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Golgi protein 73 (GP73) is implicated in key pathogenic processes, particularly those related to inflammation and fibrogenesis. In the last years, its measurement has emerged as a promising biomarker for detection of liver fibrosis (LF), a common consequence of chronic liver disease that can progress to cirrhosis and eventually hepatocellular carcinoma. GP73 concentrations in blood appear significantly increased in LF patients, correlating with disease severity, making this biomarker a possible non-invasive alternative for detecting and monitoring this condition regardless of etiology. Understanding the molecular mechanisms involving GP73 expression could also lead to new therapeutic strategies aimed at modulating its synthesis or function to prevent or reverse LF. Despite its clinical potential, GP73 as a LF biomarker faces several challenges. The lack of demonstrated comparability among different assays as well as the lack of knowledge of individual variability can make difficult the result interpretation. Further research is therefore needed focusing on robust clinical validation of GP73 as a LF biomarker. Addressing analytical, biological, and clinical limitations will be critical to exploiting its potential for improving detection and monitoring of advanced LF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: There is conflicting evidence about the role of folate and B 12 in gestational diabetes mellitus (GDM) onset. The association of vitamin status with GDM was therefore revalued, also measuring the B 12 active form holotranscobalamin., Methods: 677 women were evaluated at 24-28 weeks of gestation when OGTT was carried out. The 'one-step' strategy was employed for GDM diagnosis. Odds ratio (OR) of having GDM was estimated to quantify the association with vitamin levels., Results: 180 women (26.6%) had GDM. They were older (median, 34.6 vs. 33.3 years, p = 0.019) and had higher body mass index (BMI) (25.8 vs. 24.1 kg/m 2 , p < 0.001). Multiparous women had lower levels of all evaluated micronutrients, while overweight lowered both folate and total B 12 , but not holotranscobalamin. Lower total B 12 (270 vs. 290 ng/L, p = 0.005), but not holotranscobalamin, was observed in GDM, being weakly negatively correlated with fasting glycemia (r = -0.11, p = 0.005) and 1-h OGTT serum insulin (r = -0.09, p = 0.014). At multivariate analysis, age, BMI and multiparity remained the strongest GDM predictors, while total B 12 (but not holotranscobalamin and folate) showed a slight protective effect (OR = 0.996, p = 0.038)., Conclusions: A weak association between total B 12 levels and GDM risk was shown, but it was not confirmed when holotranscobalamin was measured., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The ISO 15189:2012 standard section 5.9.1 requires laboratories to review results before release, considering quality control, previous results, and clinical information, if any, and to issue documented procedures about it. While laboratory result reporting is generally regarded as part of the post-analytical phase, the result release process requires a general view of the total examination process. Reviewing test results may follow with troubleshooting and test repetition, including reanalyzing an individual sample or resampling. A systematic understanding of the result release may help laboratory professionals carry out appropriate test repetition and ensure the plausibility of laboratory results. In this paper, we addressed the crucial steps in the result release process, including evaluation of sample quality, critical result notification, result reporting, and recommendations for the management of the result release, considering quality control alerts, instrument flags, warning messages, and interference indexes. Error detection tools and plausibility checks mentioned in the present paper can support the daily practice of results release., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Aspartate aminotransferase (AST) is often increased in COVID-19 and, in some studies, AST abnormalities were associated with mortality risk., Methods: 2054 hospitalized COVID-19 patients were studied. To identify sources of AST release, correlations between AST peak values and other biomarkers of tissue damage, i.e., alanine aminotransferase (ALT) for hepatocellular damage, creatine kinase (CK) for muscle damage, lactate dehydrogenase for multiorgan involvement, alkaline phosphatase and γ-glutamyltransferase for cholestatic injury, and C-reactive protein (CRP) for systemic inflammation, were performed and coefficients of determination estimated. The role of AST to predict death and intensive care unit admission during hospitalization was also evaluated. All measurements were performed using standardized assays., Results: AST was increased in 69% of patients. Increases could be fully explained by summing the effects of hepatocellular injury [AST dependence from ALT, 66.8% [95% confidence interval (CI): 64.5-69.1)] and muscle damage [AST dependence from CK, 42.6% (CI: 39.3-45.8)]. We were unable to demonstrate an independent association of AST increases with worse outcomes., Conclusion: The mechanisms for abnormal AST in COVID-19 are likely multifactorial and a status