Over two decades, the Organic Analysis Working Group (OAWG) of the Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology (CCQM) has organized a number of comparisons for clinically relevant small molecule organic biomarkers. The aim of the OAWG community is to be part of the coordinated international movement towards accuracy and comparability of clinical measurements that will, in turn, minimize the wastage of repeat testing and unnecessary therapy to create a sustainable healthcare industry. International and regional directives/requirements on metrological traceability of calibrators and control materials are in place. Metrology institutes worldwide maintain infrastructure for the practical realization of metrological traceability and demonstrate the equivalence of their measurement capabilities through participation in key comparisons organized under the auspices of the CCQM. These institutes provide certified reference materials, as well as other dedicated value-assignment services benefiting the in-vitro diagnostic (IVD) industry, reference (calibration) laboratories and the clinical chemistry laboratories. The roles of these services in supporting national, regional, and international activities to ensure the metrological traceability of clinical chemistry measurements are described.
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International Bureau of Weights and Measures
Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology
International Committee for Weights and Measures
certified reference material
Dried Blood Spot
Vitamin D External Quality Assessment Scheme
External Quality Assurance Programmes in Laboratory Medicine
European Association of National Metrology Institutes
External Quality Assessment Schemes
International Consortium for Harmonization of Clinical Laboratory Results
Isotope dilution-mass spectrometry
International Measurement Evaluation Programme
International Federation for Clinical Chemistry and Laboratory Medicine
International Laboratory Accreditation Cooperation
International Organization for Standardization
Joint Committee for Traceability in Laboratory Medicine
Mutual Recognition Arrangement
National Metrology Institute
Organic Analysis Working Group
Reference measurement procedures
International System of Units
Royal Australasian College of Pathologists Quality Assurance Programs
Standard Reference Material®
Vitamin D Standardization Program
Vitamin D Metabolites Quality Assurance Program
Chen XH, Huang S, Kerr D. Biomarkers in clinical medicine. IARC Sci Publ. 2011;163:303–22.
Strimbu K, Tavel JA. What are biomarkers? Cur Opin HIV AIDS. 2010;5(6):463–6.
Stewart BA, Fernandes S, Rodriguez-Huertas E, Landzberg M. A preliminary look at duplicate testing associated with lack of electronic health record interoperability for transferred patients. J Am Med Inform Assoc. 2010;17(3):341–4.
Christopher PP, Robert HC. Evidence-based laboratory medicine: principles, practice, and outcomes. 2nd ed. Washington, DC: AACC Press; 2007.
World Health Organisation, International Diabetes Federation. (2006). Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. Report of a WHO/IDF consultation 2006. https://www.who.int/diabetes/publications/diagnosis_diabetes2006/en/. Accessed 25 Jun 2019.
World Health Organisation. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated report of a WHO consultation. 2011. https://www.int/diabetes/publications/diagnosis_diabetes2011/en/. Accessed 25 Jun 2019.
Andrew SL, Lesley AI. GFR as the “gold standard”: estimated, measured and true. Am J Kidney Dis. 2016;67(1):9–12.
Armbruster D, Miller RR. The joint Committee for Traceability in laboratory medicine (JCTLM): a global approach to promote the standardisation of clinical laboratory test results. Clin Biochem Rev. 2007;28(3):105–14.
Jones GR, Jackson C. The joint Committee for Traceability in laboratory medicine (JCTLM) - its history and operation. Clin Chim Acta. 2016;453:86–94.
JCTLM Mission Statement. https://www.bipm.org/jctlm/. Accessed 25 Jun 2019.
International Organisation for Standardisation. In vitro diagnostic medical devices - measurement of quantities in biological samples – metrological traceability of values assigned to calibrators and control materials (ISO 17511:2003). 2003. https://www.iso.org/standard/30716.html. Accessed 25 Jun 2019.
International Organisation for Standardisation. In vitro diagnostic medical devices -- Measurement of quantities in samples of biological origin -- Requirements for content and presentation of reference measurement procedures (ISO 15193: 2009). 2002. https://www.iso.org/standard/42021.html. Accessed 25 Jun 2019.
International Organisation for Standardisation. In vitro diagnostic medical devices -- Measurement of quantities in samples of biological origin -- Requirements for certified reference materials and the content of supporting documentation (ISO 15194:2009). 2009. https://www.iso.org/standard/42022.html. Accessed 25 Jun 2019.
International Organisation for Standardisation. Laboratory medicine – Requirements for reference measurement laboratories (ISO 15195:2003). 2003. https://www.iso.org/standard/38363.html. Accessed 25 Jun 2019.
