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In addition to the correct implementation of calibration traceability, the definition and fulfillment of maximum allowable measurement uncertainty (MAU) are essential in assuring that laboratory measurements are clinically usable. Across the entire calibration hierarchy, three major contributors to the measurement uncertainty (MU) budget are identified, starting with the higher-order reference providers, extending through the in vitro diagnostic (IVD) manufacturers and their processes for assigning calibrator values, and ending with medical laboratories generating the random variability of results reported to clinicians. To understand if it is possible to achieve MAU and, consequently, to fix the possible drawbacks, the definition of combined MU budget limits across the entire calibration hierarchy has a central role. In particular, quality specifications for MU of reference and commercial calibrator materials should be defined according to the MAU on clinical samples. All involved stakeholders (i.e., higher-order reference providers, IVD manufacturers, medical laboratories) should be prepared to improve their performance whenever the clinical application of the test is made questionable by the failure to achieve MAU. [ABSTRACT FROM AUTHOR]

To be accurate and equivalent among assays, laboratory results should be traceable to higher-order references and their quality should fulfill maximum allowable measurement uncertainty (MU) as defined to fit the intended clinical use. Accordingly, laboratory professionals should estimate and validate MU of performed tests using appropriate analytical performance specifications (APS). Current consensus supports the derivation of APS by using one of the three models established by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Strategic Conference held in Milan in 2014. It is recognized that some models are better suited for certain measurands than for others and the attention should be primarily directed towards their biological and clinical characteristics. Among others, model 3 should reflect the state of the art of the measurements that can be defined as the best analytical performance that is technically achievable. Taking serum C-reactive protein and ferritin as examples, here we describe the theoretical premises and the experimental protocol to be used to derive APS for MU when a measurand is allocated to this model. Although the model lacks a direct relationship with clinical outcomes, useful information about the in vitro diagnostic medical device performance and the average quality of provided results may be obtained. [ABSTRACT FROM AUTHOR]

Analytical performance specifications (APS) represent the criteria that specify the quality required for laboratory test information to satisfy clinical needs. In 2014 the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) considered timely to update the topic of APS by organizing a conference in Milan in which some strategic concepts were proposed. Here I summarize the essential points representing the EFLM Strategic Conference heritage and discuss the approaches that will permit us to become more concrete, including roles and main actions expected from each of involved stakeholders for contributing a quantum leap forward in the way of practicality of Milan consensus about APS. [ABSTRACT FROM AUTHOR]

Non-harmonization of laboratory results represents a concrete risk for patient safety. To avoid harms, it is agreed that measurements by in vitro diagnostic medical devices (IVD-MD) on clinical samples should be traceable to higher-order references and adjusted to give the same result. However, metrological traceability is not a formal claim and has to be correctly implemented, which in practice does not happen for a non-negligible number of measurands. Stakeholders, such as higher-order reference providers, IVD manufacturers, and External Quality Assessment organizers, have major responsibilities and should improve their contribution by unambiguously and rigorously applying what is described in the International Organization for Standardization 17511:2020 standard and other documents provided by the international scientific bodies, such as Joint Committee on Traceability in Laboratory Medicine and IFCC. For their part, laboratory professionals should take responsibility to abandon non-selective methods and move to IVD-MDs displaying proper selectivity, which is one of the indispensable prerequisites for the correct implementation of metrological traceability. The practicality of metrological traceability concepts is not impossible but relevant education and appropriate training of all involved stakeholders are essential to obtain the expected benefits in terms of standardization. [ABSTRACT FROM AUTHOR]

