Jean Sanderson

Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis

Objective To evaluate the association of chocolate consumption with the risk of developing cardiometabolic disorders. Design Systematic review and meta-analysis of randomised controlled trials and observational studies. Data sources Medline, Embase, Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, reference lists of relevant studies to October 2010, and email contact with authors. Study selection Randomised trials and cohort, case-control, and cross sectional studies carried out in human adults, in which the association between chocolate consumption and the risk of outcomes related to cardiometabolic disorders were reported. Data extraction Data were extracted by two independent investigators, and a consensus was reached with the involvement of a third. The primary outcome was cardiometabolic disorders, including cardiovascular disease (coronary heart disease and stroke), diabetes, and metabolic syndrome. A meta-analysis assessed the risk of developing cardiometabolic disorders by comparing the highest and lowest level of chocolate consumption. Results From 4576 references seven studies met the inclusion criteria (including 114 009 participants). None of the studies was a randomised trial, six were cohort studies, and one a cross sectional study. Large variation was observed between these seven studies for measurement of chocolate consumption, methods, and outcomes evaluated. Five of the seven studies reported a beneficial association between higher levels of chocolate consumption and the risk of cardiometabolic disorders. The highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease (relative risk 0.63 (95% confidence interval 0.44 to 0.90)) and a 29% reduction in stroke compared with the lowest levels. Conclusions Based on observational evidence, levels of chocolate consumption seem to be associated with a substantial reduction in the risk of cardiometabolic disorders. Further experimental studies are required to confirm a potentially beneficial effect of chocolate consumption.

Sepsis: the LightCycler SeptiFast Test MGRADE®, SepsiTest™ and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi – a systematic review and economic evaluation

BACKGROUND Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity. OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of three tests [LightCycler SeptiFast Test MGRADE(®) (Roche Diagnostics, Risch-Rotkreuz, Switzerland); SepsiTest(TM) (Molzym Molecular Diagnostics, Bremen, Germany); and the IRIDICA BAC BSI assay (Abbott Diagnostics, Lake Forest, IL, USA)] for the rapid identification of bloodstream bacteria and fungi in patients with suspected sepsis compared with standard practice (blood culture with or without matrix-absorbed laser desorption/ionisation time-of-flight mass spectrometry). DATA SOURCES Thirteen electronic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched from January 2006 to May 2015 and supplemented by hand-searching relevant articles. REVIEW METHODS A systematic review and meta-analysis of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. A decision tree was used to estimate the costs and quality-adjusted life-years (QALYs) associated with each test; all other parameters were estimated from published sources. The model was populated with evidence from the systematic review or individual studies, if this was considered more appropriate (base case 1). In a secondary analysis, estimates (based on experience and opinion) from seven clinicians regarding the benefits of earlier test results were sought (base case 2). A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Scenario analyses were used to assess uncertainty. RESULTS For the review of diagnostic test