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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]

This document discusses the concept of analytical performance specifications (APS) in laboratory medicine. It provides an overview of previous conferences and consensus documents on setting APS, including the 2014 EFLM Strategic Conference. The 2023 CELME conference aimed to explore the three models from the Milan conference and offer practical recommendations for their application. The document emphasizes the importance of APS in ensuring harmonized medical laboratory results for patient care. It also discusses the challenges in determining measurement uncertainty and the need for education on APS usage. The document concludes by highlighting important questions for further consideration, such as the creation of a single database for APS and the intended use and aspirational nature of APS. [Extracted from the article]

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]

This document discusses the measurement uncertainty (MU) of total protein in urine (TPU) and its importance in evaluating the quality of laboratory results. The ISO Technical Specification 20914 provides guidance for estimating MU, but information about MU of TPU is lacking. The study applied this approach to four commercial measuring systems for TPU and found that the MU on clinical samples was consistent across the systems. However, there are challenges in defining the measurand and establishing metrological traceability. The study suggests that the performance of the evaluated systems could be used to establish analytical performance specifications for TPU. [Extracted from the article]

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]

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]

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]

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]

Appropriateness in Laboratory Medicine has been the object of various types of interventions. From published experiences, it is now clear that to effectively manage the laboratory test demand it is recommended to activate evidence-based preventative strategies stopping inappropriate requests before they can reach the laboratory. To guarantee appropriate laboratory test utilization, healthcare institutions should implement and optimize a computerized provider order entry (CPOE), exploiting the potential of electronic requesting as "enabling factor" for reinforcing appropriateness and sustaining its effects over time. In our academic institution, over the last 15 years, our medical laboratory has enforced various interventions to improve test appropriateness, all directly or indirectly based on CPOE use. The following types of intervention were implemented: (1) applying specific recommendations supported by monitoring by CPOE as well as a continuous consultation with clinicians (tumour markers); (2) removing outdated tests and avoiding redundant duplications (cardiac markers, pancreatic enzymes); (3) order restraints to selected wards and gating policy (procalcitonin, B-type natriuretic peptide, homocysteine); (4) reflex testing (bilirubin fractions, free prostate-specific antigen, aminotransferases, magnesium in hypocalcemia); and (5) minimum retesting interval (D-Dimer, vitamin B12, C-reactive protein, γ-glutamyltranspeptidase). In this paper, we reviewed these interventions and summarized their outcomes primarily related to the changes in total test volumes and cost savings, without neglecting patient safety. Our experience confirmed that laboratory professionals have an irreplaceable role as "stewards" in designing, implementing, evaluating, and maintaining interventions focused to improving test appropriateness. [ABSTRACT FROM AUTHOR]

Alignment of the new generation of Abbott Alinity -glutamyltransferase assay to the IFCC reference measurement system should be improved Table 1: -Glutamyltransferase (GGT) results on serum pools obtained by IFCC reference measurement procedure (RMP) and Alinity c GGT2 measuring system. Keywords: -glutamyltransferase; measurement uncertainty; metrological traceability; systematic error; trueness EN -glutamyltransferase measurement uncertainty metrological traceability systematic error trueness e228 e231 4 08/30/22 20220901 NES 220901 To the Editor, Serum enzymes are important for the diagnosis and monitoring of many organ-related diseases and therefore the standardization of their measurements is essential [[1]]. [Extracted from the article]

In medical laboratories, the appropriateness challenge directly revolves around the laboratory test and its proper selection, data analysis, and result reporting. However, laboratories have also a role in the appropriate management of those phases of total testing process (TTP) that traditionally are not under their direct control. So that, the laboratory obligation to act along the entire TTP is now widely accepted in order to achieve better care management. Because of the large number of variables involved in the overall TTP structure, it is difficult to monitor appropriateness in real time. However, it is possible to retrospectively reconstruct the body of the clinical process involved in the management of a specific laboratory test to track key passages that may be defective or incomplete in terms of appropriateness. Here we proposed an appropriateness check-list scheme along the TTP chain to be potentially applied to any laboratory test. This scheme consists of a series of questions that healthcare professionals should answer to achieve laboratory test appropriateness. In the system, even a single lacking answer may compromise the integrity of all appropriateness evaluation process as the inability to answer may involve a significant deviation from the optimal trajectory, which compromise the test appropriateness and the quality of subsequent steps. Using two examples of the check-list application, we showed that the proposed instrument may offer an objective help to avoid inappropriate use of laboratory tests in an integrated way involving both laboratory professionals and user clinicians. [ABSTRACT FROM AUTHOR]

