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1.  Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials 
BMJ Open  2012;2(6):e001803.
In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM.
Methods and analysis
In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs.
Ethics and dissemination
The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM.
The study will be disseminated by peer-review publication and conference presentation.
Protocol registration
PROSPERO CRD42012002552.
PMCID: PMC3533035  PMID: 23148345
2.  Health Outcome Measures in Atopic Dermatitis: A Systematic Review of Trends in Disease Severity and Quality-of-Life Instruments 1985–2010 
PLoS ONE  2011;6(4):e17520.
A number of disease-severity and quality-of-life (QoL) instruments have emerged in atopic dermatitis (AD) in the last decade.
To identify trends in outcomes instruments used in AD clinical trials and to provide a useful summary of the dimensions and validation studies for the most commonly used measures.
All randomized control trials (RCTs) from 1985 to 2010 in the treatment of AD were examined.
Among the 791 RCTs reviewed, we identified 20 disease-severity and 14 QoL instruments. Of these outcomes instruments, few have been validated. SCORAD, EASI, IGA and SASSAD were the most commonly used disease-severity instruments and CDLQI, DFI, DLQI and IDQOL were the most frequently used QoL measures.
The small number of RCTs using QoL scales makes identifying trends for QoL instruments difficult.
Overall, there is an increase in the use of disease-severity and QoL instruments in AD clinical trials.
PMCID: PMC3076368  PMID: 21533286
3.  Tea Consumption Enhances Endothelial-Dependent Vasodilation; a Meta-Analysis 
PLoS ONE  2011;6(3):e16974.
Tea consumption is associated with a lower risk of cardiovascular disease including stroke. Direct effects of tea components on the vasculature, particularly the endothelium, may partly explain this association.
We performed a meta-analysis of controlled human intervention studies on the effect of tea on flow-mediated dilation (FMD) of the brachial artery, a measurement of endothelial function, which is suggested to be associated with cardiovascular risk.
Human intervention studies were identified by systematic search of the databases Medline, Embase, Chemical Abstracts and Biosis through March 2009 and by hand-searching related articles. Studies were selected based on predefined criteria: intervention with tea as the sole experimental variable, placebo-controlled design, and no missing data on FMD outcome or its variability. A random effects model was used to calculate the pooled overall effect on FMD due to the intake of tea. The impact of various subject and treatment characteristics was investigated in the presence of heterogeneity.
In total, 9 studies from different research groups were included with 15 relevant study arms. The overall absolute increase in FMD of tea vs. placebo was 2.6% of the arterial diameter (95% CI: 1.8-3.3%; P-value <0.001) for a median daily dose of 500 mL of tea (2–3 cups). This is a relative increase of approximately 40% compared to the average FMD of 6.3% measured under placebo or baseline conditions. There was significant heterogeneity between studies (P-value <0.001) that might partly be explained by the cuff position either distal or proximal to the area of FMD measurement. No indication for publication bias was found.
Moderate consumption of tea substantially enhances endothelial-dependent vasodilation. This may provide a mechanistic explanation for the reduced risk of cardiovascular events and stroke observed among tea drinkers.
PMCID: PMC3048861  PMID: 21394199
4.  Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study 
BMJ : British Medical Journal  2008;336(7644):601-605.
Objective To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome.
Design Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses.
Data sources 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes.
Main outcome measures Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates.
Results In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses.
Conclusions The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.
PMCID: PMC2267990  PMID: 18316340
5.  Healthy Lifestyle Behaviour Decreasing Risks of Being Bullied, Violence and Injury 
PLoS ONE  2008;3(2):e1585.
Bullying and violence are problems of aggression in schools among adolescents. Basic daily healthy practices including nutritious diet, hygiene and physical activity are common approaches in comprehensive health promotion programs in school settings, however thier relationship to these aggressive behaviours is vague. We attempted to show the advantages of these healthy lifestyle behaviours in 9 developing countries by examining the association with being frequently bullied, violence and injury.