* Context.--A relevant portion of coronavirus disease 2019 (COVID-19) patients develop severe disease with negative outcomes. Several biomarkers have been proposed to predict COVID-19 severity, but no definite interpretative criteria have been established to date for stratifying risk. Objective.--To evaluate 6 serum biomarkers (C-reactive protein, lactate dehydrogenase, D-dimer, albumin, ferritin, and cardiac troponin T) for predicting COVID-19 severity and to define related cutoffs able to aid clinicians in risk stratification of hospitalized patients. Design.--A retrospective study of 427 COVID-19 patients was performed. Patients were divided into groups based on their clinical outcome: nonsurvivors versus survivors and patients admitted to an intensive care unit versus others. Receiver operating characteristic curves and likelihood ratios were employed to define predictive cutoffs for evaluated markers. Results.--Marker concentrations at peak were significantly different between groups for both selected outcomes. At univariate logistic regression analysis, all parameters were significantly associated with higher odds of death and intensive care. At the multivariate analysis, high concentrations of lactate dehydrogenase and low concentrations of albumin in serum remained significantly associated with higher odds of death, whereas only low lactate dehydrogenase activities remained associated with lower odds of intensive care admission. The best cutoffs for death prediction were greater than 731 U/L for lactate dehydrogenase and 18 g/L or lower for albumin, whereas a lactate dehydrogenase activity lower than 425 U/L was associated with a negative likelihood ratio of 0.10 for intensive treatment. Conclusions.--Our study identifies which biochemistry tests represent major predictors of COVID-19 severity and defines the best cutoffs for their use. doi: 10.5858/arpa.2020-0389-SA, At the end of 2019, an outbreak of atypical pneumonia of unknown cause was detected in Wuhan, the capital of the province of Hubei, China. (1) The etiologic agent of [...]

According to ISO 15189:2022, analytical performance specifications (APS) should relate to intended clinical use and impact on patient care. Therefore, we aimed to develop a web application for laboratory professionals to calculate APS based on a simulation of the impact of measurement uncertainty (MU) on the outcome using the chosen decision limits, agreement thresholds, and data of the population of interest. We developed the "APS Calculator" allowing users to upload and select data of concern, specify decision limits and agreement thresholds, and conduct simulations to determine APS for MU. The simulation involved categorizing original measurand concentrations, generating measured (simulated) results by introducing different degrees of MU, and recategorizing measured concentrations based on clinical decision limits and acceptable clinical misclassification rates. The agreements between original and simulated result categories were assessed, and values that met or exceeded user-specified agreement thresholds that set goals for the between-category agreement were considered acceptable. The application generates contour plots of agreement rates and corresponding MU values. We tested the application using National Health and Nutrition Examination Survey data, with decision limits from relevant guidelines. We determined APS for MU of six measurands (blood total hemoglobin, plasma fasting glucose, serum total and high-density lipoprotein cholesterol, triglycerides, and total folate) to demonstrate the potential of the application to generate APS. The developed data-driven web application offers a flexible tool for laboratory professionals to calculate APS for MU using their chosen decision limits and agreement thresholds, and the data of the population of interest. [ABSTRACT FROM AUTHOR]

Alanine aminotransferase (ALT) represents the first-level test to detect individuals with hepatocellular damage of any etiology. However, it has been highlighted that the lack of assay harmonization may lead to overdiagnosis and unnecessary further testing if guideline-recommended fixed cut-offs are uncritically employed. To solve the issue of ALT (dis)harmonization and improve the interpretation of its values, a series of urgent actions for documenting and validating metrological traceability of serum ALT measurements, as described in this paper, are no longer postponeable. It is time that all medical laboratory stakeholders (in vitro diagnostic manufacturers, laboratorians, external quality assessment scheme organizers) actively co-operate to implement the ALT standardization in a concerted action following well-established theoretical assumptions and applying experimental approaches described in literature. [ABSTRACT FROM AUTHOR]