CHE activity in serum is stable for several years if stored at temperature lower than -20 °C [[1]]. To check the quality of CHE measurements it is essential to correctly define analytical performance specifications (APS). Keywords: analytical performance specifications; biological variation; serum cholinesterase EN analytical performance specifications biological variation serum cholinesterase e177 e180 4 06/21/22 20220701 NES 220701 To the Editor, Measurements of serum cholinesterase (CHE, also called pseudocholinesterase) catalytic concentrations are primarily used as a test of liver function and, less frequently, as an indicator of possible organic phosphorous insecticide poisoning in agriculture or organic chemical industry workers [[1]]. Supplemental Figure shows the individual mean and absolute range of CHE in evaluated subjects and Table 2 displays the derived results, including APS derived from BV data. [Extracted from the article]

Clinicians trust medical laboratories to provide reliable results on which they rely for clinical decisions. Laboratories fulfil their responsibility for accurate and consistent results by utilizing an arsenal of approaches, ranging from validation and verification experiments to daily quality control procedures. All these procedures verify, on different moments, that the results of a certain examination procedure have analytical performance characteristics (APC) that meet analytical performance specifications (APS) set for a particular intended use. The APC can in part be determined by estimating the measurement uncertainty component under conditions of within-laboratory precision (uRw), which comprises all components influencing the measurement uncertainty of random sources. To maintain the adequacy of their measurement procedures, laboratories need to distinguish aspects that are manageable vs. those that are not. One of the aspects that may influence uRw is the momentary significant bias caused by shifts in reagent and/or calibrator lots, which, when accepted or unnoticed, become a factor of the APC. In this paper, we postulate a model for allocating a part of allowable uRw to between-reagent lot variation, based on the need for long-term consistency of the measurement variability for that specific measurand. The allocation manages the ratio between short-term and long-term variation and indicates laboratories when to reject or correct certain variations due to reagent lots. [ABSTRACT FROM AUTHOR]

Results are automatically calculated by the system as follows: HbA SB 1c sb (mmol/mol)=[HbA SB 1c sb ( mol/L)/total haemoglobin (mol/L)] × 1,000. A bias >1 mmol/mol for Alinity became however evident only in samples with HbA SB 1c sb values >=69 mmol/mol. Keywords: clinical governance; diabetes; HbA1c; metrological traceability; total laboratory automation EN clinical governance diabetes HbA1c metrological traceability total laboratory automation 441 450 10 02/07/22 20220201 NES 220201 Introduction There are approximately 500 million people living with diabetes mellitus (DM) worldwide [[1]]. Alinity showed a mean positive absolute bias of 0.54 mmol/mol (range: -0.4 to 2.6 mmol/mol), corresponding to a mean percentage difference of 0.87% (range: -1.13 to 2.74%). [Extracted from the article]

Previous studies reported lipase elevations in serum of COVID-19 patients trying to establish a causal link between SARS-CoV-2 infection and pancreatic damage. However, the degree and prevalence of hyperlipasemia was not uniform across studies. We retrospectively evaluated 1,092 hospitalized patients with COVID-19 and at least one available lipase result. The number and frequency of patients with lipase above the upper reference limit (URL), >3 URL, and >6 URL were estimated. Correlations between lipase values and other biomarkers of organ or tissue damage were performed to identify possible extra-pancreatic sources of lipase release. The potential prognostic role of lipase to predict death and intensive care unit (ICU) admission during hospitalization was also evaluated. Lipase was >URL in 344 (31.5%) of COVID-19 patients. Among them, 65 (5.9%) and 25 (2.3%) had a peak lipase >3 URL and >6 URL, respectively. In the latter group, three patients had acute pancreatitis of gallstone or drug-induced etiology. In others, the etiology of lipase elevations appeared multifactorial and could not be directly related to SARS-CoV-2 infection. No correlation was found between lipase and other tested biomarkers of organ and tissue damage. Lipase concentrations were not different between survivors and non-survivors; however, lipase was significantly increased (p<0.001) in patients admitted to the ICU, even if the odds ratio for lipase as predictor of ICU admission was not significant. Lipase was elevated in ∼1/3 of COVID-19 patients, but the clinical significance of this finding is unclear and irrelevant to patient prognosis during hospitalization. [ABSTRACT FROM AUTHOR]

