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Primary aldosteronism (PA) is the most common and potentially curable form of secondary hypertension, affecting 5–10% of primary care patients with hypertension. Primary care physicians have an important role in initiating the screening for PA in patients with hypertension and referring to a specialist service depending on the screening test results. The currently recommended screening test for PA is the plasma aldosterone-to-renin ratio (ARR). Test results are influenced by medications so careful patient preparation is required including adjusting existing antihypertensive medications to avoid diagnostic errors. A range of laboratory method-dependent ARR thresholds are used for the screening of PA around the world. Periodic clinical audits and case reviews by clinicians and the laboratory may help refine the local thresholds. Patients with an abnormally elevated ARR should be referred to a specialist for confirmatory testing while patients with a high pre-test probability but a normal ARR could have a repeat test in view of the within-individual variability. Despite the heterogenous ARR thresholds, measuring the ARR is still more likely to detect PA than not screening at all.

Background Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED. Methods This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses. Results Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P Conclusions NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Background Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. Methods Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration–time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. Results Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3−12.1% (amikacin), 16.2−19.0% (tobramycin), 12.2−45.8% (gentamicin), and 9.6−19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). Conclusions Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

Analytical performance specifications (APS) for measurands describe the minimum analytical quality requirements for their measurement. These APS are used to monitor and contain the systematic (trueness/ bias) and random errors (precision/ imprecision) of a laboratory measurement to ensure the results are “fit for purpose” in informing clinical decisions about managing a patient’s health condition. In this review, we highlighted the wide variation in the setting of APS, using different levels of evidence, as recommended by the Milan Consensus, and approaches. The setting of a priori defined outcome-based APS for HbA1c remains challenging. Promising indirect alternatives seek to link the clinical utility of HbA1c and APS by defining statistical confidence for interpreting the laboratory values, or through simulation of clinical performance at varying levels of analytical performance. APS defined based on biological variation estimates in healthy individuals using the current formulae are unachievable by nearly all routine laboratory methods for HbA1c testing. On the other hand, the APS employed in external quality assurance programs have been progressively tightened, and greatly facilitate the improved quality of HbA1c testing. Laboratories should select the APS that fits their intended clinical use and should document the data and rationale underpinning those selections. Where possible common APS should be adopted across a region or country to facilitate the movement of patients and patient data across health care facilities.

Cross reactivity with high molecular weight complexes of prolactin known as macroprolactin is a common cause of positive interference in assays for serum prolactin. All prolactin assays currently available are affected with 5-25% of results indicating hyperprolactinaemia falsely elevated due to macroprolactinaemia - hyperprolactinaemia due to macroprolactin with normal concentrations of bioactive monomeric prolactin. Macroprolactinaemia has no pathological significance but, if it is not recognised as the cause, the apparent hyperprolactinaemia can lead to clinical confusion, unnecessary further investigations, inappropriate treatment and waste of healthcare resources. Macroprolactinaemia cannot be distinguished from true hyperprolactinaemia on clinical grounds alone but can be detected by a simple laboratory test based on the precipitation of macroprolactin with polyethylene glycol. Laboratory screening of all cases of hyperprolactinaemia to exclude macroprolactinaemia has been advised as best practice but has not been implemented universally and reports of clinical confusion caused by macroprolactinaemia continue to appear in the literature. Information provided by manufacturers to users of assays for prolactin regarding interference by macroprolactin is absent or inadequate and does not comply with the European Union Regulation covering

Highlights • Test selection/ evaluation needs a priori defined performance specifications. • At low prevalence, minimal sensitivity is required to achieve NPV of 60%-95%. • At high prevalence, relatively low clinical sensitivity can achieve a desired PPV. • NPV-PPV trade-offs should be weighed based on prevalence, sensitivity, specificity. • A spreadsheet tool is provided for determining these a priori considerations., Objectives Several guidelines for the evaluation of laboratory tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection have recommended establishing an a priori definition of minimum clinical performance specifications before test selection and method evaluation. Methods Using positive (PPV) and negative predictive values (NPV), we constructed a spreadsheet tool for determining the minimum clinical specificity (conditional on NPV or PPV, sensitivity and prevalence) and minimum clinical sensitivity (conditional on NPV or PPV, specificity and prevalence) of tests. Results At a prevalence of 1%, there are no minimum sensitivity requirements to achieve a desired NPV of 60%-95% for a given clinical specificity above 20%. It is not possible to achieve 60–95% PPV even with 100% clinical sensitivity, except when the clinical specificity is near 100%. The opposite trend is seen in high prevalence settings (60%), where a relatively low minimum clinical sensitivity is required to achieve a desired PPV for a given clinical specificity, and a higher minimum clinical specificity is required to achieve a desired NPV for a given clinical sensitivity. Discussion The selection of laboratory tests and the testing strategy for SARS-CoV-2 involves delicate trade-offs between NPV and PPV based on prevalence and clinical sensitivity and clinical specificity. Practitioners and health authorities should carefully consider the clinical scenarios under which the test result will be used and select the most appropriate testing strategy that fulfils the a priori defined clinical performance specification.