related to tissue suffering could play a significant role. The clinical significance of AST elevations remains unclear., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: We investigated factors influencing pre-biopsy prostate-specific antigen (PSA) retesting as recommended by clinical guidelines., Materials and Methods: 333 patients screened for prostate cancer (PCa) repeated PSA (Roche Cobas systems) after a median of 3.9 months, before performing biopsy. Multiple regression models were used to assess effects of patients' characteristics on PSA results and changes over time., Results: PCa [n = 132 (40.7%)] and cancer-free [n = 192 (59.3%)] patients had similar rate of PSA positive results at baseline (84.8% vs. 83.9%, P = 0.931). Their rate of reversion to normal PSA after retesting was negligible (0.9% in PCa and 3.7% in PCa-free patients, P = 0.286). 31.1% of PCa and 31.3% of cancer-free patients (P = 0.426) showed a significant PSA increase after retesting. Age was a confounder since not only PSA increased in older PCa patients, but it was also related to PCa histological grade, in turn associated to PSA increase. In PCa-free patients, glandular inflammation, present in 1/3 of subjects, was also associated to higher PSA concentrations., Conclusion: When obtained with the same immunoassay under controlled analytical conditions, a PSA positive result is confirmed after retesting in the great majority of screened patients. Neither analytical factors nor intraindividual variability appeared to justify PSA retesting before biopsy referral., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sepsis is a life-threatening organ dysfunction caused by a dysregulated response of the host to infection. It represents one of the major health care problems worldwide. Unfortunately, the diagnosis of sepsis is challenging for many reasons, including a lack of a sufficiently sensitive and specific diagnostic test. When procalcitonin (PCT) was discovered, it was thought that it could become the best test for identifying patients with sepsis. From the evidence sources in the available literature, it is now clear that the power of PCT in differentiating infectious from non-infectious forms of systemic inflammatory response syndrome in adults, and in stratifying morbidity and mortality risk, is limited. Nevertheless, PCT determination can be a useful tool for diagnosing late-onset neonatal sepsis, bacterial meningitis and other forms of organ-related bacterial infections and, above all, it can be used for guiding antibiotic stewardship in critical patients. The real impact of this application of PCT testing, however, still needs to be clearly defined. Laboratories should offer unrestricted PCT testing only to intensive care units (as an aid in decision for continuing or stopping antibiotics) and pediatric wards. For all other clinical wards, the laboratory should guide PCT requests and give them support towards the most appropriate approach to testing., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: To evaluate the impact of age- and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI)., Methods: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14ng/L to previously proposed age- and gender-dependent hs-cTnT 99th percentile cut-offs (28ng/L for ≥65years, 9ng/L for female and 15.5ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS., Results: For patients ≥65years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n=557) and 54.7% to 40.9% in the ACS subcohort (n=225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n=477) and 62.6% to 71.7% (ACS subcohort, n=99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n=805) and 48.8% to 45.9% (ACS, n=281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p<0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs., Conclusions: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Harmonization in laboratory testing is more far-reaching than merely analytical harmonization. It includes all aspects of the total testing process from the "pre-pre-analytical" phase through analysis to the "post-post-analytical" phase. Harmonizing the pre-analytical phase requires use of standardized operating procedures for correct test selection, sample collection and handling, while standardized test terminology, and units and traceability to ISO standard 17511 are required to ensure equivalency of measurement results. Use of harmonized reference intervals and decision limits for analytes where platforms share allowable bias requirements will reduce inaccurate clinical interpretation and unnecessary laboratory testing. In the post-analytical phase, harmonized procedures for the management of critical laboratory test results are required to improve service quality and ensure patient safety. Monitoring of the outcomes of harmonization activities is through surveillance by external quality assessment schemes that use commutable materials and auditing of the "pre-pre-analytical" and "post-post-analytical" phases. Successful implementation of harmonization in laboratory testing requires input by all stakeholders, including the clinical laboratory community, diagnostics industry, clinicians, professional societies, IT providers, consumer advocate groups and governmental bodies., (© 2013.)

