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The Australasian Association of Clinical Biochemists (AACB) has over the past 5 years been actively working to achieve harmonized reference intervals (RIs) for common clinical chemistry analytes using an evidence-based checklist approach where there is sound calibration and metrological traceability. It has now recommended harmonized RIs for 18 common clinical chemistry analytes which are performed in most routine laboratories and these have been endorsed by the Royal College of Pathologists of Australasia (RCPA). In 2017 another group of analytes including urea, albumin and arterial blood gas parameters were considered and suggested harmonized RIs proposed. This report provides an update of those harmonization efforts. [ABSTRACT FROM AUTHOR]

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies. [ABSTRACT FROM AUTHOR]

Reference Intervals (RIs) and clinical decision limits (CDLs) are a vital part of the information supplied by laboratories to support the interpretation of numerical clinical pathology results. RIs describe the typical distribution of results seen in a healthy reference population while CDLs are associated with a significantly higher risk of adverse clinical outcomes or are diagnostic for the presence of a specific disease. However, as the two concepts are sometimes confused, there is a need to clarify the differences between these terms and to ensure they are easily distinguished, especially because CDLs have a clinical association with specific diseases and risks, thereby implying that effective clinical interventions are available. It is important to note that, because population-based RIs are derived from the range of values expected in a typical community population, laboratory results that fall outside a RI do not necessarily indicate a disease but rather that additional medical follow-up and/or treatment may be warranted. In contrast, CDLs are associated with a risk of specific adverse outcomes, and are commonly used to interpret laboratory test results, including lipid parameters, glucose, hemoglobin A1c (HbA1c), and tumor markers, to determine risk of disease, to diagnose or to treat. In recent years, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) has focused primarily on RIs and has performed multicenter studies to obtain common RIs. However, the broader responsibility of the Committee, from its name, includes “decision limits”. C-RIDL now aims to emphasize the importance of the correct use of both RIs and CDLs and to encourage laboratories to specify the appropriate information to clinicians as needed. This review discusses RIs and CDLs in detail, describes the similarities and the differences between these two important tools in laboratory medicine, and clearly explains the processes used to define them. C-RIDL encourages the involvement of laboratory professionals in the establishment of both RIs and CDLs. [ABSTRACT FROM AUTHOR]

Objective: Gestational Diabetes Mellitus (GDM) increases the risk of type 2 diabetes. A register can be used to follow-up high risk women for early intervention to prevent progression to type 2 diabetes. We evaluate the performance of the world’s first national gestational diabetes register. Research design and methods: Observational study that used data linkage to merge: (1) pathology data from the Australian states of Victoria (VIC) and South Australia (SA); (2) birth records from the Consultative Council on Obstetric and Paediatric Mortality and Morbidity (CCOPMM, VIC) and the South Australian Perinatal Statistics Collection (SAPSC, SA); (3) GDM and type 2 diabetes register data from the National Gestational Diabetes Register (NGDR). All pregnancies registered on CCOPMM and SAPSC for 2012 and 2013 were included–other data back to 2008 were used to support the analyses. Rates of screening for GDM, rates of registration on the NGDR, and rates of follow-up laboratory screening for type 2 diabetes are reported. Results: Estimated GDM screening rates were 86% in SA and 97% in VIC. Rates of registration on the NGDR ranged from 73% in SA (2013) to 91% in VIC (2013). During the study period rates of screening at six weeks postpartum ranged from 43% in SA (2012) to 58% in VIC (2013). There was little evidence of recall letters resulting in screening 12 months follow-up. Conclusions: GDM Screening and NGDR registration was effective in Australia. Recall by mail-out to young mothers and their GP’s for type 2 diabetes follow-up testing proved ineffective. [ABSTRACT FROM AUTHOR]

