaMedical School, Universities ofExeter & Plymouth

Professor Miranda Mugford,Professor of Health Economics,University of East Anglia

Dr Linda Patterson, Consultant Physician,Department of Medicine,Burnley General Hospital

Professor Ian Roberts, Professor of Epidemiology &Public Health, InterventionResearch Unit, London Schoolof Hygiene and TropicalMedicine

Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York

Professor Kate Thomas,Professor of Complementaryand Alternative Medicine,University of Leeds

Professor David John Torgerson,Director of York Trial Unit,Department of Health Sciences,University of York

Professor Hywel Williams,Professor of Dermato-Epidemiology,University of Nottingham

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)


Health Technology Assessment Programme

360

Diagnostic Technologies & Screening PanelMembers

Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Ms Norma Armston,Freelance Consumer Advocate,Bolton

Professor Max Bachmann,Professor of Health CareInterfaces, Department ofHealth Policy and Practice,University of East Anglia

Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust

Ms Dea Birkett, Service UserRepresentative, London

Dr Paul Cockcroft, ConsultantMedical Microbiologist andClinical Director of Pathology,Department of ClinicalMicrobiology, St Mary'sHospital, Portsmouth

Professor Adrian K Dixon,Professor of Radiology,University Department ofRadiology, University ofCambridge Clinical School

Dr David Elliman, Consultant inCommunity Child Health,Islington PCT & Great OrmondStreet Hospital, London

Professor Glyn Elwyn, Research Chair, Centre forHealth Sciences Research,Cardiff University, Departmentof General Practice, Cardiff

Professor Paul Glasziou,Director, Centre for Evidence-Based Practice,University of Oxford

Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist, NationalPerinatal Epidemiology Unit,Oxford

Dr Susanne M Ludgate, Clinical Director, Medicines &Healthcare Products RegulatoryAgency, London

Mr Stephen Pilling, Director,Centre for Outcomes, Research & Effectiveness, Joint Director, NationalCollaborating Centre for MentalHealth, University CollegeLondon

Mrs Una Rennard, Service User Representative,Oxford

Dr Phil Shackley, SeniorLecturer in Health Economics,Academic Vascular Unit,University of Sheffield

Dr Margaret Somerville,Director of Public HealthLearning, Peninsula MedicalSchool, University of Plymouth

Dr Graham Taylor, ScientificDirector & Senior Lecturer,Regional DNA Laboratory, TheLeeds Teaching Hospitals

Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull

Professor Martin J Whittle,Clinical Co-director, NationalCo-ordinating Centre forWomen’s and Childhealth

Dr Dennis Wright, Consultant Biochemist &Clinical Director, The North West LondonHospitals NHS Trust, Middlesex

Pharmaceuticals PanelMembers

Chair,Professor Robin Ferner,Consultant Physician andDirector, West Midlands Centrefor Adverse Drug Reactions, City Hospital NHS Trust,Birmingham

Ms Anne Baileff, ConsultantNurse in First Contact Care,Southampton City Primary CareTrust, University ofSouthampton

Professor Imti Choonara,Professor in Child Health,Academic Division of ChildHealth, University ofNottingham

Professor John Geddes,Professor of EpidemiologicalPsychiatry, University of Oxford

Mrs Barbara Greggains, Non-Executive Director,Greggains Management Ltd

Dr Bill Gutteridge, MedicalAdviser, National SpecialistCommissioning Advisory Group(NSCAG), London

Mrs Sharon Hart, Consultant PharmaceuticalAdviser, Reading

Dr Jonathan Karnon, SeniorResearch Fellow, HealthEconomics and DecisionScience, University of Sheffield

Dr Yoon Loke, Senior Lecturerin Clinical Pharmacology,University of East Anglia

Ms Barbara Meredith,Lay Member, Epsom

Dr Andrew Prentice, SeniorLecturer and ConsultantObstetrician & Gynaecologist,Department of Obstetrics &Gynaecology, University ofCambridge

Dr Frances Rotblat, CPMPDelegate, Medicines &Healthcare Products RegulatoryAgency, London

Dr Martin Shelly, General Practitioner, Leeds

Mrs Katrina Simister, AssistantDirector New Medicines,National Prescribing Centre,Liverpool

Dr Richard Tiner, MedicalDirector, Medical Department,Association of the BritishPharmaceutical Industry,London

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Therapeutic Procedures PanelMembers

Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Departmentof Surgery, Royal Devon &Exeter Hospital

Dr Mahmood Adil, DeputyRegional Director of PublicHealth, Department of Health,Manchester

