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Choosing a reference group
Louise Coole
Sources:EPIET courses (from 1995 to 2011)J Stewart, A Moren
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Objectives
• Define “source population”
• Explore the meaning of representativeness
• Understand the importance of a reference group in analytical studies
• Describe advantages and disadvantages of selecting different types of controls
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• Compare – disease incidence in exposed and
unexposed (cohort studies)
– exposure in cases and controls
– disease incidence in different time-periods in a population
Epidemiologists .... compare
Measure and compare
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Comparison / Reference group
• Unexposed in cohort studies• Controls in case control studies
Focus on controls since selection of controls
can be an important source of bias.
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Cohort study:Purpose of the comparison group
• “The comparison group serves to
provide an estimate of the
expected disease incidence
in the exposed group
if the exposure had been absent.”
Rothman KJ, 1986
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Cohort study - Challenge
• To identify a population similar to the exposed populationand only differing by the absence of exposure
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Cohort - Well defined population
• Nursing home, school, weddinge.g. food borne outbreak
Retrospectively identify
have eaten % disease
did not eat % disease
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Does HIV infection increase risk of developing TB among a population of
drug users?
Population TB Cases
HIV + 215 8
HIV - 289 1
Source: Selwyn et al., New York, 1989
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Reference group in case control studies
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Reference group in a case control study= control group
“The comparison group serves to providean estimate of the
exposure distribution in the source population
from which the cases originate.”
Rothman KJ, 1986
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Controls
Controls should be representative of population from which cases arise (source population)
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Exposed
Unexposed
Source population
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CasesExposed
Unexposed
Source population
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CasesExposed
Unexposed
Source population
Sample
ControlsRothman KJ, Oxfort Univ Press, 2002
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CasesExposed
Unexposed
Source population
Controls:Sample of the denominator Representative with regard to exposure
Controls
Sample
Case control studies
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Control characteristics
If controls represent source population
• be representative of exposures in source population
• be identified as cases if they had disease under study
• have same exclusion and restriction criteria as cases
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Case control study
Outbreak
• 32 cases of Salmonella Enteritidis • North Yorkshire(population 500,000)• onset through April 2012• age range 15 – 48 years• 19 male, 13 female • no recent travel abroad
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Who are the right controls?
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Who is source population?
Start with your case definition
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Case definition
Resident of North Yorkshire aged above 14 years with isolate of Salmonella Enteritidis in faecal sample during April 2012 Exclusion: Travel abroad in week before illness
What is source population?
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Source population
Residents of North Yorkshire aged above 14 yearsduring April 2012 who have not recently travelled abroad
Controls should then be representative of this population
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How to select controls?
• Aim for random sample of source population
• Not always feasible
Case control studies
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Selecting controls (examples)
• Populationrandom from register/list/directory stratified (age/sex/general practice)
• Friends • Neighbourhood • Hospital
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Population / community controls
• Is there a list or register of source population?
• Such a list should
– be complete
– contain all cases
– be readily accessible
– identify specified characteristics
e.g. age
Take random sample
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or... random digit dialling
• using residential directories or mobile numbers (e.g. add 5 to case number)
• quick and easy • but may be biased in selection
– telephone ownership– availability– geographical area– participation
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Friends / family controls
AdvantagesGood matching for social and
genetic factors
Can be quick and easy
DisadvantagesEffectively link the cases and controls
May not be able to detect a diference
in exposure of importance
Co-operation may be limited
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Neighbourhood controls
Advantages – no need for population register– similar socio-economic status and environmental exposure
Disadvantages– might be too similar to cases
– low co-operation
– may be time consuming, expensive
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Hospital controls
• Advantages– useful if all cases identified from hospital register– easily identified – cost and time efficient
• Disadvantages– different catchments for different diseases – May not be representative of source population – overmatching on exposures for other diseases
• Tobacco / lung cancer and controls with CVD
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Controls may not be easy to find
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Case control study
Outbreak
• 32 cases of Salmonella Enteritidis • North Yorkshire(population 500,000)• onset through April 2012• age range 15 – 48 years• 19 male, 13 female • no recent travel abroad
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Source population
Residents of North Yorkshire aged above 14 yearsduring April 2012 who have not recently travelled abroad
Controls should then be representative of this population
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Which reference group ?
