Reference measurement procedure

If no measurement procedure has been devised with a completely describing measurement equation in terms of quantities using SI units, then empirical elements enter, and the unequivocal line from the defined SI unit is broken. The best substitute becomes an international conventional reference measurement procedure, which assigns a quantity value and measurement uncertainty to an international conventional calibrator. 

Any change in the international procedure or a shift to another measurement method means a new stated reference, usually giving new quantity values and measurement uncertainty as shown in the outcome of EQA. The international conventional reference measurement procedure is a part of the definition of the measurand. 

Lack of primary reference measurement procedure and international conventional calibrator... 

An international conventional reference measurement procedure may indicate a measuring system allowing the assignment of quantity value and measurement uncertainty directly to the manufacturer s working calibrator. This is the case for number concentration of erythrocytes in blood by the ICSH measurement procedure [10]. 

When a calibration hierarchy starts with the definition of an SI unit followed by a primary reference measurement procedure and descends through commutable calibrators and specific and selective measurement procedures full calibration hierarchy above the traceability to an SI unit is automatically ensured. The other four types of hierarchy do not preclude the use of a bona fide SI unit in the expression of a measurement result for a differential or rational quantity, but it is mandatory to specify the top measurement procedure and/or calibrator in the designation for the measurand. For example, amount-of-substance concentration of nitrogen(N) in human plasma by Kjeldahl procedure no. 3 (referring to the laboratory s list of procedures). The result in millimole per litre, however, is not unequivocally comparable with that of another Kjeldahl procedure, because the kinds-of-quanti-ty are differently specified, but the unit is unchanged. 

It is relevant to ask how often the routine measurement procedures currently used in laboratory medicine provide results that are traceable to high-level calibrators and reference measurement procedures (Lequin personal communication). It turns out that primary reference measurement procedures and primary calibrators are only available for about 30 types of quantity such as blood plasma concentration of bilirubins, cholesterols and sodium ion. International reference measurement procedures from the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and corresponding certified reference material from BCR are available for the catalytic activity concentration of a few enzymes such as alkaline phosphatase and creatine kinase in plasma. For another 25 types of quantity, such... 

Measurement of quantities in samples of biological origins Presentation of reference measurement procedures Description of reference materials... 

Dissemination of information on reference measurement procedures and certified reference materials... 

Keywords Traceability Clinical chemistry Reference measurement procedure Isotope dilution mass spectrometry (IDMS) External quality assessment... 

Traceability is not really a new fundamental concept in the field of laboratory medicine. Many years before the concept traceability had been mentioned in general chemical metrology, reference measurement procedures and reference materials had been established in clinical chemistry. Some basic experimental work for the development of reference measurement procedures and reference materials had already been undertaken in expert laboratories. 

In many instances a selected and agreed reference measurement procedure forms the basis of the definition of the quantity and thereby represents the top of the calibration hierarchy. This is particularly true for establishing reference systems for the catalytic concentrations of enzymes. In 1999 members of the IFCC working group and some enzyme reference laboratories decided to establish new 37 C measurement procedures as IFCC reference procedures on the basis of the existing 30 C IFCC procedures and to certify enzyme reference materials for AFT, AST, GGT, CK, FD and amylase in collaboration with the IRMM. The enzymes having IFCC reference measurement procedures have catalytic concentra-... 

In summary it can be stated that for SI- traceable me-asurands the concept of traceability and the use of reference measurement procedures has been successfully implemented at least in the German external quality control scheme since 1988 although the full implementation of the traceability concept on a global basis still requires considerable effort. 

For non-SI traceable quantities the predominant objective must be an agreement on the definition of these quantities on an international basis before reference measurement procedures can be developed and used for assigning target values in external quality assessment. 

Thus the responsibility of IRMM is illustrated it must disseminate independent Si-traceable reference values with certified combined/expanded uncertainties, carried by test samples of a similar nature as those being measured routinely in the field laboratory. The values must be obtained by reference measurement procedures so that they can serve as independent and objective references for the measurement and accreditation communities alike. The uncertainties of these values must be small enough for the intended use of the reference value. If not, better measurement procedures must be developed in order to arrive at a better reference value (i.e. with a smaller combined/expanded uncertainty). 

Abstract Manufacturers support the concept of traceability. However, only a small number of the medically relevant measurands can be traced to the highest metrological order. In many cases, the measured substances are heterogeneous mixtures where traceability can be established only to either an international conventional reference measurement procedure or to a manufacturer s own in-house reference system. The traceability concept needs to be seen in the context that the results of medical laboratories are not an aim per se, but are meant to provide useful medical information to clinicians, and that pre-... 

