reference measurement procedures emphasis on …€¦ · · 2018-02-19institutes (irmm, nist)...

Reference Measurement Procedures – Emphasis on performance

specifications and operating laboratories

Introduction

Thienpont & Stöckl Wissenschaftliches Consulting 2

The measurement paradigm

Routine assays claiming that they measure the

same measurand should give equivalent results

within clinically meaningful limits/agreed upon

performance specifications

Accomplishing this requires the establishment of

metrological traceability, ideally to the SI (also

called standardization)

Establishment of traceability

ISO 17511: 2003

In vitro diagnostic medical devices –

Measurement of quantities in biological samples –

Metrological traceability of values assigned to

calibrators and control materials (under revision)

to the highest metrological

standard available at a certain time for a

particular quantity subject to measurement


Origin of the traceability concept


Cali JP An idea whose time has come. Clin Chem 1973;19:

291-3.

Tietz NW A model for a comprehensive measurement system

in clinical chemistry. Clin Chem 1979; 25:833-9.

Precursor of the ISO 17511

reference measurement system/

metrological traceability chain

Reference measurement system

Traceability to the SI


Gravimetry

Assay xyz

master procedure

Assay xyz

end user’s procedure

Primary calibrator

Product calibrator

Routine sample

Unit realizationCrystalline material of certified purity

Patient xyz

*** mmol/L

Reference method

Commutable working

calibrator

SI – Measurand (system/component/kind-of-

quantity)

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Metric anchor Meter Convention/General Conference on Weights and

Measures – SI

Amount of substance: mole (symbol mol)

Amount of substance concentration: mol/L



.

Measurement anchor Measurand

Quantity ‘intended’ to be measured

To specify by 3 elements:

System/component or analyte/kind-of-quantity



Material and analytical anchors

Reference materials1

• Primary calibrators (certified purity)

• Commutable secondary matrix-based calibrators

Trueness-based reference measurement procedures2

Reference measurement laboratories3

1ISO 15194:2009

In vitro diagnostic medical devices – Measurement of quantities in samples of

biological origin – Requirements for certified reference materials and the content of

supporting documentation.

2ISO 15193: 2009 In vitro diagnostic medical devices – Measurement of quantities in samples of biological origin – Requirements for content and presentation of reference measurement procedures.

3ISO 15195: 2003

Laboratory medicine – Requirements for reference measurement laboratories.



Anchors Organization Responsibilities

Unit

(preferably: the SI)

International Committee

& International Bureau for

Weights and Measures

Establishment/

maintenance of a

coherent system of

units

Measurand

(system-component-

kind of quantity)

IFCC Definition of the relevant

component (analyte)

Reference materials

(RM’s)

National Metrology

Institutes (IRMM, NIST)

Realization of the SI:

production and

certification of RM’s

Reference

measurement

procedures (RMP’s)

Reference laboratories or

other competent

analytical laboratories

Development and

validation of RMP’s

Reference laboratories

Networks

Application of RMP’s

Reference measurement procedures


Requirements that must be fulfilled

• Genuine/analytical characteristics

• Quality of performance

• Performed by competent laboratories

Trueness of measurement



Requirements#

(i) Genuine/analytical characteristics

• Measurement principle

• Analytical validity

• Directly calibratable with a primary calibrator

• Potential to high specificity (matrix-insensitive) and

trueness of measurement

• Proof of full exploitation of this potential by

validation/documentation

Examples: IDMS, coulometry, gravimetry,

AAS, … #ISO 15193: 2009 In vitro diagnostic medical devices – Measurement of quantities in samples of biological origin – Requirements for content and presentation of reference measurement procedures.

Overarching control


http://www.bipm.org/en/committees/jc/jctlm/

Database of reference materials &

reference measurement procedures

with ISO compliance

Joint Committee for Traceability

in Laboratory Medicine (JCTLM)

http://www.google.be/url?sa=i&rct=j&q=BIPM&source=images&cd=&cad=rja&docid=R4pvWrYQyFpXmM&tbnid=mJB0oSBJjnRDDM:&ved=0CAUQjRw&url=http://www.inmetro.gov.br/ccqm/organization.asp&ei=gQdwUc7wLcKx0AXB-oCACw&bvm=bv.45368065,d.d2k&psig=AFQjCNFNW2nt7fOnhejvR3YXEi4dmZjcPg&ust=1366382843172958

Pioneers in IDMS RMP’s


Siekmann L et al.