Introduction: Dyslipidemia affects up to 75% of morbidly obese individuals and is a key driver of cardiovascular disease. Weight loss is an established strategy to improve metabolic risk, including dyslipidemia. We aimed to determine weight loss goals for resolution of serum lipid abnormalities, by measuring improvements during progressive weight loss in obese individuals.Methods: We performed a prospective cohort study of obese individuals with the metabolic syndrome undergoing adjustable gastric banding. Lipid levels were monitored monthly for 9 months, then three monthly until 24 months.Results: There were 101 participants included, age 47.4 ± 10.9 years with body mass index 42.6 ± 5.9 kg/m2. At 24 months, total body weight loss (TBWL) was 18.3 ± 7.9%. This was associated with significant improvements in high-density lipoprotein (HDL) (1.18 vs 1.47, p < 0.001), triglyceride (2.0 vs 1.4, p < 0.001), and total cholesterol to HDL ratio (TC:HDL) (4.6 vs 3.6, p < 0.001). Over this time, progressive and linear improvements in HDL, triglycerides, and TC:HDL were seen with incremental weight loss (observed at 2.5% TBWL intervals). Significant improvements occurred after a threshold weight loss of 7.5-12.5% TBWL was achieved, with odds ratio (OR) 1.48-2.50 for normalization. These odds improved significantly with increasing weight loss (OR 18.2-30.4 with > 25% TBWL). Despite significant weight loss, there was no significant change in low-density lipoprotein (LDL).Conclusion: Significant improvements in triglycerides, HDL, and TC:HDL occur after 7.5-12.5% TBWL, with ongoing benefit after greater weight loss. LDL needs to be addressed independently, as this was not observed to respond to weight loss alone.Trial registration number: Australian Clinical Trials Registry (ACTRN12610000049077) [ABSTRACT FROM AUTHOR]

Background Biotin interference is a significant problem to which at-risk laboratories must now be attuned. We sought to systematically characterize the nature of this interference in Roche immunoassays. Methods Known concentrations of biotin were titrated into serum samples and the effects on competitive and sandwich immunoassays were analysed. The maximum and minimum concentrations examined reflect those likely to be achieved in individuals on 5 to 10 mg supplements at the lower end, and 100 to 300 mg biotin at the high end. Results A high variability in biotin tolerance was observed. Some assays, such as troponin T, TSH and antithyroid antibodies, were extremely sensitive to the lower concentrations of biotin (15.6 and 31.3 ng/mL), whereas the majority of assays were relatively resistant. At concentrations ≥500 ng/mL, all assays showed significant interference from biotin but, again, the magnitude of the interference was variable. The more sensitive assays showed profound analytical bias at biotin concentrations that occur with high-dose therapy. Conclusion Our data demonstrate high variability in biotin tolerance across Roche immunoassays. The shape of the dose-response curves provides more detailed information than the single manufacturer-quoted figure for biotin tolerance. Accordingly, these data may be used by laboratories for more accurate risk assessment in predicting the effects of biotin. Our data may also be extrapolated to guide timing of blood tests in patients on high-dose biotin therapy: it demonstrates the number of half-lives required to withhold biotin in order to decrease its concentration to below a given assay tolerance. [ABSTRACT FROM AUTHOR]

Background Biotin interference in streptavidin-based immunoassays causes widespread analytical distortions that may lead to clinical confusion, inappropriate patient management and, ultimately, adverse events. Its prevalence has increased recently due to the increased use of high-dose biotin therapy in specific patient groups (notably multiple sclerosis) and possibly the general community. Methods We have developed a method to deplete biotin from samples using the streptavidin-coated magnetic microparticles that are a component of most susceptible assays. Results We show that high concentrations of spiked biotin can be adequately depleted from serum using this approach, and that gross biochemical derangements can be restored to normality. We also show that biotin in samples derived from multiple sclerosis patients receiving 300 mg biotin daily can be adequately depleted to remove associated analytical interference and restore normal results. The method is applicable to competitive and sandwich immunoassays and importantly, because it does not change the volume of the sample, suitable for the measurement of free thyroid hormone assays. Application of the method does not significantly change the precision of measurement, and for the majority of analytes, the accuracy is not substantially altered. Conclusions Adopting this method enables laboratories to confirm biotin interference in the appropriate clinical setting. Moreover, it enables laboratories to remove the interference and report accurate and reliable results, without the need for patients to withhold beneficial therapy prior to blood tests. Until the biotin tolerance of susceptible assays is improved, our method gives laboratories a safe alternative for reporting results using streptavidin-based methods. [ABSTRACT FROM AUTHOR]

