Towards an SI-Traceable Reference Measurement System for Seven Serum Apolipoproteins Using Bottom-Up Quantitative Proteomics: Conceptual Approach Enabled by Cross-Disciplinary/Cross-Sector Collaboration

Current dyslipidemia management in patients with atherosclerotic cardiovascular disease (ASCVD) is based on traditional serum lipids. Yet, there is some indication from basic research that serum apolipoproteins A-I, (a), B, C-I, C-II, C-III, and E may give better pathophysiological insight into the root causes of dyslipidemia. To facilitate the future adoption of clinical serum apolipoprotein (apo) profiling for precision medicine, strategies for accurate testing should be developed in advance. Recent discoveries in basic science and translational medicine set the stage for the IFCC Working Group on Apolipoproteins by Mass Spectrometry. Main drivers were the convergence of unmet clinical needs in cardiovascular disease (CVD) patients with enabling technology and metrology. First, the residual cardiovascular risk after accounting for established risk factors demonstrates that the current lipid panel is too limited to capture the full complexity of lipid metabolism in patients. Second, there is a need for accurate test results in highly polymorphic and atherogenic apolipoproteins such as apo(a). Third, sufficient robustness of mass spectrometry technology allows reproducible protein quantification at the molecular level. Fourth, several calibration hierarchies in the revised ISO 17511:2020 guideline facilitate metrological traceability of test results, the highest achievable standard being traceability to SI. This article outlines the conceptual approach aimed at achieving a novel, multiplexed Reference Measurement System (RMS) for seven apolipoproteins based on isotope dilution mass spectrometry and peptide-based calibration. This RMS should enable standardization of existing and emerging apolipoprotein assays to SI, within allowable limits of measurement uncertainty, through a sustainable network of Reference Laboratories.

Lactate dehydrogenase: an old enzyme reborn as a COVID-19 marker (and not only)

BackgroundHistorically, the lactate dehydrogenase (LDH) measurement was introduced into Laboratory Medicine as component (together with creatine kinase (CK) and aspartate aminotransferase) of the classical enzyme triad employed for the diagnosis of myocardial infarction, which was subsequently replaced by CK-MB, and more recently by cardiac troponins. Afterwards, for many years, the clinical application of serum LDH measurement has been limited to the evaluation of anemias and to as a rough prognostic tool for certain tumors.ContentIn the last few years, significant changes have happened. First, the test has been confirmed as a robust predictor of poor outcomes in many neoplastic conditions. Furthermore, in the Revised International Staging System adopted in the 2015 by the International Myeloma Working Group, LDH acts as determinant of disease biology in differentiating myeloma stages. Finally, in the last few months, LDH is definitively reborn given its proven significant contribution in defining the COVID-19 severity.ConclusionsThis increased clinical role calls for an improvement of LDH assay standardization through the implementation of traceability of results of clinical samples to the available reference measurement system.

Implementation of metrological traceability in laboratory medicine: where we are and what is missing

