Linda MR Thienpont
Ghent University
Long Abstract
Introduction: The fundament of mass spectrometry (MS) to serve as metrological anchor in laboratory medicine is the SI base unit “mole”. More in particular, MS is the measurement principle par excellence for quantitative determination of the amount of substance concentration of an analyte/component in a system, with traceability to the SI (results expressed in mol/L, preferably), of course within the constraints of measurement uncertainty. The latter should be adapted to the intended use of the measurements. Therefore, after development of any quantitative MS measurement procedure, validation against predefined performance specifications is a conditio sine qua non to give evidence that the achieved measurement uncertainty is commensurate with the intended use.
Methods: When I entered the field of quantitative MS as a young postdoc, most of the anchors needed to implement SI-traceability in laboratory medicine had already been realized. I refer to the “metrological” anchor of defining the measurand (quantity “intended” to be measured), which is particularly challenging for complex analytes present in the biological system as heterogeneous mixture (1-3), the “conceptual” anchor of a reference measurement system or calibration hierarchy (4,5), the “analytical” anchor of Isotope Dilution (ID)/MS for measurement of analytes in complex biological matrices (6), and the “pragmatic” anchor to overcome matrix effects in immunoassay calibration (7). My personal MS reference work started end of the eighties with the “certification of progesterone in two lyophilized serum materials CRM 347 and CRM 348” coordinated by the Community Bureau of Reference of the European Commission (8). It lasted until the end of the nineties before the regulatory surrounding to establishing SI-traceability in laboratory medicine was established, i.e., the European legislation (Directive 98/79/EC) for in vitro Diagnostic (IVD) Medical Devices (9). Then, the International Standard Organization (ISO) fully elaborated the so-called reference measurement systems (10), and later on, the traceability circle was closed by establishing the Joint Committee for Traceability in Laboratory Medicine (JCTLM) to do the overarching control of the ISO conformity of established reference measurement systems (see (http://www.bipm.org/en/committees/jc/jctlm/). Through the years metrology and academic institutes developed several ID-MS reference measurement procedures. In my young enthusiasm, I thought this was for me as clinical chemist a unique chance to give input to trueness in my discipline. In these years I also had in mind that my scientific life would be a fast-flowing river, easily overcoming obstacles, if any. However, getting older, I learned obstacles are always there and may be that resistant that they force a river to meander.
Results: “My river”, flowing in the IVD test environment, came across many obstacles. Indeed, when applying MS as metrological anchor in the clinical laboratory (“MSACL”), I had to cope, like my colleagues clinical chemists, with many challenging aspects. In my presentation, I will reflect on i) biological variation, ii) analytical performance goals, iii) commutability, and iv) putting MS in routine (focus: method validation/statistics). Facing these obstacles, I decided it was time to also engage conceptually and practically in most of these challenges. Nevertheless, I have the feeling “my river” continues to “meander” around. I know there is the vast ocean out there, but I don’t know when “my river” will reach it, if ever. Fortunately, even at a later age, “my river” still flows with sufficient inventiveness and endeavor to improve traceability and stability of laboratory testing to the benefit of public healthcare.
Conclusion: As an outlook, I will present some of my most recent work, namely, the “Empower” project (11). It centers around the use of native samples in external quality assessment (“Master Comparisons”) and patient data for continuous monitoring of analytical stability and comparability of tests across manufacturers and laboratories (“The Percentiler” and “The Flagger”). I close here with a quote from “American Dream” (Crosby, Stills, Nash & Young): “Don’t know when things went wrong, might have been when you were young and strong”.
References
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8. Thienpont L et al. Report EUR 12 282. Brussels, Belgium: Commission of the European Communities, Community Bureau of Reference, 1989.
9. Directive 98/79/EC of the European Parliaments and of the Council of 27 October 1998 on in vitro diagnostic medical devices. L331. Off J Eur Comm 1998;41:1–37.
10. International Organization for Standardization. In vitro diagnostic medical devices. Measurement of quantities in samples of biological origin—metrological traceability of values assigned to calibrators and control materials. EN/ISO 17511. Geneva: ISO; 2003.
11. De Grande LA et al. Clin Chem Lab Med 2015 Jan 15. pii: /j/cclm.ahead-of-print/cclm-2014-0959/cclm-2014-0959.xml. doi:10.1515/cclm-2014-0959. [Epub ahead of print].