Dr Aileen Clarke,Consultant in Public Health,Public Health Resource Unit,Oxford

Professor Matthew Cooke,Professor of EmergencyMedicine, Warwick EmergencyCare and Rehabilitation,University of Warwick

Mr Mark Emberton, SeniorLecturer in OncologicalUrology, Institute of Urology,University College Hospital

Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofGeneral Practice and PrimaryCare, South Tees Hospital NHSTrust, Middlesbrough

Ms Maryann L Hardy, Lecturer, Division ofRadiography, University ofBradford

Dr Simon de Lusignan,Senior Lecturer, Primary CareInformatics, Department ofCommunity Health Sciences,St George’s Hospital MedicalSchool, London

Dr Peter Martin, ConsultantNeurologist, Addenbrooke’sHospital, Cambridge

Professor Neil McIntosh,Edward Clark Professor of ChildLife & Health, Department ofChild Life & Health, Universityof Edinburgh

Professor Jim Neilson,Professor of Obstetrics andGynaecology, Department ofObstetrics and Gynaecology,University of Liverpool

Dr John C Pounsford,Consultant Physician,Directorate of Medical Services,North Bristol NHS Trust

Dr Karen Roberts, NurseConsultant, Queen ElizabethHospital, Gateshead

Dr Vimal Sharma, ConsultantPsychiatrist/Hon. Senior Lecturer, Mental HealthResource Centre, Cheshire andWirral Partnership NHS Trust,Wallasey

Professor Scott Weich, Professor of Psychiatry, Division of Health in theCommunity, University ofWarwick

Disease Prevention PanelMembers

Chair, Dr Edmund Jessop, MedicalAdviser, National SpecialistCommissioning Advisory Group(NSCAG), London

Mrs Sheila Clark, ChiefExecutive, St James’s Hospital,Portsmouth

Mr Richard Copeland, Lead Pharmacist: ClinicalEconomy/Interface, Wansbeck General Hospital,Northumberland

Dr Elizabeth Fellow-Smith,Medical Director, West London Mental HealthTrust, Middlesex

Mr Ian Flack, Director PPIForum Support, Council ofEthnic Minority VoluntarySector Organisations, Stratford

Dr John Jackson, General Practitioner, Newcastle upon Tyne

Mrs Veronica James, ChiefOfficer, Horsham District AgeConcern, Horsham

Professor Mike Kelly, Director, Centre for PublicHealth Excellence, National Institute for Healthand Clinical Excellence, London

Professor Yi Mien Koh, Director of Public Health andMedical Director, London NHS (North West LondonStrategic Health Authority),London

Ms Jeanett Martin, Director of Clinical Leadership& Quality, Lewisham PCT,London

Dr Chris McCall, GeneralPractitioner, Dorset

Dr David Pencheon, Director,Eastern Region Public HealthObservatory, Cambridge

Dr Ken Stein, Senior ClinicalLecturer in Public Health,Director, Peninsula TechnologyAssessment Group, University of Exeter, Exeter

Dr Carol Tannahill, Director,Glasgow Centre for PopulationHealth, Glasgow

Professor Margaret Thorogood,Professor of Epidemiology,University of Warwick, Coventry

Dr Ewan Wilkinson, Consultant in Public Health,Royal Liverpool UniversityHospital, Liverpool


361Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Health Technology Assessment Programme

362Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Expert Advisory NetworkMembers

Professor Douglas Altman,Professor of Statistics inMedicine, Centre for Statisticsin Medicine, University ofOxford

Professor John Bond,Director, Centre for HealthServices Research, University ofNewcastle upon Tyne, School ofPopulation & Health Sciences,Newcastle upon Tyne

Professor Andrew Bradbury,Professor of Vascular Surgery,Solihull Hospital, Birmingham

Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury

Mrs Stella Burnside OBE,Chief Executive, Regulation and ImprovementAuthority, Belfast

Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London

Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton

Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale

Professor Collette Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham

Professor Barry Cookson,Director, Laboratory ofHealthcare Associated Infection,Health Protection Agency,London

Dr Carl Counsell, ClinicalSenior Lecturer in Neurology,Department of Medicine &Therapeutics, University ofAberdeen

Professor Howard Cuckle,Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds

Dr Katherine Darton, Information Unit, MIND – The Mental Health Charity,London

Professor Carol Dezateux, Professor of PaediatricEpidemiology, London

Dr Keith Dodd, ConsultantPaediatrician, Derby

Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge

Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester

Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne

Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield

Professor Gene Feder, Professorof Primary Care Research &Development, Centre for HealthSciences, Barts & The LondonQueen Mary’s School ofMedicine & Dentistry, London

Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust

Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield

Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham

Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol

Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester

Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield

Professor Peter Jones, Professorof Psychiatry, University ofCambridge, Cambridge

Professor Stan Kaye, CancerResearch UK Professor ofMedical Oncology, Section ofMedicine, Royal MarsdenHospital & Institute of CancerResearch, Surrey

Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame

Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London

Mr George Levvy,Chief Executive, Motor Neurone Disease Association,Northampton

Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital

Professor Julian Little,Professor of Human GenomeEpidemiology, Department ofEpidemiology & CommunityMedicine, University of Ottawa

Professor Rajan Madhok, Consultant in Public Health,South Manchester Primary Care Trust, Manchester

Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds

Professor Alistaire McGuire,Professor of Health Economics,London School of Economics

Dr Peter Moore, Freelance Science Writer, Ashtead

Dr Andrew Mortimore, PublicHealth Director, SouthamptonCity Primary Care Trust,Southampton

Dr Sue Moss, Associate Director,Cancer Screening EvaluationUnit, Institute of CancerResearch, Sutton

Mrs Julietta Patnick, Director, NHS Cancer ScreeningProgrammes, Sheffield

Professor Robert Peveler,Professor of Liaison Psychiatry,Royal South Hants Hospital,Southampton

Professor Chris Price, Visiting Professor in ClinicalBiochemistry, University ofOxford

Professor William Rosenberg,Professor of Hepatology andConsultant Physician, Universityof Southampton, Southampton

Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh

Dr Susan Schonfield, Consultantin Public Health, HillingdonPCT, Middlesex

Dr Eamonn Sheridan,Consultant in Clinical Genetics,Genetics Department,St James’s University Hospital,Leeds

Professor Sarah Stewart-Brown, Professor of Public Health,University of Warwick, Division of Health in theCommunity Warwick MedicalSchool, LWMS, Coventry

Professor Ala Szczepura, Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick

Dr Ross Taylor, Senior Lecturer, Department ofGeneral Practice and PrimaryCare, University of Aberdeen

Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network

How to obtain copies of this and other HTA Programme reports.An electronic version of this publication, in Adobe Acrobat format, is available for downloading free ofcharge for personal use from the HTA website (http://www.hta.ac.uk). A fully searchable CD-ROM isalso available (see below).

Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public andprivate sector purchasers from our Despatch Agents.

Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is£2 per monograph and for the rest of the world £3 per monograph.

You can order HTA monographs from our Despatch Agents:

– fax (with credit card or official purchase order) – post (with credit card or official purchase order or cheque)– phone during office hours (credit card only).

Additionally the HTA website allows you either to pay securely by credit card or to print out yourorder and then post or fax it.

Contact details are as follows:HTA Despatch Email: [email protected]/o Direct Mail Works Ltd Tel: 02392 492 0004 Oakwood Business Centre Fax: 02392 478 555Downley, HAVANT PO9 2NP, UK Fax from outside the UK: +44 2392 478 555

NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of £100 for each volume (normally comprising 30–40 titles). The commercial subscription rate is £300 per volume. Please see our website for details. Subscriptions can only be purchased for the current orforthcoming volume.

Payment methods

Paying by chequeIf you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltdand drawn on a bank with a UK address.

Paying by credit cardThe following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard,Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email.

Paying by official purchase orderYou can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK.We cannot at present accept purchase orders from commercial companies or from outside the UK.

How do I get a copy of HTA on CD?

Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (seecontact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.

The website also provides information about the HTA Programme and lists the membership of the variouscommittees.

HTA


JM Burr, G Mowatt, R Hernández, MAR Siddiqui, J Cook, T Lourenco, C Ramsay, L Vale, C Fraser, A Azuara-Blanco, J Deeks, J Cairns, R Wormald, S McPherson, K Rabindranath and A Grant


HTAHealth Technology AssessmentNHS R&D HTA Programmewww.hta.ac.uk

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278

FeedbackThe HTA Programme and the authors would like to know

your views about this report.

The Correspondence Page on the HTA website(http://www.hta.ac.uk) is a convenient way to publish

your comments. If you prefer, you can send your comments to the address below, telling us whether you would like

us to transfer them to the website.

We look forward to hearing from you.

October 2007

Health Technology Assessm

ent 2007;Vol. 11: No. 41

Screening for open angle glaucoma

jm burr, g mowatt, r hernández, mar siddiqui, j cook, t...

Documents