Outcome-based analytical performance specifications: current status and future challenges.

Analytical performance specifications (APS) based on outcomes refer to how 'good' the analytical performance of a test needs to be to do more good than harm to the patient. Analytical performance of a measurand affects its clinical performance. Without first setting clinical performance requirements, it is difficult to define how good analytically the test needs to be to meet medical needs. As testing is indirectly linked to health outcomes through clinical decisions on patient management, often simulation-based studies are used to assess the impact of analytical performance on the probability of clinical outcomes which is then translated to Model 1b APS according to the Milan consensus. This paper discusses the related key definitions, concepts and considerations that should assist in finding the most appropriate methods for deriving Model 1b APS. We review the advantages and limitations of published methods and discuss the criteria for transferability of Model 1b APS to different settings. We consider that the definition of the clinically acceptable misclassification rate is central to Model 1b APS. We provide some examples and guidance on a more systematic approach for first defining the clinical performance requirements for tests and we also highlight a few ideas to tackle the future challenges associated with providing outcome-based APS for laboratory testing.

Applying the Milan models to setting analytical performance specifications - considering all the information.

Analytical performance specifications (APS) are used for decisions about the required analytical quality of pathology tests to meet clinical needs. The Milan models, based on clinical outcome, biological variation, or state of the art, were developed to provide a framework for setting APS. An approach has been proposed to assign each measurand to one of the models based on a defined clinical use, physiological control, or an absence of quality information about these factors. In this paper we propose that in addition to such assignment, available information from all models should be considered using a risk-based approach that considers the purpose and role of the actual test in a clinical pathway and its impact on medical decisions and clinical outcomes in addition to biological variation and the state-of-the-art. Consideration of APS already in use and the use of results in calculations may also need to be considered to determine the most appropriate APS for use in a specific setting.

A New Concept for Reference Change Values-Regression to the Population Mean.

BACKGROUND: Reference change values (RCV) are used to indicate a change in analyte concentration that is unlikely to be due to random variation in the patient or the measurement. Current theory describes RCV relative to a first measurement result (X1). We investigate an alternative view predicting the starting point for RCV calculations from X1 and its location in the reference interval. METHODS: Data for serum sodium, calcium, and total protein from the European Biological Variation study and from routine clinical collections were analyzed for the effect of the position of X1 within the reference interval on the following result from the same patient. A model to describe the effect was determined, and an equation to predict the RCV for a sample in a population was developed. RESULTS: For all data sets, the midpoints of the RCVs were dependent on the position of X1 in the population. Values for X1 below the population mean were more likely to be followed by a higher result, and X1 results above the mean were more likely to be followed by lower results. A model using population mean, reference interval dispersion, and result diagnostic variation provided a good fit with the data sets, and the derived equation predicted the changes seen. CONCLUSIONS: We have demonstrated that the position of X1 within the reference interval creates an asymmetrical RCV. This can be described as a regression to the population mean. Adding this concept to the theory of RCVs will be an important consideration in many cases.

Sharing reference intervals and monitoring patients across laboratories - findings from a likely commutable external quality assurance program.

OBJECTIVES: Laboratory results are increasingly interpreted against common reference intervals (CRIs), published clinical decision limits, or previous results for the same patient performed at different laboratories. However, there are no established systems to determine whether current analytical performance justifies these interpretations. We analysed data from a likely commutable external quality assurance program (EQA) to assess these interpretations. METHODS: The use of CRIs was assessed by evaluating instrument group medians against minimum specifications for bias. The use of clinical decision limits was assessed using specifications from professional bodies, and the monitoring of patients by testing at different laboratories was assessed by comparing all-laboratory imprecision to within-subject biological variation. RESULTS: Five of the 18 analytes with Australasian CRIs did not meet specification for all instrument groups. Among these, calcium and magnesium failed for one instrument group out of seven, while bicarbonate, chloride, and lipase failed for two instrument groups. Of the 18 analytes reviewed currently without CRIs in Australasia, 10 candidates were identified. Among analytes with clinical decision limits, i.e. lipids, glucose, and vitamin D, only triglycerides met both bias and imprecision specifications, while vitamin D met the imprecision specification. Monitoring patients by testing at different laboratories was supported for 15 of the 46 (33 %) analyte-method principles groups that met minimum imprecision specifications. CONCLUSIONS: Analysis of data from commutable EQA programs can provide a mechanism for monitoring whether analytical performance justifies the interpretations made in contemporary laboratory practice. EQA providers should establish systems for routinely providing this information to the laboratory community.