BackgroundThe Joint Committee on Traceability in Laboratory Medicine (JCTLM) has recently created the Task Force on Reference Measurement System Implementation (TF-RMSI) for providing guidance on traceability implementation to in vitro diagnostics (IVD) manufacturers. Using serum creatinine (sCr) as an example, a preliminary exercise was carried out by checking what type of information is available in the JCTLM database and comparing this against derived analytical performance specifications (APS) for measurement uncertainty (MU) of sCr.ContentAPS for standard MU of sCr measurements were established as a fraction (≤0.75, minimum quality; ≤0.50, desirable quality; and ≤0.25, optimum quality) of the intra-individual biological variation of the measurand (4.4%). By allowing no more than one third of the total MU budget for patient samples to be derived from higher-order references, two out of the four JCTLM reference materials (RMs) at least allow minimum APS to be achieved for the MU of patient samples. Commutability was explicitly assessed for one of the JCTLM-listed matrixed RMs, which was produced in compliance with ISO 15194:2009 standard, whereas the remaining three RMs were assessed against the ISO 15194:2002 version of the standard, which only required the extent of commutability testing to be reported. Regarding the three listed reference methods, the MU associated with isotopic dilution-mass spectrometry coupled to gas chromatography (ID/GC/MS) and isotopic dilution-mass spectrometry coupled to liquid chromatography (ID/LC/MS) would allow APS to be fulfilled, while the isotope dilution surface-enhanced Raman scattering (ID/SERS) method displays higher MU.SummaryThe most recently listed RM for sCr in the JCTLM database meets the ISO 15194:2009 requirements with MU that would allow APS to be fulfilled and has had commutability demonstrated for use as a common calibrator in implementing traceability of sCr measurements. Splitting clinical samples with a laboratory performing ID/GC/MS or ID/LC/MS provides an alternative but would also require all components of uncertainty of these materials to be assessed.OutlookUsing appropriately derived APS to judge whether reference measurement system components are fit for purpose represents a novel approach. The TF-RMSI is planning to review a greater number of measurands to provide more robust information about the state of the art of available reference measurement systems and their impact on the ability of clinical measurements to meet APS.

Spatial Measurements for Artificial Turf Systems Using Hall Effect Sensors

The purpose of this study was to evaluate a bespoke spatial measurement methodology using Hall Effect Sensors (HES), i.e., utilizing inductance between a permanent magnet and sensor to indirectly measure the magnet position. The aim is to embed the magnet in a boot’s stud and use an array of sensors in the artificial turf. To evaluate the accuracy and applicability of a HES system in sports turf, two studies were carried out. To measure the spatial position vertically, a standard mechanical dynamic impact testing with the magnet embedded, and the sensors below the turf carpet, was compared to the gold standard optical reference measurement system (GOM UK Ltd.: Coventry, UK) . A second study evaluated the horizontal spatial accuracy for sensors in a variable array with a controlled incremental step movement of the magnet on a precise engineering workshop table.

Irregular analytical errors in diagnostic testing – a novel concept

Background:In laboratory medicine, routine periodic analyses for internal and external quality control measurements interpreted by statistical methods are mandatory for batch clearance. Data analysis of these process-oriented measurements allows for insight into random analytical variation and systematic calibration bias over time. However, in such a setting, any individual sample is not under individual quality control. The quality control measurements act only at the batch level. Quantitative or qualitative data derived for many effects and interferences associated with anindividualdiagnostic sample can compromise any analyte. It is obvious that a process for a quality-control-sample-based approach of quality assurance is not sensitive to such errors.Content:To address the potential causes and nature of such analytical interference in individual samples more systematically, we suggest the introduction of a new term called theirregular(individual)analytical error. Practically, this term can be applied in any analytical assay that is traceable to a reference measurement system. For an individual sample an irregular analytical error is defined as an inaccuracy (which is the deviation from a reference measurement procedure result) of a test result that is so high it cannot be explained by measurement uncertainty of the utilized routine assay operating within the accepted limitations of the associated process quality control measurements.Summary:The deviation can be defined as the linear combination of the process measurement uncertainty and the method bias for the reference measurement system. Such errors should be coinedirregular analytical errorsof the individual sample. The measurement result is compromised either by an irregular effect associated with the individual composition (matrix) of the sample or an individual single sample associated processing error in the analytical process.Outlook:Currently, the availability of reference measurement procedures is still highly limited, but LC-isotope-dilution mass spectrometry methods are increasingly used for pre-market validation of routine diagnostic assays (these tests also involve substantial sets of clinical validation samples). Based on this definition/terminology, we list recognized causes of irregular analytical error as arisk catalogfor clinical chemistry in this article. These issues include reproducible individual analytical errors (e.g. caused by anti-reagent antibodies) and non-reproducible, sporadic errors (e.g. errors due to incorrect pipetting volume due to air bubbles in a sample), which can both lead to inaccurate results and risks for patients.