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., (© 2013.)

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 © 2013 Elsevier B.V. All rights reserved.)

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., (© 2013.)

Determination of serum soluble transferrin receptor (sTfR) has been proposed to identify iron-deficiency anemia (IDA) in patients affected by concurrent inflammatory disease that may spuriously increase ferritin concentration. The aim of this study was to critically review the available literature to assess the diagnostic efficacy of sTfR in complicated anemia. The criteria for study selection were: enrolment of patients with complicated anemia; bone marrow examination used as diagnostic gold standard for IDA; evaluation of sTfR vs. ferritin and binary data presentation. Six published studies met the criteria. However, the small size and wide heterogeneity of the studies did not allow us to conduct a meta-analysis. sTfR was overall more sensitive, even though it was evident that the ferritin sensitivity was influenced by selected cut-offs. Well-designed studies are still needed to define the added value, if any, of sTfR to ferritin for IDA detection in complicated anemia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Creatinine determination in serum is a key indicator of kidney glomerular function. A reference measurement system for its standardization is available and virtually all IVD manufacturers have aligned their assays to this system. In this study, we verified the impact of these standardization efforts on the results of an Italian EQAS involving about 430 laboratories., Method: We considered data obtained during 2006, 2010 and 2011 schemes of EQAS Prolarit for control materials with target values assigned by a traceable method (enzymatic assay calibrated against the NIST SRM 967)., Results: The results showed a good alignment at concentrations ~170μmol/L, with 2011 results - except for one method group - well inside the desirable bias (±4%). At higher concentrations, whereas the bias was small in 2010, for some groups using alkaline-picrate (AP) methods it became significantly negative in 2011. The performance seems to worsen when measuring physiologic concentrations, where a significant positive bias (up to ~20%) is shown by most of the AP-based analytical systems. With few exceptions, no evident improvement in individual assay bias was noted from pre- (2006) to post-standardization (2011) periods. The enzymatic method groups were the only always presenting an acceptable bias at all creatinine concentrations, also showing the lowest between-laboratory variability., Conclusion: Our data seem to indicate that the standardization efforts are still having effects lower than expected. Even taking into consideration that some of the bias may derive from non commutability problems, most of the current "standardized" AP-based methods, at the lower creatinine concentrations, seem to present accuracy problems. This inaccuracy can adversely impact the estimation of GFR by equations and the evaluation of kidney function in pediatrics., (© 2013.)

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 © 2013 Elsevier B.V. All rights reserved.)

