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Objectives: As high-sensitivity cardiac troponin T (hs-cTnT) is making the transition from diagnostic to prognostic use, a long-term stability study of 5th generation hs-cTnT according to EFLM CRESS recommendations was set up for investigation of frozen clinical specimens (two matrices)., Methods: Study samples collected in serum tubes and lithium heparin tubes with gel from patients admitted for suspected minor myocardial damage were measured directly after completion of the study (0 years), and after 3-year and 6-year storage at -80 °C, and recovery of hs-cTnT concentrations after long-term storage (%hs-cTnT concentration compared to 0-year) was calculated. Hs-cTnT changes were also compared to decisive delta changes, such as the ones proposed in the ESC NSTEMI 0 h/1 h algorithm (<3 or >5 ng/L for ruling out and ruling in suspected NSTEMI patients)., Results: Eighty-six patients were included in the study, whereof 28 both lithium heparin plasma and serum samples were collected simultaneously, in others only serum (n=30) or plasma (n=28). Multiple aliquots per patient were made, so that 479 serum and 473 plasma samples were available for analysis. Across the overall hs-cTnT measuring range, median recovery after 6 years was 105.4 % and 106.2 % for serum and plasma, respectively. Based on these decisive delta changes, serum showed consistent results upon long term storage (max 0.8 % of samples above delta threshold of >5 ng/L) as compared to heparin plasma (up to 19.2 % of samples above threshold)., Conclusions: Over 6 years of storage at -80 °C, recovery of hs-cTnT in serum and heparin plasma was similar and within common lot-to-lot variation. Yet, when evaluating absolute delta increments around hs-cTnT clinical decision points, long-term stored sera displayed better clinical performance compared to heparin plasma samples., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Quantitative protein mass spectrometry (MS) is ideally suited for precision diagnostics and for reference standardization of protein analytes. At the Leiden Apolipoprotein Reference Laboratory we apply MS strategies to obtain detailed insight into the protein-to-peptide conversion in order to verify that quantifier peptides are not partly concealed in miscleaved protein backbone., Methods: Apolipoprotein(a) (apo(a)) was digested in a non-optimal manner to enhance the number of miscleaved peptides that were identified by high resolution liquid chromatography tandem-MS measurements. The protein-to-peptide conversion was carefully mapped with specific attention for miscleaved peptides that contain an apo(a) quantifier peptide. Four different isotopologues of each apo(a)-quantifier peptide were applied to evaluate linearity of internal peptide standards during measurement of specific real-life samples., Results: Two apo(a) quantifier peptides that were concealed in two different miscleaved peptides were included into a multiple reaction monitoring list in our targeted MS-based apo(a) quantifications to alert for potential protein digestion discrepancies. The presence of miscleaved peptides could be ruled out when applying our candidate reference measurement procedure (RMP) for apo(a) quantification., Conclusions: These data further corroborate the validity of our apo(a) candidate RMP as higher order method for certification of commercial Lp(a) tests that is endorsed by the International Federation of Clinical Chemistry and Laboratory Medicine. MS-based molecular detection and quantification of heterogeneous apo(a) proteoforms will allow manufacturers' transitioning from confounded lipoprotein(a) [Lp(a)] mass levels into accurate molar apo(a) levels., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

European Union (EU) regulations on in vitro diagnostics (IVD) and on serious cross-border threats to health provide for the establishment of European Reference Laboratories (EURLs) and their harmonization and cooperation with National Reference Laboratories (NRLs). While the EURLs under the IVD Regulation will be operational by 1 October 2024, the EURLs under the Regulation on serious cross-border threats to health will be operational by January 2025. Although NRLs may have been operating for a long time on the basis of national legislation, they should now cooperate with each other and with EURLs in a network of centers of excellence for the authorization and post-market surveillance of IVDs and for the epidemiological surveillance and control of communicable diseases. The term "reference laboratory" has long been used colloquially to refer to many kinds of laboratories, regardless of their tasks, competencies, responsibilities and designation. A literature search and analysis confirmed this by showing that a considerable proportion of scientific publications in 2024 use the term "reference laboratory" inappropriately. In order to clarify the roles and functioning of EURLs and NRLs, we have evaluated the relevant current EU provisions and compared the findings with those of reference laboratories designated by other organizations, calibration (reference) laboratories and referral laboratories, which are simply referred to as "reference laboratories". With the forthcoming implementation of the EU regulations, at least the goals of providing safe and high-quality IVDs and adequate public health surveillance for communicable diseases appear to be achievable., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The ultimate goal of value-based laboratory medicine is maximizing the effectiveness of laboratory tests in improving patient outcomes, optimizing resources and minimizing unnecessary costs. This approach abandons the oversimplified notion of test volume and cost, in favor of emphasizing the clinical utility and quality of diagnostic tests in the clinical decision-making. Several