You are in charge of the case control study!
How would you select controls ?
No population register or list is available
Please discuss with a person next to you (2 minutes!)
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Some common questions
• Immune populations
• 100% exposure
• 100% ill
• Non-cases as controls
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Immune subjects
• Not eligible as cases – so not in source population
• Difficult to identify • May have been cases in the past • May have similar level of exposure
to risk factor as current cases in study • May introduce bias and under-estimation of
effect.
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What if 100% exposure ?
• What if close to 100% of population exposed? • e.g. foodborne disease outbreaks where little
choice in menu
• Try to measure dose response • Reference group lowest level of exposure
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Which control group if 100% ill ?
• What if close to 100% of population ill?
• Try to have severity
– Cases: severe cases
– Control group: less severe cases
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Outbreak of S. enteritidis in a Kebab restaurant, North East London February 2005
Food specific attack rates of severe case (AR), relatives risks (RR), 95% confidence intervals (95%) amongst cases.
Food eaten Food not eaten
Severe Total AR% Severe Total AR% RR 95% CI
Salad 10 12 83.3 32 71 45.11.9
1.3-2.7
Chips 11 14 78.5 31 69 44.91.8
1.2-2.6
Sauce 31 59 52.5 11 24 45.81.2
0.7-1.9
Salad 31 57 54.4 11 26 42.31.3
0.8-2.1
Giraudon I et al, EPIET, London HPA
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Controls are non cases
Low attack rate: non-cases likely to represent exposure in source pop
Non- casesSourcepopn
High attack rate: non-cases unlikely to represent
exposure in source population
Cases
Cases
Non- cases
endstart
endstart
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Non- cases as controls
• If attack rate high – non-cases unlikely to represent exposure in source
population
• If attack rate low – non-cases likely to represent exposures
in source population – can use as controls
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Cases
E
E 4
SourcePopulation
60
40
36
ARe = 60% ARue = 10%RR = 6
24
36
Non cases
Cohort
Outbreak of food borne disease in a nursing home. 100 residents, 40 cases
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Cases
E
E 4
SourcePopulation
60
40
Outbreak of food borne disease in a nursing Home. 100 residents, 40 cases
36
RR = 6
24
36
Non cases
Cohort
Sample Non cases
12
18
OR = 13.5
Potential control groups
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CasesSampleNon cases
E
E
12
4 18
SourcePopulation
60
40
Outbreak of food borne disease in a nursing home. 100 residents, 40 cases
36
Sample SourcePopulation
30
20
RR = 6 OR = 13.5 OR = 6
24
36
Non cases
Potential control groupsCohort
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A member of the source populationis a suitable control
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What if: Only non-cases as controls?
If attack rate is low non-cases likely to represent exposures in source
population can use them as controls
If attack rate is high, non-cases unlikely to represent exposure in source
population OR may be over-estimated
More accurate not to exclude cases from control group
Concept of case-cohort studies!
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Case-cohort design
• Control group estimates the proportion of the total population that is exposed
• Controls selected from all individuals at risk at the start of the study– sampled regardless whether or not they will fall ill
• Case may also be selected as a control and vice versa -> kept in both groups
• No need to document disease status among controls
• OR estimates relative risk
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Key points in choosing controls
• Define source population– Think of the cohort you could have done
• Aim for representative sample
• Review pros and cons of available options
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Characteristics of good controls
• Come from the same population as the cases• May be exposed like cases• Can develop the disease• Could be recruited as cases if diseased• Have exposure window identical to cases• Are adapted to study objectives
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Dealing with imperfect control groups
• Examine the limitations of your control group with respect to each criteria
• Assess in which way the limitation will affect the odds ratio
• Interpret your results in light of this review
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Conclusions
• No control group is perfect
• Consider the advantages and disadvantages of the available options
• Aim to minimise error within constraints of resources and urgency of study
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Be prepared to defend your choice…
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References
• Rothmann KJ, Greenland S. Modern epidemiology. Lippincott-Raven 1998.
• Hennekens CH, Epidemiology in Medicine. Lippincott-Williams and Wilkins 1987.