Background: Data on the correlations between biomarkers to suggest cost-effective multi-marker (MM) panels predictive for ST-elevation myocardial infarction (STEMI) patients are lacking. We sought to explore the relationship between cardiac troponin I (cTnI), C-reactive protein (CRP), B-type natriuretic peptide (BNP), and chromogranin A (CgA) accounting for biomarkers' profiles detected within 48h from successful primary percutaneous coronary intervention (PPCI)., Methods: In 73 STEMI patients cTnI, CRP, BNP, and CgA were measured before PPCI and 6, 24, and 48h later. STATIS methods generalizing Principal Component Analysis on three-way data sets were employed to extract information about: 1) similarities between patients, 2) contribution of each time of sampling and 3) correlations between biomarkers' profiles., Results: STEMI patients who underwent successful PPCI emerged to have a homogeneous profile tailored on biomarkers' evaluation within 48h. Their measurements at 24h contributed the most variability and information both to patients' and to biomarkers' profiles. BNP and cTnI were highly correlated and explained the 40.1% of the total variance, whereas CgA resulted independent and explained the 26.3% of the total variance., Conclusions: Markers' measurements at 24h after PPCI contributed most information to the definition of patients' profile. BNP and cTnI resulted interchangeable in a MM panel for reporting about the extent of necrosis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: C-reactive protein (CRP) is recognized as a marker of cardiovascular risk. The biologic variability of CRP is crucial to understanding its significance in estimation of individual risk and subsequent changes in serial analyses., Methods: We systematically reviewed publications on biologic variation of CRP to evaluate the consistency of available data. Data was evaluated with attention to number and type of enrolled subjects, duration of study, frequency of sample collection, sample type, sample storage, analytical methodology, assay sensitivity and statistical analysis., Results: A total of eleven studies on CRP biologic variability were recruited from literature. The majority of studies were limited by choice of analytic methodology, population selection, protocol application, and statistical analysis. Unfortunately, the only study that fulfilled all major pre-analytical, analytical and post-analytical requirements derived biologic variability from logarithmically transformed data, thus making application to clinical practice difficult., Conclusions: There is a paucity of robust data on biologic CRP variability in serum. It is obvious that additional well defined studies are needed to define reliable values of reference change values and of number of samples required to estimate the individual's cardiovascular risk by CRP., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Despite the growing interest in hepcidin and other relatively new biomarkers, guidelines and clinical pathways continue to recommend traditional markers, such as serum transferrin (Tf) and ferritin, as laboratory tests for the diagnostic evaluation of iron-related disorders. In this study, we aimed to critically evaluate the diagnostic role of Tf relying on the highest level of available evidence by a comprehensive literature search. The role of Tf in iron deficiency (ID) and iron overload (IO) syndrome as well as a risk marker was evaluated. The low accuracy of Tf and Tf saturation (TS) in the diagnosis and management of ID conditions does not permit definitively recommending their use, even if recently published guidelines still consider the TS investigation as a complementary test for ferritin. If a tissue IO is suspected, TS is often used, even if it may not be the best test for detecting this condition. Nevertheless, clinical guidelines strongly recommend the use of TS as a first-level test for performing genetic diagnosis of hereditary hemochromatosis. Recently reported data indicating elevated TS as a risk factor for diabetes mellitus, cancer, and total mortality, may provide useful additions to the debate over whether or not to screen for IO using TS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: No information is available on the optimal sampling time to catch the highest increase for biomarkers whose elevation after ST-elevation myocardial infarction (STEMI) is prognostic for adverse events. This study aimed to investigate release kinetics and peak times of cardiac troponin I (cTnI), C-reactive protein (CRP), B-type natriuretic peptide (BNP), chromogranin A (CgA) and cystatin C (CyC) in STEMI patients undergoing primary percutaneous coronary intervention (PPCI)., Methods: Blood concentrations of cTnI, CRP, BNP, CgA and CyC were measured before and 6 h, 24 h, and 48 h after PPCI in 84 STEMI patients. The averaged trajectory of marker kinetics was estimated by multivariable regression models adjusted for patient characteristics and orthogonal polynomials were used to describe related releases., Results: From the estimated kinetics cTnI peaked at 10 h from symptoms, BNP at 28 h and CRP within 30 h. CyC concentrations did not change, whereas CgA concentrations increased from 6 to 48 h after PPCI. The amount of BNP release was found to be affected by the interaction between gender and age: females<75 years had BNP concentrations fourfold higher than males., Conclusions: According to different release kinetics a single blood sampling for measuring all biomarkers is not recommended., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Glycated hemoglobin (HbA(1c)) has a key role for diagnosing diabetes and monitoring glycemic state. As recently reviewed, available data on HbA(1c) biological variation show marked heterogeneity. Here we experimentally revaluated these data using a well designed protocol., Methods: We took five EDTA whole blood specimens from 18 apparently healthy subjects on the same day, every two weeks for two months. Samples were stored at -80°C until analysis and assayed in duplicate in a single run by Roche Tina-quant® Gen.2 immunoassay. Data were analyzed by the ANOVA. To assess the assay traceability to the IFCC reference method, we preliminarily carried out a correlation experiment., Results: The bias (mean±SD) of the Roche immunoassay was 0.3%±0.7%, confirming the traceability of the employed assay. No difference was found in HbA(1c) values between men and women. Within- and between-subject CV were 2.5% and 7.1%, respectively. Derived desirable analytical goals for imprecision, bias, and total error resulted 1.3%, 1.9%, and 3.9%, respectively. HbA(1c) had marked individuality, limiting the use of population-based reference limits for test interpretation. The estimated critical difference was ~10%., Conclusions: For the first time we defined biological variation and derived indices for the clinical application of HbA(1c) measurements using an accurately designed protocol and an assay standardized according to the IFCC., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The measurement of glycated hemoglobin (HbA(1c)) has a pivotal role in monitoring glycemic state in diabetic patients. Furthermore, the American Diabetes Association has recently recommended the use of HbA(1c) for diabetes diagnosis, but a clear definition of the clinically allowable measurement error is still lacking. Information on biological variability of the analyte can be used to achieve this goal., Methods: We systematically reviewed the published studies on the biological variation of HbA(1c) to check consistency of available data in order to accurately define analytical goals., Results: The nine recruited studies were limited by choice of analytic methodology, population selection, protocol application and statistical analyses., Conclusions: There is an urgent need to determine biological variability of HbA(1c) using a specific and traceable assay, appropriate protocol and appropriate statistical evaluation of data., (2010 Elsevier B.V. All rights reserved.)