Although being the recommended laboratory test to diagnose acute pancreatitis, serum pancreatic lipase (LIP) is among the poorly standardized laboratory tests, and laboratory stakeholders often appear to not take enough care of the quality of its measurements. Here we discuss some important issues that, if not correctly managed and solved, make misdiagnosis of acute pancreatitis by using serum LIP a real possibility. First, the current unavailability of a suitable higher-order reference material to be used as common calibrator should be filled up to definitively improve the inter-method bias. Second, knowledge of the analytical characteristics that may explain the defective performance of LIP assays should be deepened. IVD manufacturers should be more explicit in providing this information, including description of their internal protocol for transferring LIP values from internal references to commercial calibrators. Third, recommended models for accurately estimating measurement uncertainty and reliably defining analytical performance specifications for LIP measurements should be applied. Finally, investments considering alternative options for measuring LIP (e.g., targeted to the development of automated LIP immunoassays) should be warranted. All involved stakeholders (standardization bodies, higher-order reference providers, in vitro diagnostics manufacturers, and laboratory professionals) should contribute to fill the existing gap. [ABSTRACT FROM AUTHOR]

Pre-analytical plasma glucose (PG) sampling methodology may significantly affect gestational diabetes mellitus (GDM) incidence, but no studies directly examined the impact on perinatal outcomes. We compared the effect on oral glucose tolerance test (OGTT) results of using for blood sampling the traditional sodium fluoride (NaF) tubes, batched at controlled temperature, and the more effective citrate-buffered tubes, in terms of GDM diagnosis and related outcomes. We evaluated 578 pregnant women performing OGTT between 24- and 28-weeks' gestation. Paired NaF and citrate blood samples were drawn and analyzed for PG. GDM diagnosis was made by applying the 'one-step' American Diabetes Association strategy. Data on perinatal outcomes were collected in a subset of 330 women who delivered in our hospital network. Using the standard NaF approach, 69 (11.9%) GDM women were detected. Using citrate PG values, 90 women were additionally identified as GDM, increasing the GDM prevalence to 27.5%. Perinatal outcomes were analyzed according to the different diagnostic allocation (NaF-diagnosed GDM, additional citrate-diagnosed GDM, and no GDM). NaF-diagnosed GDM showed a higher incidence of large for gestational age (LGA) (p=0.034), and of cesarean and preterm delivery (p<0.01) vs. no GDM. The only outcome remaining more frequent in the additional citrate diagnosed GDM when compared with no GDM group was LGA (17.2 vs. 6.8%, p=0.025). If a health care system plans to use citrate tubes for GDM diagnosis, considerations about clinical implications are mandatory by balancing higher sensitivity in detecting a poor glycemic control with effects on outcomes to avoid "overdiagnosis". [ABSTRACT FROM AUTHOR]

Definition and fullfillment of analytical performance specifications (APS) for measurement uncertainty (MU) allow to make laboratory determinations clinically usable. The 2014 Milan Strategic Conference have proposed models to objectively derive APS based on: (a) the effect of analytical performance on clinical outcome; (b) biological variation components; and (3) the state of the art of the measurement, defined as the highest level of analytical performance technically achievable. Using these models appropriately, we present here a proposal for defining APS for standard MU for some common biochemical measurands. We allocated a group of 13 measurands selected among the most commonly laboratory requested tests to each of the three Milan models on the basis of their biological and clinical characteristics. Both minimum and desirable levels of quality of APS for standard MU of clinical samples were defined by using information obtained from available studies. Blood total hemoglobin, plasma glucose, blood glycated hemoglobin, and serum 25-hydroxyvitamin D3 were allocated to the model 1 and the corresponding desirable APS were 2.80, 2.00, 3.00, and 10.0%, respectively. Plasma potassium, sodium, chloride, total calcium, alanine aminotransferase, creatinine, urea, and total bilirubin were allocated to the model 2 and the corresponding desirable APS were 1.96, 0.27, 0.49, 0.91, 4.65, 2.20, 7.05, and 10.5%, respectively. For C-reactive protein, allocated to the model 3, a desirable MU of 3.76% was defined. APS for MU of clinical samples derived in this study are essential to objectively evaluate the reliability of results provided by medical laboratories. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial disease with limited therapeutic options. The measurement of Krebs von den Lungen-6 (KL-6) glycoprotein has been proposed for evaluating the risk of IPF progression and predicting patient prognosis, but the robustness of available evidence is unclear. We searched Medline and Embase databases for peer-reviewed literature from inception to April 2020. Original articles investigating KL-6 as prognostic marker for IPF were retrieved. Considered outcomes were the risk of developing acute exacerbation (AE) and patient survival. Meta-analysis of selected studies was conducted, and quantitative data were uniformed as odds ratio (OR) or hazard ratio (HR) estimates, with corresponding 95% confidence intervals (CI). Twenty-six studies were included in the systematic review and 14 were finally meta-analysed. For AE development, the pooled OR (seven studies) for KL-6 was 2.72 (CI 1.22–6.06; p=0.015). However, a high degree of heterogeneity (I2=85.6%) was found among selected studies. Using data from three studies reporting binary data, a pooled sensitivity of 72% (CI 60–82%) and a specificity of 60% (CI 52–68%) were found for KL-6 measurement in detecting insurgence of AE in IPF patients. Pooled HR (seven studies) for mortality prediction was 1.009 (CI 0.983–1.036; p=0.505). Although our meta-analysis suggested that IPF patients with increased KL-6 concentrations had a significant increased risk of developing AE, the detection power of the evaluated biomarker is limited. Furthermore, no relationship between biomarker concentrations and mortality was found. Caution is also needed when extending obtained results to non-Asian populations. [ABSTRACT FROM AUTHOR]