IDMS method development

Zur gas-chromatographisch-massenspektrometrischen Bestimmung von Steroidhormonen in Körperflüssigkeiten unter Verwendung eines Multiple Ion Detectors (Fragmentographie). Z Anal Chem 1970;252:294-8.


Björkhem I et al. Assay of cortisol with a

radioimmunoassay method

calibrated by isotope dilution

- mass spectrometry.

Scand J Clin Lab Invest

1983;43:433-7.

used in the RIA method

…

Pioneers in IDMS and commutability

Commutability – Assessment


Property of a that indicates how well it mimics the characteristics of

in measurement procedures for a stated measurand


Björkhem I et al. Assay of cortisol with a

radioimmunoassay method

calibrated by isotope dilution

- mass spectrometry.

Scand J Clin Lab Invest

1983;43:433-7.

used in the RIA method

… were replaced by

in which the concentration of cortisol

had been determined by the reference IDMS

method”.

Pioneers in IDMS and commutability


Traceability to the SI


Gravimetry

Assay xyz

master procedure

Assay xyz

end user’s procedure

Primary calibrator

Product calibrator

Routine sample

Unit realizationCrystalline material of certified purity

Patient xyz

*** mmol/L

Reference method

Working calibrator:

panel of native samples

SI – Measurand (system/component/kind-of-

quantity)

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University of Gent contributions


ID-MS Reference Measurement Procedures

Substrates/Metabolites Steroid hormones &

vitamin metabolites

Cholesterol Cortisol

Creatinine Estradiol

Glucose Progesterone

Total triglycerides Total/Free Testosterone

Uric acid 25OH-Vitamin D2/D3

Peptides/Proteins Thyroid hormones

Human C-peptide Total/Free T4 & T3

Human insulin

HbA1c

University of Gent contributions


Director of an ISO 17025 & 15195

accredited reference laboratory



Requirements (continued)

(ii) Quality of performance

• Random, systematic and total error (n)

• Not fixed but commensurate with the intended use,

i.e., establishing/assessing measurement trueness

of hierarchically lower measurement procedures

Concepts defining tailor made

performance specifications

Performance specifications


Beware of stress!

Proposals

Stöckl D, et al. Diskussionsvorschlag für ein einheitliches

Referenzmethodenkonzept auf der Grundlage der "Richtlinien der

Bundesärztekammer zur Qualitätssicherung in medizinischen

Laboratorien". Lab Med 1991;15:336-9.

Stöckl D, Reinauer H. Development of criteria for the evaluation of

reference method values. Scand J Clin Lab Invest Suppl 1993;212:16-8.

Stöckl D, Franzini C, Kratochvila J, Middle J, Ricos C, Siekmann L,

Thienpont LM. Analytical specifications of reference methods –

Compilation and critical discussion (from the members of the European

EQA-Organizers Working Group B). Eur J Clin Chem Clin Biochem

1996;34:319-37 [Review].

Thienpont LMR. Quality Specifications for Reference Methods. Scand J

Clin Lab Invest 1999;59:535-8.

Stöckl D, Sluss PM, Thienpont LM. Specifications for trueness and

precision of a reference measurement system for serum/plasma 25-

hydroxyvitamin D analysis. Clin Chim Acta 2009;408:8-13.

Performance specifications


Performance specifications – Concepts


For EQA: “Outcome-related” Fraction of the EQA limit resulting in a false

discrimination rate of 0.7%#

#Stöckl D et al. Eur J Clin Chem Clin Biochem 1996;34:319-37 [Review].

Analyte CV (%)# Bias (%)#

Chloride 1 0.5

Calcium 1.5 0.5

Creatinine 1.5 0.6

Thyroxine 2 0.9

Cortisol 2 1.4

#Together with specified n measurements



For the complete RMS (25OHD) Start from desirable performance goals for

routine measurement procedures and cascade down#

#Stöckl D, Sluss PM, Thienpont LM. Specifications for trueness and precision

of a reference measurement system for serum/plasma 25-hydroxyvitamin D

analysis. Clin Chim Acta 2009;408:8-13.