Methodology/Principal Findings
A cross-sectional cross-national survey of 9 countries using the WHO Global School Based Student Health Survey dataset was used. Measurements included experiences of “being frequently bullied” in the preceding 30 days and violence/injury in the past 12 months. Association of risk behaviours (smoking, alcohol, sexual behaviour) and healthy lifestyle (nutrition, hygiene practices, physical activity) to being bullied, and violence/injury were assessed using multivariate logistic regression. Hygiene behaviour showed lower risks of being frequently bullied [male: RR = 0.7 (97.5CI: 0.5, 0.9); female: RR = 0.6 (0.5, 0.8)], and lower risk of experiences of violence/injury [RR = 0.7 (0.5, 0.9) for males], after controlling for risk behaviours, age, education, poverty, and country.
Healthy lifestyle showed an association to decreased relative risk of being frequently bullied and violence/injury in developing countries. A comprehensive approach to risk and health promoting behaviours reducing bullying and violence is encouraged at school settings.
PMCID: PMC2249928  PMID: 18297133
6.  Evidence based diagnostics 
BMJ : British Medical Journal  2005;330(7493):724-726.
Diagnostic tests are often much less rigorously evaluated than new drugs. It is time to ensure that the harms and benefits of new tests are fully understood
PMCID: PMC555641  PMID: 15790646
7.  Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials 
Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
Design Systematic review with meta-analyses.
Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011).
Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.
Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.
Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.
Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
PMCID: PMC3256253  PMID: 22236411
8.  Hospital Presenting Self-Harm and Risk of Fatal and Non-Fatal Repetition: Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(2):e89944.
Non-fatal self-harm is one of the most frequent reasons for emergency hospital admission and the strongest risk factor for subsequent suicide. Repeat self-harm and suicide are key clinical outcomes of the hospital management of self-harm. We have undertaken a comprehensive review of the international literature on the incidence of fatal and non-fatal repeat self-harm and investigated factors influencing variation in these estimates as well as changes in the incidence of repeat self-harm and suicide over the last 30 years.
Methods and Findings
Medline, EMBASE, PsycINFO, Google Scholar, article reference lists and personal paper collections of the authors were searched for studies describing rates of fatal and non-fatal self-harm amongst people who presented to health care services for deliberate self-harm. Heterogeneity in pooled estimates of repeat self-harm incidence was investigated using stratified meta-analysis and meta-regression. The search identified 177 relevant papers. The risk of suicide in the 12 months after an index attempt was 1.6% (CI 1.2–2.4) and 3.9% (CI 3.2–4.8) after 5 years. The estimated 1 year rate of non-fatal repeat self-harm was 16.3% (CI 15.1–17.7). This proportion was considerably lower in Asian countries (10.0%, CI 7.3–13.6%) and varies between studies identifying repeat episodes using hospital admission data (13.7%, CI 12.3–15.3) and studies using patient report (21.9%, CI 14.3–32.2). There was no evidence that the incidence of repeat self-harm was lower in more recent (post 2000) studies compared to those from the 1980s and 1990s.
One in 25 patients presenting to hospital for self-harm will kill themselves in the next 5 years. The incidence of repeat self-harm and suicide in this population has not changed in over 10 years. Different methods of identifying repeat episodes of self-harm produce varying estimates of incidence and this heterogeneity should be considered when evaluating interventions aimed at reducing non-fatal repeat self-harm.
PMCID: PMC3938547  PMID: 24587141
9.  Hepatitis B Screening and Vaccination Strategies for Newly Arrived Adult Canadian Immigrants and Refugees: A Cost-Effectiveness Analysis  
PLoS ONE  2013;8(10):e78548.
Immigrants have increased mortality from hepatocellular carcinoma as compared to the host populations, primarily due to undetected chronic hepatitis B virus (HBV) infection. Despite this, there are no systematic programs in most immigrant-receiving countries to screen for chronic HBV infection and immigrants are not routinely offered HBV vaccination outside of the universal childhood vaccination program.