ObjectiveTo estimate the extent that BP measurement variability may drive over- and underdiagnosis of 'hypertension' when measurements are made according to current guidelines.MethodsUsing data from the National Health and Nutrition Examination Survey and empirical estimates of within-person variability, we simulated annual SBP measurement sets for 1 000 000 patients over 5 years. For each measurement set, we used an average of multiple readings, as recommended by guidelines.ResultsThe mean true SBP for the simulated population was 118.8 mmHg with a standard deviation of 17.5 mmHg. The proportion overdiagnosed with 'hypertension' after five sets of office or nonoffice measurements using the 2017 American College of Cardiology guideline was 3-5% for people with a true SBP less than 120 mmHg, and 65-72% for people with a true SBP 120-130 mmHg. These proportions were less than 1% and 14-33% using the 2018 European Society of Hypertension and 2019 National Institute for Health and Care Excellence guidelines (true SBP ConclusionMore people are at risk of overdiagnosis under the 2017 American College of Cardiology guideline than the other two guidelines, even if nonoffice measurements are used. Making clinical decisions about cardiovascular prediction based primarily on absolute risk, minimizes the impact of blood pressure variability on overdiagnosis.

Coronavirus disease 2019 (COVID-19) is the third coronavirus outbreak that has emerged in the past 20 years, after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). One important aspect, highlighted by many global health organizations, is that this novel coronavirus outbreak may be especially hazardous to healthcare personnel, including laboratory professionals. Therefore, the aim of this document, prepared by the COVID-19 taskforce of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), is to provide a set of recommendations, adapted from official documents of international and national health agencies, on biosafety measures for routine clinical chemistry laboratories that operate at biosafety levels 1 (BSL-1; work with agents posing minimal threat to laboratory workers) and 2 (BSL-2; work with agents associated with human disease which pose moderate hazard). We believe that the interim measures proposed in this document for best practice will help minimazing the risk of developing COVID-19 while working in clinical laboratories.

BACKGROUND Acute kidney injury (AKI) is a rapid deterioration of renal function, often caused by a variety of co-existing morbidities complicating its recognition and treatment, leading to short- and long-term adverse clinical outcomes. There are limited data on the incidence of AKI in Australia using the Kidney Disease Improving Global Outcomes creatinine-based consensus definition. AIM To determine the incidence and estimate the extent of under-reporting of AKI in four hospitals in the South-Eastern Sydney/Illawarra regions of New South Wales, Australia. METHOD A laboratory algorithm based on the Kidney Disease Improving Global Outcomes creatinine-based definition for AKI was applied retrospectively to laboratory data for adult patients admitted to the study hospitals between 2009 and 2013 to identify those with AKI. The results were compared with the incidence of AKI based on diagnostic codes for AKI reported for the same period. RESULTS AKI was detected in 12.4% of all hospitalisations (46 101/370 969) and 16.4% of patients (31 448/192 133) across the 5-year study period using the laboratory algorithm. Of these, 72.1% were AKI Stage 1 (33 246/46101). AKI was coded in only 15.9% of hospitalisations with AKI Stage 1 (5294/33 246), 38.5% of hospitalisations with Stage 2 (2381/6185), and 46.8% with Stage 3 (3120/6670). Yearly incidence of laboratory-identified AKI trended downward between 2009 and 2013, while annual incidence determined by coding trended upward. CONCLUSION Although coding trends suggested a continuous increase in clinician awareness of AKI across the study period, AKI in hospitalised patients remained significantly under-reported.

AIM Kinetic estimated Glomerular Filtration Rate (KeGFR) approximates GFR under non-steady-state conditions. We investigated whether the ratio of KeGFR difference to baseline eGFR could predict acute kidney injury (AKI) earlier than a creatinine-based algorithm that triggered an AKI electronic Alert (eAlert). METHODS This retrospective, single-centre, proof-of-concept cohort study assessed all patients diagnosed with AKI by an automated serum creatinine-based eAlert. The kinetic eGFR, the kinetic eGFR difference from baseline and the ratio of difference to baseline was calculated in subjects with at least two serum creatinine (sCr) measurements within 72 h of AKI. RESULTS Patients in the AKI cohort (n = 140) had a significant decline in KeGFR ratio (AKI: 17% IQR 7% to 29%, Non-AKI: 0 IQR -12% to 9%; P-value

Background Biomarker discovery studies often claim ‘promising’ findings, motivating further studies and marketing as medical tests. Unfortunately, the patient benefits promised are often inadequately explained to guide further evaluation, and few biomarkers have translated to improved patient care. We present a practical guide for setting minimum clinical performance specifications to strengthen clinical performance study design and interpretation. Methods We developed a step-by-step approach using test evaluation and decision-analytic frameworks and present with illustrative examples. Results We define clinical performance specifications as a set of criteria that quantify the clinical performance a new test must attain to allow better health outcomes than current practice. We classify the proposed patient benefits of a new test into three broad groups and describe how to set minimum clinical performance at the level where the potential harm of false-positive and false-negative results does not outweigh the benefits. (1) For add-on tests proposed to improve disease outcomes by improving detection, define an acceptable trade-off for false-positive versus true-positive results; (2) for triage tests proposed to reduce unnecessary tests and treatment by ruling out disease, define an acceptable risk of false-negatives as a safety threshold; (3) for replacement tests proposed to provide other benefits, or reduce costs, without compromising accuracy, use existing tests to benchmark minimum accuracy levels. Conclusions Researchers can follow these guidelines to focus their study objectives and to define statistical hypotheses and sample size requirements. This way, clinical performance studies will allow conclusions about whether test performance is sufficient for intended use.