The recently released document by the Global Task Force on the universal definition of myocardial infarction (MI) has strengthened the role of cardiac troponin increase as the main criterion for MI diagnosis. Despite this pivotal role in clinical decisions, a number of assay-related issues can still markedly affect the test performance in the everyday practice. Regarding imprecision and analytical sensitivity, the performance of commercial assays is variable. Moreover, at least for troponin I, there is a lack of standardization among assay results. Appropriate cut points (99th percentile limit of the reference value distribution and/or 10% CV concentration value) can be established only if the assay performance is known and taken into account. Key characteristics to be defined include characterization by appropriate experimental and statistical protocols of the assay detection limit, total imprecision, and definition of the 99th percentile limit of the reference population. The widespread introduction of cardiac troponin measurements is an undoubted improvement, but some performance differences still exist with commercial assays, which most clinicians are unaware of and may give rise to wrong marker interpretation.

Background: The in vitro diagnostics directive of the European Union requires traceability to higher order reference measurement procedures and materials for analytes in assuring the result trueness and comparability of laboratory measurements. Manufacturers must ensure that the systems they market are calibrated against available reference systems. Validation of metrologically traceable calibrations is, however, required., Methods: A commutable serum-based material was analyzed in three reference laboratories and target values for six enzymes (ALT, AST, CK, GGT, LD, amylase) were assigned using IFCC reference measurement procedures. 70 laboratories in Germany, Italy, and The Netherlands measured the same enzymes in the material using procedures from six commercial companies. A system for maximum allowable error was developed from the biological variation model and the results of the various procedures were tested on their compliance to trueness and between-laboratory and within-laboratory variations relative to the maximum allowable., Results: For ALT results were relatively good. >95% of laboratories using systems from Dade, Olympus, Ortho and Roche are expected to comply traceability within the biologically derived limits, and 94% respectively 89% from Abbott and Beckman. For AST and GGT only Dade respectively Olympus fully complied. For CK all companies showed significant bias. Nevertheless >95% of laboratories applying Abbott, Beckman and Roche systems will comply. Finally, LD and amylase measurements require significant improvement. Some manufacturers continue to sell on the European market assays giving results which are not traceable to the internationally accepted reference systems., Conclusions: The traceability of enzyme measurements obtained with routine procedures to internationally accepted IFCC reference systems is not yet satisfactorily accomplished in clinical practice.

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.

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.

New biomarkers, such as cardiac troponins, have a major role to play for cost-effective management of individuals with acute chest pain and suspected coronary syndrome, and the laboratory is now poised to assume a vital role in assessing damage and determining prognosis. The redefined biochemical criterion proposed to classify acute coronary syndrome patients presenting with ischemic symptoms as patients with myocardial infarction is heavily predicated on an increased troponin concentration in blood. In an era of evidence-based medicine, we can no longer overlook the diagnostic and prognostic benefits provided by the measurement of these highly sensitive and specific proteins.