Total bilirubin assay differences may cause inconsistent treatment decisions in neonatal hyperbilirubinaemia.

OBJECTIVES: To assess interlaboratory variability of total serum bilirubin (TSB) results in newborns. Initiated following a clinical incident in which a neonate was transferred to a tertiary hospital for treatment of severe hyperbilirubinemia but on arrival was reclassified into a lower risk category due to a 20% difference in TSB between laboratories. METHODS: Fresh residual plasma samples from hospital-born infants were pooled to obtain 11 samples across a range of total bilirubin concentrations. Aliquots were light-protected and measured on 7 commercial platforms at 4 accredited medical laboratories. Data from The Royal College of Pathologists of Australasia Quality Assurance Programs' (RCPAQAP) Neonatal Bilirubin program was analysed. RESULTS: Twenty-four to 30% difference in results for individual samples, largely due to calibration differences between assays. When interpreted according to guidelines, results from different platforms would have led to different clinical interventions in some cases. RCPAQAP results showed significant within-method bias but were not shown to be commutable with patient samples. CONCLUSIONS: There are clinically significant method-dependent differences in TSB results from neonatal samples, consistent with our clinical incident. The differences are largely due to lack of standardisation of calibrator values. This has implications for healthcare resource use and possibly for the neurodevelopment of infants. Intervention is needed at a number of levels, including clinical reporting of incidents arising from discordant results, commitment by manufacturers to ensure metrological traceability of methods with sufficiently low uncertainty in the final measurements, and availability of commutable quality assurance material to monitor assay performance, especially at the clinical decision points for neonatal jaundice.

Metrological traceability and clinical traceability of laboratory results - the role of commutability in External Quality Assurance.

The role of an External Quality Assurance (EQA) program is generally seen as providing a service to routine laboratories that their analytical performance is satisfactory and stimulating corrective action in the event of poor results. It is recognised that an ideal EQA program uses materials that are commutable with patient samples and have values assigned by higher-order reference methods. Despite this, most routine EQA programs use materials without verified commutability and use consensus means (based on either peer group or all laboratories) as target values. We propose an ongoing role for EQA programs using non-commutable materials and consensus targets to support the measurement services of routine laboratories. This is provided the relevant comparators supplied by the laboratory, e.g. reference intervals and clinical decision points, are based on the same or equivalent measurement system as is used by the laboratory. Materials without verified commutability often have certain practical advantages, which may include the range of analyte concentrations, verified stability, replicate samples and, significantly, lower costs. Laboratories using such programs need to be aware of the limitations, especially comparing results from different measurement systems. However, we also recognise that as well as individual laboratories, data from EQA programs informs manufacturers, professional organisations, clinical guideline writers and other medical bodies For consideration beyond an individual laboratory, proper assessment of differences between measurement systems (results harmonization) and demonstration of correct implementation of metrological traceability (methods trueness) become vital, and for that purpose, commutability of EQA materials and traceability of target values are required.

Variability in insulin pharmacokinetics following high-dose insulin therapy.

INTRODUCTION: High dose insulin (HDI) therapy for cardiogenic shock from acute poisoning can be complicated by treatable hypoglycemia which persists following poisoning recovery. Glucose requirements post-HDI reflect supraphysiological insulin plasma concentration. A publication reported a patient treated with HDI with plasma insulin concentrations >1000 µU/mL and elimination half-life 10-18 h requiring intravenous glucose replacement for >5 days. We report two cases treated with HDI (Actrapid; soluble or regular insulin) with shorter elimination half-lives. CASE REPORTS: A man ingesting diltiazem received HDI for approximately 60 h (maximum dose 10 U/kg/h) and supplemental intravenous dextrose for 44 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 6345 µU/mL and elimination half-life 5.5 h. A man ingesting propranolol received HDI for approximately 12 h (maximum dose 1.5 U/kg/h) and supplemental intravenous dextrose for 4 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 368 µU/mL and elimination half-life 2.2 h. DISCUSSION: Markedly different insulin pharmacokinetics post-HDI is observed in two cases and a previously published report, and factors contributing to the interpatient differences are poorly defined. This pharmacokinetic variability impacts on the severity and duration of treatable hypoglycemia post-HDI. Analytical factors impacting on the measured plasma insulin concentrations include appropriate sample dilution and differing analytical specificity for the type of insulin.