Vesper HW, Thienpont LM. Traceability in laboratory medicine. Clin Chem. 2009;55(6):1067–75.
Armbruster D. Metrological traceability of assays and comparability of patient test results. Clin Lab Med. 2017;37:119–35.
European Parliament, Council of the European Union. Council directive 98/79/EC of the European Parliament and of the council of 27 October 1998 on in vitro diagnostic medical devices. Off J Eur Union L331. 2012. http://data.europa.eu/eli/dir/1998/79/2012-01-11. Accessed on 25 Jun 2019.
European Parliament, Council of the European Union. Regulation (EU) 2017/746 of the European Parliament and of the council of 5 April 2017 on in vitro diagnostic medical devices and repealing directive 98/79/EC and commission decision 2010/227/EU. Off J Eur Union L117. 2017. http://data.europa.eu/eli/reg/2017/746/oj. Accessed on 25 Jun 2019.
www.ifcc.org/ifcc-scientific-division/sd-committees/c-tlm/. Accessed on 25 Jun 2019.
www.ifcc.org/ifcc-scientific-division/sd-working-groups/. Accessed on 25 Jun 2019.
Kaarls R. The consultative Committee for Metrology in chemistry and biology – CCQM. J Chem Metrol. 2018;12(1):1–16.
IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0–9678550–9-8. https://doi.org/10.1351/goldbook.D01553. Accessed on 17 Aug 2019.
Ellerbe P, Meiselman S, Sniegoski LT, Welch MJ, White E 5th. Determination of serum cholesterol by a modification of the isotope dilution mass spectrometric definitive method. Anal Chem. 1989;61(15):1718–23.
Welch MJ, Parris RM, Sniegoski LT, May WE. CCQM-K6: key comparison on the determination of cholesterol in serum. Metrologia. 2002;39(Tech Suppl):08001.
Welch MJ, Sniegoski LT, Parris RM, May WE, Heo GS, Henrion A. CCQM-K11: The determination of glucose in serum. Metrologia. 2003;40(Tech Suppl):08003.
Welch MJ, Phinney CP, Parris RM, May WE, Heo GS, Henrion A, et al. CCQM-K12: The determination of creatinine in serum. Metrologia. 2003;40(Tech Suppl):08005.
Westwood S, Choteau T, Daireaux A, Josephs RD, Wielgosz RI. Mass balance for the SI value assignment of the purity of organic compounds. Anal Chem. 2013;85(6):3118–26.
Lee J, Kim B. Mass balance method for purity assessment of organic reference materials: for Thermolabile materials with LC-UV method. Bull Kor Chem Soc. 2014;35(11):3275–9.
Ishikawa K, Hanari N, Shimizu Y, Ihara T, Nomura A, Numata M, et al. Mass balance method for purity assay of phthalic acid esters: development of primary reference materials as traceability sources in the Japan calibration service system. Accred Qual Assur. 2011;16:311–22.
Lippa KA, Duewer DL, Nelson MA, Davies SR, Mackay LG. The role of the CCQM OAWG in providing SI traceable calibrators for organic chemical measurements. Accred. Qual. Assur. 2019. https://doi.org/10.1007/s00769-019-01407-6.
Westwood S, et al. Final report on key comparison CCQM-K55.A (estradiol): an international comparison of mass fraction purity assignment of estradiol. Metrologia. 2012;49(Tech Suppl):08009.
Westwood S, et al. Final report on key comparison CCQM-K55.B (aldrin): an international comparison of mass fraction purity assignment of aldrin. Metrologia. 2012;49(Tech Suppl):08014.
Westwood S, et al. Final report on key comparison CCQM-K55.C (L-(+)-valine): characterization of organic substances for chemical purity. Metrologia. 2014;51(Tech Suppl):08010.
Westwood S, et al. Mass fraction assignment of folic acid in a high purity material. Metrologia. 2018;55(Tech Suppl):08013.
Mike S, Rita H, Chris H. Guidelines for achieving high accuracy in isotope dilution mass spectrometry (IDMS). UK: The Royal Society of Chemistry; 2002.
Camara JE, Lippa KA, Duewer DL, Gasca-Aragon H, Toman B. An international assessment of the metrological equivalence of higher-order measurement services for creatinine in serum. Anal Bioanal Chem. 2012;403:527–35.
Camara JE, Duewer DL, Gasca Aragon H, Lippa KA, Toman B. Final report on CCQM-K80: comparison of value-assigned CRMs and PT materials: creatinine in human serum Metrologia. 2013;50(Tech Suppl):08006.