Objectives: Nonalcoholic fatty liver disease (NAFLD) affects over 80% of obese patients and is fueled by the metabolic syndrome. Weight loss is strongly advocated as a central treatment for NAFLD and has been shown to induce histological improvement. We aimed to define the patterns of improvement in NAFLD with weight loss and determine target weight goals for NAFLD resolution. Methods: A prospective study of 84 morbidly obese patients with NAFLD undergoing bariatric surgery was conducted. Intraoperative liver biopsies were taken. Monthly follow-up, including blood tests and measurements, was performed. We monitored improvements in NAFLD by monthly alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels over 1 year. Results: There was rapid improvement in ALT, particularly in the first 6 months following surgery, with statistically significant reduction in ALT at 2 months (35 vs 27 IU/L, p < 0.001). In multivariate analysis, there were significantly increased odds of ALT normalization after a %TBWL of 10-15% (odds ratio 2.49, p = 0.005). The odds of resolution increased with increasing weight loss. Triglyceride levels (odds ratio 0.59, p = 0.021) and baseline NAFLD activity score (odds ratio 0.28, p < 0.001) were also significantly related to ALT normalization. Improvements in ALT occurred prior to metabolic improvement and well before traditional ideal weight goals were reached. Conclusion: Improvements in NAFLD occurred rapidly after bariatric surgery and were closely related to weight loss and metabolic factors. A 10-15% reduction in body weight is an appropriate target to achieve substantial improvement in ALT levels. Trial registration number: Australian Clinical Trials Registry (ACTRN12610000049077). [ABSTRACT FROM AUTHOR]

Background: Obesity and its related comorbidities are significant risk factors for nonalcoholic fatty liver disease (NAFLD). Liver fibrosis is the major determinant of long-term outcomes in NAFLD. A non-invasive tool that accurately identifies obese patients at elevated risk of liver fibrosis would be of significant value. Fibrosis risk scores in patients with NAFLD have been proposed but have not been validated in obese populations. We aimed to validate established simple fibrosis scores in bariatric surgical patients. Methods: We conducted a prospective study of 107 consecutive high-risk obese patients undergoing primary bariatric surgery. Proposed fibrosis scores (NAFLD fibrosis score; body mass index (BMI), aspartate aminotransferase (AST)/alanine aminotransferase ratio (ALT), and diabetes (BARD); Fibrosis-4 (FIB-4); Forn; and AST to platelet ratio index) were calculated and compared hepatic fibrosis determined by histology of intraoperative liver biopsies. Accuracy was determined, and fibrosis score thresholds were optimized. These modified thresholds were then validated in an independent bariatric surgical population. Results: Liver biopsies were available in 101 patients. Sixty-eight patients had some degree of fibrosis, with 23 patients (23 %) having significant fibrosis (F2-4). The Forn score best predicted significant fibrosis (area under the receiver operator characteristic curve (AUROC) 0.724, p = 0.001). With standard thresholds, the sensitivity for the Forn score for identification of significant fibrosis (F2-4) was 0 %. Using modified thresholds of 3.5, the sensitivity and negative predictive value increased to 85.7 and 94.7 %. This threshold was applied to an independent validation cohort with good accuracy. Conclusions: Fibrosis risk scores using simple markers have moderate success at delineating obese patients with significant NAFLD-related fibrosis. Thresholds, however, need to be lowered to maximize diagnostic accuracy in this cohort. [ABSTRACT FROM AUTHOR]

Background: Age-specific trends of serum testosterone and sex hormone-binding globulin across the full lifespan have not been reported.Methods: We deduced age-specific trends in serum testosterone and sex hormone-binding globulin in males and females between ages 10 and 90 from a large sample of consecutive results from a single large pathology laboratory. Coded results of 110,712 consecutive blood samples requesting serum testosterone over seven years (2007-2013) comprising blood testosterone, sex hormone-binding globulin and calculated free testosterone together with gender and age were analysed create smoothed age-specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females.Results: These identified the pubertal increases in serum testosterone in males peaking at 20 years of age and remaining stable thereafter until the eighth decade. In females, circulating testosterone peaked in late adolescence and declined gradually over the next two decades but remained stable across menopause and beyond. After early childhood, serum sex hormone-binding globulin declines to a nadir in males at the age of 20 years and remains stable till the sixth decade with a gradual, progressive rise thereafter. In females, the sex hormone-binding globulin nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Females also exhibit a second sex hormone-binding globulin peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of females.Conclusions: This large sample of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age. [ABSTRACT FROM AUTHOR]

The authors discuss changes in maternal physiology which cause changes in electrolyte and acid-base status of pregnant women and the factors to consider in adopting pregnancy-specific reference intervals. Topics discussed include the role of pregnancy reference intervals in clinical biochemistry, pregnancy dating and defining partitions, and vascular and renal physiology changes during pregnancy. It also discusses analytes such as sodium, potassium and chloride.