Keywords: chloride; measurement uncertainty; metrological traceability; potassium; sodium EN chloride measurement uncertainty metrological traceability potassium sodium e129 e132 4 03/13/21 20210401 NES 210401 To the Editor, Blood electrolyte concentrations are tightly controlled by homeostatic mechanisms, with a very low intraindividual biological variability [[1]]. Importantly, despite the consistent improvement of electrolyte MU, u SB result sb for Na and Cl still exceed APS, while K widely fulfilled them, even at desirable level (i.e., 1.96%), being goals for this ion less stringent due to the relatively higher biological variability in plasma [[1]]. To be clinically useful, measurement results for these analytes should fulfil stringent analytical performance specifications (APS) for their measurement uncertainty (MU), which at minimum should not exceed 0.41% for plasma sodium (Na), 0.74% for plasma chloride (Cl), and 2.94% for plasma potassium (K), in terms of relative standard MU [[1]], [[2]], [[3]], [[4]]. [Extracted from the article]

To be accurate and equivalent, laboratory results should be traceable to higher-order references. Furthermore, their quality should fulfill acceptable measurement uncertainty (MU) 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. Medical laboratories should know and verify how manufacturers have implemented the traceability of their calibrators and estimate the corresponding MU on clinical samples. Accordingly, the internal quality control (IQC) program should be redesigned to permit IVD traceability surveillance through the verification by medical laboratories that control materials, provided by the manufacturer as a part of measuring systems, are in the clinically suitable validation range (IQC component I). Separately, laboratories should also monitor the reliability of employed IVD measuring systems through the IQC component II, devoted to estimation of MU due to random effects and to obtaining MU of provided results, in order to apply prompt corrective actions if the performance is worsening when compared to appropriate analytical specifications, thus jeopardizing the clinical validity of test results. [ABSTRACT FROM AUTHOR]

Objectives: Procalcitonin (PCT) has been proposed for differentiating viral vs. bacterial infections. In COVID-19, some preliminary results have shown that PCT testing could act as a predictor of bacterial co-infection and be a useful marker for assessment of disease severity. Methods: We studied 83 COVID-19 hospitalized patients in whom PCT was specifically ordered by attending physicians. PCT results were evaluated according to the ability to accurately predict bacterial co-infections and death in comparison with other known biomarkers of infection and with major laboratory predictors of COVID-19 severity. Results: Thirty-three (39.8%) patients suffered an in-hospital bacterial co-infection and 44 (53.0%) patients died. In predicting bacterial co-infection, PCT showed a relatively low accuracy (area under receiver-operating characteristic [ROC] curve [AUC]: 0.757; 95% confidence interval [CI]: 0.651–0.845), with a strength for detecting the outcome not significantly different from that of white blood cell count and C-reactive protein (CRP). In predicting patient death, PCT showed an AUC of 0.815 (CI: 0.714–0.892), not better than those of other more common laboratory tests, such as blood lymphocyte percentage (AUC: 0.874, p=0.19), serum lactate dehydrogenase (AUC: 0.860, p=0.47), blood neutrophil count (AUC: 0.845, p=0.59), and serum albumin (AUC: 0.839, p=0.73). Conclusions: Procalcitonin (PCT) testing, even when appropriately ordered, did not provide a significant added value in COVID-19 patients when compared with more consolidated biomarkers of infection and poor clinical outcome. The major application of PCT in COVID-19 is its ability, associated with a negative predictive value >90%, to exclude a bacterial co-infection when a rule-out cut-off (<0.25 μg/L) is applied. [ABSTRACT FROM AUTHOR]

A number of assay-related issues can affect the performance of cardiac troponin (cTn) measurement in everyday practice. In this respect, it is vital that all information on cTn assays is known and that the performance characteristics of assays are objectively assessed and adequately described. The advent of the latest generation of more sensitive cTn assays has heralded a new wave of information about low concentrations of cTn in blood. These recent generation assays have improved analytical sensitivity and corresponding performance at low cTn concentrations when compared to their predecessors, providing a convincing goal for laboratory medicine in helping clinicians in the diagnosis of acute myocardial infarction. Crucial to the clinical utility of highly sensitive cTn assays is the laboratorians' role in closely scrutinizing proposed assays and defining their value in relation to available evidence. Analytical, as well as pre-analytical and post-analytical, aspects must be documented. In this review, we describe what laboratory professionals should know about their cTn assay performance characteristics and the pre-analytical prerequisites for robustness to ensure optimal post-analytical reporting. [ABSTRACT FROM AUTHOR]