accuracy, 62 studies of varying methodological quality were included. A meta-analysis of 54 studies comparing SeptiFast with blood culture found that SeptiFast had an estimated summary specificity of 0.86 [95% credible interval (CrI) 0.84 to 0.89] and sensitivity of 0.65 (95% CrI 0.60 to 0.71). Four studies comparing SepsiTest with blood culture found that SepsiTest had an estimated summary specificity of 0.86 (95% CrI 0.78 to 0.92) and sensitivity of 0.48 (95% CrI 0.21 to 0.74), and four studies comparing IRIDICA with blood culture found that IRIDICA had an estimated summary specificity of 0.84 (95% CrI 0.71 to 0.92) and sensitivity of 0.81 (95% CrI 0.69 to 0.90). Owing to the deficiencies in study quality for all interventions, diagnostic accuracy data should be treated with caution. No randomised clinical trial evidence was identified that indicated that any of the tests significantly improved key patient outcomes, such as mortality or duration in an intensive care unit or hospital. Base case 1 estimated that none of the three tests provided a benefit to patients compared with standard practice and thus all tests were dominated. In contrast, in base case 2 it was estimated that all cost per QALY-gained values were below £20,000; the IRIDICA BAC BSI assay had the highest estimated incremental net benefit, but results from base case 2 should be treated with caution as these are not evidence based. LIMITATIONS Robust data to accurately assess the clinical effectiveness and cost-effectiveness of the interventions are currently unavailable. CONCLUSIONS The clinical effectiveness and cost-effectiveness of the interventions cannot be reliably determined with the current evidence base. Appropriate studies, which allow information from the tests to be implemented in clinical practice, are required. STUDY REGISTRATION This study is registered as PROSPERO CRD42015016724. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The Role of Decision Support System (DSS) in Prevention of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Background The potential role of DSS in CVD prevention remains unclear as only a few studies report on patient outcomes for cardiovascular disease. Methods and Results A systematic review and meta-analysis of randomised controlled trials and observational studies was done using Medline, Embase, Cochrane Library, PubMed, Amed, CINAHL, Web of Science, Scopus databases; reference lists of relevant studies to 30 July 2011; and email contact with experts. The primary outcome was prevention of cardiovascular disorders (myocardial infarction, stroke, coronary heart disease, peripheral vascular disorders and heart failure) and management of hypertension owing to decision support systems, clinical decision supports systems, computerized decision support systems, clinical decision making tools and medical decision making (interventions). From 4116 references ten studies met our inclusion criteria (including 16,312 participants). Five papers reported outcomes on blood pressure management, one paper on heart failure, two papers each on stroke, and coronary heart disease. The pooled estimate for CDSS versus control group differences in SBP (mm of Hg) was - 0.99 (95% CI −3.02 to 1.04 mm of Hg; I2 = 0; p = 0.851). Conclusions DSS show an insignificant benefit in the management and control of hypertension (insignificant reduction of SBP). The paucity of well-designed studies on patient related outcomes is a major hindrance that restricts interpretation for evaluating the role of DSS in secondary prevention. Future studies on DSS should (1) evaluate both physician performance and patient outcome measures (2) integrate into the routine clinical workflow with a provision for decision support at the point of care.