Methods and findings
A cost-effective analysis was performed to compare four HBV screening and vaccination strategies with no intervention in a hypothetical cohort of newly-arriving adult Canadian immigrants. The strategies considered were a) universal vaccination, b) screening for prior immunity and vaccination, c) chronic HBV screening and treatment, and d) combined screening for chronic HBV and prior immunity, treatment and vaccination. The analysis was performed from a societal perspective, using a Markov model. Seroprevalence estimates, annual transition probabilities, health-care costs (in Canadian dollars), and utilities were obtained from the published literature. Acute HBV infection, mortality from chronic HBV, quality-adjusted life years (QALYs), and costs were modeled over the lifetime of the cohort of immigrants. Costs and QALYs were discounted at a rate of 3% per year. Screening for chronic HBV infection, and offering treatment if indicated, was found to be the most cost-effective intervention and was estimated to cost $40,880 per additional QALY gained, relative to no intervention. This strategy was most cost-effective for immigrants < 55 years of age and would cost < $50,000 per additional QALY gained for immigrants from areas where HBV seroprevalence is ≥ 3%. Strategies that included HBV vaccination were either prohibitively expensive or dominated by the chronic HBV screening strategy.
Screening for chronic HBV infection from regions where most Canadian immigrants originate, except for Latin America and the Middle East, was found to be reasonably cost-effective and has the potential to reduce HBV-associated morbidity and mortality.
PMCID: PMC3799697  PMID: 24205255
10.  Comparison of Pooled Risk Estimates for Adverse Effects from Different Observational Study Designs: Methodological Overview 
PLoS ONE  2013;8(8):e71813.
A diverse range of study designs (e.g. case-control or cohort) are used in the evaluation of adverse effects. We aimed to ascertain whether the risk estimates from meta-analyses of case-control studies differ from that of other study designs.
Searches were carried out in 10 databases in addition to reference checking, contacting experts, and handsearching key journals and conference proceedings. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from case-control studies could be directly compared with the pooled estimate for the same adverse effect arising from other types of observational studies.
We included 82 meta-analyses. Pooled estimates of harm from the different study designs had 95% confidence intervals that overlapped in 78/82 instances (95%). Of the 23 cases of discrepant findings (significant harm identified in meta-analysis of one type of study design, but not with the other study design), 16 (70%) stemmed from significantly elevated pooled estimates from case-control studies. There was associated evidence of funnel plot asymmetry consistent with higher risk estimates from case-control studies. On average, cohort or cross-sectional studies yielded pooled odds ratios 0.94 (95% CI 0.88–1.00) times lower than that from case-control studies.
Empirical evidence from this overview indicates that meta-analysis of case-control studies tend to give slightly higher estimates of harm as compared to meta-analyses of other observational studies. However it is impossible to rule out potential confounding from differences in drug dose, duration and populations when comparing between study designs.
PMCID: PMC3748094  PMID: 23977151
11.  Prospective Study of the Quality of Colonoscopies Performed by Primary Care Physicians: The Alberta Primary Care Endoscopy (APC-Endo) Study 
PLoS ONE  2013;8(6):e67017.
The quality of colonoscopies performed by primary care physicians (PCPs) is unknown.
To determine whether PCP colonoscopists achieve colonoscopy quality benchmarks, and patient satisfaction with having their colonoscopy performed by a primary care physician.
Prospective multi-center, multi-physician observational study. Colonoscopic quality data collection occurred via completion of case report forms and pathological confirmation of lesions. Patient satisfaction was captured by a telephone survey.
Thirteen rural and suburban hospitals in Alberta, Canada.
Proportion of successful cecal intubations, average number of adenomas detected per colonoscopy, proportion of patients with at least one adenoma, and serious adverse event rates; patient satisfaction with their wait time and procedure, as well as willingness to have a repeat colonoscopy performed by their primary care endoscopist.