Background: Definitive data to establish if the use of the WHO International Standard (IS) 03/178 as a common calibrator of commercial measuring systems (MSs) has improved the harmonization of serum total folate (tFOL) measurements to a clinically suitable level are lacking. Here, we report the results of an intercomparison study aimed to verify if the current inter-assay variability is acceptable for clinical application of tFOL testing. Methods: After confirming their commutability, the IS 03/178 and National Institute for Standards and Technology SRM 3949 L1 were used for evaluating the correctness of traceability implementation by manufacturers and the MSs trueness, respectively. The inter-assay agreement was verified using 20 patient pools. The measurement uncertainty (U) of tFOL measurements on clinical samples was also estimated. An outcome-based model for defining desirable performance specifications for bias and imprecision for serum tFOL measurements was applied. Results: The majority of evaluated MSs overestimated the WHO IS value of +5% or more with the risk to produce an unacceptably high number of false-negative results in clinical practice. The mean inter-assay CV on all pools and on those with tFOL values >3.0 μg/L (n = 15) was 12.5% and 7.1%, respectively. In neither case the goal of 3.0% was fulfilled. The residual bias resulted in an excessive U of tFOL measurement on clinical samples. Conclusions: The implementation of traceability of tFOL MSs to the WHO IS 03/178 is currently inadequate, resulting in an inter-assay variability that does not permit the use of a common threshold for detecting folate deficiency. [ABSTRACT FROM AUTHOR]

The definition and enforcement of reference measurement systems, based on the implementation of metrological traceability of patient results to higher-order (reference) methods and/or materials, together with a clinically acceptable level of measurement uncertainty (MU), are fundamental requirements to produce accurate and equivalent laboratory results. The MU associated with each step of the traceability chain should be governed to obtain a final combined MU on clinical samples fulfilling the requested performance specifications. MU is useful for a number of reasons: (a) for giving objective information about the quality of individual laboratory performance; (b) for serving as a management tool for the medical laboratory and in vitro diagnostics (IVD) manufacturers, forcing them to investigate and eventually fix the identified problems; (c) for helping those manufacturers that produce superior products and measuring systems to demonstrate the superiority of those products; (d) for identifying analytes that need analytical improvement for their clinical use and ask IVD manufacturers to work for improving the quality of assay performance and (e) for abandoning assays with demonstrated insufficient quality. Accordingly, the MU should not be considered a parameter to be calculated by medical laboratories just to fulfill accreditation standards, but it must become a key quality indicator to describe both the performance of an IVD measuring system and the laboratory itself. [ABSTRACT FROM AUTHOR]

Background: The 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. Content: APS 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. Summary: The 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. Outlook: Using 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. [ABSTRACT FROM AUTHOR]

Background: Laboratory professionals should independently verify the correct implementation of metrological traceability of commercial measuring systems and determine if their performance is fit for purpose. We evaluated the trueness, uncertainty of measurements, and transferability of six clinically important enzyme measurements (alanine aminotransferase [ALT], alkaline phosphatase [ALP], aspartate aminotransferase [AST], creatine kinase [CK], γ-glutamyltransferase [γGT], and lactate dehydrogenase [LDH]) performed on the Abbott Alinity c analytical system. Methods: Target values and associated uncertainties were assigned to three pools for each enzyme by using the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference measurement procedures (RMPs) and the pools were then measured on the Alinity system. Bias estimation and regression studies were performed, and the uncertainty associated with Alinity measurements was also estimated, using analytical performance specifications (APS) derived from biological variability of measurands as goals. Finally, to validate the transferability of the obtained results, a comparison study between two Alinity systems located in Milan, Italy, and Bydgoszcz, Poland, was carried out. Results: Correct implementation of traceability to the IFCC RMPs and acceptable measurement uncertainty fulfilling desirable (ALP, AST, LDH) or optimal APS (ALT, CK, γGT) was verified for all evaluated enzymes. An optimal alignment between the two Alinity systems located in Milan and Bydgoszcz was also found for all enzyme measurements. Conclusions: We confirmed that measurements of ALT, ALP, AST, CK, γGT, and LDH performed on the Alinity c analytical system are correctly standardized to the IFCC reference measurement systems and the system alignment is consistent between different platforms. [ABSTRACT FROM AUTHOR]

