Meta-epidemiological Approach Research Articles

Association Between Lack of Blinding and Mortality Results in Critical Care Randomized Controlled Trials: A Meta-Epidemiological Study.

To investigate whether intervention effect estimates for mortality differ between blinded and nonblinded randomized controlled trials conducted in critical care. We used a meta-epidemiological approach, comparing effect estimates between blinded and nonblinded randomized controlled trials for the same research question. Systematic reviews and meta-analyses of randomized controlled trials evaluating a therapeutic intervention on mortality in critical care, published between January 2009 and March 2019 in high impact factor general medical or critical care journals and by Cochrane. For each randomized controlled trial included in eligible meta-analyses, we evaluated whether the trial was blinded (i.e., double-blinded and/or reporting adequate methods) or not (i.e., open-label, single-blinded, or unclear). We collected risk of bias evaluated by the review authors and extracted trial results. Within each meta-analysis, we compared intervention effect estimates between blinded and nonblinded randomized controlled trials by using a ratio of odds ratio (< 1 indicates larger estimates in nonblinded than blinded randomized controlled trials). We then combined ratio of odds ratios across meta-analyses to obtain the average relative difference between nonblinded and blinded trials. Among 467 randomized controlled trials included in 36 meta-analyses, 267 (57%) were considered blinded and 200 (43%) nonblinded. Intervention effect estimates were statistically significantly larger in nonblinded than blinded trials (combined ratio of odds ratio, 0.91; 95% CI, 0.84-0.99). We found no heterogeneity across meta-analyses (p = 0.72; I2 = 0%; τ2 = 0). Sensitivity analyses adjusting the main analysis on risk of bias items yielded consistent results. Intervention effect estimates of mortality were slightly larger in nonblinded than blinded randomized controlled trials conducted in critical care, but confounding cannot be excluded. Blinding of both patients and personnel is important to consider when possible in critical care trials, even when evaluating mortality.

Prevention of Venous Thromboembolic Events in Patients with Lower Leg Immobilization after Trauma: Systematic Review and Network Meta-Analysis with Meta-Epidemiological Approach

Prevention of Venous Thromboembolic Events in Patients with Lower Leg Immobilization after Trauma: Systematic Review and Network Meta-Analysis with Meta-Epidemiological Approach

What is a meta-epidemiological study? Analysis of published literature indicated heterogeneous study designs and definitions.

Aim: To analyze descriptors/definitions of meta-epidemiological studies as well as study design of articles that were self-described as meta-epidemiological studies. Methods: We searched MEDLINE and Embase on 6 August2019. We extracted definitions of meta-epidemiological studies, as well as study designs, statistics and units of analysis that were reported in studies self-labelled as meta-epidemiological studies. Results: We included 175 information sources in the analysis. Definitions of meta-epidemiological studies varied and some studies used the term meta-epidemiological study to describe methodological research-on-research studies. Less than a half of the studies (n=54;42.9%) used the two-step meta-epidemiological approach in data analysis. Among studies self-labelled as meta-epidemiological, 9.4% reported registration in PROSPERO and 11% indicated they reported the study in line with PRISMA. Conclusion: Research community would benefit from consensus about definition of meta-epidemiological study.

A Meta-Epidemiological Appraisal of the Effects of Interdisciplinary Multimodal Pain Therapy Dosing for Chronic Low Back Pain.

Using a meta-analysis, meta-regression, and a meta-epidemiological approach, we conducted a systematic review to examine the influence of interdisciplinary multimodal pain therapy (IMPT) dosage on pain, disability, return to work, quality of life, depression, and anxiety in published randomised controlled trials (RCTs) in patients with non-specific chronic low back pain (CLBP). We considered all RCTs of IMPT from a Cochrane review and searched PubMed for additional RCTs through 30 September 2018. A subgroup random-effects meta-analysis by length, contact, and intensity of treatment was performed followed by a meta-regression analysis. Using random and fixed-effect models and a summary relative odds ratio (ROR), we compared the effect sizes (ES) from short-length, non-daily contact, and low-intensity RCTs with long-length, daily contact, and high-intensity RCTs. Heterogeneity was quantified with the I2 metric. A total of 47 RCTs were selected. Subgroup meta-analysis showed that there were larger ES for pain and disability in RCTs with long-length, non-daily contact, and low intensity of treatment. Larger ES were also observed for quality of life in RCTs with short-length, non-daily contact, and low intensity treatment. However, these findings were not confirmed by the meta-regression analysis. Likewise, the summary RORs were not significant, indicating that the length, contact, and intensity of treatment did not have an overall effect on the investigated outcomes. For the outcomes investigated here, IMPT dosage is not generally associated with better ES, and an optimal dosage was not determined.

