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.

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.

Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review.

The aim of this systematic review was to determine whether B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) independently add incremental value for predicting mortality and morbidity in patients with acute decompensated heart failure (ADHF). Medline(®), Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL were searched from 1989 to June 2012. We also searched reference lists of included articles, systematic reviews, and the gray literature. Studies were screened for eligibility criteria and assessed for risk of bias. Data were extracted on study design, population demographics, assay cutpoints, prognostic risk prediction model covariates, statistical methods, outcomes, and results. From 183 citations, only seven studies (5 BNP and 2 NT-proBNP) considered incremental value in ADHF subjects admitted to acute care centers. Admission assay levels and length of follow-up varied for BNP studies (31 days to 12 months) and for NT-proBNP studies (25-82 months). All studies presented at least one estimate of incremental value of BNP/NT-proBNP relative to the base prognostic model. Using discrimination or likelihood statistics, these studies consistently showed that BNP or NT-proBNP increased model performance. Three studies used reclassification and model validation computations to establish incremental value; these studies showed less consistency with respect to added value. In conclusion, the literature assessing incremental value of BNP/NT-proBNP in ADHF populations is limited to seven studies evaluating only mortality outcomes and at moderate risk of bias. Although there were differences in the base risk prediction models, assay cutpoints, and lengths of follow-up, there was consistency in BNP/NT-proBNP adding incremental value in prediction models in ADHF patients.

Prediction of clinical outcomes using B-type natriuretic peptides in the general population: a systematic review.

The use of B-type natriuretic peptides to predict outcomes in general populations has been investigated in a number of primary studies. A previous systematic review considering natriuretic peptides in cardiovascular disease included a subgroup of general population studies, which suggested an association with a number of clinical outcomes. We electronically searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published between 1989 and mid-2012. We utilized trained reviewers and standardized forms to screen articles for inclusion and extract data from included articles. All included studies (n = 7) were summarized in narrative and tabular form. A general population was defined as one that was randomly selected from a community setting where no specific inclusion or exclusion criteria were specified. The seven included studies all used FDA approved assays for NT-proBNP. The range of clinical outcomes and heterogeneity did not allow for meta-analysis. The hazard ratios for predicting outcomes in the included studies ranged from 1.0 to 4.1 (all p values <0.05). The discrimination statistics reported in four studies all demonstrated statistically significant improvements in predicting outcomes. NT-proBNP is associated with heart failure, all-cause and cardiovascular mortality, and other combined cardiovascular events in a general unselected population. The discrimination statistics suggest modest improvements in risk stratification. No prospective studies exist to demonstrate the clinical utility of using B-type natriuretic peptides to predict clinical outcomes in a general population.

Incremental predictive value of natriuretic peptides for prognosis in the chronic stable heart failure population: a systematic review.

The aim of this study was to determine whether measurement of natriuretic peptides independently adds incremental predictive value for mortality and morbidity in patients with chronic stable heart failure (CSHF). We electronically searched Medline®, Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL from 1989 to June 2012. We also searched reference lists of included articles, systematic reviews, and the gray literature. Studies were screened for eligibility criteria and assessed for methodological quality. Data were extracted on study design, population demographics, assay cutpoints, prognostic risk prediction model covariates, statistical methods, outcomes, and results. One hundred and eighty-three studies were identified as prognostic in the systematic review. From these, 15 studies (all NT-proBNP) considered incremental predictive value in CSHF subjects. Follow-up varied from 12 to 37 months. All studies presented at least one estimate of incremental predictive value of NT-proBNP relative to the base prognostic model. Using discrimination or likelihood statistics, these studies consistently showed that NT-proBNP increased model performance. Three studies used re-classification and model validation computations to establish incremental predictive value; these studies showed less consistency with respect to added value. Although there were differences in the base risk prediction models, assay cutpoints, and lengths of follow-up, there was consistency in NT-proBNP adding incremental predictive value for prognostic models in chronic stable CSHF patients. The limitations in the literature suggest that studies designed to evaluate prognostic models should be undertaken to evaluate the incremental value of natriuretic peptide as a predictor of mortality and morbidity in CSHF.

BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart failure: a systematic review.