Clinical practice guidelines for the management of germ cell tumors recommend the measurements of human chorionic gonadotropin (hCG) and/or free hCGβ subunit for earlier diagnosis/recognition of the residual disease, for the prognostic evaluation and for the post-chemotherapy surveillance. However, the marketed hCG assays are validated and approved only for pregnancy purposes, with the sole exception of the Elecsys 'hCG+β' assay (Roche Diagnostics), cleared in Europe for oncological application. Theoretically, the hCG assay design for oncological purposes should fulfil the recommendations of the International Society of Oncology and Biomarkers requiring the use of antibodies displaying an equimolar recognition of both intact hCG and hCGβ monomer. Further analytical requirements should also be considered, such as optimal analytical sensitivity to allow an early tumor detection and low cross-reactivity for luteinizing hormone (LH). For the Elecsys assay, the detection limit (0.2 U/L) and the reported cross-reactivity for LH (0.12%) may be considered adequate if compared with the recommended requirements. Another issue is the definition of decision limits for oncologic purposes. After 3 years of clinical experience using the Elecsys assay in the oncology setting, we were able to define limits partitioned by sex and age as follows: males <50 years, 0.3 U/L; males >50 years, 2.3 U/L; female <50 years, 2.1 U/L; female >50 years, 5.6 U/L. There is an urgent need to disseminate appropriate educational information and to boost the clinical use of selective, highly sensitive and precise assays, specifically manufactured for cancer application. [ABSTRACT FROM AUTHOR]

The immunohistochemistry was negative for human chorionic gonadotropin (hCG) subunit, even in the areas with intratubular neoplasia. At admission, serum AFP was undetectable, total hCG (Elecsys "hCG+ " assay, Roche Diagnostics) was 30 U/L (recommended cut-off for men <50 years, 0.3 U/L) and lactate dehydrogenase (LDH) 898 U/L (upper reference limit [URL], 220 U/L). We observed that the behavior of LDH and hCG+ paralleled, and the hCG+ peak at 1.1 U/L was anticipated of 1 week by a sudden increase in LDH (547 U/L). At admission of the patient, clinicians erroneously ordered the hCG Abbott, so laboratory professionals corrected the request and then recommended the ordering of hCG+ Roche for further evaluation. [Extracted from the article]

Background: Highly sensitive cardiac troponin assays (hs-cTn) are not available as point-of-care (POC) measurements. As rapid testing cannot be achieved at the expense of clinical performance, there is an urgent need to develop and rigorously validate POC hs-cTn. Konica Minolta (KM) has recently developed a surface plasmon-field enhanced fluorescence spectroscopy-based POC hs-cTn I system. Methods: We validated the analytical characteristics of the KM POC system according to the international guidelines. Results: Limit of blank (LoB) and limit of detection (LoD) were 0.35 and 0.62 ng/L, respectively, hs-cTn I concentrations corresponding to a total CV of 20%, 10% and 5% were 1.5, 3.9 and 11.0 ng/L, respectively. Method comparison studies showed that KM calibration was successfully traced to higher-order references. Limit of quantitation (LoQ), i.e. the hs-cTn I concentration having a total error of measurement of ≤34%, was 10.0 ng/L. The upper reference limit (URL) for 600 healthy blood donors was calculated at 12.2 ng/L (90% confidence interval [CI]: 9.2–39.2), while sex-partitioned URLs were 20.6 (males) and 10.7 ng/L (females), respectively (p < 0.0001). KM assay measured hs-cTn I concentrations >LoD in 65.7% of all reference individuals, in 76.7% of males and in 54.7% of females, respectively. Conclusions: The KM system joins the characteristics of POC systems to the analytical performance of hs-cTn. [ABSTRACT FROM AUTHOR]

Background: Blood loss for laboratory testing may contribute to hospital-acquired anemia. When implementing the core laboratory (core-lab) section, we consolidated first-line tests decreasing the number of tubes previously dispatched to different sites. Here, hypothesized benefits of the amount of blood volume drawn were explored. Methods: We retrieved, using a laboratory information system (LIS), the number of tubes received by laboratories interested in the change from all clinical wards in a year-based period, i.e. 2013 for pre-core-lab and 2015 for core-lab system, respectively. Data were expressed as the overall number of tubes sent to laboratories, the corresponding blood volume, and the number of laboratory tests performed, normalized for the number of inpatients. Results: After consolidation, the average number of blood tubes per inpatient significantly decreased (12.6 vs. 10.7, p < 0.001). However, intensive care units (ICUs) did not reduce the number of tubes per patient, according to the needs of daily monitoring of their clinical status. The average blood volume sent to laboratories did not vary significantly because serum tubes for core-lab required higher volumes for testing up to 55 analytes in the same transaction. Finally, the number of requested tests per patient during the new osystem slightly decreased (−2.6%). Conclusions: Total laboratory automation does not automatically mean reducing iatrogenic blood loss. The new system affected the procedure of blood drawing in clinical wards by significantly reducing the number of handled tubes, producing a benefit in terms of costs, labor and time consumption. Except in ICUs, this also slightly promoted some blood saving. ICUs which engage in phlebotomizing patients daily, did not take advantage from the test consolidation. [ABSTRACT FROM AUTHOR]