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events—a meta-analysis

BackgroundPrevious meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methodsWe searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. ResultsThe literature-based meta-analysis included 166 trials (72024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12–2.73; P<0.001], but this risk was overestimated by 1.68 (95% CI 1.33–2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04–1.35; P=0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83–1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19–1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30–1.94; P<0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13–2.43) in open-label trials. ConclusionsOpen-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

Use of available clinical evidence to extrapolate drug effects from adults to children

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Design Characteristics Influence Performance of Clinical Prediction Rules in Validation: A Meta-Epidemiological Study.

BackgroundMany new clinical prediction rules are derived and validated. But the design and reporting quality of clinical prediction research has been less than optimal. We aimed to assess whether design characteristics of validation studies were associated with the overestimation of clinical prediction rules’ performance. We also aimed to evaluate whether validation studies clearly reported important methodological characteristics.MethodsElectronic databases were searched for systematic reviews of clinical prediction rule studies published between 2006 and 2010. Data were extracted from the eligible validation studies included in the systematic reviews. A meta-analytic meta-epidemiological approach was used to assess the influence of design characteristics on predictive performance. From each validation study, it was assessed whether 7 design and 7 reporting characteristics were properly described.ResultsA total of 287 validation studies of clinical prediction rule were collected from 15 systematic reviews (31 meta-analyses). Validation studies using case-control design produced a summary diagnostic odds ratio (DOR) 2.2 times (95% CI: 1.2–4.3) larger than validation studies using cohort design and unclear design. When differential verification was used, the summary DOR was overestimated by twofold (95% CI: 1.2 -3.1) compared to complete, partial and unclear verification. The summary RDOR of validation studies with inadequate sample size was 1.9 (95% CI: 1.2 -3.1) compared to studies with adequate sample size. Study site, reliability, and clinical prediction rule was adequately described in 10.1%, 9.4%, and 7.0% of validation studies respectively.ConclusionValidation studies with design shortcomings may overestimate the performance of clinical prediction rules. The quality of reporting among studies validating clinical prediction rules needs to be improved.

CORR Insights®: Kaplan-Meier Survival Analysis Overestimates the Risk of Revision Arthroplasty: A Meta-analysis

I t is well known that the KaplanMeier estimator overestimates the probability of events of interest in the presence of competing risks [1, 8]. For example, if a study seeks to examine the durability of a particular arthroplasty implant (so the event of interest is revision), and a substantial proportion of the patients die, the Kaplan-Meier approach will overestimate the frequency of revision, since patients who have died cannot subsequently undergo revision. As such, death is considered a competing event to the event of interest (implant revision). The more frequent the competing events, the more KaplanMeier-based estimates will depart from the true probability of occurrence of the event of interest. In light of this, alternative analytic approaches that account for the occurrence of such competing events have been developed to estimate the cumulative incidence [1, 8]. While these issues are mathematically demonstrated and have been illustrated in various medical domains [2, 3, 6], they have received less attention in orthopaedic research until recently [7, 8]. But while some work has been done in individual datasets [8], to my knowledge, no study has taken a broader look at the influence of the phenomenon of competing risks on Kaplan-Meier survivorship estimates across orthopaedics more generally. In their study, Lacny et al. [4] adopted a meta-epidemiological approach to quantify the overestimation of the probability of revision by Kaplan-Meier estimator. They performed a systematic review and included studies that presented the probability of revision after hip or knee arthroplasty using both KaplanMeier and competing risks methods. Results showed that using KaplanMeier estimator overestimated the probability of revision by 7% in the strata with highest number of revision, and by 55% in those with highest proportion of patients who died during followup, which is a substantial difference indeed. While the study failed to demonstrate the effect of a higher proportion of competing events (deaths) on the overestimation, the data still This CORR Insights is a commentary on the article ‘‘Kaplan-Meier Survival Analysis Overestimates the Risk of Revision Arthroplasty: A Meta-analysis’’ by Lacny and colleagues available at: DOI: 10.1007/ s11999-015-4235-8. The author certifies that he, or any member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or the Association of Bone and Joint Surgeons. This CORR Insights comment refers to the article available at DOI:10.1007/s11999-0154235-8. R. Porcher PhD (&) Center of Clinical Epidemiology, Hopital Hotel-Dieu, 1 Parvis NotreDame Place Jean-Paul II, 75004 Paris, France e-mail: raphael.porcher@htd.aphp.fr CORR Insights Published online: 11 April 2015 The Association of Bone and Joint Surgeons1 2015