Background Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. Methods 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. Results Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975–1.078), and 1.019 (range 0.963–1.081), and intercepts of −0.584 (−53.736 to 54.790) and −3.194 (−17.152 to 5.933), respectively. The mean bias between methods was 1.2% (−11.6% to 16.0%) for metanephrine and 0.1% (−18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from −32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. Conclusions Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.

Testing for SARS-CoV-2 infection is key in managing the current pandemic. More than 1700 preprints and peer reviewed journal articles evaluating tests for SARS-CoV-2 infection have been published as of January 2021. However, evaluations of these studies have identified many methodological issues, leading to a high risk of bias and difficulties applying the results in practice. Better guidance is urgently needed on the conduct and interpretation of these studies. This article outlines the principles for defining the intended purpose of the test; study population selection; reference standard, test timing; and other critical considerations for the design, reporting, and interpretation of diagnostic accuracy studies. The implementation and accuracy of SARS-CoV-2 tests have major implications for individuals and communities, balancing the potential consequences of continued infection against the need for public health measures, such as the restriction of movements and social activities. Decision making in the current pandemic requires a clear understanding of the clinical performance and limitations of testing. This article provides guidance to assist researchers design robust diagnostic accuracy studies, assist publishers and peer reviewers to assess such studies, and support clinicians and policy makers in their evaluation of the evidence on SARS-CoV-2 testing for clinical and public health decisions. The guidance aims to ensure that studies evaluating the diagnostic accuracy of SARS-CoV-2 tests are conducted as rigorously as possible, in an efficient and timely way.

Highlights • It is important to minimize workplace cross-transmission during pandemic. • Impact of staff rostering arrangement on workplace cross-transmission is simulated. • From the results, less staff interaction leads to with less cross-transmission. • Laboratories should consider organizing the staff into smaller teams/ shift. • Frequent staff change is preferred (more shift/day, less consecutive days worked)., Background The recent global survey promoted by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 (coronavirus disease 2019) described staff rostering and organization as significant operational challenges during the COVID-19 pandemic. Method A discrete event simulation was used to explore the impact of different permutations of staff roster, including the number of shifts per day, the number of staff on duty per shift, overall number of staff accessible to work in the laboratory (i.e. overall staff pool), the frequency of shift changes (i.e. number of consecutive days worked), fixed work-rest days and split team arrangement on workplace transmission of COVID-19 by a simulated index staff who acquired the infection from the community over 21 days. Additionally, the impact of workplace social distancing (physical distancing) and use of personal protective equipment (PPE) were investigated. Results A higher rate of transmission was associated with smaller overall staff pool (expressed as multiples of the number of staff per shift), higher number of shifts per day, higher number of staff per shift, and longer consecutive days worked. Having fixed work-rest arrangement did not significantly reduce the transmission rate unless the workplace outbreak was prolonged. Social distancing and PPE use significantly reduced the transmission rate. Conclusion Laboratories should consider organizing the staff into smaller teams/shift and reduce the number of consecutive days worked. Additionally, our observation aligns with the IFCC biosafety recommendation of monitoring staff health (to detect early infection), split team arrangement, workplace social distancing and use of PPE.

Routine biochemical and hematological tests have been reported to be useful in the stratification and prognostication of pediatric and adult patients with diagnosed coronavirus disease (COVID-19), correlating with poor outcomes such as the need for mechanical ventilation or intensive care, progression to multisystem organ failure, and/or death. While these tests are already well established in most clinical laboratories, there is still debate regarding their clinical value in the management of COVID-19, particularly in pediatrics, as well as the value of composite clinical risk scores in COVID-19 prognostication. This document by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications for testing, (B) recommendations for test selection and interpretation, (C) considerations in test interpretation, and (D) current limitations of biochemical/hematological monitoring of COVID-19 patients. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide, underscoring the contribution of biochemical and hematological testing to our collective pandemic response.

Objectives Venous blood gas (VBG) analysis is becoming a popular alternative to arterial blood gas (ABG) analysis due to reduced risk of complications at phlebotomy and ease of draw. In lack of published data, this study aimed to establish reference intervals (RI) for correct interpretation of VBG results. Methods One hundred and 51 adult volunteers (101 females, 50 males, 18–70 years) were enrolled after completion of a health questionnaire. Venous blood was drawn into safePICO syringes and analysed on ABL827 blood gas analyser (Radiometer Pacific Pty. Ltd.). A non-parametric approach was used to directly establish the VBG RI which was compared to a calculated VBG RI based on a meta-analysis of differences between ABG and VBG Results After exclusions, 134 results were used to derive VBG RI: pH 7.30–7.43, partial pressure of carbon dioxide (pCO2) 38–58 mmHg, partial pressure of oxygen (pO2) 19–65 mmHg, bicarbonate (HCO3−) 22–30 mmol/L, sodium 135–143 mmol/L, potassium 3.6–4.5 mmol/L, chloride 101–110 mmol/L, ionised calcium 1.14–1.29 mmol/L, lactate 0.4–2.2 mmol/L, base excess (BE) −1.9–4.5 mmol/L, saturated oxygen (sO2) 23–93%, carboxyhaemoglobin 0.4–1.4% and methaemoglobin 0.3–0.9%. The meta-analysis revealed differences between ABG and VBG for pH, HCO3−, pCO2 and pO2 of 0.032, −1.0 mmol/L, −4.2 and 39.9 mmHg, respectively. Using this data along with established ABG RI, calculated VBG RI of pH 7.32–7.42, HCO3− 23 – 27 mmol/L, pCO2 36–49 mmHg (female), pCO2 39–52 mmHg (male) and pO2 43–68 mmHg were formulated and compared to the VBG RI of this study. Conclusions An adult reference interval has been established to assist interpretation of VBG results.

