1. Joint Committee for Traceability in Laboratory Medicine
Bureau International des Poids et Mesures
Joint Committee for Traceability in Laboratory Medicine
JCTLM Approach to Higher Order Standards
R.I. Wielgosz, BIPM

2. JOINT COMMITTEE for TRACEABILITY in LABORATORY MEDICINE (JCTLM)
Declaration of co-operation
establishing
A framework for the international recognition of available higher-order reference materials, measurement procedures and reference measurement laboratories
Bureau International des Poids et Mesures

3. JOINT COMMITTEE on TRACEABILITY in LABORATORY MEDICINE
Established in Sevres on 12 June 2002, to meet the need for a worldwide platform to promote and give guidance on internationally recognized and accepted equivalence of measurements in Laboratory Medicine and traceability to appropriate measurement standards. The Declaration of Cooperation between the International Committee of Weights and Measures (CIPM), the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC),and the International Laboratory Accreditation Cooperation (ILAC) for establishment of the JCTLM can be found at

4. JCTLM - Structure JCTLM Executive Chair: J. Thijssen (IFCC)
Executive Secretary: R. Wielgosz (BIPM)
Priority setting
Approval of WG’s results
JCTLM Working Groups: Task oriented
1. Reference Materials and Reference Methods
Co-Chairs: W.E. May (NIST), H. Schimmel (IRMM)
2. Reference Laboratories - Networks
Co-Chairs: L. Siekmann (U. Bonn), L. Thienpont (U. Gent)
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5. JCTLM Working Group I on Reference Materials and Reference Measurement Procedures
Charged with:
establishing a process for identifying, and reviewing against agreed upon criteria “higher order” Certified Reference Materials and Reference Measurement Procedures required for IVD industry compliance with the EC IVD Directive regarding in vitro diagnostic medical devices.
publishing a List of “higher order” Certified Reference Materials and Reference Measurement Procedures required for IVD industry compliance with the EC IVD Directive regarding in vitro diagnostic medical devices.
Co-Chairs: W.E. May (NIST), H. Schimmel (IRMM)

6. “.... the traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or reference materials of a higher order ...”
Annex 1 (3) 2nd para
IVD Manufacturers have requested
that NMIs develop internationally recognized reference methods and CRMs
to meet this assist them in meeting this traceability requirement.
Bureau International des Poids et Mesures

7. Relevant ISO Standards
ISO In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values assigned to calibrators and control materials
ISO Presentation of reference measurement procedures
ISO Description of reference materials
ISO Reference Measurement Laboratories
ISO Metrological traceability of values for catalytic concentration of enzymes assigned to calibrators and control materials

8. Definitions (International Vocabulary of Basic and General Terms in Metrology –VIM)
(Metrological) traceability property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties
Uncertainty parameter, associated with the result of a measurement, that characterizes the dispersion of the values that could reasonably be attributed to the measurand
Quantity attribute of a phenomenon, body or substance that may be distinguished qualitatively and determined quantitatively
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9. SI traceability - Primary Calibrators (ISO 17511)
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10. Traceability to an international conventional calibrator (ISO 17511)
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11. Traceability to manufacturer’s selected measurement procedure (ISO 17511)
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12. JCTLM WG1 Review Process (ISO 15194)
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13. JCTLM Reference Materials Nominations Template (1/3)
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14. JCTLM Reference Materials Nominations Template (2/3)
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15. JCTLM Reference Materials Nominations Template (3/3)
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16. Priority Analyte Areas for Cycle I Review Process
(Sept 2002 – March 2004)
Review Teams established with worldwide representation from Lab Accreditation Organizations, NMIs, Professional Societies, and IVD Industry in order to facilitate a fair and transparent review process.
Electrolytes Enzymes
Metabolites and Substrates Proteins
Nucleic Acids Drugs
Hormones Coagulation Factors
Quality Systems and Implementation Protocols
Additional Priority Areas for Cycle II Review Process
(April Dec 2004)
Blood Grouping/ Typing
Blood Gases
Microbial Serology
Non-Electrolyte Metals
Vitamins and Micronutrients
Bureau International des Poids et Mesures