A systematic review was undertaken to examine the evidence for B-type natriuretic peptides (BNP and NT-proBNP) as independent predictors of mortality, morbidity, or combined mortality and morbidity outcomes in persons with acute decompensated heart failure (ADHF). Electronic databases (Medline(®), Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL) were searched from 1989 to June 2012. Reference lists of included articles, systematic reviews, and the gray literature were also searched. English language studies were eligible if they included subjects with ADHF and measured BNP/NT-proBNP using FDA approved assays. Standardized forms were used to select studies, extract data, and assess risk of bias. Seventy-nine studies, ranging over followup intervals from 14 days to 7 years, evaluating levels of BNP (n = 38), NT-proBNP (n = 35), or both (n = 6) were eligible. The majority of studies predicted mortality outcomes for admission BNP/NT-proBNP levels, with fewer studies evaluating serial, change from admission, or discharge levels. In general, higher levels of admission BNP or NT-proBNP predicted greater risk for all outcomes. Decreased levels post-admission predicted decreased risk. Overall, these studies were rated as having moderate risk of bias. This systematic review shows that BNP and NT-proBNP are independent predictors of mortality (all-cause and cardiovascular) in ADHF despite different cutpoints, time intervals, and prognostic models. Findings for morbidity and composite outcomes were less frequently evaluated and showed inconsistency. Further research is required to assess cutpoints for admission, serial measurements, change following admission, and discharge levels to assist clinical decision-making.

B-type natriuretic peptide-guided therapy: a systematic review.

BNP/NT-proBNP measurement has not gained widespread use for the management of patients with heart failure (HF) despite several randomized controlled trials. A systematic review addressing the question of whether patients with HF benefit from BNP-assisted therapy or intensified therapy compared with usual care was undertaken. Relevant randomized controlled trial (RCTs) were selected by searching Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published from 1980 to 2012. Selected studies required patients to be treated for chronic HF with medical therapy based on BNP/NT-proBNP or usual care. There were no restrictions except that BNP/NT-proBNP measurement had to be done by an FDA approved method. Nine RCTs were identified with 2,104 patients with study duration that ranged from 3 to 18 months. Overall, there was a wide variation in study design and how parameters were reported including patient selection, baseline characteristics, therapy goals, BNP/NT-proBNP cutpoint, and outcome types. Meta-analysis was not appropriate given this study heterogeneity. The strength of evidence for the outcome of mortality, reported in seven studies, was found to be low due to inconsistency and imprecision. This systematic review showed that the evidence is of low quality and insufficient to support the use of BNP/NT-proBNP to guide HF therapy. Further trials with improved design are needed.

Applicability of the AGREE II instrument in evaluating the development process and quality of current National Academy of Clinical Biochemistry guidelines.

BACKGROUND: Laboratory medicine practice guidelines (LMPGs) are an important part of clinical laboratory medicine. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument has been developed to evaluate the process of practice-guideline development and the quality of reporting. We assessed the applicability of AGREE II in assessing the National Academy of Clinical Biochemistry (NACB) LMPGs. METHODS: The NACB website was searched for all available LMPGs up to December 2011. Two independent appraisers used the AGREE II instrument to assess each LMPG identified by the search. Quality was assessed across 6 domains (scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence), comprising a total of 23 items and 2 overall assessments, each scored on a 7-point scale (1, strongly disagree, to 7, strongly agree). All scores were expressed as AGREE II calculated percentages (100% indicates that all items scored 7 by all appraisers). RESULTS: Eleven LMPGs were identified. All of the LMPGs provided some information seen as applicable to clinical practice by the appraisers. Only 5 of the LMPGs had overall scores ≥50%, with a median score of 42% (range: 8%-92%). Individual domain scores varied considerably from 0% to 100%. One guideline achieved a very high score on the instrument. CONCLUSIONS: The AGREE II instrument is applicable and useful to evaluate LMPGs. All domains were evaluated as being useful to assess LMPGs, some were addressed well (e.g., clarity of presentation), whereas others could be improved (e.g., applicability).

Testing for gluten-related disorders in clinical practice: the role of serology in managing the spectrum of gluten sensitivity.

Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity.

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.

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.

Evaluation of natriuretic peptide recommendations in heart failure clinical practice guidelines.