The In-Vitro-Diagnostic (IVD)-Directive [1] requires manufacturers to assure traceability of assigned values to calibrators and trueness control materials to reference measurement procedures and/or reference materials of a higher order, where available. This is a legal requirement for products marketed in Europe, and manufacturers are interested in applying the principle of traceability on a global scale, because it allows products to be marketed world-wide. The benefit to patients and users is perceived as the direct comparability of laboratory measurement results over regions and time. 

In cases where no suitable reference material or reference measurement procedure exists, the manufacturers need to establish their own reference system based on a suitable, reproducible and stable (manufacturer s) working calibrator. 

Nevertheless, manufacturers are interested in the further development of reference materials and reference measurement procedures suited for application in human serum for medical purposes. Therefore, industry appreciates the efforts started by the Joint Committee of Trace-ability and Laboratory Medicine (JCTLM), an initiative supported by the Bureau International des Poids et Mesures (BIPM) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) in order to develop suitable reference materials and measurement procedures, as well as to collect information on the activities of reference laboratories. In view of the limited resources and large efforts connected with these activities, clear priorities need to be set. Projects need to take into account the clinical importance of the analyte, consider the technical difficulties that must be overcome, and, most importantly, decide whether improvement of the metrological side is reflected in a gain of medically relevant information. 

Tai SS-C, Welch MJ (2005) Development and evaluation of a reference measurement procedure for the determination of estradiol-17b in human serum using ID-LC/MS/MS. Anal Chem 77 6359-6363... 

Definitive methods (i.e., ratio primary reference measurement procedures, RPRMPs) based on radiochemical NAA (RNAA) were elaborated for several elements [46-48]. As methods of the highest metrological quality, they served as a tool for independent verification of reliability of the certified values. In all cases where these methods could be used, there was very good agreement between the certified values established by the procedure described above and the results obtained by RPRMPs. Certified values are presented in the form ... 

Dyhczynski, R.S., Polkowska-Motrenko, H., Chajduk, E., Danko, B., Pyszynska, M. Recent advances in ratio primary reference measurement procedures (definitive methods) and their use in certification of reference materials and controlling assigned values in proficiency testing. J. Radioanal. Nucl. Chem. 302, 1295-1302 (2014). doi 10.1007/sl0967-014-3607-y... 

Figure 8-12 The proposed reference system for enzyme measurement showing the traceability of the laboratory result to the reference measurement procedure. (From Panteghini et al, Clin Chem Lab Med 2001 39 795-800. Reprinted with permission of Walter de Gruyter.)...

This relationship is established by measurement of samples with known amounts of analyte (calibrators). One may distinguish between solutions of pure chemical standards and samples with known amounts of analyte present in the typical matrix that is to be measured (e.g., human serum). The first situation applies typically to a reference measurement procedure, which is not influenced by matrix effects, and the second case corresponds typically to a field method that often is influenced by matrix components and so preferably is calibrated using the relevant matrix. Calibration functions may be linear or curved, and in the case of immunoassays often of a special form (e.g., modeled by the four-parameter logistic curve) This model (logistic in log x) has been used for both radioimmunoassay and enzyme immunoassay techniques and can be written in several forms as shown (Table 14-1). Nonlinear regression analysis is applied to estimate the relationship, or a logit transforma-... 

Community on In-Vitro Diagnostics) is a European legislative regulation directed at in vitro manufacturers. The directive demands that the manufacturer have a quality management system and that products are validated by competent laboratories. It is required that the traceability of values assigned to calibrators or control materials or both must be ensured through available reference measurement procedures and/or available materials of higher order. Explicit statement of the uncertainty of calibrator values is not required, but indirectly the manufacturers have to... 

Reference measurement procedure Thoroughly investigated measurement procedure shown to yield values having an uncertainty of measurement commensurate with its intended use, especially in assessing the trueness of other measurement procedures for the same quantity and in characterizing reference materials. 

Many organizations have been involved in developing a traceable accuracy base for analytes of clinical interest (see Chapter 14). A driver for current efforts to develop such a base is the European Directive 98/79/EC on in vitro diagnostic medical devices (www.ce-mark.com/ivd.pdf), which requires that The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order. ... 

In the IFCC reference measurement procedure for GGT, L-y-glutamyl-3-carboxy-4-nitroanilide serves as the substrate, with glycylglycine serving as an acceptor. Buffering is provided by glycylglycine itself. The temperature of reaction is 37 °C and the wavelength of measurement of the reaction product, 5-amino-2-nitrobenzoate, is 410 nm. ... 

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