In the two-month study period, 10 study physicians performed 577 colonoscopies. The overall adjusted proportion of successful cecal intubations was 96.5% (95% CI 94.6–97.8), and all physicians achieved the adjusted cecal intubation target of ≥90%. The average number of ademonas detected per colonoscopy was 0.62 (95% CI 0.5–0.74). 46.4% (95% CI 38.5–54.3) of males and 30.2% (95% CI 22.3–38.2) of females ≥50 years of age having their first colonoscopy, had at least one adenoma. Four serious adverse events occurred (three post polypectomy bleeds and one perforation) and 99.3% of patients were willing to have a repeat colonoscopy performed by their primary care colonoscopist.
Two-month study length and non-universal participation by Alberta primary care endoscopists.
Primary care physician colonoscopists can achieve quality benchmarks in colonoscopy. Training additional primary care physicians in endoscopy may improve patient access and decrease endoscopic wait times, especially in rural settings.
PMCID: PMC3695091  PMID: 23826186
12.  Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(6):e65835.
Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI.
Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochran's Q and I2. Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530.
Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohran's Q p<0.0001, I2 = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias.
Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.
PMCID: PMC3686844  PMID: 23840373
13.  The Impact of Study Size on Meta-analyses: Examination of Underpowered Studies in Cochrane Reviews 
PLoS ONE  2013;8(3):e59202.
Most meta-analyses include data from one or more small studies that, individually, do not have power to detect an intervention effect. The relative influence of adequately powered and underpowered studies in published meta-analyses has not previously been explored. We examine the distribution of power available in studies within meta-analyses published in Cochrane reviews, and investigate the impact of underpowered studies on meta-analysis results.
Methods and Findings
For 14,886 meta-analyses of binary outcomes from 1,991 Cochrane reviews, we calculated power per study within each meta-analysis. We defined adequate power as ≥50% power to detect a 30% relative risk reduction. In a subset of 1,107 meta-analyses including 5 or more studies with at least two adequately powered and at least one underpowered, results were compared with and without underpowered studies. In 10,492 (70%) of 14,886 meta-analyses, all included studies were underpowered; only 2,588 (17%) included at least two adequately powered studies. 34% of the meta-analyses themselves were adequately powered. The median of summary relative risks was 0.75 across all meta-analyses (inter-quartile range 0.55 to 0.89). In the subset examined, odds ratios in underpowered studies were 15% lower (95% CI 11% to 18%, P<0.0001) than in adequately powered studies, in meta-analyses of controlled pharmacological trials; and 12% lower (95% CI 7% to 17%, P<0.0001) in meta-analyses of controlled non-pharmacological trials. The standard error of the intervention effect increased by a median of 11% (inter-quartile range −1% to 35%) when underpowered studies were omitted; and between-study heterogeneity tended to decrease.
When at least two adequately powered studies are available in meta-analyses reported by Cochrane reviews, underpowered studies often contribute little information, and could be left out if a rapid review of the evidence is required. However, underpowered studies made up the entirety of the evidence in most Cochrane reviews.
PMCID: PMC3609745  PMID: 23544056
14.  Diagnostic Performance of a Rapid Magnetic Resonance Imaging Method of Measuring Hepatic Steatosis 
PLoS ONE  2013;8(3):e59287.
Hepatic steatosis is associated with an increased risk of developing serious liver disease and other clinical sequelae of the metabolic syndrome. However, visual estimates of steatosis from histological sections of biopsy samples are subjective and reliant on an invasive procedure with associated risks. The aim of this study was to test the ability of a rapid, routinely available, magnetic resonance imaging (MRI) method to diagnose clinically relevant grades of hepatic steatosis in a cohort of patients with diverse liver diseases.
Materials and Methods
Fifty-nine patients with a range of liver diseases underwent liver biopsy and MRI. Hepatic steatosis was quantified firstly using an opposed-phase, in-phase gradient echo, single breath-hold MRI methodology and secondly, using liver biopsy with visual estimation by a histopathologist and by computer-assisted morphometric image analysis. The area under the receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of the MRI method against the biopsy observations.
