Reference Methods and Standards for Clinical Diagnostics/Assessments and Therapeutic Monitoring

The accuracy of healthcare measurements is critical to the evaluation of health status and the diagnosis and treatment of disease. CSTL works with other government agencies (e.g., CDC, NCI, NIH), professional organizations (e.g., AACC, CAP, CLSI (formerly NCCLS)), the private sector (e.g., AdvaMED, Mayo Clinic), and the international community through the Joint Committee on Traceability in Laboratory Medicine (JCTLM) to prioritize measurement and standards needs. CSTL works closely with the clinical and medical community to transfer the accuracy of the highest level of metrology to high-throughput clinical laboratory measurements: NIST reference methods and reference materials for health care markers provide a major traceability anchor for millions of routine tests performed annually in the U.S. and around the world.

Project components include: [1] development and validation of reference methods for selected health status markers (electrolytes, toxic and/or speciated metals, small organic markers, protein-based markers) [2] provision of Standard Reference Materials (SRMs) (pure primary chemical standards, optical filter standards for instrument calibration/assessment, body fluid-based materials), [3] interactive measurement quality assessment activities, and [4] strategic international comparison exercises.

• Critical leadership, input, and participation in JCTLM critical review of “higher order” clinical Certified Reference Materials and Reference Procedures that can be used for compliance with European Directive 98/79/EC on in vitro diagnostic medical devices (IVD MD) ( http://www.cstl.nist.gov/nist839/jctlm.htm , http://www.bipm.org/en/committees/jc/jctlm/jctlm-db/ ).
  - Established 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.
  - Published a list (April 1, 2004) of “higher order” Certified Reference Materials and Reference Measurement Procedures
  - 30 NIST Reference Methods are included in the current listing of approximately 100 Reference Measurement Procedure entries for 58 different health status markers
  - 72 NIST Reference Materials are included in the approximately 150 Reference Material entries for 96 measurands.
• Maintaining reference systems (definitive methods, based primarily on isotope-dilution mass spectrometry, and SRMs) currently in place for well-defined health-status markers such as calcium, chloride, cholesterol, creatinine, glucose, potassium, triglycerides, etc.
• Progress in development and validation of reference procedures needed for new generation health markers, which are often large biomolecules present in body fluids at very low concentrations. Recently published NIST reference procedures ( see “Recent Publications” below for citations) include:
  - Reference methods for the determination of thyroid function markers thyroxine (T4) and triiodothyronine (T3) in human serum
  - Reference method for the determination of total cortisol (an important hormone in metabolism) in human serum
  - Compilation of Higher-Order Methods for the Determination of Electrolytes in Clinical Materials.
• Development and validation of new rapid isotope dilution LC/MS method for serum creatinine
• Development and validation of new method for the determination of toxic trace elements in whole blood using collision cell inductively coupled plasma mass spectrometry.
• Development and dissemination of new and renewal clinical SRMs that meet “higher order” criteria established by international community through JCTLM.
• Provision of interactive measurement proficiency assessment services for hospital and clinical laboratories making measurements of vitamins in serum for nutritional assessment.
• Participation in BIPM Consultative Committee on the Quantity of Matter (CCQM) comparison exercises to establish measurement comparability internationally.
• Established collaborations to provide NIH medical researchers with improved measurement capabilities through applications of NIST microfluidics and microengineering expertise. Initial activities focus on enhanced measurements for NIH study of the immune response to Herpes Papilloma Virus and NIH study of aspects of various vision-related diseases.

• Continuing research (in NIST collaborations with national metrology institutes (LGC of the United Kingdom and PTB of Germany) on development of a reference method for C-reactive protein, a risk factor for heart disease that incorporates a proteomics approach for isolation of characteristic peptides from CRP for measurement by LC/MS
• Development and evaluation of new approaches for quantification of biomolecules including peptides, proteins, hormones, and species containing inorganic elements such as transferring (important iron-transporting protein in the blood), selenium-containing proteins, and other iron-containing proteins.
• Continue leadership and participation in JCTLM activities.
• Continue working with clinical diagnostic community to prioritize reference procedure and reference standard needs; provision and maintenance of needed reference procedure and reference standards