17. Initial Provisional Lists of Higher Order Reference Materials and Reference Measurement Procedures
Certified Reference Materials and Reference Measurement Procedures for well-defined chemical entities or internationally recognized reference method-defined measurands, such as enzymes. Reference Materials included in this category are those that are traceable to the SI units. [Electrolytes, Drugs, Metabolites and Substrates, Non-Peptide Hormones, Enzymes and some Proteins]
Reference Materials that are value-assigned using an internationally agreed upon protocol e.g., reference materials for Blood Typing, Coagulation Factors, Microbial Serology, Nucleic Acids, and some Proteins. The values of the measurands in the reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedures exist.
Bureau International des Poids et Mesures

18. Initial Lists of Higher Order Reference Materials and Reference Measurement Procedures published April 2004
Certified Reference Materials and Reference Measurement Procedures for well-defined chemical entities or internationally recognized reference method-defined measurands, such as enzymes. Reference Materials included in this category are those that are traceable to the SI units. [Electrolytes, Drugs, Metabolites and Substrates, Non-Peptide Hormones, Enzymes and some Proteins]
approximately 100 Reference Measurement Procedure entries for 58 different health status markers
approximately 150 Reference Material entries for 96 measurands
Bureau International des Poids et Mesures

19. Hereafter, Lists I and II to be updated in April of each year
List updated in January 2005 to include – based on Cycle I nominations: Reference Materials that are value-assigned using an internationally agreed upon protocol e.g., reference materials for Blood Typing, Coagulation Factors, Microbial Serology, Nucleic Acids, and some Proteins. The values of the measurands in the reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedures exist.
10 CRMs for Coagulation Factors
7 CRMs for Proteins
Hereafter, Lists I and II to be updated in April of each year
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20. Home page
JCTLM Database: Laboratory medicine and in vitro diagnostics
JCTLM-DB
JCTLM-DB home
Search form
Preamble
Quality manual
Review Teams
Nomination forms
JCTLM
Useful links
ILAC
IFCC
KCDB
Metrologia
Contact
JCTLM Secretariat
Database of higher-order reference materials and reference measurement procedures
Search the database
List I : Certified Reference Materials and Reference Measurement Procedures for well-defined chemical entities or internationally recognized reference method-defined measurands. Reference Materials and Measurement Procedures included in this category are those that provide values that are traceable to the SI units; e.g., electrolytes, enzymes, drugs, metabolites and substrates, non-peptide hormones and some proteins.
List II: Reference Materials (e.g. reference materials for blood typing, coagulation factors, microbial serology, nucleic acids, and some proteins) that are value-assigned using an internationally agreed upon protocol. The values of the measurands in the reference materials on this List are not SI-traceable and/or no internationally-recognized reference measurement procedure exist. List II also contains a group of purified substances that due to the absence of reference measurement procedures should not be directly used for calibration unless commutability is established.
Bureau International des Poids et Mesures

