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      Meta‐analysis of Gaussian individual patient data: Two‐stage or not two‐stage?

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          Abstract

          Quantitative evidence synthesis through meta‐analysis is central to evidence‐based medicine. For well‐documented reasons, the meta‐analysis of individual patient data is held in higher regard than aggregate data. With access to individual patient data, the analysis is not restricted to a “two‐stage” approach (combining estimates and standard errors) but can estimate parameters of interest by fitting a single model to all of the data, a so‐called “one‐stage” analysis. There has been debate about the merits of one‐ and two‐stage analysis. Arguments for one‐stage analysis have typically noted that a wider range of models can be fitted and overall estimates may be more precise. The two‐stage side has emphasised that the models that can be fitted in two stages are sufficient to answer the relevant questions, with less scope for mistakes because there are fewer modelling choices to be made in the two‐stage approach. For Gaussian data, we consider the statistical arguments for flexibility and precision in small‐sample settings. Regarding flexibility, several of the models that can be fitted only in one stage may not be of serious interest to most meta‐analysis practitioners. Regarding precision, we consider fixed‐ and random‐effects meta‐analysis and see that, for a model making certain assumptions, the number of stages used to fit this model is irrelevant; the precision will be approximately equal. Meta‐analysts should choose modelling assumptions carefully. Sometimes relevant models can only be fitted in one stage. Otherwise, meta‐analysts are free to use whichever procedure is most convenient to fit the identified model.

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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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            The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies

            Background Adjustment for prognostic covariates can lead to increased power in the analysis of randomized trials. However, adjusted analyses are not often performed in practice. Methods We used simulation to examine the impact of covariate adjustment on 12 outcomes from 8 studies across a range of therapeutic areas. We assessed (1) how large an increase in power can be expected in practice; and (2) the impact of adjustment for covariates that are not prognostic. Results Adjustment for known prognostic covariates led to large increases in power for most outcomes. When power was set to 80% based on an unadjusted analysis, covariate adjustment led to a median increase in power to 92.6% across the 12 outcomes (range 80.6 to 99.4%). Power was increased to over 85% for 8 of 12 outcomes, and to over 95% for 5 of 12 outcomes. Conversely, the largest decrease in power from adjustment for covariates that were not prognostic was from 80% to 78.5%. Conclusions Adjustment for known prognostic covariates can lead to substantial increases in power, and should be routinely incorporated into the analysis of randomized trials. The potential benefits of adjusting for a small number of possibly prognostic covariates in trials with moderate or large sample sizes far outweigh the risks of doing so, and so should also be considered.
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              Get real in individual participant data (IPD) meta‐analysis: a review of the methodology

              Individual participant data (IPD) meta‐analysis is an increasingly used approach for synthesizing and investigating treatment effect estimates. Over the past few years, numerous methods for conducting an IPD meta‐analysis (IPD‐MA) have been proposed, often making different assumptions and modeling choices while addressing a similar research question. We conducted a literature review to provide an overview of methods for performing an IPD‐MA using evidence from clinical trials or non‐randomized studies when investigating treatment efficacy. With this review, we aim to assist researchers in choosing the appropriate methods and provide recommendations on their implementation when planning and conducting an IPD‐MA. © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                Stat Med
                Stat Med
                10.1002/(ISSN)1097-0258
                SIM
                Statistics in Medicine
                John Wiley and Sons Inc. (Hoboken )
                0277-6715
                1097-0258
                18 January 2018
                30 April 2018
                : 37
                : 9 ( doiID: 10.1002/sim.v37.9 )
                : 1419-1438
                Affiliations
                [ 1 ] London Hub for Trials Methodology Research MRC Clinical Trials Unit at UCL London UK
                [ 2 ] Ashkirk UK
                [ 3 ] Department of Medical Statistics London School of Hygiene and Tropical Medicine London UK
                Author notes
                [*] Correspondence

                Tim P. Morris, London Hub for Trials Methodology Research, MRC Clinical Trials Unit at UCL, London, UK.

                Email: tim.morris@ 123456ucl.ac.uk

                Author information
                http://orcid.org/0000-0001-5850-3610
                http://orcid.org/0000-0003-0808-4192
                Article
                SIM7589 sim.7589
                10.1002/sim.7589
                5901423
                29349792
                ae6504ad-a4ac-4bc0-a6cc-6412d9cbda7b
                © 2018 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 October 2016
                : 19 October 2017
                : 19 November 2017
                Page count
                Figures: 3, Tables: 3, Pages: 20, Words: 12778
                Funding
                Funded by: Medical Research Council
                Award ID: MC_UU_12023/21
                Award ID: MC_UU_12023/29
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                sim7589
                sim7589-hdr-0001
                30 April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:16.04.2018

                Biostatistics
                individual‐patient data,meta‐analysis,one‐stage,two‐stage
                Biostatistics
                individual‐patient data, meta‐analysis, one‐stage, two‐stage

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