key elements characterize value-based laboratory medicine, which can be summarized in some basic concepts, such as organization of in vitro diagnostics (including appropriateness, integrated diagnostics, networking, remote patient monitoring, disruptive innovations), translation of laboratory data into clinical information and measurable outcomes, sustainability, reimbursement, ethics (e.g., patient empowerment and safety, data protection, analysis of big data, scientific publishing). Education and training are also crucial, along with considerations for the future of the profession, which will be largely influenced by advances in automation, information technology, artificial intelligence, and regulations concerning in vitro diagnostics. This collective opinion paper, composed of summaries from presentations given at the two-day European Federation of Laboratory Medicine (EFLM) Strategic Conference "A vision to the future: value-based laboratory medicine" (Padova, Italy; September 23-24, 2024), aims to provide a comprehensive overview of value-based laboratory medicine, projecting the profession into a more clinically effective and sustainable future., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The introduction of the vacuum tube in 1949 revolutionized blood collection, significantly improving sample quality and patient comfort. Over the past 75 years, laboratory diagnostics have evolved drastically, from manual to automated processes, reducing required test volumes by over 1,000 times. Despite these advancements, venous blood collection presents logistical challenges, including centralized scheduling and a large volume of biological waste due to the imbalance between the needed blood volume (often very little) and the collected volume (often in excess). The COVID-19 pandemic further emphasized the need for decentralized healthcare solutions and patient empowerment. Capillary blood collection, widely used in point-of-care testing, offers a promising alternative, particularly for patients facing frequently, or difficulties with, venous sampling. The Leiden University Medical Center in the Netherlands experienced a 15 % reduction in volume of laboratory tests during and after the pandemic, attributed to patient preference for local blood collection and testing. To address these challenges, self-sampling devices are emerging, empowering patients and streamlining sample logistics. However, challenges such as cost, transportation regulations, and sample volume adequacy persists. Robust devices tailored for total lab automation and sustainable practices are crucial for widespread adoption. Despite hurdles, the integration of self-sampling into diagnostic processes is inevitable, heralding a shift towards patient-centered, proactive healthcare. Practical recommendations include robust device design, ease of use, affordability, sustainability, sufficient quality and acceptability by seamless integration into laboratory workflows. Although obstacles remain, self-sampling represents the future of laboratory diagnostics, offering convenience, cost-effectiveness, interoperability and patient empowerment., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Advances in technology have transformed healthcare and laboratory medicine. Biosensors have emerged as a promising technology in healthcare, providing a way to monitor human physiological parameters in a continuous, real-time, and non-intrusive manner and offering value and benefits in a wide range of applications. This position statement aims to present the current situation around biosensors, their perspectives and importantly the need to set the framework for their validation and safe use. The development of a qualification framework for biosensors should be conceptually adopted and extended to cover digitally measured biomarkers from biosensors for advancing healthcare and achieving more individualized patient management and better patient outcome., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: The aim of this study was to harmonize the criteria for the Bhattacharya indirect method Microsoft Excel Spreadsheet for reference intervals calculation to reduce between-user variability and use these criteria to calculate and evaluate reference intervals for eight analytes in two different years., Methods: Anonymized laboratory test results from outpatients were extracted from January 1st 2018 to December 31st 2019. To assure data quality, we examined the monthly results from an external quality control program. Reference intervals were determined by the Bhattacharya method with the St Vincent's hospital Spreadsheet firstly using original criteria and then using additional harmonized criteria defined in this study. Consensus reference intervals using the additional harmonized criteria were calculated as the mean of four users' lower and upper reference interval results. To further test the operation criteria and robustness of the obtained reference intervals, an external user validated the Spreadsheet procedure., Results: The extracted test results for all selected laboratory tests fulfilled the quality criteria and were included in the present study. Differences between users in calculated reference intervals were frequent when using the Spreadsheet. Therefore, additional criteria for the Spreadsheet were proposed and applied by independent users, such as: to set central bin as the mean of all the data, bin size as small as possible, at least three consecutive bins and a high proportion of bins within the curve., Conclusions: The proposed criteria contributed to the harmonization of reference interval calculation between users of the Bhattacharya indirect method Spreadsheet., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