Implementing a Reference Measurement System for C-Peptide: Successes and Lessons Learned

BACKGROUND Assessment of endogenous insulin secretion by measuring C-peptide concentrations is widely accepted. Recent studies have shown that preservation of even small amounts of endogenous C-peptide production in patients with type 1 diabetes reduces risks for diabetic complications. Harmonization of C-peptide results will facilitate comparison of data from different research studies and later among clinical laboratory results at different sites using different assay methods. CONTENT This review provides an overview of the general process of harmonization and standardization and the challenges encountered with implementing a reference measurement system for C-peptide. SUMMARY Efforts to harmonize C-peptide results are described, including those by the National Institute of Diabetes and Digestive and Kidney Diseases–led C-peptide Standardization Committee in the US, activities in Japan, efforts by the National Institute for Biological Standards and Control in the UK, as well as activities led by the Bureau International des Poids et Mesures and the National Metrology Institute in China. A traceability scheme is proposed along with the next steps for implementation. Suggestions are made for better collaboration to optimize the harmonization process for other measurands.

PENETAPAN SISTEM ACUAN DAYA AC UNTUK LABORATORIUM STANDAR NASIONAL BERDASARKAN STANDARD WATT CONVERTER

<p>Abstrak</p><p><br />Puslit KIM-LIPI telah mengembangkan suatu sistem pengukuran acuan daya AC untuk laboratorium standar nasional dengan ketelitian pengukuran yang lebih baik dari 75 ppm pada faktor cakupan 2 dan tingkat kepercayaan 95%. Sistem tersebut berbasis Standard Watt Converter (SWC), beban semu, dan digital DC voltmeter yang telah diketahui koreksinya melalui proses kalibrasi kepada standar yang dimiliki Lembaga Metrologi Nasional Australia (NMIA) dan Lembaga Metrologi Nasional Indonesia (Puslit KIM-LIPI). Metode perbandingan terhadap sistem acuan tersebut telah diterapkan pada suatu Unit Under Calibration (UUC) yang berupa power meter berketelitian tinggi. Hal ini dilakukan untuk menampilkan unjuk kerja sistem acuan daya AC dalam proses pengukuran koreksi pembacaan dari power meter. Hasil evaluasi pada titik-titik pengukuran 120 V, 5 A, dan 53 Hz menunjukkan bahwa koreksi pembacaan terbesar adalah 133 ppm. Nilai tersebut berkesesuian dengan kelas akurasi power meter ZERA RMM3001 yaitu 0,02% atau sebesar 200 ppm. Dari hasil unjuk kerja sistem pengukuran ini maka penetapan acuan daya AC untuk laboratorium standar nasional seperti Puslit KIM-LIPI mencukupi.<br />Kata kunci: sistem pengukuran acuan, daya AC, standard watt converter, koreksi pembacaan, power meter.</p><p><br />Abstract</p><p><br />Puslit KIM-LIPI has developed an AC power reference measurement system for a national standard laboratory with a measurement precision better than 75 ppm at coverage factor 2 and confidence level 95 %. The system was based on the instruments of a standard watt converter, a phantom load, and a standard digital voltmeter, which the corrections of those readings are known by calibration processes to both National Metrology Institute of Australia (NMIA) and Puslit KIM-LIPI. The comparison method of the AC power reference system has been applied to the high precision power meter as a unit under calibration (UUC). This was done to show the measurement performance of AC power reference system in the process to find the reading correction of the power meter under calibration. The measurement evaluation at 120 V, 5 A, and 53 Hz showed that the worst reading correction was 133 ppm. That value was on the agreement with the class accuracy of ZERA RMM3001 power meter which is 0,02 % or 200 ppm. The performance of the measurement system indicated that the establishment of the ac power reference for a national standard laboratory such as Puslit KIM-LIPI was adequate.<br />Keywords: reference measurement system, AC power, standard watt converter, reading correction, power meter.</p>