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In addition to the correct implementation of calibration traceability, the definition and the achievement of an appropriate analytical performance specification for the total uncertainty budget (G U ) is essential to ensure that laboratory measurements are clinically usable. To understand if it is possible to fulfil these specifications, limits for combined uncertainty across the entire metrological traceability chain should be defined. We recommended that no more than one third of G U should be consumed by the uncertainty of higher order references and ≤50% of G U by the combined measurement uncertainty at the manufacturer's calibration level. The remaining allowable uncertainty should be available for random sources, i.e. for the imprecision of the commercial measuring system (including the reagent batch-to-batch variation) and the individual laboratory performance, as a safety margin to fulfil G U . Based on this approach, it is of interest to assess for each analyte measured in the clinical laboratory the status of the uncertainty budget of its measurement associated with the selected metrological traceability chain. Accordingly, we report three didactic cases that could occur in the clinical practice. This approach is very helpful to identify those analytes for which further technological improvements are probably needed to reduce uncertainty associated with their measurement. [ABSTRACT FROM AUTHOR]

The definition and enforcement of a reference measurement system, based on the implementation of metrological traceability of patients' results to higher order reference methods and materials, together with a clinically acceptable level of measurement uncertainty, are fundamental requirements to produce accurate and equivalent laboratory results. The uncertainty associated with each step of the traceability chain should be governed to obtain a final combined uncertainty on clinical samples fulfilling the requested performance specifications. It is important that end-users (i.e., clinical laboratory) may know and verify how in vitro diagnostics (IVD) manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. However, full information about traceability and combined uncertainty of calibrators is currently very difficult to obtain. Laboratory professionals should investigate the need to reduce the uncertainty of the higher order metrological references and/or to increase the precision of commercial measuring systems. Accordingly, the measurement uncertainty should not be considered a parameter to be calculated by clinical laboratories just to fulfil the 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]

This review highlights the role of laboratory professionals and the strategies to be promoted in strict cooperation with clinicians for auditing, monitoring and improving the appropriateness of test request. The introduction of local pathways and care maps in agreement with international and national guidelines as well as the implementation of reflex testing and algorithms have a central role in guiding test request and in correcting the overuse/misuse of tests. Furthermore, removing obsolete tests from laboratory menu and vetting of restricted tests is recommended to increase cost-effectiveness. This saves costs and permits to introduce new biomarkers with increased diagnostic accuracy with a better impact on patient outcome. An additional issue is concerning the periodicity of (re)testing, accounting that only a minority of tests may be ordered as often as necessary. In the majority of cases, a minimum retesting interval should be introduced. The availability of effective computerised order entry systems is relevant in ensuring appropriate test requests and in providing an aid by automated rules that may stop inappropriate requests before they reach the laboratory. [ABSTRACT FROM AUTHOR]