21. Higher-order reference materials
RM Producer’s Contact Information
NIST, United States
Website:
Tel: (301)
Fax: (301)
JCTLM Database: Results of the search
JCTLM-DB
JCTLM-DB home
Search form
Preamble
Quality manual
Review Teams
Nomination forms
JCTLM
Higher-order reference materials
Results of the search
Cholesterol in human serum
National Institute of Standards and Technology (NIST), United States
Name of reference material: SRM 1951a, lipids in frozen human serum
Quantity: Amount-of-substance concentration
Range of analyte certified/assigned value: mmol/l to mmol/l
Range of expanded uncertainty at a 95% level of confidence: mmol/l to mmol/l
Traceability: SI
CRM listing: List I RM
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RM no longer listed
Cholesterol in human serum (lyophilized)
National Institute of Standards and Technology (NIST), United States
Name of reference material: SRM 909b, human serum
Quantity: Amount-of-substance concentration
Range of analyte certified/assigned value: mmol/l to mmol/l
Range of expanded uncertainty at a 95% level of confidence: mmol/l to mmol/l
Comparability assessment study among listed RMs: See summary of Comparability Assessment for Cholesterol in Human Serum CRMs on JCTLM List I at
Other relevant publication(s) : Certification process: Fresenius’ J. Anal. Chem. 361: (1998); Method used for certification: Anal Chem 61, (1989)
Traceability: SI
CRM listing: List I
Contact
JCTLM Secretariat
Useful links
ILAC
IFCC
KCDB
Metrologia
Create a .PDF file
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22. Higher-order reference measurement procedures
RMP
-Create a .PDF file
-Modify your selection
Refine your search
RMP no longer listed
Bureau International des Poids et Mesures
JCTLM Database: Results of the search
JCTLM-DB
JCTLM-DB home
Search form
Preamble
Quality manual
Review Teams
Nomination forms
JCTLM
Useful links
ILAC
IFCC
KCDB
Metrologia
Contact
JCTLM Secretariat
Create a .PDF file
Higher-order reference measurement procedures
Results of the search
CDCAbell-Kendall method for cholesterol
Cholesterol in blood serum
Applicable matrices: human serum; lyophilized, fresh or frozen serum
Measurement principles: Spectrophotometry
Citation(s): Clin Chem, 1986, 32,
Comparability assessment studies: Clin Chem, 1990, 36,
DGKC definitive Method for Serum Cholesterol
Cholesterol in blood serum
Applicable matrices: human serum or plasma; lyophilized, fresh or frozen
Measurement principles: ID/GC/MS
Citation(s): Z. anal Chem, 1976, 279,
Comparability assessment studies: See CCQM-P6 results in CCQM-K6 Report
NIST definitive method for serum cholesterol
Cholesterol in blood serum
Applicable matrices: human serum: lyophilized, fresh or frozen serum
Measurement principles: ID/GC/MS
Citation(s): Anal Chem, 1989, 61,
Comparability assessment studies: CCQM-K6 Final Report, Clin Chem, 1990, 36,

23. Fig 1: Ratio Display Fig 2: Scattergram Display
All Listed Reference Materials will be assessed for comparability by a reference measurement procedure under repeatability conditions:
to assess veracity of the Normative Standards-Based Review Process
To establish bias that could be introduced by randomly selecting any material from the List
Example: Potassium in Human Serum CRMs on provisional JCTLM List 1 were assessed for comparability by a single laboratory (NIST) using a reference measurement procedure under repeatability conditions.
Fig 1: Ratio Display Fig 2: Scattergram Display
Fig 1: The vertical axis reports the ratio between the measured and certified values of each CRM, Xi/Ci. The dark vertical lines represent the approximate 95% CI about the ratios. The light horizontal lines represent the certified 95% CIs. The dotted line represents the expected ratio for the suite of all materials given the observed identity between the measured and certified values. (CI = Confidence Interval)
Fig 2: The data demonstrate that these CRMs are comparable over a wide concentration range. The horizontal axis reports the certified values, Ci; the vertical reports the average measured values, Xi. Each level of each CRM is displayed as approximate 95% CIs along both axes. The intersection of these intervals is bounded by an open circle to aid visual inspection.

24.  CRM comparability independent of analyte level
Comparability of Cholesterol in Serum CRMs on JCTLM LIST
 CRM comparability independent of analyte level
The measured/certified ratios for this set of CRMs are:
~ normally distributed
with a standard deviation of ~0.7%
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25. Upcoming JCTLM Meetings
JCTLM WG1+WG2– September 19-20, IRMM, Geel, Belgium
JCTLM Members meeting – September 21, IRMM
JCTLM WG2 – July 27, AACC/IFCC meeting, Orlando USA
Bureau International des Poids et Mesures