The MRI approach had high sensitivity and specificity at all hepatic steatosis thresholds. Areas under ROC curves were 0.962, 0.993, and 0.972 at thresholds of 5%, 33%, and 66% liver fat, respectively. MRI measurements were strongly associated with visual (r2 = 0.83) and computer-assisted morphometric (r2 = 0.84) estimates of hepatic steatosis from histological specimens.
This MRI approach, using a conventional, rapid, gradient echo method, has high sensitivity and specificity for diagnosing liver fat at all grades of steatosis in a cohort with a range of liver diseases.
PMCID: PMC3605443  PMID: 23555650
15.  A Randomized Controlled Trial of the Efficacy and Safety of CCX282-B, an Orally-Administered Blocker of Chemokine Receptor CCR9, for Patients with Crohn’s Disease 
PLoS ONE  2013;8(3):e60094.
CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease.
Trial Registration NCT00306215.
PMCID: PMC3603920  PMID: 23527300
16.  Addressing Dichotomous Data for Participants Excluded from Trial Analysis: A Guide for Systematic Reviewers 
PLoS ONE  2013;8(2):e57132.
Systematic reviewer authors intending to include all randomized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data.
The objective of this paper is to provide systematic reviewer authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of randomized trials.
This guide is based on a review of the Cochrane handbook and published methodological research. The guide deals with participants excluded from the analysis who were considered ‘non-adherent to the protocol’ but for whom data are available, and participants with missing data.
Systematic reviewer authors should include data from ‘non-adherent’ participants excluded from the primary study authors' analysis but for whom data are available. For missing, unavailable participant data, authors may conduct a complete case analysis (excluding those with missing data) as the primary analysis. Alternatively, they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data. When the primary analysis suggests important benefit, sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis. The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta-analysis. The proposed guide does not take into account the uncertainty associated with assumed events.
This guide proposes methods for handling participants excluded from analyses of randomized trials. These methods can help in establishing the extent to which risk of bias impacts meta-analysis results.
PMCID: PMC3581575  PMID: 23451162
17.  Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial 
PLoS ONE  2013;8(1):e53719.
Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD.
58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment.
Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively).
Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis.
Trial Registration ISRCTN83972743.
PMCID: PMC3544843  PMID: 23341981
18.  Correction of Liver Steatosis by a Hydrophobic Iminosugar Modulating Glycosphingolipids Metabolism 
PLoS ONE  2012;7(10):e38520.
The iminosugar N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of glycosphingolipid (GSL) biosynthesis is known to ameliorate diabetes, insulin sensitivity and to prevent liver steatosis in ob/ob mice. Thus far the effect of GSL synthesis inhibition on pre-existing NASH has not yet been assessed. To investigate it, LDLR(−/−) mice were kept on a western-type diet for 12 weeks to induce NASH. Next, the diet was continued for 6 weeks in presence or not of AMP-DNM in the diet. AMP-DNM treated mice showed less liver steatosis, inflammation and fibrosis. Induction of fatty acid beta-oxydation was observed, as well as a reduction of plasma lipids. Our study demonstrates that AMP-DNM treatment is able to significantly correct pre-existing NASH, suggesting that inhibiting GSL synthesis may represent a novel strategy for the treatment of this pathology.
PMCID: PMC3466229  PMID: 23056165
19.  Statin Use and Risk of Prostate Cancer: A Meta-Analysis of Observational Studies 
PLoS ONE  2012;7(10):e46691.
Emerging evidence suggests that statins may decrease the risk of cancers. However, available evidence on prostate cancer (PCa) is conflicting. We therefore examined the association between statin use and risk of PCa by conducting a detailed meta-analysis of all observational studies published regarding this subject.
Literature search in PubMed database was undertaken through February 2012 looking for observational studies evaluating the association between statin use and risk of PCa. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects model (DerSimonian and Laird method). Subgroup analyses, sensitivity analysis and cumulative meta-analysis were also performed.
