Search

Background Standardized results for laboratory tests are particularly important when their interpretation depends on fixed medical practice guidelines or common reference intervals. The medical laboratory community has developed a roadmap for an infrastructure to achieve standardized test results described in the International Organization for Standardization standard 17511:2020 In vitro diagnostic medical devices - Requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples. Among the challenges to implementing metrological traceability are the availability of fit-for-purpose matrix-based certified reference materials (CRMs) and requirements for regulatory review that differ among countries. A workshop in December 2021 focused on these two challenges and developed recommendations for improved practices. Discussion The participants agreed that prioritization of measurands for standardization should be based on their impact on medical decisions in a clinical pathway. Ensuring that matrix-based CRMs are globally available for more measurands will enable fit-for-purpose calibration hierarchies for more laboratory tests. Regulation of laboratory tests is important to ensure safety and effectiveness for the populations served. Because regulations are country or region specific, manufacturers must submit recalibration changes intended to standardize results for regulatory review to all areas in which a measuring system is marketed. Recommendations A standardization initiative requires collaboration and planning among all interested stakeholders. Global collaboration should be further developed for prioritization of measurands for standardization, and for coordinating the production and supply of CRMs worldwide. More uniform regulatory submission requirements are desirable when recalibration is implemented to achieve internationally standardized results.

Background: The STAtins Reduce Thrombophilia trial showed that, in patients with prior venous thrombosis, rosuvastatin decreased various coagulation factor levels. Objectives: Here, we investigated the hypothesis that statins decrease coagulation factor levels through shared mechanisms of synthesis or regulatory pathways with apolipoproteins. Methods: We measured the levels of apolipoprotein (Apo)A-I, A-II, A-IV, (a), B-100, B-total, C-I, C-II, C-III, and E in patients (n = 126) randomized to 28 days of rosuvastatin use. We assessed the association between apolipoproteins and coagulation factors at baseline using linear regression. The mean difference in apolipoprotein levels between baseline and after 28 days of rosuvastatin use was determined through linear regression, adjusting for age, sex, and body mass index. Coagulation factors were added to this model to determine if the lowering of apolipoproteins by rosuvastatin was linked with coagulation factor levels. Results: At baseline, levels of all apolipoproteins, except Apo(a), were positively associated with FVII, FIX, and FXI. Apolipoproteins levels, except for ApoA-I, A-IV, and Apo(a), were decreased after 28 days of rosuvastatin. ApoB-100 showed the largest mean decrease of -0.43 g/L (95% CI = −0.46 to −0.40). The decrease in ApoC-I and C-III levels was associated with a decrease in FVII, whereas the decrease in apoA-II, B-100, and B-total was associated with a decrease in FXI. The decrease in apolipoproteins was neither associated with FVIII or vWF decrease nor with endogenous thrombin potential changes. Conclusions: Rosuvastatin decreases the level of several apolipoproteins, but this decrease was associated only with a decrease in FVII and XI and not with FVIII/vWF.

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L00 79&qid=1628781352814) to IVDR 2017/746 https://eur-lex. europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infra structural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its droit d'exister.

With the implementation of Regulation (European Union [EU]) 2017/746 on in vitro diagnostic medical devices (IVDR), from May 26, 2022, onwards, the development and use of diagnostic tests will be governed by a vastly expanded and upgraded EU regulatory framework. We provide here an overview of the amended transition timelines, the role of notified bodies, EU reference laboratories, expert panels, and the Medical Device Coordination Group (MDCG). We also describe the implications of the IVDR for innovative laboratory medicine by explaining the exemption for in-house devices (IH-IVDs). Two key challenges faced by the academic diagnostic sector are: (1) the stipulation on equivalence of tests (article 5.5d), which poses a new condition for the use of IH-IVDs and (2) the gray area between CE marked in vitro diagnostics (CE-IVDs), modified CE-IVDs, Research Use Only (RUO) tests, and IH-IVDs. Furthermore, the results of a questionnaire on current diagnostic practice conducted by European medical societies collaborating in the BioMed Alliance indicate widespread use of IH-IVDs in diagnostic laboratories across Europe and emphasize the need for support and guidance to comply with the IVDR. Diagnostic equivalents of the European Reference Networks (ERNs) for rare diseases could help ensure affordable and equal access to specialized diagnostics across the EU. Concerted action by clinical and laboratory disciplines, regulators, industry, and patient organizations is needed to support the efficient and effective implementation of the IVDR in a way that preserves innovation and safeguards the quality, safety, and accessibility of innovative diagnostics.

Background: Mutations in genes encoding lipoprotein lipase (LPL) or its regulators can cause severe hypertriglyceridemia (HTG). Thus far, the effect of genetic HTG on the lipid profile has been mainly determined via conventional techniques. Objective: To show detailed differences in the (apo)lipoprotein profile of patients with genetic HTG by combining LC-MS and NMR techniques. Methods: Fasted serum from 7 patients with genetic HTG and 10 normolipidemic controls was used to measure the concentration of a spectrum of apolipoproteins by LC-MS, and to estimate the concentration and size of lipoprotein subclasses and class-specific lipid composition using NMR spectroscopy. Results: Patients with genetic HTG compared to normolipidemic controls had higher levels of apoB48 (fold change [FC] 11.3, P<0.001), apoC-I (FC 1.5, P<0.001), apoC-II (FC 4.3, P=0.007), apoC-III (FC 3.4, P<0.001), and apoE (FC 4.3, P<0.001), without altered apoB100. In addition, patients with genetic HTG had higher concentrations of TG-rich lipoproteins (i.e., chylomicrons and very low-density lipoproteins [VLDL]; FC 3.0, P<0.001), but lower LDL (FC 0.4, P=0.001), of which medium and small-sized LDL particles appeared even absent. While the correlation coefficient between NMR and enzymatic analysis in normolipidemic controls was high, it was considerably reduced in patients with genetic HTG. Conclusion: The lipoprotein profile of patients with genetic HTG is predominated with large lipoproteins (i.e., chylomicrons, VLDL), explaining high levels of apoC-I, apoC-II, apoC-III and apoE, whereas small atherogenic LDL particles are absent. The presence of chylomicrons in patients with HTG weakens the accuracy of the NMR-based model as it was designed for normolipidemic fasted individuals.

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.