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., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Quantitative protein mass-spectrometry (QPMS) in blood depends on tryptic digestion of proteins and subsequent measurement of representing peptides. Whether serum and plasma can be used interchangeably and whether in-vitro anticoagulants affect the recovery is unknown. In our laboratory serum samples are the preferred matrix for QPMS measurement of multiple apolipoproteins. In this study, we investigated the effect of different matrices on apolipoprotein quantification by mass spectrometry., Methods: Blood samples were collected from 44 healthy donors in Beckton Dickinson blood tubes simultaneously for serum (with/without gel) and plasma (heparin, citrate or EDTA). Nine apolipoproteins were quantified according to standard operating procedure using value-assigned native serum calibrators for quantitation. Tryptic digestion kinetics were investigated in the different matrices by following formation of peptides for each apolipoprotein in time, up to 22 h., Results: In citrate plasma recovery of apolipoproteins showed an overall reduction with a bias of -14.6%. For heparin plasma only -0.3% bias was found compared to serum, whereas for EDTA-plasma reduction was more pronounced (-5.3% bias) and variable with >14% reduction for peptides of apoA-I, A-II and C-III. Digestion kinetics revealed that especially slow forming peptides showed reduced formation in EDTA-plasma., Conclusions: Plasma anticoagulants affect QPMS test results. Heparin plasma showed comparable results to serum. Reduced concentrations in citrate plasma can be explained by dilution, whereas reduced recovery in EDTA-plasma is dependent on altered proteolytic digestion efficiency. The results highlight the importance of a standardized pre-analytical phase for accurate QPMS applications in clinical chemistry., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Moving average quality control (MA QC) is a patient-based real-time quality control system. Advantages compared to conventional periodic internal quality control (IQC) include absence of commutability problems and continuous monitoring of performance. We implemented MA QC for multiple routine hematology and chemistry parameters. We describe the evaluation process and provide practical tools to aid MA QC implementation., Methods: Nine parameters (serum sodium, calcium, bicarbonate and free thyroxine, hemoglobin [Hb], mean corpuscular volume, mean corpuscular hemoglobin concentration [MCHC], reticulocyte count and erythrocyte sedimentation rate [ESR]) were chosen for initial consideration. Using data extractions from the laboratory information system (LIS; General Laboratory Information Management System), evaluation of usefulness and optimization of MA QC settings was performed using bias detection curves. After this, MA QC settings were incorporated in our LIS for further evaluation and implementation in routine care., Results: Three out of nine parameters (Hb, ESR, and sodium) were excluded from MA QC implementation due to high variation and technical issues in the LIS. For the six remaining parameters, MA QC showed added value to IQC and was therefore implemented in the LIS. For three parameters a direct MA alarm work-up method was set up, including newly developed built-in features in the LIS. For the other parameters, we identified MA utilization beyond real-time monitoring., Conclusions: Implementation of MA QC has added value for our laboratory setting. Additional utilization beyond real-time QC monitoring was identified. We find MA QC especially useful for trend monitoring, detection of small shifts after maintenance and inter-analyzer comparisons., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Cross reactivity with high molecular weight complexes of prolactin known as macroprolactin is a common cause of positive interference in assays for serum prolactin. All prolactin assays currently available are affected with 5-25% of results indicating hyperprolactinaemia falsely elevated due to macroprolactinaemia - hyperprolactinaemia due to macroprolactin with normal concentrations of bioactive monomeric prolactin. Macroprolactinaemia has no pathological significance but, if it is not recognised as the cause, the apparent hyperprolactinaemia can lead to clinical confusion, unnecessary further investigations, inappropriate treatment and waste of healthcare resources. Macroprolactinaemia cannot be distinguished from true hyperprolactinaemia on clinical grounds alone but can be detected by a simple laboratory test based on the precipitation of macroprolactin with polyethylene glycol. Laboratory screening of all cases of hyperprolactinaemia to exclude macroprolactinaemia has been advised as best practice but has not been implemented universally and reports of clinical confusion caused by macroprolactinaemia continue to appear in the literature. Information provided by manufacturers to users of assays for prolactin regarding interference by macroprolactin is absent or inadequate and does not comply with the European Union Regulation covering in vitro diagnostic medical devices (IVDR). As the IVDR is implemented notified bodies should insist that manufacturers of assays for serum prolactin comply with the regulations by informing users that macroprolactin is a source of interference which may have untoward clinical consequences and by providing an estimate of the magnitude of the interference and a means of detecting macroprolactinaemia. Laboratories should institute a policy for excluding macroprolactinaemia in all cases of hyperprolactinaemia., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

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.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&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 infrastructural 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 "., (© 2021 Christa Cobbaert et al., published by De Gruyter, Berlin/Boston.)