Recently, Abbott Diagnostics marketed a new generation of Alinity enzyme assays, introducing a multiparametric calibrator [Consolidated Chemistry Calibrator (ConCC)] in place of or in addition to factor-based calibrations. For alkaline phosphatase (ALP), both calibration options are offered, i.e., with ConCC (ALP2) and with an experimental calibration factor (ALP2F). Both options are declared traceable to the 2011 IFCC reference measurement procedure (RMP). Before to replace the old generation (ALP1) with the new one, we decided to validate the trueness of ALP2/ALP2F. Three approaches were employed: (a) preliminary comparison on 48 native frozen serum samples with ALP1, of which traceability to RMP was previously successfully verified; (b) examination of three banked serum pools (BSP) with values assigned by RMP; (c) direct comparison with RMP on a set of 24 fresh serum samples. Bias estimation and regression studies were performed, and the standard measurement uncertainty associated with ALP measurements on clinical samples (uresult) was estimated and compared with established analytical performance specifications (APS). ConCC commutability was also assessed. A positive proportional bias was found with both ALP2 and ALP2F when compared to ALP1 and RMP. This positive bias was confirmed on BSP: in average, +13.1 % for ALP2 and +10.0 % for ALP2F, respectively. uresult were 13.28 % for ALP2 and 10.04 % for ALP2F, both not fulfilling the minimum APS of 4.0 %. Furthermore, ConCC was not commutable with clinical samples. Our results unearth problems in the correct implementation of traceability of Alinity ALP2/ALP2F, with the risk for the new assay to be unfit for clinical purposes. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) may progress to advanced liver fibrosis (ALF). We evaluated the diagnostic accuracy of a novel Liver Fibrosis Risk Index (LFRI) in MAFLD subjects using transient elastography (TE) as the reference method for liver fibrosis measurement and then the diagnostic performance of a new two-step non-invasive algorithm for the detection of ALF risk in MAFLD, using Fibrosis-4 (FIB-4) followed by LFRI and comparing it to the reference algorithm based on FIB-4 and TE. We conducted a prospective study on 104 MAFLD European adult subjects. All consenting subjects underwent TE and measurements of FIB-4 and LFRI. For FIB-4 and TE, validated cut-offs were used. An ROC analysis showed that LFRI diagnosed severe fibrosis with moderate accuracy in MAFLD subjects with a negative predictive value above 90%. Using the new algorithm with LFRI thresholds recommended by the manufacturer, the number of subjects classified into ALF risk groups (low, intermediate, or high) differed significantly when compared with the reference algorithm (p = 0.001), with moderate agreement between them (weighted kappa (95% CI) = 0.59 (0.41–0.77)). To improve the performance of the LFRI-based algorithm, we modified cut-off points based on ROC curves obtained by dividing the study population according to the reference algorithm and observed no difference between algorithms (p = 0.054) in categorizing ALF risk, with a slight increase in the total agreement (weighted kappa (95% CI) = 0.63 (0.44–0.82)). Our findings suggest that using the novel LFRI as a second-line test may represent a potential alternative for liver fibrosis risk stratification in MAFLD patients; however, modified cut-offs are needed to optimize its performance. [ABSTRACT FROM AUTHOR]

This document discusses the measurement uncertainty (MU) of serum ferritin, a key performance indicator for laboratory measurements. The authors collected data from four commercial measuring systems and calculated the standard MU associated with clinical samples. The results showed that the Architect i2000 had the best performance in terms of MU on clinical samples. However, without an objectively defined analytical performance specification (APS), it is difficult to determine the suitability of this figure. The authors suggest using the 'state of the art-based' (SoA) APS model to temporarily define APS for MU. The data from this study can help provide information for defining APS for clinical sample measurements. The authors conclude that the practical application of the traceability concept and the procedural implementation of calibration traceability are often poorly managed, and comparative information like this study should be used to improve the analytical quality of measuring systems. [Extracted from the article]