Keywords: expert system; serum protein electrophoresis; turnaround time EN expert system serum protein electrophoresis turnaround time e367 e369 3 08/06/21 20210815 NES 210815 To the Editor, In previous papers, we discussed the rationale of a clinical decision making-based laboratory medicine department, where first-line tests are rapidly performed in a core laboratory and results immediately reported to clinical users, and tests requiring a specialized knowledge are carried out in dedicated sections with the objective of enhancing patient care [[1]], [[2]]. Table 1: Number of serum protein electrophoresis (SPE) performed in 2016 - before Neurosoft implementation - and 2018-2019 - after Neurosoft implementation - and corresponding turnaround time (TAT). [Extracted from the article]

3 Padoan, A, Cosma, C, Sciacovelli, L, Faggian, D, Plebani, M. Analytical performances of a chemiluminescence immunoassay for SARS-CoV-2 IgM/IgG and antibody kinetics. Keywords: COVID-19; immunoassay; measurement uncertainty; quality control; SARS-CoV-2 EN COVID-19 immunoassay measurement uncertainty quality control SARS-CoV-2 e175 e177 3 04/12/21 20210501 NES 210501 To the Editor, Although the detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA in respiratory specimens remains the diagnostic standard for COVID-19, SARS-CoV-2 antibody testing has been advocated for identifying individuals who suffered infection. [Extracted from the article]

Background: Measurement of human epididymis protein 4 (HE4) in serum has recently been proposed for clinical use in the framework of ovarian cancer (OvCa). We sought to retrace the translational phase and the clinical implementation steps boosting HE4's clinical value and discuss the effects of its introduction on the diagnostic and management pathways. Methods: Meta-analyses of running evidence have preliminarily suggested that HE4 may overcome carbohydrate antigen 125 (CA125) in identifying OvCa, showing however several gaps that need to be considered, i.e. definition of biomarker diagnostic performance in the early detection of OvCa, added diagnostic value, biological and lifestyle factors of variation, and optimal interpretative criteria. Investigation of the influencing factors has shown that renal impairment represents a major limitation for HE4's diagnostic power. On the other hand, the demonstration of the substantial equivalence of results obtained by commercially available assays allows recommending harmonized thresholds for diagnostic purpose, even if the study of HE4's biological variation has clarified that the longitudinal interpretation of the biomarker changes according to the reference change value could be more appropriate. Summary: We used HE4 as an example for describing the long and bumpy road for making a new biomarker a reality, and the issues that should be checked and the information that should be provided in moving a novel biomarker from its discovery to an effective clinical adoption. [ABSTRACT FROM AUTHOR]

Traceability to a common reference ensures equivalence of results obtained by different assays. Traceability is achieved by an unbroken sequence of calibrations, using reference materials (RMs) that must be commutable. Using non-commutable RMs for calibration will introduce a bias in the calibrated method producing incorrect results for clinical samples (CS). Commutability was defined in 1973 as "the ability of an enzyme material to show inter-assay activity changes comparable to those of the same enzyme in human serum" and later extended as a characteristic of all RMs. However, the concept is still poorly understood and appreciated. Commutability assessment has been covered in CLSI guidelines and requires: (a) selection of 20 CS spanning the relevant concentration range; (b) analysis of both RM and CS with the pair of procedures; (c) data elaboration using regression analysis and calculation if RM fall within the 95% prediction interval defined by CS. This approach has been criticized and to improve it The International Federation of Clinical Chemistry and Laboratory Medicine established a working group that recently finalized recommendations. Commutability is also a requirement for the applicability of external quality assessment (EQA) results in the evaluation of the performance of participating laboratories in terms of standardization of their measurements. Unfortunately, EQA materials are usually not validated for commutability. [ABSTRACT FROM AUTHOR]

The article highlights role of genetic predisposition in hyperbilirubinemia in a patient with pre-existing hepatitis A. Topics discussed include information on the Acute hepatitis A virus serologically diagnosed by the detection of anti-HAV Immunoglobulin M (IgM); hepatocyte by passive transmembrane diffusion combined with active mediated transport; and the prsents a case study of a 33-year-old man asthenia, nausea and diarrhea and blood tests revealed increase of serum ALT activity.