To more comprehensively support clinical management of patients in our hospital, we redesigned the diagnostic Total Testing Process (TTP) from request to report. To that end, clinical needs were identified and a vision on Total Laboratory Automation (TLA) of the TTP was developed. The Delft Systems Engineering Approach was used for mapping a desirable laboratory testing process. The desirable "To Be" diagnostic process was tendered and the translation of a functional design into a specific TLA-configuration - compliant with the vision and the predefined functional design - was accomplished using a competitive dialogue tender variant (based on art. 29 of the EU guideline 2014/24). Realization of this high-end TLA-solution enabled a high-quality testing process with numerous improvements such as clear and supportive digital request forms, specimen consolidation, track and trace and non-conformity registration at the specimen level, better blood management (∼40% less blood sampled), lean and in line processing with increased productivity (42% rise in test productivity per capita), and guaranteed total turn-around-times of medical tests (95% of TLA-rooted in line tests are reported <120 min). The approach taken for improving the brain-to-brain loop of medical testing, as fundament for better diagnostic stewardship, is explained.

Objectives Frozen and freeze-dried plasmas may be used for local prothrombin time system calibration, for direct international normalized ratio (INR) determination, and for quality assessment. The purpose of the present study was to evaluate the usefulness of INRs assigned with various types of thromboplastins to frozen and freeze-dried pooled plasmas obtained from patients treated with vitamin K antagonists. Methods INRs were calculated according to the international sensitivity index (ISI) model using various thromboplastins and instruments, i.e. International Standards for thromboplastin as well as six commercial reagents prepared from rabbit and bovine brain, and recombinant human tissue factor. The uncertainty of the INRs was assessed using the standard deviations of clotting times and ISI values. Commutability of the plasmas was assessed according to the approved Clinical and Laboratory Standards Institute (CLSI) Guideline EP30-A. Validation of a set of six frozen plasma pools for direct INR determination was performed according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC/ISTH) guidelines. Results For all frozen and freeze-dried plasmas, the INRs calculated with bovine thromboplastin Thrombotest were lower than the INRs assigned with other thromboplastins. With a few exceptions, the frozen and freeze-dried pooled plasmas were commutable. When the set of six frozen plasma pools was used for local calibration, the analytical bias of the INR was less than ±10% for all commercial reagents except Thrombotest. Conclusions Processing of fresh plasmas to prepare pooled frozen plasmas and freeze-dried plasmas may lead to different INR assignments depending on the thromboplastin used. Despite minor INR differences, a set of six frozen plasma pools could be used for local calibration by direct INR determination.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.

