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World Metrology Day is celebrated annually on the 20th of May and this year’s focus on health provides an opportunity to emphasize the importance of comparable and reliable measurement results in laboratory medicine. Especially in the age of globalization, with increasing mobility of people and diseases, comparable clinical measurement results are the basis of common efforts to solve global health issues such as cancer or the spread of viruses.
Laboratory analyses to support physicians in their diagnosis have been performed for a long time. Even in medieval times physicians had a chart with the description of different textures and colors to compare a patient urine sample, the so-called uroscopy. Nowadays, it is recognized that clinical laboratory analysis can play a vital role in disease diagnosis and prognosis. However, the results of these analyses can vary greatly depending on the experience and skill of the laboratory technician or method used. Therefore, standards such as ISO 15189 (Medical laboratories – requirements for quality and competence) and external quality assurance (EQA) programs were developed to address these issues as described in more detail in [1]. In Germany, according to the Guidelines of the German Medical Association (RiliBÄK) [2], it is mandatory for clinical laboratories to participate regularly in proficiency testing (PT) schemes organized by a reference laboratory. In this context, proof of metrological traceability is an essential requirement in accordance with international standards. This article will explain what traceability means and how it is ensured for measurement results at an international, national and routine level.
Fig. 1 Traceability chain from the analyte in the patient’s sample to the SI ensured through calibrators, reference measurement procedures and interlaboratory comparisons organized at a national and in-ternational level
The best way to ensure comparability of results over time and space is to trace the results to a common reference system. With the International System of Units (SI), such a system is already available. Figure 1 illustrates how traceability to the SI can be achieved in laboratory medicine from a primary calibrator (pure substance of the analyte) down to the measurement results from patient samples.
The calibrators and methods required in the lower part of the pyramid, which concerns the routine laboratories, are often provided by the manufacturer of an in-vitro diagnostic device (IVD) for one or more analytes. The methods used are routine, such as immunoassays or rapid optical methods. For some of these devices Regulation (EU) 2017/746 of the European Parliament and of the Council (IVDR) requires explicitly: ”Where the performance of devices depends on the use of calibrators and/or control materials, the metrological traceability of values assigned to calibrators and/or control materials shall be assured through suitable reference measurement procedures and/or suitable reference materials of a higher metrological order”. The upper part of the pyramid is the responsibility of the national metrology institutes (NMIs) such as the Physikalisch-Technische Bundesanstalt (PTB) in Germany. Where possible they develop reference measurement procedures and certify reference materials to be used as a source of traceability to the SI.
But who assures the accuracy of the measurements at the top of this pyramid? In the case of chemical and biological measurements, this is the responsibility of the BIPM Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology (CCQM). In comparisons organized for certain analytes the participating laboratories must demonstrate that they can quantify the analyte accurately and with a realistic and reasonable measurement uncertainty. What is reasonable depends on the deviation permitted for a certain analyte in national regulations such as the RiliBÄK.
Fig. 2 Observed relative DoE (%) from reference measurement results provided by PTB in key compar-ison studies organized by CCQM for a selection of small molecule clinical measurands
For instance, if the routine laboratories have to measure an analyte to within ± 20 % of the reference value (RV), the reference laboratories must be able to measure it within 5 % and the laboratories at the top of the pyramid in Figure 1 within 2 %. Only if a NMI or DI has proven that it is capable to measure a certain analyte within these limits, can it claim the calibration and measurement capability (CMC) which is then listed in the key comparison database (KCDB) by the International Office of Weights and Measures (BIPM) together with the results of the studies (https://www.bipm.org/kcdb/). Figure 2 shows the performance of PTB in key comparisons organized by the organic analysis working group of CCQM for a set of priority clinical analytes represented by the degree of equivalence (DoE) obtained in each study. The DoE shows the relative distance in percent, of a measurement result from the RV so that it can be compared even if different scales are used for the various analytes.
Fig. 3 Performance of the NMIs and DIs from different countries operating at the highest metrological level for their respective countries. To evaluate the performance of each laboratory, the mean of the DoEs obtained in CCQM-K6, CCQM-K11 CCQM-K12, CQM-K63, CCQM-K109, CCQM-K132 and their sub-sequent key comparisons is calculated and plotted against the mean of the uncertainties of these DoEs. PTB is represented by the red circle on the graph.