A total of 27 (15 cohort and 12 case-control) studies contributed to the analysis. There was heterogeneity among the studies but no publication bias. Statin use significantly reduced the risk of both total PCa by 7% (RR 0.93, 95% CI 0.87–0.99, p = 0.03) and clinically important advanced PCa by 20% (RR 0.80, 95% CI 0.70–0.90, p<0.001). Long-term statin use did not significantly affect the risk of total PCa (RR 0.94, 95% CI 0.84–1.05, p = 0.31). Stratification by study design did not substantially influence the RR. Furthermore, sensitivity analysis confirmed the stability of results. Cumulative meta-analysis showed a change in trend of reporting risk from positive to negative in statin users between 1993 and 2011.
Our meta-analysis provides evidence supporting the hypothesis that statins reduce the risk of both total PCa and clinically important advanced PCa. Further research is needed to confirm these findings and to identify the underlying biological mechanisms.
PMCID: PMC3462187  PMID: 23049713
20.  Designing and Analyzing Clinical Trials with Composite Outcomes: Consideration of Possible Treatment Differences between the Individual Outcomes 
PLoS ONE  2012;7(4):e34785.
When the individual outcomes within a composite outcome appear to have different treatment effects, either in magnitude or direction, researchers may question the validity or appropriateness of using this composite outcome as a basis for measuring overall treatment effect in a randomized controlled trial. The question remains as to how to distinguish random variation in estimated treatment effects from important heterogeneity within a composite outcome. This paper suggests there may be some utility in directly testing the assumption of homogeneity of treatment effect across the individual outcomes within a composite outcome. We describe a treatment heterogeneity test for composite outcomes based on a class of models used for the analysis of correlated data arising from the measurement of multiple outcomes for the same individuals. Such a test may be useful in planning a trial with a primary composite outcome and at trial end with final analysis and presentation. We demonstrate how to determine the statistical power to detect composite outcome treatment heterogeneity using the POISE Trial data. Then we describe how this test may be incorporated into a presentation of trial results with composite outcomes. We conclude that it may be informative for trialists to assess the consistency of treatment effects across the individual outcomes within a composite outcome using a formalized methodology and the suggested test represents one option.
PMCID: PMC3328496  PMID: 22529934
21.  Performance of Biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in Patients with Severe Obesity: Meta Analysis of Individual Patient Data 
PLoS ONE  2012;7(3):e30325.
Liver biopsy is considered as the gold standard for assessing non-alcoholic fatty liver disease (NAFLD) histologic lesions in patients with severe obesity. The aim of this study was to perform an overview of 3 studies which assessed the performance of non-invasive markers of fibrosis (FibroTest), steatosis (SteatoTest) and steato-hepatitis (NashTest, ActiTest) in these patients.
494 patients with interpretable biopsy and biomarkers using of three prospective cohorts of patients with severe obesity (BMI >35 kg/m2) were included. Histology (NAS score) and the biochemical measurements were blinded to any other characteristics. The area under the ROC curves (AUROC), sensitivity, specificity, positive and negative predictive values were assessed. Weighted AUROC (wAUROC Obuchowski method) was used to prevent multiple testing and spectrum effect. Two meta-analyses were performed; one used the individual patient, and the other a classical meta-analysis.
Prevalence of advanced fibrosis (bridging) was 9.9%, advanced steatosis (>33%) 54.2%, and steato-hepatitis (NAS score >4) 17.2%. The mean wAUROCs were: FibroTest for advanced fibrosis (95%CI; significance)  =  0.85 (0.83–0.87; P<0.0001); SteatoTest for advanced steatosis = 0.80 (0.79–0.83); and ActiTest for steato-hepatitis = 0.84 (0.82–0.86; P<0.0001). Using the classical meta-analysis (random effect model) the mean AUROCs were: FibroTest = 0.72 (0.63–0.79; P<0.0001); SteatoTest = 0.71 (0.66–0.75; P<0.0001); and ActiTest = 0.74 (0.68–0.79; P<0.0001). Despite more metabolic risk factors in one cohort, results were similar according to gender, presence of diabetes and between the 3 cohorts.
In patients with severe obesity, a significant diagnostic performance of FibroTest, SteatoTest and ActiTest was observed for liver lesions.
