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 HbA_1c.^9,10 Garry John, Chair of the IFCC Working Group (WG) on Standardization of HbA_1c, 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 HbA_1c measurement. Following a recent consensus statement in support of the IFCC reference system for HbA_1c 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 HbA_1c 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.

Abbreviations

BIPM

Bureau International des Poids et Mesures (International Bureau of Weights and Measures)

CCQM

Consultative Committee on the Quantity of Material

CIPM MRA

International Committee on Weights and Measures Mutual Recognition Arrangement

CLSI

Clinical and Laboratory Standards Institute (formerly NCCLS)

DGKL

German Society for Clinical Chemistry and Laboratory Medicine

EU

European Union

GUM

Guide to the Expression of Uncertainty in Measurement

IFCC

International Federation of Clinical Chemistry and Laboratory Medicine

ILAC

International Laboratory Accreditation Cooperation

IMEP

International Measurement Evaluation Program

IRMM

Institute of Reference Materials and Measurements of the European Union

ISO

International Organization for Standardization

IVDD

In Vitro Diagnostics Directive of the European Union

JCTLM

Joint Committee for Traceability in Laboratory Medicine

KCDB

Key Comparison Database

LMPG

Laboratory Medicine Practice Guidelines

NIST

National Institute of Standards and Technology

NMI

National Metrology Institute

PT/EQA

Proficiency Testing/External Quality Assessment

SRM

Standard Reference Material

VIM

Vocabulary in Metrology

WHO

World Health Organization

Glossary of terms

Accuracy of measurement

the result of the measurement agrees closely with the true value of the measurand. Accuracy is related to both trueness and precision of the measurement

Analyte

the chemical component or substance that is intended to be measured

Analytical specificity

the property of a method to measure only the analyte

Certified reference material (CRM)

a material that is used as a standard or reference and whose assigned value is traceable to a reference measurement system. An accompanying certificate states the analyte value and its measurement uncertainty

Commutability of a material

indicates the similarity between a patient sample and manufactured material, e.g. a quality control, in terms of analytical reactivity. Non-commutable materials that are used to calibrate or monitor the trueness of a method may lead to inaccurate values

Manufacturer’s product calibrator

calibration material provided to the customer

Manufacturer’s selected measurement procedure

highest level measurement procedure within the manufacturer’s operation unless the manufacturer maintains their own reference laboratory. Generally used to transfer a value to the “manufacturer’s working calibrator”. The calibration may make use of a primary calibrator or a secondary calibrator

Manufacturer’s standing measurement procedure

testing procedure used to assess the product calibrator, calibrated with a reference material or with the “manufacturer’s working calibrator”

Manufacturer’s working calibrator

material used to calibrate the “manufacturer’s standing measurement procedure”

Matrix

constitutes all other components of the analytical system, except for the analyte

Matrix effect

the effect of all other components of the analytical system, except for the analyte, on the value of the measurand

Measurand

the analyte that is measured with respect to a specified condition, e.g. creatinine in plasma

Metrological traceability

the property of a measurement tracing its value and measurement uncertainty to a manufacturer’s calibrator, which in turn may have traceability to a higher-order, metrologically-based reference measurement system

Primary calibrator/primary reference material

a reference material having the highest metrological qualities and whose value is determined by means of a primary reference measurement procedure directly to the SI or indirectly by determining the impurities of the material by appropriate analytical methods

Primary reference measurement procedure

a reference measurement procedure of the highest metrological level whose measurements in SI units are independent of a reference standard

Reference measurement laboratory

laboratory that performs a reference measurement procedure and provides results with stated uncertainties

Reference measurement procedure

measurement procedure that has been validated for its fitness of purpose and is used to assess lower-order methods for trueness, and to value-assign reference materials

Secondary calibrator

a reference material whose value is assigned using a reference (secondary or primary) procedure calibrated with a primary calibrator

Secondary reference measurement procedure

a procedure usually calibrated with a primary calibrator. Often these procedures are appropriate for a patient’s sample

Trueness

closeness of agreement between the average value obtained from a large series of results of measurements and the true value of the measurand. Bias is used to express numerically the degree of trueness

Uncertainty of measurement

parameter, associated with the result of a measurement, which characterises the dispersion of the values that could reasonably be attributed to the measurand. Inaccuracy is expressed by the uncertainty of measurement