Study Objective: We aim to prospectively validate the diagnostic accuracy of the recently developed 0-h/1-h algorithm, using high-sensitivity cardiac troponin T (hs-cTnT) for the early rule-out and rule-in of acute myocardial infarction.Methods: We enrolled patients presenting with suspected acute myocardial infarction and recent (<6 hours) onset of symptoms to the emergency department in a global multicenter diagnostic study. Hs-cTnT (Roche Diagnostics) and sensitive cardiac troponin I (Siemens Healthcare) were measured at presentation and after 1 hour, 2 hours, and 4 to 14 hours in a central laboratory. Patient triage according to the predefined hs-cTnT 0-hour/1-hour algorithm (hs-cTnT below 12 ng/L and Δ1 hour below 3 ng/L to rule out; hs-cTnT at least 52 ng/L or Δ1 hour at least 5 ng/L to rule in; remaining patients to the "observational zone") was compared against a centrally adjudicated final diagnosis by 2 independent cardiologists (reference standard). The final diagnosis was based on all available information, including coronary angiography and echocardiography results, follow-up data, and serial measurements of sensitive cardiac troponin I, whereas adjudicators remained blinded to hs-cTnT.Results: Among 1,282 patients enrolled, acute myocardial infarction was the final diagnosis for 213 (16.6%) patients. Applying the hs-cTnT 0-hour/1-hour algorithm, 813 (63.4%) patients were classified as rule out, 184 (14.4%) were classified as rule in, and 285 (22.2%) were triaged to the observational zone. This resulted in a negative predictive value and sensitivity for acute myocardial infarction of 99.1% (95% confidence interval [CI] 98.2% to 99.7%) and 96.7% (95% CI 93.4% to 98.7%) in the rule-out zone (7 patients with false-negative results), a positive predictive value and specificity for acute myocardial infarction of 77.2% (95% CI 70.4% to 83.0%) and 96.1% (95% CI 94.7% to 97.2%) in the rule-in zone, and a prevalence of acute myocardial infarction of 22.5% in the observational zone.Conclusion: The hs-cTnT 0-hour/1-hour algorithm performs well for early rule-out and rule-in of acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Abstract: The major source of errors producing unreliable laboratory test results is the pre-analytical phase with hemolysis accounting for approximately half of them and being the leading cause of unsuitable blood specimens. Hemolysis may produce interference in many laboratory tests by a variety of biological and analytical mechanisms. Consequently, laboratories need to systematically detect and reliably quantify hemolysis in every collected sample by means of objective and consistent technical tools that assess sample integrity. This is currently done by automated estimation of hemolysis index (HI), available on almost all clinical chemistry platforms, making the hemolysis detection reliable and reportable patient test results more accurate. Despite these advantages, a degree of variability still affects the HI estimate and more efforts should be placed on harmonization of this index. The harmonization of HI results from different analytical systems should be the immediate goal, but the scope of harmonization should go beyond analytical steps to include other aspects, such as HI decision thresholds, criteria for result interpretation and application in clinical practice as well as report formats. With regard to this, relevant issues to overcome remain the objective definition of a maximum allowable bias for hemolysis interference based on the clinical application of the measurements and the management of unsuitable samples. Particularly, for the latter a recommended harmonized approach is required when not reporting numerical results of unsuitable samples with significantly increased HI and replacing the test result with a specific comment highlighting hemolysis of the sample. [Copyright &y& Elsevier]

Abstract: To be accurate and equivalent, laboratory results should be traceable to higher-order references. Furthermore, their analytical performance should fulfill acceptable measurement uncertainty criteria 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 laboratory results. It is important that end-users may know and verify how manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. However, full information about traceability and combined uncertainty of calibrators is currently not available. Important tools for IVD traceability surveillance are the verification by laboratories of the consistency of declared performance during daily operations performed in accordance with the manufacturer's instructions and the organization of appropriately structured External Quality Assessment (EQA) programs. The former activity should be accomplished by analyzing system control materials and confirming that current measurements are in the manufacturer's established control range. With regard to EQA, it is mandatory that target values for materials are assigned with reference procedures by accredited laboratories, that materials are commutable and that a clinically allowable inaccuracy for participant's results is defined. [Copyright &y& Elsevier]

Abstract: The lack of interchangeable results in current practice among clinical laboratories has underpinned greater attention to standardization and harmonization projects. Although the focus was mainly on the standardization and harmonization of measurement procedures and their results, the scope of harmonization goes beyond method and analytical results: it includes all other aspects of laboratory testing, including terminology and units, report formats, reference limits and decision thresholds, as well as test profiles and criteria for the interpretation of results. In particular, as evidence collected in last decades demonstrates that pre-pre- and post-post-analytical steps are more vulnerable to errors, harmonization initiatives should be performed to improve procedures and processes at the laboratory–clinical interface. Managing upstream demand, down-stream interpretation of laboratory results, and subsequent appropriate action through close relationships between laboratorians and clinicians remains a crucial issue of the laboratory testing process. Therefore, initiatives to improve test demand management from one hand and to harmonize procedures to improve physicians' acknowledgment of laboratory data and their interpretation from the other hand are needed in order to assure quality and safety in the total testing process. [Copyright &y& Elsevier]