Within-subject

variation (CVw = 8%)

CV: 4%

Bias: 2.6%

Reference interval

(CVg = 20%)

CV: 10%

Bias: 5%

Monitoring

Diagnosis

Monitoring

Diagnosis



Reference performance goals

Cascade down from routine performance goals

Uncertainty of primary calibrators

Cascade down from reference bias goals

Model Routine Reference

Monitoring CV = 4%

Bias: 2.6%

CV: 2%

Bias 0.9%

U: 0.3%

Diagnosis CV: 10%

Bias: 5%

CV: 5%

Bias: 1.7%

U: 0.6%

CVref = 0.5 CVrou

Bref = 0.33 Brou

Urm = 0.33 Bref

Routine

measurements

CV: 10%

Bias: 5%

Reference

measurements

CV: 5%

Bias: 1.7%

Primary calibrators U: 0.6%



Proposal for current “working specifications”

Hold the balance between “desirable” Q-goals - “state-

of-the-art” performance - certification capabilities

Select performance goals based on “diagnosis model”

(= maximum values)

Note: Stable imprecision and bias should be ~1/2 of the

limit in order to not exceed it!

Routine

measurements

CV: 10%

Bias: 5%

Reference

measurements

CV: 5%

Bias: 1.7%

Primary calibrators U: 0.6%

Performance specifications 25OHD RMS


Vitamin D

Standardization

Program (VDSP)# #Sempos CT, Vesper HW , Phinney KW, Thienpont LM, Coates PM & The Vitamin D

Standardization Program (VDSP). Scand J Clin Lab Invest 2012; 72(Suppl 243): 32-40.

#Thienpont LM et al. Scand J Clin Lab Invest 2012; 72(Suppl 243): 41–49.

http://www.cdc.gov/

Requirements (continued)

(iii) Performed by competent laboratories

• Be accredited (ISO 15195/17025#)

• Use published reference measurement procedures

• Perform rigorous internal accuracy control with

SRM’s/CRM’s

• Participate in round robin trials for reference

laboratories

• Preferably work under network conditions

#ISO 15195:2003

Laboratory medicine – Requirements for reference measurement laboratories.

#ISO/IEC 17025:2017

General requirements for the competence of testing and calibration

laboratories.



Overarching control


http://www.bipm.org/en/committees/jc/jctlm/

Database of reference measurement

services with ISO compliance

Joint Committee for Traceability

in Laboratory Medicine (JCTLM)

http://www.google.be/url?sa=i&rct=j&q=BIPM&source=images&cd=&cad=rja&docid=R4pvWrYQyFpXmM&tbnid=mJB0oSBJjnRDDM:&ved=0CAUQjRw&url=http://www.inmetro.gov.br/ccqm/organization.asp&ei=gQdwUc7wLcKx0AXB-oCACw&bvm=bv.45368065,d.d2k&psig=AFQjCNFNW2nt7fOnhejvR3YXEi4dmZjcPg&ust=1366382843172958

JCTLM database


http://www.bipm.org

JCTLM-Newsletter-2017#

#For 80 different analytes in 9 categories: 293 CRM’s – 184 RMP’s – 161 reference

measurement services by 17 reference laboratories

Future of reference laboratories




Bright? Regulatory environment: Directive & ISO

Traceability of IVD assays

EQA/PT emphasis on traceability

JCTLM

…



Bright?

Viability of the “lonely-rider” academic

reference laboratory is a real challenge

Money, money, money





Willingness to standardize!

R. S. Yalow and S. A. Berson Assay of Plasma Insulin in Human Subjects by

Immunological Methods. Nature 1959;184:1648-1649.

The Nobel Prize in Physiology and Medicine 1977,

Rosalyn Yalow "for the development of

radioimmunoassays of peptide hormones".

Insulin measurement – Still NOT standardized



The “lonely-rider” academic reference laboratory



Embedded in a big organization

• EQA/PT organization

• Metrological institute (NIM’s)

• NIST, IRMM, CDC



Leadership in a certain domain (e.g.,

endocrinology, TDM)

• Not for a single analyte but groups of analytes, e.g.,

− Steroid hormones

− Thyroid hormones

− Therapeutics

• Get all IVD manufacturers on board, cf., IFCC projects

PATH Initiative

Need advice – Ask a question!


reference measurement procedures emphasis on …€¦ · · 2018-02-19institutes (irmm, nist)...

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