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      Methods to estimate the between‐study variance and its uncertainty in meta‐analysis†

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          Abstract

          Meta‐analyses are typically used to estimate the overall/mean of an outcome of interest. However, inference about between‐study variability, which is typically modelled using a between‐study variance parameter, is usually an additional aim. The DerSimonian and Laird method, currently widely used by default to estimate the between‐study variance, has been long challenged. Our aim is to identify known methods for estimation of the between‐study variance and its corresponding uncertainty, and to summarise the simulation and empirical evidence that compares them. We identified 16 estimators for the between‐study variance, seven methods to calculate confidence intervals, and several comparative studies. Simulation studies suggest that for both dichotomous and continuous data the estimator proposed by Paule and Mandel and for continuous data the restricted maximum likelihood estimator are better alternatives to estimate the between‐study variance. Based on the scenarios and results presented in the published studies, we recommend the Q‐profile method and the alternative approach based on a ‘generalised Cochran between‐study variance statistic’ to compute corresponding confidence intervals around the resulting estimates. Our recommendations are based on a qualitative evaluation of the existing literature and expert consensus. Evidence‐based recommendations require an extensive simulation study where all methods would be compared under the same scenarios. © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.

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          Improved tests for a random effects meta-regression with a single covariate.

          The explanation of heterogeneity plays an important role in meta-analysis. The random effects meta-regression model allows the inclusion of trial-specific covariates which may explain a part of the heterogeneity. We examine the commonly used tests on the parameters in the random effects meta-regression with one covariate and propose some new test statistics based on an improved estimator of the variance of the parameter estimates. The approximation of the distribution of the newly proposed tests is based on some theoretical considerations. Moreover, the newly proposed tests can easily be extended to the case of more than one covariate. In a simulation study, we compare the tests with regard to their actual significance level and we consider the log relative risk as the parameter of interest. Our simulation study reflects the meta-analysis of the efficacy of a vaccine for the prevention of tuberculosis originally discussed in Berkey et al. The simulation study shows that the newly proposed tests are superior to the commonly used test in holding the nominal significance level. Copyright 2003 John Wiley & Sons, Ltd.
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            Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data.

            We consider random effects meta-analysis where the outcome variable is the occurrence of some event of interest. The data structures handled are where one has one or more groups in each study, and in each group either the number of subjects with and without the event, or the number of events and the total duration of follow-up is available. Traditionally, the meta-analysis follows the summary measures approach based on the estimates of the outcome measure(s) and the corresponding standard error(s). This approach assumes an approximate normal within-study likelihood and treats the standard errors as known. This approach has several potential disadvantages, such as not accounting for the standard errors being estimated, not accounting for correlation between the estimate and the standard error, the use of an (arbitrary) continuity correction in case of zero events, and the normal approximation being bad in studies with few events. We show that these problems can be overcome in most cases occurring in practice by replacing the approximate normal within-study likelihood by the appropriate exact likelihood. This leads to a generalized linear mixed model that can be fitted in standard statistical software. For instance, in the case of odds ratio meta-analysis, one can use the non-central hypergeometric distribution likelihood leading to mixed-effects conditional logistic regression. For incidence rate ratio meta-analysis, it leads to random effects logistic regression with an offset variable. We also present bivariate and multivariate extensions. We present a number of examples, especially with rare events, among which an example of network meta-analysis.
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              Explaining heterogeneity in meta-analysis: a comparison of methods.

              Exploring the possible reasons for heterogeneity between studies is an important aspect of conducting a meta-analysis. This paper compares a number of methods which can be used to investigate whether a particular covariate, with a value defined for each study in the meta-analysis, explains any heterogeneity. The main example is from a meta-analysis of randomized trials of serum cholesterol reduction, in which the log-odds ratio for coronary events is related to the average extent of cholesterol reduction achieved in each trial. Different forms of weighted normal errors regression and random effects logistic regression are compared. These analyses quantify the extent to which heterogeneity is explained, as well as the effect of cholesterol reduction on the risk of coronary events. In a second example, the relationship between treatment effect estimates and their precision is examined, in order to assess the evidence for publication bias. We conclude that methods which allow for an additive component of residual heterogeneity should be used. In weighted regression, a restricted maximum likelihood estimator is appropriate, although a number of other estimators are also available. Methods which use the original form of the data explicitly, for example the binomial model for observed proportions rather than assuming normality of the log-odds ratios, are now computationally feasible. Although such methods are preferable in principle, they often give similar results in practice. Copyright 1999 John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                Res Synth Methods
                Res Synth Methods
                10.1002/(ISSN)1759-2887
                JRSM
                Research Synthesis Methods
                John Wiley and Sons Inc. (Hoboken )
                1759-2879
                1759-2887
                02 September 2015
                March 2016
                : 7
                : 1 ( doiID: 10.1002/jrsm.v7.1 )
                : 55-79
                Affiliations
                [ 1 ]Li Ka Shing Knowledge Institute St. Michael's Hospital 209 Victoria Street, East Building Toronto Ontario M5B 1T8Canada
                [ 2 ] MRC Biostatistics UnitInstitute of Public Health Robinson Way Cambridge CB2 0SRUK
                [ 3 ] Department of Psychiatry and Psychology, School for Mental Health and NeuroscienceMaastricht University The Netherlands
                [ 4 ] Department of Medical BiometryInstitute for Quality and Efficiency in Health Care (IQWiG) Im Mediapark 8 50670 CologneGermany
                [ 5 ]MRC Biostatistics Unit Hub for Trials Methodology Research CambridgeUK
                [ 6 ] Department of StatisticsTU Dortmund University 44221 DortmundGermany
                [ 7 ] Institute for Biometrics and Epidemiology, German Diabetes CenterLeibniz Institute for Diabetes Research at Heinrich Heine University 40225 DüsseldorfGermany
                [ 8 ] School of Social and Community MedicineUniversity of Bristol BristolUK
                [ 9 ] Centre for Reviews and DisseminationUniversity of York YorkUK
                [ 10 ] Department of Hygiene and EpidemiologyUniversity of Ioannina School of Medicine IoanninaGreece
                Author notes
                [*] [* ] Correspondence to: Areti Angeliki Veroniki, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 209 Victoria Street, East Building, Toronto, Ontario, M5B 1T8, Canada.

                E‐mail: veronikia@ 123456smh.ca

                Article
                JRSM1164 RSM-06-2014-0023.R2
                10.1002/jrsm.1164
                4950030
                26332144
                c0264977-2765-422b-9334-917a1c1eff38
                © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 June 2014
                : 20 May 2015
                : 24 June 2015
                Page count
                Pages: 25
                Funding
                Funded by: CIHR Banting Postdoctoral Fellowship Program
                Funded by: MRC Methodology Research Fellowship
                Award ID: MR/L012286/1
                Funded by: UK Medical Research Council
                Award ID: U105260558
                Funded by: Centre for Reviews and Dissemination, University of York
                Funded by: Institute for Quality and Efficiency in Health Care, Cologne, Germany
                Funded by: European Research Council
                Award ID: 260559
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jrsm1164
                March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.2 mode:remove_FC converted:19.07.2016

                heterogeneity,mean squared error,bias,coverage probability,confidence interval

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