From External Quality Assessment data, current harmonization of CRP measuring systems appears to be satisfactory, the inter-assay CV being well below 10%. The inter-method variability is even better (close to 3%) when the widely used measuring systems are compared at CRP concentrations employed as cut-off for detecting sub-clinical infection (i.e., 10.0 mg/L) and measurement variability estimated, according to ISO 20914:2019 Technical Specification, from the intermediate within-lab reproducibility of 6-month consecutive measurement data. According to the state-of-the-art model (which is better suited for CRP), the maximum allowable measurement uncertainty (MAU) for CRP measurement on clinical samples with 10.0 mg/L concentrations is 3.76% (desirable quality). As measurement uncertainty (MU) of the only available reference material (ERM-DA474/IFCC) is ∼3%, to fulfil desirable MAU on clinical samples, IVD manufacturers should work to keep the contribution of remaining MU sources (commercial calibrator and intermediate within-lab reproducibility) lower than 2.3%. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) is a cytokine-mediated acute phase reactant with a recognized role in inflammatory conditions and infectious disease. In coronavirus disease 2019 (COVID-19), elevated CRP concentrations in serum were frequently detected and significantly associated with poor outcome in terms of disease severity, need for intensive care, and in-hospital death. For these reasons, the marker was proposed as a powerful test for prognostic classification of COVID-19 patients. In most of available publications, there was however confounding information about how interpretative criteria for CRP in COVID-19 should be derived, including quality of employed assays and optimal cut-off definition. Assuring result harmonization and controlling measurement uncertainty in terms of performance specifications are fundamental to allow worldwide application of clinical information according to specific CRP thresholds and to avoid risk of patient misclassification. [ABSTRACT FROM AUTHOR]

Selecting appropriate laboratory tests based on available evidence is central to improve clinical effectiveness and impacting on patient outcome. Although long studied, there is no mutual agreement upon pleural fluid (PF) management in the laboratory context. Given the experienced confusion about the real contribution of laboratory investigations to guide clinical interpretation, in this update, we tried to identify useful tests for the PF analysis, aiming to unravel critical points and to define a common line in requesting modalities and practical management. We performed a careful literature review and a deepened study on available guidelines to finalize an evidence-based test selection, intended for clinicians' use to streamline PF management. The following tests depicted the basic PF profile routinely needed: (1) abbreviated Light's criteria (PF/serum total protein ratio and PF/serum lactate dehydrogenase ratio) and (2) cell count with differential analysis of haematological cells. This profile fulfils the primary goal to determine the PF nature and discriminate between exudative and transudative effusions. In specific circumstances, clinicians may consider additional tests as follows: the albumin serum to PF gradient, which reduces exudate misclassification rate by Light's criteria in patients with cardiac failure assuming diuretics; PF triglycerides, in differentiating chylothorax from pseudochylothorax; PF glucose, for identification of parapneumonic effusions and other causes of effusion, such as rheumatoid arthritis and malignancy; PF pH, in suspected infectious pleuritis and to give indications for pleural drainage; and PF adenosine deaminase, for a rapid detection of tuberculous effusion. [ABSTRACT FROM AUTHOR]

To be accurate and equivalent, laboratory results should be traceable to higher-order references. Furthermore, their quality should fulfill acceptable measurement uncertainty as defined to fit the intended clinical use. With this aim, in vitro diagnostics (IVD) manufacturers should define a calibration hierarchy to assign traceable values to their system calibrators and to fulfill during this process uncertainty limits for calibrators, which should represent a proportion of the uncertainty budget allowed for clinical laboratory results. It is therefore important that, on one hand, the laboratory profession clearly defines the clinically acceptable uncertainty for relevant tests and, on the other hand, end-users may know and verify how manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. Important tools for IVD traceability surveillance are quality control programmes through the daily verification by clinical laboratories that control materials of analytical systems are in the manufacturer's declared validation range [Internal Quality Control (IQ C) component I] and the organization of External Quality Assessment Schemes meeting metrological criteria. In a separate way, clinical laboratories should also monitor the reliability of employed commercial systems through the IQC component II, devoted to estimation of the measurement uncertainty due to random effects, which includes analytical system imprecision together with individual laboratory performance in terms of variability.