Abstract: Albumin is the major plasma protein and its determination is used for the prognostic assessment of several diseases. Clinical guidelines call for monitoring of serum albumin with specific target cut-offs that are independent of the assay used. This requires accurate and equivalent results among different commercially available methods (i.e., result standardization) through a consistent definition and application of a reference measurement system. This should be associated with the definition of measurement uncertainty goals based on medical relevance of serum albumin to make results reliable for patient management. In this paper, we show that, in the current situation, if one applies analytical goals for serum albumin measurement derived from its biologic variation, the uncertainty budget derived from each step of the albumin traceability chain is probably too high to fulfil established quality levels for albumin measurement and to guarantee the accuracy needed for clinical usefulness of the test. The situation is further worsened if non-specific colorimetric methods are used for albumin measurement as they represent an additional random source of uncertainty. [Copyright &y& Elsevier]

The measurement of cardiac troponin concentrations in the blood is a key element in the evaluation of patients with suspected acute coronary syndromes, according to current guidelines, and contributes importantly to the ruling in or ruling out of acute myocardial infarction. The introduction of point-of-care testing for cardiac troponin has the potential to reduce turnaround time for assay results, compared with central laboratory testing, optimizing resource use. Although, in general, many point-of-care cardiac troponin tests are less sensitive than cardiac troponin tests developed for central laboratory–automated analyzers, point-of-care systems have been used successfully within accelerated protocols for the reliable ruling out of acute coronary syndromes, without increasing subsequent readmission rates for this condition. The impact of shortened assay turnaround times with point-of-care technology on length of stay in the emergency department has been limited to date, with most randomized evaluations of this technology having demonstrated little or no reduction in this outcome parameter. Accordingly, the point-of-care approach has not been shown to be cost-effective relative to central laboratory testing. Modeling studies suggest, however, that reengineering overall procedures within the emergency department setting, to take full advantage of reduced therapeutic turnaround time, has the potential to improve the flow of patients through the emergency department, to shorten discharge times, and to reduce cost. To properly evaluate the potential contribution of point-of-care technology in the emergency department, including its cost-effectiveness, future evaluations of point-of-care platforms will need to be embedded completely within a local decision-making structure designed for its use. [Copyright &y& Elsevier]

Abstract: The standardization of measurements is of high priority in Laboratory Medicine, its purpose being to achieve closer comparability of results obtained using routine analytical systems. In order to achieve standardization, an approach is required that provides reliable transfer of the measurement values from the highest hierarchical level to methods which are routinely used in the clinical laboratories. Such a structure is presented by the reference measurement system (RS), based on the concepts of metrological traceability. Key elements of a comprehensive RS are the reference measurement procedure and reference materials. Other essential elements include the definition of the measurand in regards to the intended clinical use and the reference laboratories that may collaborate in a network. At present, there is international cooperation in developing RS for analytes of clinical significance. Thanks to the work of the Joint Committee on Traceability in Laboratory Medicine (JCTLM), a list of higher order reference materials and reference methods is now publicly available. JCTLM has also published the list of reference laboratories that are able to deliver a reference measurement service. As soon as a new RS is implemented, clinical validation of the correctly calibrated routine methods (the IVD products sold onto the market) should take place. Other important issues concerning the implementation of a metrologically-correct approach for result standardization are: 1) the clear definition of the clinically allowable error of measurements and 2) the post-market surveillance of the performance of IVD products. These are tasks of our profession through the organization of appropriate External Quality Assessment programs. [Copyright &y& Elsevier]

