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Development of Reference Methods and Reference Materials for Clinical Diagnostic Markers

Summary:


The accuracy of clinical diagnostic measurements is essential for reliable diagnosis and cost-effective treatment of disease. NIST's involvement in reference methods and reference materials to support accuracy in health-related measurements began more than forty years ago, and NIST is continually expanding the range of SRMs available. NIST works closely with the in-vitro diagnostic (IVD) community to identify and address reference material and methods needs, and to ensure that these SRMs are commutable with routine clinical assays. As part of this effort, new higher-order analytical methods have also been developed. These new reference methods and the associated SRMs provide critical traceability to the IVD industry and help improve the reliability of routine clinical measurements.

Description:


Reference measurement procedures and standard reference materials help ensure accuracy and comparability of routine clinical assays. In addition, this work allows U.S. clinical diagnostic manufacturers to comply with the European Union directive regarding in-vitro diagnostic medical devices (IVD MD), which requires that values assigned to calibrators and control materials be traceable to reference materials and reference measurement procedures of a higher order. The Joint Committee for Traceability in Laboratory Medicine (JCTLM) maintains a listing of these higher-order reference materials and methods. The SRMs also support accuracy in measurements performed as part of the National Health and Nutrition Examination Survey (NHANES) that is conducted by CDC.

Additional Technical Details:


NIST continually updates its portfolio of SRMs for clinical diagnostics to meet the needs of the clinical chemistry community. Listed below are materials that are currently available. Early serum-based SRMs for clinical diagnostics were lyophilized materials. NIST is now moving toward fresh-frozen matrices because these materials are anticipated to have improved commutability with routine assays. In addition, certain SRMs, such as SRM 900 Antiepilepsy Drug Level Assay, are being updated with new analytes to better reflect current medical testing. SRM 955c Lead in Caprine Blood has been developed as a replacement for SRM 966 Toxic Elements in Bovine Blood. In addition to values for lead, this SRM will include values for inorganic and organic mercury species. New SRMs are also in development for several vitamins in serum, including vitamin B6, B12, and D. 

Many of the original reference measurement procedures for clinical analytes (formerly known as definitive methods) were based upon gas chromatography-mass spectrometry (GC/MS). These methods often required multi-step sample preparation as well as derivatization of the analyte of interest. More recently, liquid chromatography-mass spectrometry (LC/MS and LC-MS/MS) has been investigated as an alternative approach. Analyte derivatization is typically not required, and protein precipitation may be sufficient to release the analytes of interest. Both GC/MS and LC/MS methods were used to certify SRM 967 Creatinine in Human Serum, and the two techniques provided comparable results. The new LC/MS method is now listed as a higher-order method by the Joint Committee for Traceability in Laboratory Medicine (JCTLM).  

Major Accomplishments:

  • NIST now has over 30 SRMs available in the area of clinical diagnostics.   
  • New reference measurement procedures have been developed for analytes of clinical diagnostic significance.    
  • New SRMs have been developed in consultation with the IVD industry, the clinical chemistry community, and other government agencies.

Photograph of clinical SRMs

End Date:

Ongoing

Lead Organizational Unit:

mml

Staff:

Mary Bedner
David M. Bunk
Johanna E. Camara
Steven J. Christopher
Jennifer M. Keller
Eric L. Kilpatrick
Stephen E. Long
Karen E. Murphy
Karen W. Phinney
Kenneth W. Pratt
Catherine A. Rimmer
Lane C. Sander
Michele M. Schantz
Katherine E. Sharpless
Lorna T. Sniegoski
Susan S-C. Tai
Jeanice B. Thomas
Gregory C. Turk
Thomas W. Vetter
Robert D. Vocke
Michael J. Welch

Associated Products:

SRM 900a Antiepilepsy Drug Level Assay - Phenytoin, phenobarbital, ethosuxmide, and primidone
SRM 909c Human Serum - Routine clinical analytes SRM 911c Cholesterol - Purity
SRM 912a Urea - Purity
SRM 913a Uric Acid - Purity
SRM 914a Creatinine - Purity
SRM 915b Calcium Carbonate - Mass fraction
SRM 916a Bilirubin - Purity
SRM 917b D-Glucose - Purity
SRM 918b Potassium Chloride - Mass fraction
SRM 919b Sodium Chloride - Mass fraction
SRM 920 D-Mannitol - Purity
SRM 921 Cortisol - Purity
SRM 924a Lithium Carbonate - Purity
SRM 927d Bovine Serum Albumin - BSA, total protein
SRM 928 Lead Nitrate - Purity
SRM 929a Magnesium Gluconate - Magnesium
SRM 937 Iron Metal - Purity
SRM 955c Toxic Elements in Caprine Blood - Lead, cadmium, mercury
SRM 956b Electrolytes in Frozen Human Serum - Electrolytes, three levels
SRM 965a Glucose in Frozen Human Serum - Glucose, four levels
SRM 967 Creatinine in Frozen Human Serum - Creatinine, two levels
SRM 968e Fat-Soluble Vitamins, Carotenoids, and Cholesterol in Human Serum - Retinol, tocopherols, β-carotene, and cholesterol
SRM 970 Ascorbic Acid in Frozen Human Serum - Ascorbic acid, two levels
SRM 971 Hormones in Frozen Human Serum - Cortisol, progesterone
SRM 972 Vitamin D in Human Serum - Vitamin D metabolites, four levels
SRM 998 Angiotensin I - Purity
SRM 1400 Bone Ash - Elements
SRM 1486 Bone Meal - Elements
SRM 1595 Tripalmitin - Purity
SRM 1598a Inorganic Constituents in Animal Serum - Elements
SRM 1599 Anticonvulsant Drug Level Assay Standard - Carbamazepine, valproic acid
SRM 1951b Lipids in Frozen Human Serum - Cholesterol, triglycerides
SRM 1952a Cholesterol in Human Serum - Cholesterol, three levels
SRM 1955 Homocysteine and Folate in Human Serum - Homocysteine, folate, 5MT
SRM 2389a Amino Acids in HCl - Amino acids
SRM 2670a Toxic Elements in Urine - Elements, two levels
SRM 2921 Human Cardiac Troponin Complex - Cardiac troponin I
SRM 2972 25-Hydroxyvitamin D2 and D3 Calibration Solutions

Associated Publications:

Bunk, D.M., “Reference Materials and Reference Measurement Procedures: An Overview from a National Metrology Institute,” Clin. Biochem. Rev., 28(4):131-137 (2007).

Dodder, N.G., Tai, S.S-C., Sniegoski, L.T., and Welch, M.J., “Certification of Creatinine in a Human Serum Reference Material by GC-MS and LC-MS,” Clin. Chem., 53(9):1694-1699 (2007).

Murphy, K.E., Long, S.E., and Vocke, R.D., “On the Certification of Cadmium at Trace and Ultratrace Levels in Standard Reference Materials using ID ICP-MS,” Anal. Bioanal. Chem., 387(7): 2453-2461 (2007).

Schantz, M.M., Keller, J.M., Leigh, S.D., Patterson, Jr., D.G., Sharpless, K.E., Sjödin, A., Stapleton, H.M., Swarthout, R., Turner, W.E., and Wise, S.A., “Certification of SRM 1589a PCBs, Pesticides, PBDEs, and Dioxins/Furans in Human Serum,” Anal. Bioanal. Chem., 389(4):1201-1208 (2007).

Tai, S.S-C., Xu, B., Welch, M.J., and Phinney, K.W., “Development and Evaluation of a Candidate Reference Measurement Procedure for the Determination of Testosterone in Human Serum Using Isotope-Dilution Liquid Chromatography-Tandem Mass Spectrometry,” Anal. Bioanal. Chem., 388(5-6):1087-1094 (2007).

Nelson, B.C., Pfeiffer, C., Zhang, M., Duewer, D.L., Sharpless, K.E., and Lippa, K.A., “Commutability of NIST SRM 1955 Homocysteine and Folate in Frozen Human Serum with Selected Total Homocysteine Immunoassays and Enzymatic Assays,” Clin. Chim. Acta, 395:99-105 (2008).

Phinney, K.W., “Development of a Standard Reference Material for Vitamin D in Serum,” Am. J. Clin. Nutr., 88(2):511S-512S, Suppl. S (2008).

Contact

David Bunk
Phone 301-975-5071
david.bunk@nist.gov

Stephen E. Long
Phone 301-975-4101
stephen.long@nist.gov

Karen W. Phinney
Phone 301-975-4457
karen.phinney@nist.gov