BACKGROUND: The B-type naturietic peptides (NPs) are associated with heart failure (HF). This investigation was designed to evaluate heart failure clinical practice guideline (CPG) recommendations for the use of NPs. METHODS: A search for English language CPGs for HF published since 2011 was conducted. A search for systematic reviews (SR) and meta-analysis for NPs in HF was conducted for the years 2004-2012. Each HF CPG was evaluated by two independent reviewers. Key recommendations for NPs and the supporting references were abstracted. The key findings from each SR were abstracted. RESULTS: Seven English language HF CPGs were found, all of which made recommendations for the use of NPs in diagnosis. Four made recommendations for prognosis and three for management. The European CPG scored highly for rigor of development with the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) while the others did not. North American CPGs made stronger recommendations citing higher grades of evidence for the use of NPs in HF than the European or Australian CPGs. The CPGs mostly cited primary studies 47/66 to support the recommendations. From twelve available SRs, five were cited by CPGs. One CPG conducted a SR. CONCLUSIONS: The SR evidence to support NP use in CPGs has not been well cited in the CPGs and the recommendations are only partially supported by the SR evidence. Future CPGs should consider improving the methodology used to evaluate laboratory tests.

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.

Evidence based application of BNP/NT-proBNP testing in heart failure.

BACKGROUND: The B-type natriuretic peptides are now available on many automated clinical analysers. Clinical practice guidelines for heart failure include recommendations for where the B-type natriuretic peptides are possibly useful for clinical practice. A number of systematic reviews considering B-type natriuretic peptides in relation to heart failure patients have been published. METHODS: This review will consider the evidence presented in the systematic reviews and how this can be applied to clinical practice. RESULTS: Twenty-six systematic reviews are summarised in tables considering applications to diagnostic, prognostic and guiding therapy. Important clinical considerations for these applications are discussed to facilitate appropriate implementation in the clinical laboratory. CONCLUSION: Most clinical laboratories should be considering the appropriate implementation of the B-type natriuretic peptide as a diagnostic test to assist in ruling out heart failure. In the application of prognosis and guiding therapy a number of questions remain to be answered.

Grading Evidence for Laboratory Test Studies Beyond Diagnostic Accuracy: Application to Prognostic Testing.

BACKGROUND: Evidence-based guideline development requires transparent methodology for gathering, synthesizing and grading the quality and strength of evidence behind recommendations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) project has addressed diagnostic test use in many of their publications. Most of the work has been directed at diagnostic tests and no consensus has been reached for prognostic biomarkers. AIM OF THIS PAPER: The GRADE system for rating the quality of evidence and the strength of a recommendation is described. The application of GRADE to diagnostic testing is discussed and a description of application to prognostic testing is detailed. Some strengths and limitations of the GRADE process in relation to clinical laboratory testing are presented. CONCLUSIONS: The GRADE system is applicable to clinical laboratory testing and if correctly applied should improve the reporting of recommendations for clinical laboratory tests by standardising the style of recommendation and by encouraging transparent reporting of the actual guideline process.

Successful reintroduction of statin therapy after statin-associated rhabdomyolysis.

The case report demonstrates the successful use of an alternative statin after a statin-related episode of rhabdomyolysis. Statin-associated rhabdomyolysis is a serious adverse event with a very low incidence and is considered the most severe of the muscle-related side effects of the statins. Rechallenge with statins is not a recommended practice after rhabdomyolysis. The patient experienced a myocardial infarct 1 y after the episode of rhabdomyolysis. He used alternative lipid-lowering therapy for 2 y. His low-density lipoprotein cholesterol was not meeting typical secondary prevention targets. An alternative statin was introduced and the patient has been followed for 4 years without recurrence of the rhabdomyolysis. This case suggests it may be time to reconsider the accepted practice of permanently avoiding statin therapy after rhabdomyolysis.

Laboratory challenges in primary aldosteronism screening and diagnosis.

BACKGROUND AND OBJECTIVE: The laboratory has a critical role to play in the screening and diagnosis of primary aldosteronism. This review highlights some of the important analytical considerations and the new developments in the determination of aldosterone and renin. METHODS: The review considered the published literature and clinical practice guidelines in the area of primary aldosteronism. RESULTS: A brief introduction to primary aldosteronism is provided. A detailed description of the pre-analytical, analytical and post-analytical considerations for the laboratory determination of aldosterone, renin and the aldosterone to renin ratio follows. CONCLUSIONS: The lack of internationally accepted standardized methodologies and standard reference material has impeded screening and diagnosis of primary aldosteronism. The development of more accurate and sensitive methods by LC-MS/MS has improved the reliability of aldosterone and renin testing and the availability of commercial chemiluminescent assays may improve the standardization of reporting. Laboratorians need to understand the strengths and weaknesses of their analytical approach and ensure that their interpretative reports are appropriate to their assays.