Abstract: Objective: To discuss the more controversial clinical and laboratory aspects in the application of the new biochemical diagnostic standard for myocardial infarction, 4 years after its introduction, and to make some suggestions, which could allow for a more realistic application of the new definition in the current clinical practice. Methods: Studies published in the last 4 years in the most important cardiology and laboratory medicine journals (including proceedings of the international meetings), discussing advantages and limits of the new definition of myocardial infarction, were reviewed and pertinent data were discussed and compared with similar information available in literature. Results and conclusions: Although the exact status of implementation of the new definition of myocardial infarction cannot yet be known, the trend toward such recommendation is evolving significantly, even if at different rates in different countries. To make the transition smoother, major educational efforts are required to disseminate the conceptual reasoning behind the new guidelines. On the other hand, more knowledge is needed for some relevant issues, such as the different analytical performance of cardiac troponin assays or the prognostic significance of biomarker changes after a percutaneous coronary intervention. [Copyright &y& Elsevier]

Background: Myoglobin is a low-molecular weight protein present in the cytosol of striated muscles. Its concentrations in serum can be measured by immunoassays and are used as an early indicator of myocardial necrosis. Since variability among commercial myoglobin assays exists, standardization of myoglobin assays is needed. Methods: An international collaborative study was organized with the involvement of seven companies using 12 different automated platforms for measuring myoglobin. Five candidate secondary, i.e., matrixed, reference materials were assayed in relation to linearity, imprecision, recovery rate and commutability to demonstrate a possible identity between the materials and the usual routine serum samples. Results: One lyophilized candidate material (human heart myoglobin in human serum) was selected as the most suitable secondary reference material, based on the criteria examined. Used as a calibrator a posteriori, the bias between the various myoglobin assays for a frozen human serum pool was reduced from 32% to 13%. Conclusion: This study provides the basis for the selection of an internationally recognized secondary reference material. [Copyright &y& Elsevier]

Once an in-vitro diagnostic (IVD) measuring system has been marketed and introduced into daily practice, the possible sources of degradation of its performance are numerous. It is therefore essential to put in place a continuous post-market surveillance of the quality of performance of the IVD system and of the laboratories that perform measurements in clinical setting. The participation to external quality assessment (EQA) schemes that meet specific metrological criteria is central to the evaluation of performance of clinical laboratories in terms of standardization 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 (and uncertainty) to them with reference procedures and to define and apply clinically permissible analytical performance specifications to substantiate the suitability of laboratory measurements in the clinical setting. Unfortunately, there are still few permanent EQA programs fully covering these requirements because some practical constraints, including technical and economic aspects, which limit their introduction. It is, however, clear that these issues should be quickly overcome, since EQA schemes are in a unique position to add substantial value to the practice of laboratory medicine, by identifying analytes that need improved harmonization and by stimulating and sustaining standardization initiatives that are needed to support clinical practice. Importantly, this will definitively help those manufacturers that produce superior products to demonstrate the superiority of those products and oblige end users (and consequently industry) to abandon assays with demonstrated insufficient quality. [ABSTRACT FROM AUTHOR]

The measurement of plasma glucose (PG) plays a central role in recognizing disturbances in carbohydrate metabolism, with established decision limits that are globally accepted. This requires that PG results are reliable and unequivocally valid no matter where they are obtained. To control the pre-analytical variability of PG and prevent in vitro glycolysis, the use of citrate as rapidly effective glycolysis inhibitor has been proposed. However, the commercial availability of several tubes with studies showing different performance has created confusion among users. Moreover, and more importantly, studies have shown that tubes promptly inhibiting glycolysis give PG results that are significantly higher than tubes containing sodium fluoride only, used in the majority of studies generating the current PG cut-points, with a different clinical classification of subjects. From the analytical point of view, to be equivalent among different measuring systems, PG results should be traceable to a recognized higher-order reference via the implementation of an unbroken metrological hierarchy. In doing this, it is important that manufacturers of measuring systems consider the uncertainty accumulated through the different steps of the selected traceability chain. In particular, PG results should fulfil analytical performance specifications defined to fit the intended clinical application. Since PG has tight homeostatic control, its biological variability may be used to define these limits. Alternatively, given the central diagnostic role of the analyte, an outcome model showing the impact of analytical performance of test on clinical classifications of subjects can be used. Using these specifications, performance assessment studies employing commutable control materials with values assigned by reference procedure have shown that the quality of PG measurements is often far from desirable and that problems are exacerbated using point-of-care devices. [ABSTRACT FROM AUTHOR]

