Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies

Background: Standard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling. Methods: We consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches. Results: Empirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems. Conclusions: In the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise

Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including <100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations

Meta-analysis data extracted from IQWiG publications

This data set contains data on 40 meta-analyses extracted from publications by the German Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; IQWiG). In April 2017, IQWiG publications were screened chronologically, starting with the most recent one. Each publication was searched for reported meta-analyses involving binary endpoints, and non-zero event counts in all study arms, and the first qualifying analysis within each report was entered into the database. The search was continued (going back to March 2012) until a total of 40 analyses had been found. For more details see also the related publication referenced below (Seide et al., 2018). The data set consists of two CSV files; the first one, IQWiG-metadata.csv, contains metadata regarding each of the 40 meta-analyses; these are in particular the following variables (columns): no: running number identifier: IQWiG project identifier date: publication date of IQWiG project report endpoint: name of endpoint page: page number in IQWiG project report studies: number of studies included in the meta-analysis effect.measure: effect measure used The second file, IQWiG-data.csv, contains the actual count data from 131 individual studies that went into the 40 meta-analyses (each row corresponding to a study that was meta-analysed, and several rows corresponding to each meta-analysis). It contains the following variables (columns): no: running number identifier: IQWiG project identifier study: study label treat.events: number of events in the treatment group treat.total: total number of cases in the treatment group control.events: number of events in the control group control.total: total number of cases in the control group Running number and identifier allow to match the entries from both files. </p

Continuous wound infiltration versus epidural analgesia for midline abdominal incisions – a randomized-controlled pilot trial (Painless-Pilot trial; DRKS Number: DRKS00008023)

OBJECTIVES:To test the feasibility of a randomized controlled study design comparing epidural analgesia (EDA) with continuous wound infiltration (CWI) in respect to postoperative complications and mobility to design a future multicentre randomized controlled trial. DESIGN, SETTING, PARTICIPANTS:CWI has been developed to address drawbacks of EDA. Previous studies have established the equivalent analgesic potential of CWI compared to EDA. This is a single centre, non-blinded pilot randomized controlled trial at a tertiary surgical centre. Patients undergoing elective non-colorectal surgery via a midline laparotomy were randomized to EDA or CWI. Endpoints included recruitment, feasibility of assessing postoperative mobility with a pedometer and morbidity. No primary endpoint was defined and all analyses were explorative. INTERVENTIONS:CWI with local anaesthetics (experimental group) vs. thoracic EDA (control). RESULTS:Of 846 patients screened within 14 months, 71 were randomized and 62 (31 per group) included in the intention-to-treat analysis. Mobility was assessed in 44 of 62 patients and revealed no differences within the first 3 postoperative days. Overall morbidity did not differ between the two groups (measured via the comprehensive complication index). Median pain scores at rest were comparable between the two groups, while EDA was superior in pain treatment during movement on the first, but not on the second and third postoperative day. Duration of preoperative induction of anaesthesia was shorter with CWI than with EDA. Of 17 serious adverse events, 3 were potentially related to EDA, while none was related to CWI. CONCLUSION:This trial confirmed the feasibility of a randomized trial design to compare CWI and EDA regarding morbidity. Improvements in the education and training of team members are necessary to improve recruitment. TRIAL REGISTRATION:DRKS00008023

Automated mechanical cardiopulmonary resuscitation devices versus manual chest compressions in the treatment of cardiac arrest: protocol of a systematic review and meta-analysis comparing machine to human

Introduction Cardiac arrest is a leading cause of death in industrialised countries. Cardiopulmonary resuscitation (CPR) guidelines follow the principles of closed chest compression as described for the first time in 1960. Mechanical CPR devices are designed to improve chest compression quality, thus considering the improvement of resuscitation outcomes. This protocol outlines a systematic review and meta-analysis methodology to assess trials investigating the therapeutic effect of automated mechanical CPR devices at the rate of return of spontaneous circulation, neurological state and secondary endpoints (including short-term and long-term survival, injuries and surrogate parameters for CPR quality) in comparison with manual chest compressions in adults with cardiac arrest.Methods and analysis A sensitive search strategy will be employed in established bibliographic databases from inception until the date of search, followed by forward and backward reference searching. We will include randomised and quasi-randomised trials in qualitative analysis thus comparing mechanical to manual CPR. Studies reporting survival outcomes will be included in quantitative analysis. Two reviewers will assess independently publications using a predefined data collection form. Standardised tools will be used for data extraction, risks of bias and quality of evidence. If enough studies are identified for meta-analysis, the measures of association will be calculated by dint of bivariate random-effects models. Statistical heterogeneity will be evaluated by I2-statistics and explored through sensitivity analysis. By comprehensive subgroup analysis we intend to identify subpopulations who may benefit from mechanical or manual CPR techniques. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Ethics and dissemination No ethical approval will be needed because data from previous studies will be retrieved and analysed. Most resuscitation studies are conducted under an emergency exception for informed consent. This publication contains data deriving from a dissertation project. We will disseminate the results through publication in a peer-reviewed journal and at scientific conferences.PROSPERO registration number CRD42017051633

Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials

Introduction: Disease-free survival (DFS) is increasingly being used as surrogate end-point for overall survival (OS) in cancer trials. So far, there has been no validation of the surrogacy of DFS for OS for neoadjuvant treatment of gastroesophageal adenocarcinoma. Methods: The study uses individual patient data (IPD) from eight randomised controlled trials (RCTs) (n = 1126 patients) comparing neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. Correlation between OS time and DFS time was calculated to evaluate individual-level surrogacy. For each trial, survival curves using the Kaplan-Meier method were plotted and hazard ratios (HRs) on the treatment effects were calculated for OS and DFS separately. Those HRs were pooled in a random-effects meta-analysis. Observed HRs were compared with predicted HRs for OS using results from an error-in-variables linear regression model accounting for the uncertainty about the estimated effect. The strength of the association was quantified by the coefficient of determination to assess trial-level surrogacy. The surrogate threshold effect was calculated to determine the minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS. Results: A strong correlation between OS time and DFS time was observed, indicating a high individual-level surrogacy. For all RCTs, estimated HRs for OS and DFS were highly similar. In the meta-analysis, the overall HR for OS was virtually identical to that for DFS. The estimated coefficient of determination r for the association between HRs for OS and DFS was 0.912 (95% confidence interval: 0.75–1.0), indicating a very good fit of the regression model and thus a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect based on the regression analysis was 0.79. Discussion: Based on strong correlations between DFS and OS, as well as a strong correlation of the treatment effects of the two end-points in the error-in-variable regression, DFS seems an appropriate surrogate marker for OS in randomised trials of neoadjuvant chemotherapy or chemoradiotherapy for gastroesophageal adenocarcinoma