AACC Guidance Document on Laboratory Investigation of Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a sudden episode of kidney damage or failure affecting up to 15% of hospitalized patients and is associated with serious short- and long-term complications, mortality, and health care costs. Current practices to diagnose and stage AKI are variable and do not factor in our improved understanding of the biological and analytical variability of creatinine. In addition, the emergence of biomarkers, for example, cystatin C, insulin-like growth factor binding protein 7, and tissue inhibitor of metalloproteinases 2, and electronic notification tools for earlier detection of AKI, highlights the need for updated recommendations to address these developments. CONTENT: This AACC Academy guidance document is intended to provide laboratorians and clinicians up-to-date information regarding current best practices for the laboratory investigation of AKI. Topics covered include: clinical indications for further investigating potential AKI, analytical considerations for creatinine assays, the impact of biological variability on diagnostic thresholds, defining "baseline" creatinine, role of traditional markers (urine sodium, fractional excretion of sodium, fractional excretion of urea, and blood urea-to-creatinine ratio), urinary microscopic examination, new biomarkers, improving AKI-associated test utilization, and the utility of automated AKI alerts. SUMMARY: The previous decade brought us a significant number of new studies characterizing the performance of existing and new biomarkers, as well as potential new tools for early detection and notification of AKI. This guidance document is intended to inform clinicians and laboratorians on the best practices for the laboratory investigation of AKI, based on expert recommendations where the preponderance of evidence is available.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Thyroid Peroxidase Antibody Positivity is Associated With Relapse-Free Survival Following Antithyroid Drug Treatment for Graves Disease.

OBJECTIVE: Graves' disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown. METHODS: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease. RESULTS: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse. CONCLUSION: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves' disease.

Is hyperfiltration associated with higher urine albumin-to-creatinine ratio at follow up among Indigenous Australians? The eGFR follow-up study.

BACKGROUND: Glomerular hyperfiltration is not able to be detected in clinical practice. We assessed whether hyperfiltration is associated with albuminuria progression among Indigenous Australians at high risk of diabetes and kidney disease to determine its role in kidney disease progression. METHODS: Longitudinal observational study of Indigenous Australians aged ≥18 years recruited from >20 sites, across diabetes and/or kidney function strata. At baseline, iohexol clearance was used to measure glomerular filtration rate (mGFR) and hyperfiltration was defined as (i) a mGFR of ≥125 mL/min/1.73 m2, and (ii) an age-adjusted definition, with the top 10% of the mGFR for each 10 year age group at baseline. Baseline and follow-up urine albumin-to-creatinine ratio (uACR) was collected, and linear regression was used to assess the associations of hyperfiltration and uACR at follow up. RESULTS: 407 individuals (33% men, mean age 47 years) were followed-up for a median of 3 years. At baseline, 234 had normoalbuminuria and 173 had albuminuria. Among participants with normoalbuminuria, those with mGFR ≥125 mL/min/1.73 m2 had 32% higher uACR at follow-up (p = 0.08), and those with age-adjusted hyperfiltration had 60% higher uACR (p = 0.037) compared to those who had normofiltration. These associations were independent of uACR at baseline, but attenuated by HbA1c. Associations were stronger among those without than those with albuminuria at baseline. CONCLUSIONS: Although not available for assessment in current clinical practice, hyperfiltration may represent a marker of subsequent albuminuria progression among individuals who have not yet developed albuminuria.

Divergence Estimation in the Presence of Incomplete Lineage Sorting and Migration.

This article focuses on the problem of estimating a species tree from multilocus data in the presence of incomplete lineage sorting and migration. I develop a mathematical model similar to IMa2 (Hey 2010) for the relevant evolutionary processes which allows both the population size parameters and the migration rates between pairs of species tree branches to be integrated out. I then describe a BEAST2 package DENIM (Divergence estimation notwithstanding ILS and migration) which is based on this model and which uses an approximation to sample from the posterior. The approximation is based on the assumption that migrations are rare, and it only samples from certain regions of the posterior which seem likely given this assumption. The method breaks down if there is a lot of migration. Using simulations, Leaché et al. (2014) showed that using the standard multispecies coalescent model to infer a species tree can result in poor accuracy if migration is present. I reanalyze this simulated data to explore DENIM's performance and demonstrate substantial improvements in accuracy over *BEAST. I also reanalyze an empirical data set.

Quantitation of Tapentadol by Liquid Chromatography: Tandem Mass Spectrometry.