Flat shaped glucose curves (FC) during oral glucose tolerance test (OGTT) in pregnant women (PW) are a not uncommon finding. We aimed to define the FC incidence in a large PW cohort and to describe the status of insulin and C-peptide secretion in women with FC when compared with a well-matched control group. 1050 PW performing OGTT for gestational diabetes screening were enrolled. An increase <6 % in plasma glucose (PG) during OGTT defined a FC. Serum samples for measuring insulin and C-peptide were also obtained. 61 (5.8 %) women showed a FC. 60 of them, paired to a group of 60 no-FC women matched for age, body mass index and gestational age, were further investigated. C-peptide and insulin concentrations were significantly lower (P < 0.001) in FC in both 1-h and 2-h OGTT samples. When incremental area under the curves (AUC) normalized to PG were estimated, only AUC insulin remained however significantly lower. The insulin sensitivity index was higher in FC. PW with FC showed a hypersensitivity to insulin with normal β-cell function. Moreover, a delayed glucose absorption could be hypothesised because of the slight but continuously increasing shape of insulin curve found in FC group. Both phenomena could occur in parallel and contribute to FC. [ABSTRACT FROM AUTHOR]

Background Amongst the newly proposed biomarkers for ovarian cancer, serum human epididymis protein 4 (HE4) shows the greatest potential for clinical use. However, systematic appraisals of its biological characteristics are not available. This study sought to critically revise the available literature on biological and lifestyle factors affecting HE4 concentrations in serum to understand their possible influence on the marker interpretation. Methods A literature search was undertaken on electronic databases and references from retrieved articles. Article results were analyzed by evaluating study design, sample size, statistical approach, employed assay and, when available, by collecting similar information for carbohydrate antigen 125 (CA-125). Results Several factors may influence serum HE4 concentrations. In contrast to CA-125, higher HE4 concentrations are reported in the elderly. Although no variations in HE4 concentrations can be clearly associated to menopausal status, a strong difference in biomarker biological intra-individual variation according to the fertility status is reported. Smoking and renal function can also significantly influence HE4 results. Conclusion The knowledge of factors influencing HE4 concentrations is relevant to promote more adequate interpretative criteria for use of this biomarker in the clinical setting. [ABSTRACT FROM AUTHOR]

• The management strategy of affected results in haemolysed samples is widely debated. • A dedicated approach tailored to the characteristics of young patients is desirable. • We propose an alternative approach for laboratory reports of paediatric wards. • Our report can act as a driving force for improving the phlebotomy quality. The management of affected results in haemolysed samples (HS) is debated. In an infant-maternity setting, for reporting interfered test results, we provided the result itself, the degree of haemolysis (as free haemoglobin concentration), and a warning recommending sample recollection. We investigated the impact of this approach on sample quality and clinicians' decision-making. Free haemoglobin was measured on Beckman Coulter AU680 as haemolytic index. We estimated the total HS number, the clinical wards more affected by HS, the most interfered analytes, and the retesting rate of interfered tests, by comparing data from Apr-Dec 2017, the period just after the introduction of the new policy, vs. Apr-Dec 2018. One year after the new report introduction, a significant HS decrease (5.8% vs. 7.8%, P < 0.001) was detected, together with a reduction of the frequency by which haemolysis affected results. The most affected wards, i.e., Paediatric and Neonatal Intensive Care Units, showed an improvement in sample quality (HS rate, 30.6% to 16.1%, P < 0.001, and 25.2% to 20.9%, P = 0.048, respectively). We noted a significant decrease in retesting after an alerted result for aspartate aminotransferase, magnesium, potassium, conjugated bilirubin, and lactate dehydrogenase. Our approach led to a HS decrease, suggesting that the provided report could be a driving force for improvement of phlebotomy quality, also helping clinicians in deciding if retesting is essential or not. [ABSTRACT FROM AUTHOR]