Background High-sensitivity cardiac troponin T/I (hs-cTnT/I) assays have improved analytical sensitivity for the detection of myocardial infarction (MI). To gain clinical specificity and sensitivity, interpretation of changes in cTn concentrations over time is crucial. The 2015 ESC NSTEMI guideline defines absolute delta values as additional rule-in and rule-out criteria for MI. A critical assumption for application of this rule is that total analytical imprecision within the delta period, including inter-instrument bias, is comparable to analytical imprecision in the validation studies. Methods Data from the Dutch External Quality Assessment Scheme (EQAS) were used to calculate inter-instrument bias and estimate imprecision for the measuring range where the proposed delta values are relevant: for Roche Elecsys hs-cTnT, 5-52 and 5-12 ng/L; for Abbott Architect hs-cTnI, 2-52 and 2-5 ng/L for rule-in and rule-out, respectively. Results For Elecsys, the median inter-instrument bias is 0.3 ng/L (n = 33 laboratories), resulting in reference change values (RCVs) of 3.0 and 1.7 ng/L, respectively, for rule-in and rule-out with imprecision as claimed by the manufacturer. With RCVs smaller than the guideline's delta thresholds, 100% of the laboratories have adequate specifications. RCVs for rule-in/rule-out increased to 4.6 ng/L/2.5 ng/L, respectively, with individual imprecisions as estimated from EQA data, resulting in 64% and 82% of laboratories with adequate specifications. For Architect, 40% of instruments (n = 10) might falsely qualify the result as clinically relevant; hence, inter-instrument bias could not be determined. Conclusions We advise laboratories that use the fast 0/1-h algorithm to introduce stringent internal quality procedures at the relevant/low concentration level, especially when multiple analyzers are randomly used.

Background In the Netherlands, each new lot of test strips for the CoaguChek XS is validated by a group of collaborating centers. The purpose of this study was to assess the accuracy of the international normalized ratio (INR) measured with consecutive test strip lots and the suitability of frozen plasma pools for accuracy evaluation. Methods Each year, a particular lot of CoaguChek XS test strips is used as reference lot. The reference lots have been validated with the International Standard for thromboplastin rTF/09, yielding a mathematical relationship (R1) between reference lot INR and International Standard INR. New lots are compared to the reference lot using patients' capillary blood samples, yielding a relationship (R2) between the new lot INR and the reference lot INR. INRs of the blood samples were within the 1.5-4.5 interval. In parallel, three frozen plasmas pools are analyzed with the test strips. The distance of each plasma point to the line of relationship R2 was assessed. Results Fifty-four test strip lots have been evaluated during 3 years (2014-2016). Mean INR differences between test strip lot and International Standard rTF/09 varied between -0.14 and +0.20 (-4% and +8%, respectively). A positive trend with strip lot sequence number was observed (p<0.001). In several cases, the distance of the frozen plasmas to the whole blood relationship (R2) was greater than the critical value for commutability. Conclusions Using whole blood, all evaluated test strip lots met the analytical bias criterion of ±10%. Frozen plasma pools behave differently compared to whole blood and are not suitable for assessing absolute accuracy of new CoaguChek XS test strips.

Background External quality assessment (EQA) programs for general chemistry tests have evolved from between laboratory comparison programs to trueness verification surveys. In the Netherlands, the implementation of such programs has reduced inter-laboratory variation for electrolytes, substrates and enzymes. This allows for national and metrological traceable reference intervals, but these are still lacking. We have initiated a national endeavor named NUMBER (Nederlandse UniforMe Beslisgrenzen En Referentie-intervallen) to set up a sustainable system for the determination of standardized reference intervals in the Netherlands. Methods We used an evidence-based 'big-data' approach to deduce reference intervals using millions of test results from patients visiting general practitioners from clinical laboratory databases. We selected 21 medical tests which are either traceable to SI or have Joint Committee for Traceability in Laboratory Medicine (JCTLM)-listed reference materials and/or reference methods. Per laboratory, per test, outliers were excluded, data were transformed to a normal distribution (if necessary), and means and standard deviations (SDs) were calculated. Then, average means and SDs per test were calculated to generate pooled (mean±2 SD) reference intervals. Results were discussed in expert meetings. Results Sixteen carefully selected clinical laboratories across the country provided anonymous test results (n=7,574,327). During three expert meetings, participants found consensus about calculated reference intervals for 18 tests and necessary partitioning in subcategories, based on sex, age, matrix and/or method. For two tests further evaluation of the reference interval and the study population were considered necessary. For glucose, the working group advised to adopt the clinical decision limit. Conclusions Using a 'big-data' approach we were able to determine traceable reference intervals for 18 general chemistry tests. Nationwide implementation of these established reference intervals has the potential to improve unequivocal interpretation of test results, thereby reducing patient harm.