The global coronavirus disease 2019 (COVID-19) has presented major challenges for clinical laboratories, from initial diagnosis to patient monitoring and treatment. Initial response to this pandemic involved the development, production, and distribution of diagnostic molecular assays at an unprecedented rate, leading to minimal validation requirements and concerns regarding their diagnostic accuracy in clinical settings. In addition to molecular testing, serological assays to detect antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now becoming available from numerous diagnostic manufacturers. In both cases, the lack of peer-reviewed data and regulatory oversight, combined with general misconceptions regarding their appropriate use, have highlighted the importance of laboratory professionals in robustly validating and evaluating these assays for appropriate clinical use. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management. This review summarizes the latest evidence and status of molecular, serological, and biochemical testing in COVID-19 and highlights some key considerations for clinical laboratories operating to support the global fight against this ongoing pandemic. Confidently this consolidated information provides a useful resource to laboratories and a reminder of the laboratory’s critical role as the world battles this unprecedented crisis.

Objectives The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 conducted a global survey to understand how biochemistry laboratories manage the operational challenges during the coronavirus disease 2019 (COVID-19) pandemic. Materials and methods An electronic survey was distributed globally to record the operational considerations to mitigate biosafety risks in the laboratory. Additionally, the laboratories were asked to indicate the operational challenges they faced. Results A total of 1210 valid submissions were included in this analysis. Most of the survey participants worked in hospital laboratories. Around 15% of laboratories restricted certain tests on patients with clinically suspected or confirmed COVID-19 over biosafety concerns. Just over 10% of the laboratories had to restrict their test menu or services due to resource constraints. Approximately a third of laboratories performed temperature monitoring, while two thirds of laboratories increased the frequency of disinfection. Just less than 50% of the laboratories split their teams. The greatest reported challenge faced by laboratories during the COVID-19 pandemic is securing sufficient supplies of personal protective equipment (PPE), analytical equipment, including those used at the point of care, as well as reagents, consumables and other laboratory materials. This was followed by having inadequate staff, managing their morale, anxiety and deployment. Conclusions The restriction of tests and services may have undesirable clinical consequences as clinicians are deprived of important information to deliver appropriate care to their patients. Staff rostering and biosafety concerns require longer-term solutions as they are crucial for the continued operation of the laboratory during what may well be a prolonged pandemic.

Objectives A global survey was conducted by the IFCC Task Force on COVID-19 to better understand how general biochemistry laboratories manage the pre-analytical, analytical and post-analytical processes to mitigate biohazard risks during the coronavirus disease 2019 (COVID-19) pandemic. Methods An electronic survey was developed to record the general characteristics of the laboratory, as well as the pre-analytical, analytical, post-analytical and operational practices of biochemistry laboratories that are managing clinical samples of patients with COVID-19. Results A total of 1210 submissions were included in the analysis. The majority of responses came from hospital central/core laboratories that serve hospital patient groups and handle moderate daily sample volumes. There has been a decrease in the use of pneumatic tube transport, increase in hand delivery and increase in number of layers of plastic bags for samples of patients with clinically suspected or confirmed COVID-19. Surgical face masks and gloves are the most commonly used personal protective equipment (PPE). Just >50% of the laboratories did not perform an additional decontamination step on the instrument after analysis of samples from patients with clinically suspected or confirmed COVID-19. A fifth of laboratories disallowed add-on testing on these samples. Less than a quarter of laboratories autoclaved their samples prior to disposal. Conclusions The survey responses showed wide variation in pre-analytical, analytical and post-analytical practices in terms of PPE adoption and biosafety processes. It is likely that many of the suboptimal biosafety practices are related to practical local factors, such as limited PPE availability and lack of automated instrumentation.