Abstract Background We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI). Methods 922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin <10, <14 or < 20 pmol/L and hs-cTnT≤14 ng/L), the 1 h-algorithm (hs-cTnT<12 ng/L and change <3 ng/L at 1 h), as well as the hs-cTnT limit-of-blank (LoB, <3 ng/L) and -detection (LoD, <5 ng/L) were compared. Outcomes were assessed as combined end-points of death and myocardial re-infarction. Results True-negative rule-out using the DMS could be achieved in 50.9%–62.3% of all patients compared to 35.0%, 45.3% and 64.5% using LoB, LoD or the 1 h-algorithm, respectively. The DMS showed NPVs of 98.1%–98.3% compared to 99.2% for the 1 h-algorithm, 99.4% for the LoB and 99.3% for the LoD. Sensitivities were 93.5%–94.8%, as well as 96.8%, 98.7% and 98.1%, respectively. Addition of clinical low-risk criteria such as a HEART-score ≤ 3 to the DMS resulted in NPVs and sensitivities of 100% with a true-negative rule-out to 33.8%–41.6%. Rates of the combined end-point of death/MI within 30 days ranged between 0.2% and 0.3% for all fast-rule-out protocols. Conclusion Depending on the applied copeptin cut-off and addition of clinical low-risk criteria, the DMS might be an alternative to the hs-cTn-only-based algorithms for rapid AMI rule-out with comparable diagnostic measures and outcomes. Highlights Combined testing of copeptin and high-sensitivity troponin T resulted in: • Incremental clinical value to high-sensitivity troponin T alone at presentation • Rule-out rates for myocardial infarction up to 62.3% in acute chest pain patients • Negative predictive values >98% without and 100% with clinical low-risk criteria • Similar diagnostic measures in comparison to other rapid rule-out algorithms • Excellent prognosis for ruled-out patients in short- and long-term follow-up [ABSTRACT FROM AUTHOR]

Abstract Background The addition of human epididymis protein 4 (HE4) to carbohydrate antigen 125 (CA125) in ovarian cancer (OC) assessment has been proposed. We compared the clinical value of biomarker changes in a prospective series of patients undergoing OC monitoring. Methods We studied 43 patients (79% post-menopausal), followed for 3.5 ± 3.1 years. Serous OC was prevalent (53.5%), with 81.4% of patients diagnosed at late stages. Both cut-offs and reference change values (RCV) were used for assessing significant marker changes. Results The use of cut-offs for CA125 and HE4 interpretation appeared equally fitting the evaluation of disease progression defined according to running guidelines, performing better than RCV criterion. However, both markers were simultaneously over cut-offs only in 46% of samples and changed in agreement in 35% of cases. The inspection of individual longitudinal trends indicated as main causes of disagreement the influence of renal impairment on HE4 concentrations and the more significant rate of decrease of CA125 vs. HE4 concentrations early after treatment. CA125 and HE4 changes according to RCV were not predictive of OC progression. Conclusions CA125 appears the most reliable biomarker for OC monitoring, whereas HE4 contributes additional information only in a minority of cases. Highlights • We compared CA125 and HE4 changes in ovarian cancer monitoring. • The use of cut-offs for CA125 and HE4 interpretation equally fitted the evaluation of disease progression. • CA125 and HE4 in the ovarian cancer follow-up may disagree for renal impairment/response to treatment. [ABSTRACT FROM AUTHOR]