To ensure an unbroken chain of traceability, it is important that the measurement procedures applied on all levels are described thoroughly and a complete uncertainty budget is provided. As the NMIs are to be used to disseminate traceability in their country, it is essential that they are capable of having both an uncertainty and %DoE that is fit for purpose. For most small molecules of clinical interest, the mean %DoE for the majority of NMIs is less than 2 % with an expanded relative uncertainty of less than 3 % (Fig. 3). Notably, almost all the participant’s mean %DoE (i.e. mean deviation from the RVs) are less than the mean estimated uncertainties (%UDoE), placing them above the diagonal line in Figure 3, suggesting agreement of the NMIs results with the reference values.
The NMIs and DIs in each country are often responsible for the dissemination of traceability in many different sectors. Therefore, the mechanisms by which this is achieved can vary greatly. In chemistry, the gravimetric preparation of primary calibrators, substances of known determined chemical purity, and the transfer of these gravimetric quantities to matrix materials is the preferred mode of dissemination. The reason for this is simply that for many chemical analyses the matrix/analyte combination provides the real measurement challenge. Therefore, in many areas of chemistry NMIs produce matrix certified reference materials (CRMs) or participate in interlaboratory comparisons where the NMI’s reported values can be used to assure the participants measurement results are fit for purpose. In these comparisons, the NMI will use the same measurement procedures as used in CCQM key comparisons for which the NMI has a peer reviewed CMC.
Fig. 4 Relative DoE of RELA ring trails of the two German reference laboratories compared to the val-ues obtained by PTB over 13 years for the analytes cholesterol, cortisol, creatinine, digoxin, digitoxin, urea and uric acid
One way of disseminating metrological traceability to the clinical reference laboratories is for NMIs/DIs together with the reference laboratories to participate in the RELA ring trials organized by the German society for clinical chemistry and laboratory medicine (DGKL) and the Joint Committee on Traceability in Laboratory Medicine (JCTLM) [4]. Such comparisons between NMIs and clinical reference laboratories are already an integral part of the quality assurance process in clinical chemistry. As the NMI calibration procedures are labor intensive, time consuming and costly, a small selection of priority measurands are used to assure the general “fit for purpose” nature of the German clinical reference laboratories. From time to time, when concerns are raised or issues arise, follow up bi/tri-lateral studies between the NMI and the reference laboratories are performed within Germany on a voluntary basis. This enables the continuous improvement of the performance of the measurement procedures and an increased awareness of incorporating all relevant parameters in the estimation of the measurement uncertainty. Figure 4 shows the relative DoE of the German reference labs compared to the value obtained by PTB in each study over 13 years for several measurands.
Under RiliBÄK rules, routine clinical testing laboratories must participate and record a satisfactory score in a PT scheme. For many priority measurands the RVs assigned to the materials used in the PT are provided by the reference measurement procedures of the reference laboratories. As the equivalence and traceability of the results produced by the reference laboratories are assured through regular intercomparisons with the NMI, the routine clinical laboratories can assure both the traceability and the fit-for-purpose nature of their results by successfully participating in such a PT scheme. Thus, they demonstrate that they are operating in accordance with international quality standards and the German national regulation.
It is often at the level of the routine clinical laboratories that larger trends between different methods, laboratories and/or IVD providers become visible. All these issues require all stakeholders to work together, for example within the framework of the European Metrology Network for Traceability in Laboratory Medicine (EMN-TLM) [5], to ensure that all results from patient samples can be confidently expressed in an SI traceable unit. Such approaches are essential in ensuring the long-term comparability of measurement results.
Traceability is an achievable concept that enables the long-term comparability of measurement results. A well-established and functioning system for assuring the traceability of clinical data for small molecules now exists.
As with all areas of chemistry, the correct determination of an amount of substance in a particular sample does not address the impact that subtle changes in the matrix have on the final determination via a routine method. These issues need to be addressed by the whole community if fully traceable patient measurement results are to be realized.
This project (JNP18NET02) has received funding from the EMPIR program co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme.
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Category: Metrology | Laboratory Medicine
Literature:
[1] E. Aman, q&more 2015, Quality assurance in medical laboratories – Paths to global competence standards, https://q-more.chemeurope.com/q-more-articles/204/quality-assurance-in-medical-laboratories.html (Ger.: Qualitätssicherung in medizinischen Laboratorien – Wege zu weltweiten Kompetenzstandards, https://q-more.chemie.de/q-more-artikel/204/qualitaetssicherung-in-medizinischen-laboratorien.html)
[2] Deutsches Ärzteblatt (2019), DOI: 10.3238/arztebl.2019.rili_baek_QS_Labor20192312
[3] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU
[4] https://www.bipm.org/jctlm/home.do
[5] www.euramet.org/laboratory-medicine
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