A guide to conducting systematic reviews of clinical laboratory tests.

Clinical laboratory professionals have an instrumental role in supporting clinical decision making with the optimal use of laboratory testing for screening, risk stratification, diagnostic, prognostic, treatment selection and monitoring of different states of health and disease. Delivering evidence-based laboratory medicine relies on review of available data and literature. The information derived, supports many national policies to improve patient care through clinical practice guidelines or best practice recommendations. The quality, validity and bias of this literature is variable. Hence, there is a need to collate similar studies and data and analyse them critically. Systematic review, thus, becomes the most important source of evidence. A systematic review, unlike a scoping or narrative review, involves a thorough understanding of the procedure involved and a stepwise methodology. There are nuances that need some consideration for laboratory medicine systematic reviews. The purpose of this article is to describe the process of performing a systematic review in the field of laboratory medicine, describing the available methodologies, tools and software packages that can be used to facilitate this process.

Lipid distributions in the Global Diagnostics Network across five continents.

AIMS: Lipids are central in the development of cardiovascular disease, and the present study aimed to characterize variation in lipid profiles across different countries to improve understanding of cardiovascular risk and opportunities for risk-reducing interventions. METHODS AND RESULTS: This first collaborative report of the Global Diagnostics Network (GDN) evaluated lipid distributions from nine laboratory organizations providing clinical laboratory testing in 17 countries on five continents. This cross-sectional study assessed aggregated lipid results from patients aged 20-89 years, tested at GDN laboratories, from 2018 through 2020. In addition to mean levels, the World Health Organization total cholesterol risk target (<5.00 mmol/L, <193 mg/dL) and proportions in guideline-based low-density lipoprotein cholesterol (LDL-C) categories were assessed. This study of 461 888 753 lipid results found wide variation by country/region, sex, and age. In most countries, total cholesterol and LDL-C peaked at 50-59 years in females and 40-49 years in males. Sex- and age-group adjusted mean total cholesterol levels ranged from 4.58 mmol/L (177.1 mg/dL) in the Republic of Korea to 5.40 mmol/L (208.8 mg/dL) in Austria. Mean total cholesterol levels exceeded the World Health Organization target in Japan, Australia, North Macedonia, Switzerland, Germany, Slovakia, and Austria. Considering LDL-C categories, North Macedonia had the highest proportions of LDL-C results >4.91 mmol/L (>190 mg/dL) for both females (9.9%) and males (8.7%). LDL-C levels <1.55 mmol/L (<60 mg/dL) were most common among females in Canada (10.7%) and males in the UK (17.3%). CONCLUSION: With nearly a half billion lipid results, this study sheds light on the worldwide variability in lipid levels, which may reflect inter-country differences in genetics, lipid testing, lifestyle habits, and pharmacologic treatment. Despite variability, elevated atherogenic lipid levels are a common global problem, and these results can help inform national policies and health system approaches to mitigate lipid-mediated risk of cardiovascular disease.

Current use of bone turnover markers in the management of osteoporosis.

The adult bone is continuously being remodelled to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis. Bone turnover markers are products of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers) providing a dynamic assessment of remodelling (turnover). Resorption-specific bone turnover markers are typically degradation products of bone collagen molecules (N- [NTX] and C-telopeptide cross-linked type 1 collagen [CTX]), which are released into the circulation and excreted in urine; or enzymatic activities reflecting osteoclastic resorption, tartrate-resistant acid phosphatase [TRACP]. Formation-specific bone turnover markers embrace different osteoblastic activities: type 1 collagen synthesis (Procollagen type I N- propeptide [PINP]), osteoblast enzymes (bone-specific alkaline phosphatase [BALP]), or bone matrix proteins [osteocalcin]. Among individuals not receiving osteoporosis treatment, resorption and formation markers are tightly linked and highly correlated (r = 0.6-0.8). Significant biological variability was reported in the past, but these issues have been greatly improved with automated assays and attention to pre-analytical and analytical factors that are known to influence bone turnover marker levels. Bone turnover markers are not useful in the diagnosis of osteoporosis, the individual prediction of bone loss, fracture, or rare complications, or in the selection of pharmacological treatment. Despite remaining issues with reference intervals and assays harmonization, bone turnover markers have proven to be useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medications in clinical trials. As an alternative to BMD testing, BTMs may be useful to monitor osteoporosis therapies.

Lot verification practices in Ontario clinical chemistry laboratories - Results of a patterns-of-practice survey.

