Standardisation--the theory and the practice.

It is thanks to Hans-Ulrich Bergmeyer, who in the late 1980s initiated a series of conferences known as the Bergmeyer Conferences, that there exists today a unified approach towards improved comparability of laboratory assay results in the life sciences. Dr Bergmeyer had the foresight to gather together clinical chemistry societies, such as the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), diagnostic industry, metrology institutes and other stakeholders to develop standardisation as a global science.1 The standardisation and traceability model described in the August issue of the Clinical Biochemist Reviews is the outcome of these collaborations so far.2 In this issue we learn about some further advances in standardisation and also some of the practical issues that are or need to be addressed. Key components of standardisation and establishment of metrological traceability are higher-order materials and measurement procedures. Results of routine measurements are standardised through calibration to a reference method and/or material or, when the reference system is lacking, only referred to a manufacturer’s selected procedure and corresponding calibrator. In his paper, David Bunk describes how standardisation can be implemented for well-defined analytes such as electrolytes, glucose, cholesterol and creatinine due to the availability of commutable reference materials (e.g. NIST SRM 967, creatinine in frozen human serum) and higher-order reference methods for value assignment (e.g. isotope dilution mass spectrometry (IDMS)). All manufacturers of creatinine assays, for example, should use SRM 967 to revalue assign their working calibrators, which should result in standardised serum creatinine measurements with closer agreement of creatinine results in clinical practice.3 In contrast, measurement of heterogeneous protein analytes, e.g. cardiac troponin I, natriuretic peptides and tumour markers, which frequently show inherent variability due to differences in antibody specificity and the antigenic epitope to be measured, are usually traceable only to a manufacturer’s selected measurement procedure and calibrators, reference material or reference method being not available.4 When reference materials for heterogeneous analytes become available, the evaluation of their commutability is important, as matrix effects with manufacturers’ assays are often observed for reference materials based on purified proteins that may impede their use for direct assay calibration.5 Hubert Vesper, Greg Miller and Gary Myers in their paper focus on this characteristic that describes “the ability of a reference or control material … to have interassay properties comparable to the properties demonstrated by authentic clinical samples when measured by more than one analytical method”. Assessment of commutability by statistical analysis is used to determine if a reference material is a member of a patient sample distribution when measured by two or more measurement procedures. A consensus guideline to enable consistent assessment of commutability of reference materials is being developed by the Clinical and Laboratory Standards Institute (CLSI). 6 Lothar Siekmann describes how reference laboratories play an integral role in the implementation of measurement traceability in Laboratory Medicine through the assignment of higher-order reference method values to reference materials, calibrators and external quality assessment (EQA) materials. Pre-requisites for the listing of reference (calibration) measurement services include the high metrological level of the principle of measurement, laboratory accreditation and participation in a specific external proficiency testing program. Under the auspices of the IFCC, ring trials are currently available for more than 30 different analytes measured by laboratories using reference methods listed in the website of the Joint Committee for Traceability in Laboratory Medicine (JCTLM). 7 In the fourth paper in this issue, Ilenia Infusino, Roberto Bonora and Mauro Panteghini describe the approach to achieving traceability in clinical enzymology. Reference materials and reference methods, described in detailed standard operating procedures, for the measurement of the most relevant clinical enzymes have been developed by the IFCC Committee for Reference Systems of Enzymes (C-RSE) and validated by a network of reference laboratories. The significant improvement in comparability of CK, ALT, AST and GGT results obtained in routine laboratories using commercial methods represents the main practical outcome of this standardisation activity.8 Another standardisation achievement has been the establishment of a reference system for HbA1c.9,10 Garry John, Chair of the IFCC Working Group (WG) on Standardization of HbA1c, together with some WG members (Andrea Mosca, Cas Weykamp, and Ian Goodall) describe the colourful history, the science and politics involved with the standardisation of HbA1c measurement. Following a recent consensus statement in support of the IFCC reference system for HbA1c made jointly by the IFCC and the clinical diabetes associations, including the American Diabetes Association, the European Association for the Study of Diabetes and the International Diabetes Federation, a homogeneous way of reporting HbA1c results is now recommended.11 A further outcome of standardisation and the ability to compare results that are method-independent and traceable to a reference measurement system is the possibility to obtain standardised reference intervals. Graham Jones and Tony Barker discuss the current situation in clinical laboratories, in which the variation between analyte reference intervals is greater than the variation between assay results for the same analyte. They outline the advantages of using “common” reference intervals and give a practical guide to the setting of standardised reference intervals in clinical practice. At the end of the traceability chain are the results provided by clinical laboratories on patient samples. Laboratories need to be confident that results reported to clinicians and patients are adequately accurate (true and precise) to allow for correct medical interpretation and comparability over time and space. EQA schemes are a vital tool allowing the laboratory to judge its performance against target values traceable to a reference measurement system. Renze Bais describes the major Australian EQA scheme, the RCPA Quality Assurance Programs Pty. Ltd., and how the development of such programs has made a significant contribution to the quality of laboratories in this region. Several papers published in the two Clinical Biochemist Reviews special issues (August and November 2007) show the success of global standardisation in Clinical Chemistry and Laboratory Medicine. It has been the unified, collaborative approach envisaged by Bergmeyer and other pioneers that has progressed standardisation as a global science, frequently resulting in an improvement of clinical interpretation of laboratory results to benefit patient care.