Analytical performance specifications, lot-to-lot variation, measurement uncertainty, method evaluation, CLSI-ep26 Keywords: analytical performance specifications; CLSI-ep26; lot-to-lot variation; measurement uncertainty; method evaluation EN analytical performance specifications CLSI-ep26 lot-to-lot variation measurement uncertainty method evaluation e218 e220 3 10/03/23 20231001 NES 231001 To the Editor, We appreciate the attention that Bayat et al. have paid to our paper proposing an approach for determining allowable between reagent lot variation [[1]]. [Extracted from the article]

New millennium diagnostic criteria for acute myocardial infarction precipitated a revolutionary shift from an approach based primarily on electrocardiography and clinical symptoms to a strategy based on biomarkers, and preferably cardiac troponins (cTn) I and T. In the last 20 years, clinical recommendations have strengthened the role of cTn and led to the development of highly sensitive (hs-cTn) assays, which are now leading players in all current clinical practice guidelines. To optimize the clinical use of these hs-cTn assays, focus on their analytical aspects has become increasingly important, emphasizing the need for the establishment of suitable analytical performance by the definition and implementation of appropriate specifications. An accurate estimate of measurement uncertainty, together with the acquisition of the highest analytical quality when very low concentrations of hs-cTn are measured, are essential requirements and should represent a practical laboratory standard in assuring optimal clinical use. Additional goals for further improving the quality of laboratory information should be the establishment of robust data concerning biological variation of cTn and the resolution of practical challenges opposed to the harmonization of cTn I results obtained by differing commercial measuring systems. [ABSTRACT FROM AUTHOR]

IVD manufacturers have total responsibility in terms of the traceability of marketed in vitro diagnostic medical devices (IVD-MD). This includes the provision of a quality control (QC) material as a part of the measuring system, suitable for traceability verification and alignment surveillance by end-users in daily practice. This material [to be used for the internal QC (IQC) component I as described in this paper] should have unbiased target values and an acceptability range corresponding to analytical performance specifications (APS) for suitable (expanded) measurement uncertainty (MU) on clinical samples. On the other hand, medical laboratories (by the IQC component II as described in this paper) should improve the IQC process and its judging criteria to establish a direct link between their performance, estimated as MU of provided results, and APS defined according to recommended models to apply corrective actions if the performance is worsening with the risk to jeopardize the clinical validity of test results. The participation to external quality assessment (EQA) programs that meet specific metrological criteria is also central to the evaluation of performance of IVD-MDs and of medical laboratories in terms of harmonization and clinical suitability of their measurements. In addition to the use of commutable materials, in this type of EQA it is necessary to assign values to them with selected reference procedures and to define and apply maximum allowable APS to substantiate the suitability of laboratory measurements in the clinical setting. [ABSTRACT FROM AUTHOR]

Laboratories should estimate and validate [using analytical performance specifications (APS)] the measurement uncertainty (MU) of performed tests. It is therefore essential to appropriately define APS for MU, but also to provide a perspective on suitability of the practical application of these APS. In this study, 23 commonly ordered measurands were allocated to the models defined during the 2014 EFLM Strategic Conference to derive APS for MU. Then, we checked if the performance of commercial measuring systems used in our laboratory may achieve them. Most measurands (serum alkaline phosphatase, aspartate aminotransferase, creatine kinase, γ-glutamyltransferase, lactate dehydrogenase, pancreatic amylase, total proteins, immunoglobulin G, A, M, magnesium, urate, and prostate-specific antigen, plasma homocysteine, and blood red and white cells) were allocated to the biological variation (BV) model and desirable APS were defined accordingly (2.65%, 4.75%, 7.25%, 4.45%, 2.60%, 3.15%, 1.30%, 2.20%, 2.50%, 2.95%, 1.44%, 4.16%, 3.40%, 3.52%, 1.55%, and 5.65%, respectively). Desirable APS for serum total cholesterol (3.00%) and urine albumin (9.00%) were derived using outcome-based model. Lacking outcome-based information, serum albumin, high-density lipoprotein cholesterol, triglycerides, and blood platelets were temporarily reallocated to BV model, the corresponding desirable APS being 1.25%, 2.84%, 9.90%, and 4.85%, respectively. A mix between the two previous models was employed for serum digoxin, with a 6.00% desirable APS. In daily practice by using our laboratory systems, 16 tests fulfilled desirable and five minimum APS, while two (serum albumin and plasma homocysteine) exceeded goals, needing improvements. [ABSTRACT FROM AUTHOR]