Objectives: Verifying new reagent or calibrator lots is crucial for maintaining consistent test performance. The Institute for Quality Management in Healthcare (IQMH) conducted a patterns-of-practice survey and follow-up case study to collect information on lot verification practices in Ontario. Methods: The survey had 17 multiple-choice questions and was distributed to 183 licensed laboratories. Participants provided information on materials used and approval/rejection criteria for their lot verification procedures for eight classes of testing systems. The case study provided a set of lot comparison data and was distributed to 132 laboratories. Responses were reviewed by IQMH scientific committees. Results: Of the 175 laboratories that responded regarding reagent lot verifications, 74% verified all tests, 11% some, and 15% none. Of the 171 laboratories that responded regarding calibrator lot verifications, 39% verified all calibrators, 4% some, and 57% none. Reasons for not performing verifications ranged from difficulty performing parallel testing to high reagent cost. For automated chemistry assays and immunoassays, 23% of laboratories did not include patient-derived materials in reagent lot verifications and 42% included five to six patient materials; 58% of laboratories did not include patient-derived materials in calibrator lot verifications and 23% included five to six patient materials. Different combinations of test-specific rules were used for acceptance criteria. For a failed lot, 98% of laboratories would investigate further and take corrective actions. Forty-three percent of laboratories would accept the new reagent lot in the case study. Conclusion: Responses to the survey and case study demonstrated variability in lot verification practices among laboratories.

A Cross-Platform Metabolomics Comparison Identifies Serum Metabolite Signatures of Liver Fibrosis Progression in Chronic Hepatitis C Patients.

Metabolomics offers new insights into disease mechanisms that is enhanced when adopting orthogonal instrumental platforms to expand metabolome coverage, while also reducing false discoveries by independent replication. Herein, we report the first inter-method comparison when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) and nuclear magnetic resonance (NMR) spectroscopy for characterizing the serum metabolome of patients with liver fibrosis in chronic hepatitis C virus (HCV) infection (n = 20) and non-HCV controls (n = 14). In this study, 60 and 30 serum metabolites were detected frequently (>75%) with good technical precision (median CV < 10%) from serum filtrate samples (n = 34) when using standardized protocols for MSI-CE-MS and NMR, respectively. Also, 20 serum metabolite concentrations were consistently measured by both methods over a 500-fold concentration range with an overall mean bias of 9.5% (n = 660). Multivariate and univariate statistical analyses independently confirmed that serum choline and histidine were consistently elevated (p < 0.05) in HCV patients with late-stage (F2-F4) as compared to early-stage (F0-F1) liver fibrosis. Overall, the ratio of serum choline to uric acid provided optimal differentiation of liver disease severity (AUC = 0.848, p = 0.00766) using a receiver operating characteristic curve, which was positively correlated with liver stiffness measurements by ultrasound imaging (r = 0.606, p = 0.0047). Moreover, serum 5-oxo-proline concentrations were higher in HCV patients as compared to non-HCV controls (F = 4.29, p = 0.0240) after adjustment for covariates (age, sex, BMI), indicative of elevated oxidative stress from glutathione depletion with the onset and progression of liver fibrosis. Both instrumental techniques enable rapid yet reliable quantification of serum metabolites in large-scale metabolomic studies with good overlap for biomarker replication. Advantages of MSI-CE-MS include greater metabolome coverage, lower operating costs, and smaller sample volume requirements, whereas NMR offers a robust platform supported by automated spectral and data processing software.

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.

Hypertension Canada's 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children.

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines are introduced, and 1 existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke is revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

Assessment of the Measurement Error in Cyclosporine Levels Drawn Between Peripheral and Central Sources.

OBJECTIVES: Cyclosporine is often monitored by drug levels drawn through central venous catheters (CVCs), which may be falsely elevated due to reversible drug adsorption onto the catheter. Therefore, we assessed the correlation between cyclosporine levels drawn peripherally and through CVCs. METHODS: Bone marrow transplantation patients had a weekly collection of both peripheral and CVC draws from dual-lumen catheters simultaneously to assess cyclosporine levels after research ethics approval. Our primary outcome was the proportion of paired samples that were incongruent-defined as the mean of the CVC level being greater than 2 standard deviations from the peripheral level mean. RESULTS: After approaching 27 eligible patients, 20 patients (77.8%) provided samples. Of 53 paired samples, seven were incongruent (13.2%). Peripheral and CVC levels correlated (r = 0.91) and agreed well. CONCLUSION: Despite potential for preanalytical error due to adsorption, cyclosporine infusion and monitoring via CVCs produce results similar to monitoring via peripheral blood draws.

Point-of-care testing (POCT) and evidence-based laboratory medicine (EBLM) - does it leverage any advantage in clinical decision making?