International Organisation for Standardisation. Conformity assessment – General requirements for proficiency testing (ISO/IEC 17043:2010). 2010. Retrieved from https://www.iso.org/standard/329366.html. Accessed on 25 Jun 2019.
International Organisation for Standardisation. Statistical methods for use in proficiency testing by interlaboratory comparison (ISO 13528:2015). 2016. Retrieved from https://www.iso.org/standard/56125.html. Accessed on 25 Jun 2019.
Nevel LV, Örnemark U, Smeyers P, Harper C, Taylor PDP. The international measurement evaluation Programme. IMEP-17 trace and minor constituents in human serum EUR 20657 EN report to participants. http://www.mirs.gov.si/fileadmin/um.gov.si/pageuploads/Dokpdf/SKM/IMEP17Porocilo.PDF. Accessed on 25 Jun 2019.
Vamathevan V, Murby EJ. Accurate analysis of testosterone in human serum using a heart-cutting 2D-UPLC-MS/MS procedure. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1038:49–56.
Miller, et al. Proficiency testing/external quality assessment: current challenges and future directions. Clin Chem. 2011;57(12):1670–80.
Heuillet, et al. Validation of a reference method for total cholesterol measurement in human serum and assignment of reference values to proficiency testing samples. Clin Biochem. 2013;46(4–5):359–64.
https://www.legifrance.gouv.fr/eli/decret/2016/1/26/2016-46/jo/article_2. Accessed 8 Nov 2018.
International Organisation for Standardisation. General requirements for the competence of testing and calibration laboratories (ISO/IEC 17025:2017). 2017. Retrieved from https://www.iso.org/standard/66912.html. Accessed on 25 Jun 2019.
Camara JE, Hoofnagle AN, Carter GD, Sempos CT. Take two: gearing up for the next vitamin D commutability study. AACC Clincial Laboratory News. 2015;41(2):8–10.
Bedner M, Lippa KA, Tai SSC. An assessment of 25-hydroxyvitamin D measurements in comparability studies conducted by the vitamin D metabolites quality assurance program. Clin Chim Acta. 2013;426:6–11.
George RS, Moat SJ. Effect of dried blood spot quality on newborn screening analyte concentrations and recommendations for minimum acceptance criteria for sample analysis. Clin Chem. 2016;62:466–75.
Phinney, et al. Development of an improved Standard Reference Material for vitamin D metabolites in human serum. Anal Chem. 2017;89:4907–13.
Burdette CQ, et al. Establishing an accuracy basis for the vitamin D external quality assessment scheme (DEQAS). J AOAC Int. 2017;100:1277–87.
Wise SA, et al. Role of the National Institute of Standards and Technology (NIST) in support of the vitamin D initiative of the National Institutes of Health, Office of Dietary Supplements. J AOAC Int. 2017;100:1260–76.
Phinney KW, et al. Baseline assessment of 25-hydroxyvitamin D reference material and proficiency testing/external quality assurance material commutability: a vitamin D standardization program study. J AOAC Int. 2017;100:1288–93.
The authors thank all colleagues involved in the organization and participation of the CCQM pilot studies and key comparisons for small molecule organic biomarkers over the past two decades. HSA acknowledges the contributions by Lingkai Wong, Yizhao Chen, Hong Liu, and Hui Ling Teo. NIST acknowledges the contributions by Lorna Sniegoski, Michael J. Welch, Susan S.-C. Tai, Jeanita Pritchett, Karen W. Phinney and David L. Duewer, as well as Steven A. Wise and Christopher T. Sempos in collaboration with and financial support from the NIH Office of Dietary Supplements. NMIA acknowledges the contributions by Stephen Davies, Veronica Vamathevan, Mark Lewin, Lesley Johnston, Meg Croft, and Edwin J Murby. LNE acknowledges the contributions by Catherine Perrot, Maryline Peignaux, Carine Fallot, Julie Cabillic, and Gustavo Martos. KRISS acknowledges the contributions by Byungjoo Kim, Inchul Yang, Dukjin Kang, and Hwashim Lee. NIMT acknowledges the contributions by Cheerapa Boonyakong, Charun Yafa, and the Thailand Creatinine Standardization Working Group. INMETRO acknowledges the contributions by Bruno C. Garrido, Eliane C.P. Rego and Jane L. N. Fernandes.
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Teo, T.L., Lippa, K.A., Mackay, L. et al. Enhancing the accuracy of measurement of small molecule organic biomarkers. Anal Bioanal Chem 411, 7341–7355 (2019). https://doi.org/10.1007/s00216-019-02153-x
- Clinical measurements
- Metrological traceability
- Certified reference materials (CRMs)
- Pilot studies and key comparisons
- External quality assessment schemes (EQAS)