Clinical chemists have struggled for decades to achieve harmonized results for laboratory tests. Results from clinical laboratory measurement procedures must be equivalent to enable effective use of clinical guidelines for patient management. Unfortunately, some clinical practice guidelines base a diagnosis or treatment on test results without considering the possibility or likelihood of differences between measurement procedures. Clinicians and researchers may be unaware of the extent to which test results vary among different measurement procedures, thus setting up a potential for errors in patient care.
We have managed to develop primary reference materials and reference measurement procedures for maybe 40 analytes. What is holding us back from harmonizing the rest of the analytes measured in the clinical laboratory?
Factors contributing to inadequate harmonization of results include: lack of a systematic process to identify analytes in need of harmonization, lack of systematic procedures to implement harmonization when there is no reference measurement procedure, and lack of commutable reference materials for a large number of analytes.
ISO standard 17511:2003 (1,2) describes how calibration traceability to a reference system can enable equivalent results among different measurement procedures. The IFCC and the Joint Committee for Traceability in Laboratory Medicine (JCTLM) have taken the lead in developing and credentialing reference systems for analytes for which reference measurement procedures can be developed. However, there is no systematic process for prioritizing analytes and most reference systems have been developed because an individual champion recognized a need and initiated a standardization activity.
For many analytes, it is not currently technically possible to develop a reference measurement procedure and the best approach available is to create a secondary reference material that has an analyte’s concentration assigned by a consensus process. However, there are no systematic approaches for such a consensus process. Clinical laboratory measurement procedures can, in principle, trace their calibration to a secondary reference material to enable harmonization of results. Unfortunately, the use of many existing secondary reference materials has not accomplished the desired condition of harmonized results.
The reason for the lack of effectiveness of many reference materials is that they are not commutable with native clinical samples for many of the clinical laboratory measurement procedures for which they are intended to be used. A commutable reference material is one that has, for a given analyte, a numeric relationship between measurement procedures that is equivalent to the relationship observed for native clinical samples. Establishing traceability to a reference material that is not commutable with native clinical samples for a given measurement procedure will cause erroneous calibration and results for patient samples that do not agree with other measurement procedures for the same analyte (3,4). The error in patient sample results that is caused by calibration with a non-commutable reference material has been called a matrix-related bias or a matrix-effect because it is related to differences in matrix composition between native clinical samples and a reference material, which may include differences in the molecular form of the measurand (the quantity intended to be measured) in a clinical sample and that in a reference material.
Many reference materials available from metrology institutes, WHO and other sources (some of which are listed by JCTLM) have not been investigated for their commutability characteristics with clinical laboratory measurement procedures. In many cases, reference materials have been used to calibrate clinical laboratory measurement procedures when they are not fit for that intended purpose. Unfortunately, suppliers of reference materials have frequently not provided information on commutability characteristics so a user cannot make an informed decision if a particular reference material is suitable for use as a calibrator for a clinical laboratory measurement procedure.
The AACC convened an international conference in October 2010 to stimulate progress in addressing the need to improve harmonization of laboratory results for analytes that do not have reference measurement procedures and frequently trace calibration to reference materials. Laboratory, clinical, metrology, industry and regulatory organizations were invited to send representatives. The 90 participants examined issues and potential processes, and agreed on an achievable path forward. A summary of the conference was reported in CLN (5), in an EFCC newsletter (6) and a full conference report has been submitted to Clinical Chemistry.
The conference recommended to develop: an infrastructure to provide systematic identification and prioritization of analytes for harmonization, consensus procedures for how to achieve harmonization for analytes for which no reference measurement procedure is likely to be available; guidelines for surveillance of the success of, and to sustain, harmonization; and an oversight process to coordinate the activities. It is essential for success to have international input and cooperation from clinical practice and laboratory organizations, in-vitro diagnostics industry, journal editors, research organizations, and government or regulatory agencies.