Background Diagnostic testing provides integral information for the prevention, diagnosis, treatment and management of disease. Inadequate test result reporting and follow-up is a major risk to patient safety. Factors contributing to failure to follow-up test results include unclear delineation of responsibility about who is meant to act on a test result; poor coordination across different levels of care; and the absence of integrated health information systems for the efficient information communication. Methods A 2016 Australian Stakeholder Forum brought together over 30 representatives from 14 different consumer, clinical and management stakeholder organisations to discuss safe and effective test result communication, management and follow-up. Thematic analysis was conducted drawing on multimodal data collected in the form of observational fieldnotes and document artefacts produced by participants. Results The forum identified major challenges which pose immediate risks to patient safety. Participants recommended priorities for addressing issues relating to: (i) the governance of test result management processes; (ii) integration of health care processes through the utilisation of effective digital health solutions; and (iii) involving patients as key partners in the decision-making and care process. Conclusions Stakeholder groups diverged slightly in their priorities. Consumers highlighted the lack of patient involvement in the test result management process but were less concerned about standardisation of reports and critical result thresholds than pathologists. The forum foregrounded the need for a systems approach, capable of identifying and addressing interconnections and multiple factors that contribute to poor test result follow-up, with a strong emphasis on enhancing the contribution of patients.

Individual laboratories are required to compose an alert list for identifying critical and significant risk results. The high-risk result working party of the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical Biochemists (AACB) has developed a risk-based approach for a harmonized alert list for laboratories throughout Australia and New Zealand. The six-step process for alert threshold identification and assessment involves reviewing the literature, rating the available evidence, performing a risk analysis, assessing method transferability, considering workload implications and seeking endorsement from stakeholders. To demonstrate this approach, a worked example for deciding the upper alert threshold for potassium is described. The findings of the worked example are for infants aged 0–6 months, a recommended upper potassium alert threshold of >7.0 mmol/L in serum and >6.5 mmol/L in plasma, and for individuals older than 6 months, a threshold of >6.2 mmol/L in both serum and plasma. Limitations in defining alert thresholds include the lack of well-designed studies that measure the relationship between high-risk results and patient outcomes or the benefits of treatment to prevent harm, and the existence of a wide range of clinical practice guidelines with conflicting decision points at which treatment is required. The risk-based approach described presents a transparent, evidence- and consensus-based methodology that can be used by any laboratory when designing an alert list for local use. The RCPA-AACB harmonized alert list serves as a starter set for further local adaptation or adoption after consultation with clinical users.

Objectives The objective of the study was to identify the critical factors that determine recommendations and other decisions about healthcare-related tests and diagnostic strategies (HCTDS). Methods We used a qualitative descriptive approach and conducted semi-structured in-depth interviews with 24 international experts (informants) in evidence and decisions about HCTDS. Results Although test accuracy (TA) was the factor most commonly considered by organizations when developing recommendations about HCTDS, informants agreed that TA is necessary but rarely, if ever, sufficient and may be misleading when solely considered. The informants identified factors that are important for developing recommendations about HCTDS. Informants largely agreed that laying out the potential care pathways based on the test result is an essential early step but is rarely done in developing recommendations about HCTDS. Most informants also agreed that decision analysis could be useful for organizing the clinical, cost, and preference data relevant to the use of tests in the absence of direct evidence. However, they noted that using models is limited by the lack of resources and expertise required. Conclusion Developing guidelines about HCTDS requires consideration of factors beyond TA, but implementing this may be challenging. Further development and testing of “frameworks” that can guide this process is a priority for decision makers.

BACKGROUNDPathology laboratories are required to immediately report results which indicate a patient is at critical risk, but there is little consensus about what values are deemed critical. The aim of this review was to systematically review the literature on alert thresholds for common chemistry and hematology tests in adults and to provide an explicit and ranked source of this evidence.METHODSThe literature search covered the period of 1995–2014. Evidence sources were critically appraised and ranked using the 1999 Stockholm hierarchy for analytical performance specifications in laboratory medicine modified for establishing decision limits.RESULTSThe 30 most frequently reported laboratory tests with alert thresholds are presented with evidence rankings. Similar thresholds were reported in North America, Europe and Asia. Seventy percent of papers reported thresholds set by individual institutions, while 18% contained thresholds from surveys of laboratories or clinicians. Forty-six percent of the papers referred to 1 or both of the 2 American laboratory surveys from the early 1990s. “Starter sets” of alert thresholds were recommended by 6 professional bodies, 3 of which were collaborations between pathologists and clinicians. None of the 9 outcome studies identified dealt with confounding factors.CONCLUSIONSRecommendations by professional bodies based on outdated surveys of the former state of the art or consensus are currently the best sources of evidence for laboratories to build their alert list. Well-designed outcome studies and greater collaboration between clinicians and the laboratory are needed to identify the most appropriate alert thresholds that signify actionable, critical or significant risk to patient well-being.

Background The introduction of new biomarkers can lead to inappropriate utilization of tests if they do not fill in existing gaps in clinical care. We aimed to define a strategy and checklist for identifying unmet needs for biomarkers. Methods A multidisciplinary working group used a 4-step process: 1/ scoping literature review; 2/ face-to-face meetings to discuss scope, strategy and checklist items; 3/ iterative process of feedback and consensus to develop the checklist; 4/ testing and refinement of checklist items using case scenarios. Results We used clinical pathway mapping to identify clinical management decisions linking biomarker testing to health outcomes and developed a 14-item checklist organized into 4 domains: 1/ identifying and 2/ verifying the unmet need; 3/ validating the intended use; and 4/ assessing the feasibility of the new biomarker to influence clinical practice and health outcome. We present an outcome-focused approach that can be used by multiple stakeholders for any medical test, irrespective of the purpose and role of testing. Conclusions The checklist intends to achieve more efficient biomarker development and translation into practice. We propose the checklist is field tested by stakeholders, and advocate the role of the clinical laboratory professional to foster trans-sector collaboration in this regard.