Point-of-care testing (POCT) is the analysis of patient specimens outside the clinical laboratory, near or at the site of patient care, usually performed by clinical staff without laboratory training, although it also encompasses patient self-monitoring. It is able to provide a rapid result near the patient and which can be acted upon immediately. The key driver is the concept that clinical decision making may be delayed when samples are sent to the clinical laboratory. Balanced against this are considerations of increased costs for purchase and maintenance of equipment, staff training, connectivity to the laboratory information system (LIS), quality control (QC) and external quality assurance (EQA) procedures, all required for accreditation under ISO 22870. The justification for POCT depends upon being able to demonstrate that a more timely result (shorter turnaround times (TATs)) is able to leverage a clinically important advantage in decision making compared with the central laboratory (CL). In the four decades since POCT was adapted for the self-monitoring of blood glucose levels by subjects with diabetes, numerous new POCT methodologies have become available, enabling the clinician to receive results and initiate treatment more rapidly. However, these instruments are often operated by staff not trained in laboratory medicine and hence are prone to errors in the analytical phase (as opposed to laboratory testing where the analytical phase has the least errors). In some environments, particularly remote rural settings, the CL may be at a considerable distance and timely availability of cardiac troponins and other analytes can triage referrals to the main centers, thus avoiding expensive unnecessary patient transportation costs. However, in the Emergency Department, availability of more rapid results with POCT does not always translate into shorter stays due to other barriers to implementation of care. In this review, we apply the principles of evidence-based laboratory medicine (EBLM) looking for high quality systematic reviews and meta-analyses, ideally underpinned by randomized controlled trials (RCTs), looking for evidence of whether POCT confers any advantage in clinical decision making in different scenarios.

Rates of inappropriate laboratory test utilization in Ontario.

BACKGROUND: Medical laboratory tests ordered redundantly represent one of the targets for reducing diagnostic testing without negatively, and possibly positively, affecting patient care. We study a clearly defined category of excessive laboratory utilization for nine analytes where inappropriate diagnostic testing is defined in terms of the time interval between tests; that is, ordering a test too soon following the previous order of the same test. METHODS: Population data from the near universal public Ontario Health Insurance Plan for the years 2006-2010 are employed where the tests are fulfilled by community medical laboratories. The analytes selected for consideration are thyroid stimulating hormone, hemoglobin A1c, lipid profile, serum protein electrophoresis, immunofixation, quantitative immunoglobulins, Vitamin D, Vitamin B12, and folate. RESULTS: For the nine analytes studied, the percentage of inappropriate tests ranged from 6% to 20%. Large proportions of these inappropriate tests were completed >2weeks prior to the minimum threshold to reorder defined by practice guidelines and/or were repeated excessively within a year. Between 60% and 85% of the time, the ordering physician of an inappropriate test was the same physician who ordered the previous test. Specialists were more likely than primary care physicians to order repeat tests too soon. CONCLUSIONS: A sizeable proportion of testing for these analytes was inappropriate according to practice guidelines. It is recommended that systems for preventing unnecessary repeat testing are investigated by the funding agencies and that reducing inappropriate testing be considered as a design element for electronic medical records and related information technology systems.

Clinical implications of estrone sulfate measurement in laboratory medicine.

Estrone sulfate (E1S) is the most abundant circulating estrogen and it has the potential to be used as a biomarker in certain conditions where estimation of low levels of estrogen or changes in relative levels of estrogens are important. This review will critically consider the role of estimating E1S for clinical laboratory practice. As E1S is an estrogen, a wider discussion of estrogens is included to contextualize the review. Assays have been available for a number of years for these estrogens and they have been measured in a number of clinical research studies. However, E1S remains a rarely ordered test. This review highlights the literature that suggests the possible advantages of measuring E1S in addition to, or possibly in place of, the more commonly measured estradiol (E2) and the less commonly measured estrone (E1). The potential biomarker role of E1S in risk stratification for breast cancer, in promotion of proliferation of endometrial cancer, in prognostic information in advanced prostatic carcinoma, and in the monitoring of response to certain hormonal therapy for malignancy is discussed. The methods available for the measurement of E1S are reviewed and the limitations of the current methodologies are described. In conclusion, E1S has some interesting potential applications in clinical laboratory medicine that require further investigation.

Familial partial lipodystrophy presenting as metabolic syndrome.

We report the first described case of a heterozygous p.R545H (c.1634 G > A) missense mutation in the LMNA gene with clinical features compatible with Dunnigan-type 2 familial partial lipodystrophy (FPLD2). The case presented as metabolic syndrome to a specialist clinical service and highlights the overlap between FPLD2 and the metabolic syndrome. The associations with type 2 diabetes mellitus, fatty liver disease, polycystic ovarian syndrome, and hypertriglyceridemia are highlighted. The importance of evaluating patients for these associated conditions is discussed, and the potential mechanisms of disease are briefly outlined. The mutation has been previously reported in a heart failure database without a clinical description. The links between heart failure and the clinical condition are briefly considered.

Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: Management and considerations for cardiovascular risk.

We report a novel homozygous apolipoprotein A5 (APOA5) frameshift mutation (c.G425del-C, p.Arg143AlafsTer57) identified in a 12-year-old boy of Pakistani origin with severe hypertriglyceridemia (up to 35 mmol/L) and type V hyperlipoproteinemia. The patient did not respond to fibrate therapy, but his condition improved under a very low fat diet, although compliance was suboptimal. Heterozygous status was detected in both parents (consanguineous union) and one sibling, all showing moderate hypertriglyceridemia (between 5 and 10 mmol/L). There was a significant family history of premature cardiovascular disease. The index case was also diagnosed with a coronary artery anomaly. Considering the recently reported association of rare mutations in APOA5 with the risk of early myocardial infarction, we discuss the implications of these findings for the young man and his family.