Derivation and assessment of risk prediction models using case-cohort data

BackgroundCase-cohort studies are increasingly used to quantify the association of novel factors with disease risk. Conventional measures of predictive ability need modification for this design. We show how Harrell’s C-index, Royston’s D, and the category-based and continuous versions of the net reclassification index (NRI) can be adapted.MethodsWe simulated full cohort and case-cohort data, with sampling fractions ranging from 1% to 90%, using covariates from a cohort study of coronary heart disease, and two incidence rates. We then compared the accuracy and precision of the proposed risk prediction metrics.ResultsThe C-index and D must be weighted in order to obtain unbiased results. The NRI does not need modification, provided that the relevant non-subcohort cases are excluded from the calculation. The empirical standard errors across simulations were consistent with analytical standard errors for the C-index and D but not for the NRI. Good relative efficiency of the prediction metrics was observed in our examples, provided the sampling fraction was above 40% for the C-index, 60% for D, or 30% for the NRI. Stata code is made available.ConclusionsCase-cohort designs can be used to provide unbiased estimates of the C-index, D measure and NRI.

Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: A systematic review and network meta-analysis.

OBJECTIVES To assess the relative efficacy of bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) for the treatment of osteoporosis using network meta-analysis (NMA). METHODS A systematic review of the literature was conducted using PRISMA guidelines. A network meta-analysis was used to determine the relative efficacy of treatments on four fracture outcomes (vertebral, non-vertebral, hip and wrist) and percentage change in femoral neck bone mineral density (BMD). Treatment effects were modelled using an exchangeable treatment effects model. Heterogeneity in treatment effects was explored by considering potential treatment effect modifiers using meta-regression. Where appropriate, inconsistency between direct and indirect evidence was assessed using node-splitting. RESULTS 46 randomised controlled trials (RCTs) were identified. Twenty seven RCTs provided fracture data and 35 RCTs provided BMD data for analysis. Zoledronic acid was associated with the greatest treatment effect on vertebral fractures (HR 0.41, 95% CrI: 0.28, 0.56) and percentage change in BMD (3.21, 95%: CrI 2.52, 3.86) compared to placebo. The greatest treatment effect on non-vertebral and wrist fractures was given by risedronate (HR 0.72, 95%: CrI 0.53, 0.89 and HR 0.77, 95%: CrI 0.44, 1.24, respectively). For hip fractures the greatest treatment effect was given by alendronate (HR 0.78, 95% CrI: 0.44, 1.30). CONCLUSIONS All treatments examined were associated with beneficial effects on fractures and femoral neck BMD relative to placebo. For vertebral fractures and percentage change in femoral neck BMD the treatment effects were statistically significant for all treatments. Pairwise comparisons between treatments indicated that no active treatment was statistically significantly more effective than any other active treatment for fracture outcomes. There was some heterogeneity in treatment effects between studies suggesting differential treatment effects according to study characteristics; however, there was no evidence of differential treatment effects with respect to gender and age.

Reconstructing Past Admixture Processes from Local Genomic Ancestry Using Wavelet Transformation

Admixture between long-separated populations is a defining feature of the genomes of many species. The mosaic block structure of admixed genomes can provide information about past contact events, including the time and extent of admixture. Here, we describe an improved wavelet-based technique that better characterizes ancestry block structure from observed genomic patterns. principal components analysis is first applied to genomic data to identify the primary population structure, followed by wavelet decomposition to develop a new characterization of local ancestry information along the chromosomes. For testing purposes, this method is applied to human genome-wide genotype data from Indonesia, as well as virtual genetic data generated using genome-scale sequential coalescent simulations under a wide range of admixture scenarios. Time of admixture is inferred using an approximate Bayesian computation framework, providing robust estimates of both admixture times and their associated levels of uncertainty. Crucially, we demonstrate that this revised wavelet approach, which we have released as the R package adwave, provides improved statistical power over existing wavelet-based techniques and can be used to address a broad range of admixture questions.

Standardisation of uterine natural killer (uNK) cell measurements in the endometrium of women with recurrent reproductive failure

Considerable work is being carried out on endometrial NK cells to determine whether they play a role in successful pregnancy outcome. In addition there is debate about whether measurements of uNK should be included in the clinical assessment for women with recurrent implantation failure or recurrent miscarriage. A hindrance to taking this forward is the fact that the density of uNK cells reported by different centres is very different. The aim of this study was to determine the reason for these differences and to develop a standardised method. Three centres participated in the study. Each centre exchanged five formalin fixed, wax embedded sections of endometrium from five women. Sections were immunostained for CD56. Images were taken of 10 random fields at ×400 magnification; total stromal and uNK cells were counted using Image J. Results were expressed as % positive uNK cells and the variation in counts obtained in each centre was compared. After initial analysis a standardised protocol was agreed and the process repeated. Significant variation was seen in the counts obtained after initial analysis (Centre A vs.B, mean difference=-0.72 P<0.001; A vs.C mean difference=-0.47 P<0.001; B vs.C, mean difference=0.25 P=0.085). Analysis suggested that differences may be due to duration of tissue fixation, the embedding and sectioning processes, selection of areas for assessment, definition of immunopositive cells and inclusion or exclusion of blood vessels. Adoption of a standardised protocol reduced the variation (Centre A vs.B mean difference=-0.105 P=0.744; A vs.C mean difference=0.219 P=0.150; B vs.C mean difference=0.32 P=0.031). Use of a standardised method is needed to establish a normal range for uNK cells and to develop a meaningful clinical test for uNK cell measurements.

Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

Abstract Background Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Objectives To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax® and Fosamax® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel® and Actonel Once a Week®, Warner Chilcott UK Ltd), ibandronic acid (Bonviva®, Roche Products Ltd) and zoledronic acid (Aclasta®, Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. Data sources For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. Review methods A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. Results Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. Limitations We assumed that all treatment strategies are viable alternatives across the whole population. Conclusions Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. Study registration This study is registered as PROSPERO CRD42013006883. Funding The National Institute for Health Research Health Technology Assessment programme.