In 2 recent American clinical guidelines dealing with laboratory tests for evaluation of liver disease, key recommendations relate to alanine aminotransferase (ALT) 6 upper reference limits (URLs) to be used as action limits in interpreting abnormal results of this enzyme (1, 2). In adults, the American College of Gastroenterology (ACG) recommends ALT URLs of 33 U/L for males and 25 U/L for females, respectively, and that individuals with enzyme catalytic activity concentrations above these URLs should be further investigated (1). In children, experts of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) state that the interpretation of ALT should be based upon gender-specific URLs (26 U/L for boys and 22 U/L for girls). We have some reservations about the universal application of these ALT cutoffs and we are concerned that the implementation of these recommendations may lead to overdiagnosis and unnecessary further testing. The contentious issues and our opinion about those are summarized below. The first problem is the analytical variation among commercial assays measuring ALT. The mentioned guidelines recommend the use of universal cutoffs for ALT without considering any differences between laboratory assays. Reassuring statements are rather reported as follows: “interlaboratory differences for ALT levels have not been reported to differ significantly” (1) or “the [ ALT ] assay is standardized between facilities” (2). In principle, fixed limits, be they medical decision thresholds or URLs, can be used only if the laboratory test in question is standardized and if this standardization is implemented in laboratories using the same limits. Despite the availability of a reference measurement system (RMS) for standardizing ALT results in clinical samples, the current evidence is, however, that ALT is still …

IntroductionThe failure to follow-up pathology and medical imaging test results poses patient-safety risks which threaten the effectiveness, quality and safety of patient care. The objective of this project is to: (1) improve the effectiveness and safety of test-result management through the establishment of clear governance processes of communication, responsibility and accountability; (2) harness health information technology (IT) to inform and monitor test-result management; (3) enhance the contribution of consumers to the establishment of safe and effective test-result management systems.Methods and analysisThis convergent mixed-methods project triangulates three multistage studies at seven adult hospitals and one paediatric hospital in Australia.Study 1 adopts qualitative research approaches including semistructured interviews, focus groups and ethnographic observations to gain a better understanding of test-result communication and management practices in hospitals, and to identify patient-safety risks which require quality-improvement interventions.Study 2 analyses linked sets of routinely collected healthcare data to examine critical test-result thresholds and test-result notification processes. A controlled before-and-after study across three emergency departments will measure the impact of interventions (including the use of IT) developed to improve the safety and quality of test-result communication and management processes.Study 3 adopts a consumer-driven approach, including semistructured interviews, and the convening of consumer-reference groups and community forums. The qualitative data will identify mechanisms to enhance the role of consumers in test-management governance processes, and inform the direction of the research and the interpretation of findings.Ethics and disseminationEthical approval has been granted by the South Eastern Sydney Local Health District Human Research Ethics Committee and Macquarie University. Findings will be disseminated in academic, industry and consumer journals, newsletters and conferences.

Background and objectives Monitoring N-terminal pro–B-type natriuretic peptide (NT-proBNP) may be useful for assessing cardiovascular risk in dialysis patients. However, its biologic variation is unknown, hindering the accurate interpretation of serial concentrations. The aims of this prospective cohort study were to estimate the within- and between-person coefficients of variation of NT-proBNP in stable dialysis patients, and derive the critical difference between measurements needed to exclude biologic and analytic variation. Design, setting, participants, & measurements Fifty-five prevalent hemodialysis and peritoneal dialysis patients attending two hospitals were assessed weekly for 5 weeks and then monthly for 4 months between October 2010 and April 2012. Assessments were conducted at the same time in the dialysis cycle and entailed NT-proBNP testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they became unstable. Results This study analyzed 136 weekly and 113 monthly NT-proBNP measurements from 40 and 41 stable patients, respectively. Results showed that 22% had ischemic heart disease; 9% and 87% had left ventricular systolic and diastolic dysfunction, respectively. Respective between- and within-person coefficients of variation were 153% and 27% for weekly measurements, and 148% and 35% for monthly measurements. Within-person variation was unaffected by dialysis modality, hydration status, inflammation, or cardiac comorbidity. NT-proBNP concentrations measured at weekly intervals needed to increase by at least 46% or decrease by 84% to exclude change due to biologic and analytic variation alone with 90% certainty, whereas monthly measurements needed to increase by at least 119% or decrease by 54%. Conclusions The between-person variation of NT-proBNP was large and markedly greater than within-person variation, indicating that NT-proBNP testing might better be applied in the dialysis population using a relative-change strategy. Serial NT-proBNP concentrations need to double or halve to confidently exclude change due to analytic and biologic variation alone.