Tapentadol is an orally active analgesic with a similar structure to tramadol. Its primary mechanism of action is agonist action on the mu-opioid receptor. The method described here quantitates tapentadol in the whole blood using a matching deuterated internal standard, extraction via a protein "crash" with acetonitrile, followed by analysis using liquid chromatography-tandem mass spectrometry.

At-a-glance - The role of opioid toxicity in suicide deaths in Alberta, 2000 to 2016. / Aperçu - Suicides et intoxication aux opioïdes en Alberta (2000-2016).

Given the current opioid crisis in Canada, there is interest in the role of opioid toxicity in suicide deaths, particularly in whether any observed patterns are similar to those of unintentional deaths. The present analysis examined characteristics of opioid-toxicity suicide, and its role in relation to other suicide methods, from 2000 to 2016 in Alberta. It does not appear that the opioid crisis has resulted in a disproportionately higher number of suicides in Alberta. Individuals who die from unintentional opioid toxicity and those who die by opioid-toxicity suicide are likely distinct populations, requiring nuanced public health responses for prevention.

RÉSUMÉ: Dans le cadre de la crise actuelle des opioïdes au Canada, il est important de s'intéresser au rôle joué par l'intoxication aux opioïdes dans les décès par suicide et, plus particulièrement, de déterminer si les tendances observées à cet égard sont similaires aux tendances observées pour les décès accidentels. Dans cette analyse, on examine les caractéristiques du suicide par intoxication aux opioïdes et la corrélation entre cette méthode et d'autres moyens de suicide entre 2000 et 2016 en Alberta. La crise des opioïdes ne semble pas avoir causé un nombre disproportionnellement élevé de suicides en Alberta. Les personnes qui décèdent des suites d'une intoxication accidentelle aux opioïdes et celles qui se suicident en s'intoxiquant avec des opioïdes constituent probablement des populations différentes, ce qui nécessite des interventions préventives nuancées en matière de santé publique.

An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric ß-lactam therapy.

To determine whether target concentration non-attainment can be anticipated in critically ill patients prior to initiating empiric ß-lactam antibiotic therapy based on readily available clinical factors. Retrospective review of consecutive patients treated with piperacillin or meropenem and who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015 was performed. Predefined subgroups were patients who received continuous renal replacement therapy (CRRT) and those who did not (non-CRRT). Potential risk factors were evaluated by correlation with ß-lactam antibiotic trough concentrations (Cmin) lower than or equal to targeted minimum inhibitory concentration (MIC). Only the first drug concentration after initiation of the antibiotic treatment was included to reflect empirical dose selection. A total of n = 249 patients (piperacillin, n = 169; meropenem, n = 80) were investigated. For non-CRRT patients (n = 210), multivariate analysis demonstrated the following: male gender (p = 0.006); younger age (p = 0.015); prescribed daily antibiotic dose less than 1.5 times the product information recommendations (p = 0.004); lack of positive microbiology (p = 0.006); lower overall illness severity (p = 0.005); and estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2 (p < 0.001), to be associated with Cmin ≤ MIC. No predictor variable was found to be significantly associated with Cmin ≤ MIC for the CRRT cohort. Evaluating the risk of target concentration non-attainment using simple clinical factors is possible at the bedside for non-CRRT patients prior to empiric antibiotic initiation. Clinicians should be wary of selecting doses based on the product information especially when treating younger male patients with apparently 'normal' renal function.

Report formatting in laboratory medicine - a call for harmony.

The results of medical laboratory testing are only useful if they lead to appropriate actions by medical practitioners and/or patients. An underappreciated component of the medical testing process is the transfer of the information from the laboratory report into the reader's brain. The format of laboratory reports can be determined by the testing laboratory, which may issue a formatted report, or by electronic systems receiving information from laboratories and controlling the report format. As doctors can receive information from many laboratories, interpreting information from reports in a safe and rapid manner is facilitated by having similar report layouts and formats. Using Australia as an example, there is a wide variation in report formats in spite of a body of work to define standards for reporting. In addition to standardising of report formats, consideration needs to be given to optimisation of report formatting to facilitate rapid and unambiguous reading of the report and also interpretation of the data. Innovative report formats have been developed by some laboratories; however, wide adoption has not followed. The need to balance uniformity of reporting with appropriate innovation is a challenge for safe reporting of laboratory results. This paper discusses the current status and opportunity for improvement in safety and efficiency of the reading of laboratory reports, using current practise and developments in Australia as examples.