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      Multivariate meta-analysis: Potential and promise

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          Abstract

          The multivariate random effects model is a generalization of the standard univariate model. Multivariate meta-analysis is becoming more commonly used and the techniques and related computer software, although continually under development, are now in place. In order to raise awareness of the multivariate methods, and discuss their advantages and disadvantages, we organized a one day ‘Multivariate meta-analysis’ event at the Royal Statistical Society. In addition to disseminating the most recent developments, we also received an abundance of comments, concerns, insights, critiques and encouragement. This article provides a balanced account of the day's discourse. By giving others the opportunity to respond to our assessment, we hope to ensure that the various view points and opinions are aired before multivariate meta-analysis simply becomes another widely used de facto method without any proper consideration of it by the medical statistics community. We describe the areas of application that multivariate meta-analysis has found, the methods available, the difficulties typically encountered and the arguments for and against the multivariate methods, using four representative but contrasting examples. We conclude that the multivariate methods can be useful, and in particular can provide estimates with better statistical properties, but also that these benefits come at the price of making more assumptions which do not result in better inference in every case. Although there is evidence that multivariate meta-analysis has considerable potential, it must be even more carefully applied than its univariate counterpart in practice. Copyright © 2011 John Wiley & Sons, Ltd.

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          Most cited references58

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          Small sample inference for fixed effects from restricted maximum likelihood.

          Restricted maximum likelihood (REML) is now well established as a method for estimating the parameters of the general Gaussian linear model with a structured covariance matrix, in particular for mixed linear models. Conventionally, estimates of precision and inference for fixed effects are based on their asymptotic distribution, which is known to be inadequate for some small-sample problems. In this paper, we present a scaled Wald statistic, together with an F approximation to its sampling distribution, that is shown to perform well in a range of small sample settings. The statistic uses an adjusted estimator of the covariance matrix that has reduced small sample bias. This approach has the advantage that it reproduces both the statistics and F distributions in those settings where the latter is exact, namely for Hotelling T2 type statistics and for analysis of variance F-ratios. The performance of the modified statistics is assessed through simulation studies of four different REML analyses and the methods are illustrated using three examples.
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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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              A unification of models for meta-analysis of diagnostic accuracy studies.

              Studies of diagnostic accuracy require more sophisticated methods for their meta-analysis than studies of therapeutic interventions. A number of different, and apparently divergent, methods for meta-analysis of diagnostic studies have been proposed, including two alternative approaches that are statistically rigorous and allow for between-study variability: the hierarchical summary receiver operating characteristic (ROC) model (Rutter and Gatsonis, 2001) and bivariate random-effects meta-analysis (van Houwelingen and others, 1993), (van Houwelingen and others, 2002), (Reitsma and others, 2005). We show that these two models are very closely related, and define the circumstances in which they are identical. We discuss the different forms of summary model output suggested by the two approaches, including summary ROC curves, summary points, confidence regions, and prediction regions.
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                Author and article information

                Journal
                Stat Med
                Stat Med
                sim
                Statistics in Medicine
                John Wiley & Sons, Ltd (Chichester, UK )
                0277-6715
                1097-0258
                10 September 2011
                26 January 2011
                : 30
                : 20
                : 2481-2498
                Affiliations
                [a ]MRC Biostatistics Unit Cambridge, U.K
                [b ]Department of Public Health, Epidemiology and Biostatistics, The Public Health Building, University of Birmingham Birmingham B15 2TT, U.K
                Author notes
                *Correspondence to: Dan Jackson, MRC Biostatistics Unit, Cambridge, U.K.

                Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms.

                Article
                10.1002/sim.4172
                3470931
                21268052
                c93040a8-c5b2-4106-ac70-4da3ded961aa
                Copyright © 2012 John Wiley & Sons, Ltd.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 27 August 2010
                : 01 November 2010
                Categories
                Research Articles

                Biostatistics
                statistical software,random effects models,multivariate meta-analysis
                Biostatistics
                statistical software, random effects models, multivariate meta-analysis

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