BACKGROUND LC-MS/MS with multiple reaction monitoring (MRM) is a powerful tool for quantifying target analytes in complex matrices. However, the technique lacks selectivity when plasma free metanephrines are measured. We propose the use of multistage fragmentation (MRM3) to improve the analytical selectivity of plasma free metanephrine measurement. METHODS Metanephrines were extracted from plasma with weak cation exchange solid-phase extraction before separation by hydrophilic interaction liquid chromatography. We quantified normetanephrine and metanephrine by either MRM or MRM3 transitions m/z 166→134→79 and m/z 180→149→121, respectively. RESULTS Over a 6-month period, approximately 1% (n = 21) of patient samples showed uncharacterized coeluting substances that interfered with the routine assay, resulting in an inability to report results. Quantification with MRM3 removed these interferences and enabled measurement of the target compounds. For patient samples unaffected by interferences, Deming regression analysis demonstrated a correlation between MRM3 and MRM methods of y = 1.00x − 0.00 nmol/L for normetanephrine and y = 0.99x + 0.03 nmol/L for metanephrine. Between the MRM3 method and the median of all LC-MS/MS laboratories enrolled in a quality assurance program, the correlations were y = 0.97x + 0.03 nmol/L for normetanephrine and y = 1.03x − 0.04 nmol/L for metanephrine. Imprecision for the MRM3 method was 6.2%–7.0% for normetanephrine and 6.1%–9.9% for metanephrine (n = 10). The lower limits of quantification for the MRM3 method were 0.20 nmol/L for normetanephrine and 0.16 nmol/L for metanephrine. CONCLUSIONS The use of MRM3 technology improves the analytical selectivity of plasma free metanephrine quantification by LC-MS/MS while demonstrating sufficient analytical sensitivity and imprecision.

Importance No guidelines exist currently for guideline panels and others considering changes to disease definitions. Panels frequently widen disease definitions, increasing the proportion of the population labeled as unwell and potentially causing harm to patients. We set out to develop a checklist of issues, with guidance, for panels to consider prior to modifying a disease definition. Observations We assembled a multidisciplinary, multicontinent working group of 13 members, including members from the Guidelines International Network, Grading of Recommendations Assessment, Development and Evaluation working group, and the World Health Organisation. We used a 5-step process to develop the checklist: (1) a literature review of issues, (2) a draft outline document, (3) a Delphi process of feedback on the list of issues, (4) a 1-day face-to-face meeting, and (5) further refinement of the checklist. The literature review identified 12 potential issues. From these, the group developed an 8-item checklist that consisted of definition changes, number of people affected, trigger, prognostic ability, disease definition precision and accuracy, potential benefits, potential harms, and the balance between potential harms and benefits. The checklist is accompanied by an explanation of each item and the types of evidence to assess each one. We used a panel’s recent consideration of a proposed change in the definition of gestational diabetes mellitus (GDM) to illustrate use of the checklist. Conclusions and Relevance We propose that the checklist be piloted and validated by groups developing new guidelines. We anticipate that the use of the checklist will be a first step to guidance and better documentation of definition changes prior to introducing modified disease definitions.

Increasing patient risks and costs associated with the delivery of health care services have been related to inappropriate and uncontrolled use of biomarkers which make evidence-based guideline recommendations for best practice increasingly important. The translation of basic scientific discoveries into clinically meaningful studies and then to evidence-based clinical practice guidelines (CPGs) or health policy is, however, not straightforward. CPGs are potentially the most influential publications as they aim to guide clinical decisions and impact patient outcomes; hence, current approaches to their development often fail scientific publication standards. Critical appraisal of CPGs has revealed that many do not involve laboratory professionals in formulating recommendations on the use of tests; the composition of the panel could influence the scope of guidelines and over-represent certain stakeholders’ views; numerous CPGs do not have rigorous evidence-based methodology and miss essential information important for the correct interpretation and application of laboratory results.

Summary Aim To evaluate the educational effectiveness of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduate medical trainees compared to a traditional lecture-based course of equivalent content. Methods We conducted a cluster randomized controlled trial to compare a clinically integrated e-learning EBM course (intervention) to a lecture-based course (control) among postgraduate trainees at foundation or internship level in seven teaching hospitals in the UK West Midlands region. Knowledge gain among participants was measured with a validated instrument using multiple choice questions. Change in knowledge was compared between groups taking into account the cluster design and adjusted for covariates at baseline using generalized estimating equations (GEE) model. Results There were seven clusters involving teaching of 237 trainees (122 in the intervention and 115 in the control group). The total number of postgraduate trainees who completed the course was 88 in the intervention group and 72 in the control group. After adjusting for baseline knowledge, there was no difference in the amount of improvement in knowledge of EBM between the two groups. The adjusted post course difference between the intervention group and the control group was only 0.1 scoring points (95% CI −1.2–1.4). Conclusion An e-learning course in EBM was as effective in improving knowledge as a standard lecture-based course. The benefits of an e-learning approach need to be considered when planning EBM curricula as it allows standardization of teaching materials and is a potential cost-effective alternative to standard lecture-based teaching.