Background: Growth differentiation factor 15 (GDF-15) is an emerging cardiovascular biomarker, and a fully automated immunoassay has recently become available. The objectives of the study were to identify biological and lifestyle factors affecting serum GDF-15 concentrations and derive robust reference intervals, and to estimate GDF-15 within-subject biological variation and derived indices. Methods: A presumably healthy population of 533 questionnaire-screened adults was used to identify the biological and lifestyle determinants of serum GDF-15. Following stringent exclusion criteria, a final group of 173 individuals was selected to establish GDF-15 reference interval. Twenty-six healthy volunteers were enrolled in the biological variation substudy. Results: Using a multiple regression model, age, B-type natriuretic peptide and C-reactive protein as well as smoking status were significantly related to serum GDF-15 concentrations. The upper reference limit (URL) for serum GDF-15 concentrations (90% confidence interval [CI]) was 866 ng/L (733–999 ng/L), with no sex-related difference. Although GDF-15 tended to increase with age, the weak dependence of marker from age does not justify age-related URL. The within-subject CV was 6.3% (95% CI, 4.5%–8.5%), with no sex difference in intraindividual variances. The reference change value (RCV) for GDF-15 was 23%, and two are the specimens required to ensure that the mean GDF-15 result is within ±10% of the individual's homeostatic set point. Conclusions: By identifying the main factors influencing serum GDF-15 concentrations, we robustly established the URL to be applied in adult population. As intraindividual variation of GDF-15 is relatively low, monitoring longitudinal changes in its concentrations over time using RCV can be a good alternative for interpreting GDF-15 in clinical setting. [ABSTRACT FROM AUTHOR]

Background: Measurement of α-fetoprotein (AFP) concentrations in the serum of infants is useful for the management of testicular germ cell tumors, hepatoblastoma and hepatocellular carcinoma. Here, we provide a critical review of the available information about pediatric reference intervals (RI), focusing on their utility in interpreting AFP as an aid for cancer diagnosis. Content: Evidence sources in the available literature were critically appraised. Out of 3873 retrieved papers, 24 were finally selected and carefully inspected, and six of them overcame exclusion criteria (i.e. methodological limitations in the study design, statistical gaps, drawbacks in traceability of the AFP assay to higher order materials and/or biased reporting of AFP results). Preterm and term infants up to the 3rd month of life exhibited the highest average AFP concentrations, but the attempt of defining RI by data pooling and partitioning for age intervals was impeded by the wide variability of data. The inability of defining robust RI in the first months of life made difficult, if not impossible, using upper reference limits for ruling out malignancies with a single AFP result. Evaluating the behavior of AFP concentrations 5 days from the baseline result, if this exceeds risk thresholds partitioned for age, according to the formula Xt=X0*2−t/HL (where: t=days elapsed for AFP retest; HL=AFP half-life according to age; X0=AFP baseline concentration, and Xt=predicted AFP concentration at day 5), could give a better information. Summary: Novel studies defining AFP RI in infants based on robust methodology are warranted to improve the interpretation of AFP results in pediatric oncology. In the meantime, algorithms based on both serum AFP absolute concentrations and HL may aid in cancer diagnosis. [ABSTRACT FROM AUTHOR]

ISO15189:2012 requires medical laboratories to document metrological traceability of their results. While the ISO17511:2003 standard on metrological traceability in laboratory medicine requires the use of the highest available level in the traceability chain, it recognizes that for many measurands there is no reference above the manufacturer's selected measurement procedure and the manufacturer's working calibrator. Some immunoassays, although they intend to measure the same quantity and may even refer to the same reference material, unfortunately produce different results because of differences in analytical selectivity as manufacturers select different epitopes and antibodies for the same analyte. In other cases, the cause is the use of reference materials, which are not commutable. The uncertainty associated with the result is another important aspect in metrological traceability implementation. As the measurement uncertainty on the clinical samples is influenced by the uncertainty of all steps higher in the traceability chain, laboratories should be provided with adequate and appropriate information on the uncertainty of the value assignment to the commercial calibrators that they use. Although the between-lot variation in value assignment will manifest itself as part of the long-term imprecision as estimated by the end-user, information on worst-case to be expected lot-lot variation has to be communicated to the end-user by the IVD provider. When laboratories use ancillary equipment that potentially could have a critical contribution to the reported results, such equipment needs verification of its proper calibration and criticality to the result uncertainty could be assessed by an approach based on risk analysis, which is a key element of ISO15189:2012 anyway. This paper discusses how the requirement for metrological traceability as stated in ISO15189 should be met by the medical laboratory and how this should be assessed by accreditation bodies. [ABSTRACT FROM AUTHOR]