Elevated liver enzyme activity may be associated with metabolic syndrome (MetS); however, it is not included in the MetS definition for children. Postprandial changes in the levels of biochemistry tests are related to manifestations of metabolic abnormalities. We assessed the association between fasting and postprandial liver enzymes levels with MetS and elevated hemoglobin A1c (HbA1c) in children aged 9–11. The study included 51 girls and 48 boys, all presumably healthy. In all participants' anthropometric indices, fasting glucose, insulin, lipid profile and HbA1c were measured. Enzymes, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were assayed in fasting and postprandial states. Individuals were divided into subgroups: with (MetS(+): n = 26); without MetS (MetS(−): n = 73); with HbA1c levels ≤ 5.3% (n = 39); and ≥5.7% (n = 11). Elevated fasting GGT levels were found in 23% of MetS(+) children and rarely in MetS(−) children; increased postprandial GGT was noted in 35% of MetS(+) individuals. Postprandial GGT changes tend to predict MetS (OR = 1.16; p = 0.092). Increased fasting ALT was found rarely in MetS(+) children, but did not occur in MetS(−) children. HbA1c ≥ 5.7% occurred rarely and neither fasting ALT nor GGT were related to elevated HbA1c. However, postprandial change of ALT was a good positive predictor of increased HbA1c (OR = 1.33; p = 0.021). Postprandial GGT performs better as an indicator of metabolic syndrome occurrence, and instead postprandial ALT may predict prediabetes in prepubertal children. [ABSTRACT FROM AUTHOR]

In the recent years, new CRP candidate reference materials (RM) were nominated to be listed in the Joint Committee for Traceability in Laboratory Medicine (JCTLM) database. In other words, it was unclear if the new CRP candidate RM providers proposed an alternative calibration hierarchy to that currently used in the clinical community, already listed on the JCTLM database [[10]]. Keywords: C-reactive protein; metrological traceability; result comparability; standardization EN C-reactive protein metrological traceability result comparability standardization 1537 1539 3 07/18/23 20230801 NES 230801 Of current inflammatory markers identified, C-reactive protein (CRP) has the assay and biological characteristics most conducive to use in clinical practice [[1]]. [Extracted from the article]

The Joint Committee for Traceability in Laboratory Medicine (JCTLM) currently lists the secondary commutable certified reference material (CRM) ERM DA-474/IFCC (DA-474) "C-Reactive Protein in Human Serum" and two generic immunoassay-based method principles as the basis for implementing the metrological traceability of C-reactive protein (CRP) measurements by end-user measurement procedures used by medical laboratories. The current metrological traceability has produced well harmonized results for clinical samples among different end-user measurement procedures. New higher-order pure substance and secondary commutable CRMs have been nominated for listing by the JCTLM. However, the data supporting performance of these new candidate CRMs, including use of new mass spectrometry based candidate reference measurement procedures (RMPs), was not clear regarding the influence that introducing these new CRMs would have on the current well harmonized results achieved with the existing metrological traceability to DA-474. The clinically relevant CRP measurand in blood serum or plasma is a pentamer of identical subunits, which adds complexity to the application of higher-order CRMs and RMPs. The JCTLM convened a workshop in December 2022 to review the appropriate implementation of metrological traceability of CRP measurements. The workshop consensus was that the extent-of-equivalence data must include considerations about the impact of a new CRM when used for its intended purpose in the calibration hierarchies of existing end-user measuring systems; and that a new RMP must compare results with another existing well validated candidate RMP or with a globally available end-user measurement system. [ABSTRACT FROM AUTHOR]