How should we evaluate the risk of bias of physical therapy trials?: a psychometric and meta-epidemiological approach towards developing guidelines for the design, conduct, and reporting of RCTs in Physical Therapy (PT) area: a study protocol

BackgroundNumerous tools and items have been developed in all health areas to assess the risk of bias of randomized controlled trials (RCTs). The Cochrane Collaboration (CC) released a new tool to assess bias in RCTs, based on empirical evidence quantifying the association between some design features and estimates of treatment effects (TEs). However, this evidence is limited to medicine and investigating a selected set of components. No such studies have been conducted in other health areas such as Physical Therapy (PT) and allied health professions. Evidence specific to the PT area is needed to understand and quantify the association between design features and TE estimates to inform practice and decision-making in this field. The overall goal of this project is to provide direction for the design, conduct, reporting and bias assessment of PT RCTs. We will achieve this through the following specific objectives and methods.Methods/Design1) to measure the association between methodological components and other factors (for example, PT area, type of intervention, type of outcomes) and TE estimates in RCTs in PT, 40 randomly selected meta-analyses of RCTs involving PT interventions will be identified from the Cochrane Database of Systematic Reviews. Trials will be evaluated independently by two reviewers using the most commonly used tools in the PT field. A two-level analysis will be conducted using a meta-meta-analytic approach; 2) to identify relevant items to evaluate risk of bias of PT trials, an exploratory factor analysis (EFA) will be used to identify the latent structure of the items; 3) to develop guidelines for the design, conduct, reporting, and risk of bias assessment of PT RCTs, items obtained from the factor analysis and the meta-epidemiological approach will be further evaluated by experts in PT through a web-based survey following a Delphi procedure.DiscussionThe results of this project will have a direct impact on research and practice in PT and are valuable to a number of stakeholders: researchers when designing, conducting, and reporting trials; systematic reviewers and meta-analysts when synthesizing trial results; physiotherapists when making day-to-day treatment decision; and, other healthcare decision-makers, such as those developing policy or practice guidelines.

Risk factors for violence in psychosis: systematic review and meta-regression analysis of 110 studies.

BackgroundPrevious reviews on risk and protective factors for violence in psychosis have produced contrasting findings. There is therefore a need to clarify the direction and strength of association of risk and protective factors for violent outcomes in individuals with psychosis.MethodWe conducted a systematic review and meta-analysis using 6 electronic databases (CINAHL, EBSCO, EMBASE, Global Health, PsycINFO, PUBMED) and Google Scholar. Studies were identified that reported factors associated with violence in adults diagnosed, using DSM or ICD criteria, with schizophrenia and other psychoses. We considered non-English language studies and dissertations. Risk and protective factors were meta-analysed if reported in three or more primary studies. Meta-regression examined sources of heterogeneity. A novel meta-epidemiological approach was used to group similar risk factors into one of 10 domains. Sub-group analyses were then used to investigate whether risk domains differed for studies reporting severe violence (rather than aggression or hostility) and studies based in inpatient (rather than outpatient) settings.FindingsThere were 110 eligible studies reporting on 45,533 individuals, 8,439 (18.5%) of whom were violent. A total of 39,995 (87.8%) were diagnosed with schizophrenia, 209 (0.4%) were diagnosed with bipolar disorder, and 5,329 (11.8%) were diagnosed with other psychoses. Dynamic (or modifiable) risk factors included hostile behaviour, recent drug misuse, non-adherence with psychological therapies (p values<0.001), higher poor impulse control scores, recent substance misuse, recent alcohol misuse (p values<0.01), and non-adherence with medication (p value <0.05). We also examined a number of static factors, the strongest of which were criminal history factors. When restricting outcomes to severe violence, these associations did not change materially. In studies investigating inpatient violence, associations differed in strength but not direction.ConclusionCertain dynamic risk factors are strongly associated with increased violence risk in individuals with psychosis and their role in risk assessment and management warrants further examination.