PMCID: PMC3303768  PMID: 22431959
22.  High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation as a First-Line Therapy for High-Risk Primary Breast Cancer: A Meta-Analysis 
PLoS ONE  2012;7(3):e33388.
Background and Objectives
Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies.
Design and Methods
Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol.
Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82–1.98) and higher TRM (RR = 3.42; 95% CI = 1.32–8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79–0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82–1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS.
HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer.
PMCID: PMC3299795  PMID: 22428041
23.  Liver and Muscle in Morbid Obesity: The Interplay of Fatty Liver and Insulin Resistance 
PLoS ONE  2012;7(2):e31738.
Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients.
Liver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses.
Fifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056).
In morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity.
PMCID: PMC3281005  PMID: 22359625
24.  Downgrading MELD Improves the Outcomes after Liver Transplantation in Patients with Acute-on-Chronic Hepatitis B Liver Failure 
PLoS ONE  2012;7(1):e30322.
High score of model for end-stage liver diseases (MELD) before liver transplantation (LT) indicates poor prognosis. Artificial liver support system (ALSS) has been proved to effectively improve liver and kidney functions, and thus reduce the MELD score. We aim to evaluate whether downgrading MELD score could improve patient survival after LT.
Methodology/Principal Findings
One hundred and twenty-six LT candidates with acute-on-chronic hepatitis B liver failure and MELD score ≥30 were included in this prospective study. Of the 126 patients, 42 received emergency LT within 72 h (ELT group) and the other 84 were given ALSS as salvage treatment. Of the 84 patients, 33 were found to have reduced MELD score (<30) on the day of LT (DGM group), 51 underwent LT with persistent high MELD score (N-DGM group). The median waiting time for a donor was 10 for DGM group and 9.5 days for N-DGM group. In N-DGM group there is a significantly higher overall mortality (43.1%) than that in ELT group (16.7%) and DGM group (15.2%). N-DGM (vs. ECT and DGM) was the only independent risk factor of overall mortality (P = 0.003). Age >40 years and the interval from last ALSS to LT >48 h were independent negative influence factors of downgrading MELD.
Downgrading MELD for liver transplant candidates with MELD score ≥30 was effective in improving patient prognosis. An appropriate ALSS treatment within 48 h prior to LT is potentially beneficial.
PMCID: PMC3265473  PMID: 22291934
25.  Funding Source and Research Report Quality in Nutrition Practice-Related Research 
PLoS ONE  2011;6(12):e28437.
The source of funding is one of many possible causes of bias in scientific research. One method of detecting potential for bias is to evaluate the quality of research reports. Research exploring the relationship between funding source and nutrition-related research report quality is limited and in other disciplines the findings are mixed.
The purpose of this study is to determine whether types of funding sources of nutrition research are associated with differences in research report quality.
A retrospective study of research reporting quality, research design and funding source was conducted on 2539 peer reviewed research articles from the American Dietetic Association's Evidence Analysis Library® database.
Quality rating frequency distributions indicate 43.3% of research reports were rated as positive, 50.1% neutral, and 6.6% as negative. Multinomial logistic regression results showed that while both funding source and type of research design are significant predictors of quality ratings (χ2 = 118.99, p<0.001), the model's usefulness in predicting overall research report quality is little better than chance. Compared to research reports with government funding, those not acknowledging any funding sources, followed by studies with University/hospital funding were more likely to receive neutral vs positive quality ratings, OR = 1.85, P <0.001 and OR = 1.54, P<0.001, respectively and those that did not report funding were more likely to receive negative quality ratings (OR = 4.97, P<0.001). After controlling for research design, industry funded research reports were no more likely to receive a neutral or negative quality rating than those funded by government sources.
Research report quality cannot be accurately predicted from the funding source after controlling for research design. Continued vigilance to evaluate the quality of all research regardless of the funding source and to further understand other factors that affect quality ratings are warranted.
PMCID: PMC3232225  PMID: 22163017

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