Changes in high sensitivity cardiac troponin-T (hs-cTnT) concentrations may reflect either acute myocardial injury or biological variation. Distinguishing between these entities is essential to accurate diagnosis, however, the biological variation of hs-cTnT in dialysis population is currently unknown. We sought to estimate the within- and between-person coefficients of variation of hs-cTnT in stable dialysis patients, and derive the critical difference between measurements needed to exclude biological variation with 99% confidence.Fifty-five prevalent haemo- and peritoneal-dialysis patients attending two metropolitan hospitals were assessed on 10 consecutive occasions; weekly for 5 weeks then monthly for 4 months. Assessments were conducted at the same dialysis cycle time-point and entailed hs-cTnT testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they developed clinical or physiological instability.In total 137 weekly and 114 monthly hs-cTnT measurements from 42 stable patients were analysed. Respective between- and within-person coefficients of variation were 83% and 7.9% for weekly measurements, and 79% and 12.6% for monthly measurements. Within-person variation was unaffected by dialysis modality or cardiac co-morbidity. The bidirectional 99% reference change value was –25% and +33% for weekly measurements, and –37% and +58% for monthly measurements.The between-person variation of hs-cTnT in the dialysis population is markedly greater than within-person variation indicating that hs-cTnT testing is best applied in this population using a relative change strategy. An increase of 33% or a reduction of 25% in serial hs-cTnT concentrations measured at weekly intervals excludes change due to analytical and biological variation alone with 99% confidence.

Introduction Standardisation of treatment with vitamin K antagonists (VKAs) is still an issue after 60 years of use. The study aimed to explore aspects of VKA monitoring in primary and secondary care. Methods Two case histories were distributed to physicians in 13 countries. Case history A focused on a patient with atrial fibrillation on stable anticoagulation (latest INR 2.3). Physicians were asked about frequency of INR measurement, when to change the VKA dose, and the patient's annual risk of ischemic stroke and bleeding. Case history B focused on a patient with an unexpected INR of 4.8, asking for the patient's 48-hour bleeding risk, the immediate dose reduction and time until a repeat INR. Results Altogether, 3016 physicians responded (response rate 8 – 38%), of which 82% were from primary care and 18% from secondary care. Answers varied substantially within and between countries regardless of level of care and VKA used. Median number of weeks between INR measurements was 4 – 6 weeks. Median threshold INR for increasing or decreasing the VKA dose was 1.9 and 3.1, respectively. Risk of ischemic stroke and bleeding were overestimated 2 – 3 times. In case history B, the median dose reduction the two first days was 75% for GPs and 55% for specialists, irrespective of estimates of bleeding risk; with one week to a repeat INR. Conclusion Variation in VKA monitoring is substantial implying clinical consequences. Guidelines seem either unknown or may be considered impracticable. Further efforts towards standardisation of VKA management are needed.

Aim: To determine: (i) the proportion of stable asymptomatic haemodialysis patients with elevated troponin; (ii) stability of troponin values after dialysis and over a 2-week interval; and (iii) whether high-sensitivity troponin T (hsTnT) was associated with higher prevalence of cardiovascular risk factors or cardiovascular disease in these patients. Methods: We measured hsTnT and the fourth generation troponin I before and after dialysis in 103 stable in-centre haemodialysis patients without ischaemic symptoms. Patients were divided into quartiles to test for associations with established cardiovascular risk factors or disease. Results: hsTnT was above the 99th percentile for the general population in 99% of haemodialysis patients compared with only 13% elevation for the troponin I assay (P

Representation and progression among women with advanced degrees in science and medicine have significantly improved over the past 50 years. A recent report from the Association of American Medical Colleges indicates that despite women being in the minority, the number of female division/section chiefs, department chairs, and deans has increased overall by more than 50% in the past 10 years (https://www.aamc.org/members/gwims/statistics/; accessed April 2, 2012). This information and the election of 3 consecutive female AACC presidents and a new female AACC executive vice president caused us to reflect on the increasing global presence of female leaders in clinical chemistry and laboratory medicine. As female laboratory directors, mothers, and members of AACC's Society for Young Clinical Laboratorians group, we have the perception that our profession is a supportive environment and a well-suited career for young women today, but we wondered if it has always been that way. We posed a series of questions to a multigenerational panel of female clinical chemists, who relate their experiences as women in clinical chemistry and laboratory medicine over the past several decades. How do you think the work climate has changed for women since you began your scientific career, and have you experienced any personal struggles because you are a female in clinical chemistry? What advice would you give young women starting out in the field of clinical chemistry? Helen Free: At times I felt like a second-class citizen, not because I was female, but because I didn't have a PhD! I began my career during WWII, and I was needed because all the men were in the armed forces. I'm 89 and didn't realize there were gender discrepancies in clinical chemistry. I would advise those starting out in the field to go into your career with a positive attitude and work toward equality …

OBJECTIVES Electrochemotherapy (ECT) is a novel therapeutic option for the treatment of cutaneous and subcutaneous metastases of malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver nonpermeant or poorly permeant chemotherapeutic agents into the cells, increasing local cytotoxicity of anticancer drugs. We compared the clinical effectiveness of ECT as an alternative palliative treatment option for unresectable metastatic lesions of malignant melanoma with a systematic review of reported outcomes. METHODS One hundred fifty-eight cutaneous and subcutaneous metastases of nine patients were treated with ECT. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 195 days. RESULTS In our case series, complete response rate was 23%, and partial response rate was 39%. We observed no change in 30% and progressive disease in 8% of cases. CONCLUSIONS ECT is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma with minimal side effects. Our results provide further data for the growing body of evidence in recently published studies that ECT used for palliation has clinical benefit. The authors have indicated no significant interest with commercial supporters.