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      Automated generation of node‐splitting models for assessment of inconsistency in network meta‐analysis

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          Abstract

          Network meta‐analysis enables the simultaneous synthesis of a network of clinical trials comparing any number of treatments. Potential inconsistencies between estimates of relative treatment effects are an important concern, and several methods to detect inconsistency have been proposed. This paper is concerned with the node‐splitting approach, which is particularly attractive because of its straightforward interpretation, contrasting estimates from both direct and indirect evidence. However, node‐splitting analyses are labour‐intensive because each comparison of interest requires a separate model. It would be advantageous if node‐splitting models could be estimated automatically for all comparisons of interest.

          We present an unambiguous decision rule to choose which comparisons to split, and prove that it selects only comparisons in potentially inconsistent loops in the network, and that all potentially inconsistent loops in the network are investigated. Moreover, the decision rule circumvents problems with the parameterisation of multi‐arm trials, ensuring that model generation is trivial in all cases. Thus, our methods eliminate most of the manual work involved in using the node‐splitting approach, enabling the analyst to focus on interpreting the results. © 2015 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.

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          The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.

          When little or no data directly comparing two treatments are available, investigators often rely on indirect comparisons from studies testing the treatments against a control or placebo. One approach to indirect comparison is to pool findings from the active treatment arms of the original controlled trials. This approach offers no advantage over a comparison of observational study data and is prone to bias. We present an alternative model that evaluates the differences between treatment and placebo in two sets of clinical trials, and preserves the randomization of the originally assigned patient groups. We apply the method to data on sulphamethoxazole-trimethoprim or dapsone/pyrimethamine as prophylaxis against Pneumocystis carinii in HIV infected patients. The indirect comparison showed substantial increased benefit from the former (odds ratio 0.37, 95% CI 0.21 to 0.65), while direct comparisons from randomized trials suggests a much smaller difference (risk ratio 0.64, 95% CI 0.45 to 0.90; p-value for difference of effect = 0.11). Direct comparisons of treatments should be sought. When direct comparisons are unavailable, indirect comparison meta-analysis should evaluate the magnitude of treatment effects across studies, recognizing the limited strength of inference.
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            Evidence Synthesis for Decision Making 4

            Inconsistency can be thought of as a conflict between “direct” evidence on a comparison between treatments B and C and “indirect” evidence gained from AC and AB trials. Like heterogeneity, inconsistency is caused by effect modifiers and specifically by an imbalance in the distribution of effect modifiers in the direct and indirect evidence. Defining inconsistency as a property of loops of evidence, the relation between inconsistency and heterogeneity and the difficulties created by multiarm trials are described. We set out an approach to assessing consistency in 3-treatment triangular networks and in larger circuit structures, its extension to certain special structures in which independent tests for inconsistencies can be created, and describe methods suitable for more complex networks. Sample WinBUGS code is given in an appendix. Steps that can be taken to minimize the risk of drawing incorrect conclusions from indirect comparisons and network meta-analysis are the same steps that will minimize heterogeneity in pairwise meta-analysis. Empirical indicators that can provide reassurance and the question of how to respond to inconsistency are also discussed.
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              Evaluation of inconsistency in networks of interventions.

              The assumption of consistency, defined as agreement between direct and indirect sources of evidence, underlies the increasingly popular method of network meta-analysis. No evidence exists so far regarding the extent of inconsistency in full networks of interventions or the factors that control its statistical detection. In this paper we assess the prevalence of inconsistency from data of 40 published networks of interventions involving 303 loops of evidence. Inconsistency is evaluated in each loop by contrasting direct and indirect estimates and by employing an omnibus test of consistency for the entire network. We explore whether different effect measures for dichotomous outcomes are associated with differences in inconsistency, and evaluate whether different ways to estimate heterogeneity affect the magnitude and detection of inconsistency. Inconsistency was detected in from 2% to 9% of the tested loops, depending on the effect measure and heterogeneity estimation method. Loops that included comparisons informed by a single study were more likely to show inconsistency. About one-eighth of the networks were found to be inconsistent. The proportions of inconsistent loops do not materially change when different effect measures are used. Important heterogeneity or the overestimation of heterogeneity was associated with a small decrease in the prevalence of statistical inconsistency. The study suggests that changing the effect measure might improve statistical consistency, and that an analysis of sensitivity to the assumptions and an estimator of heterogeneity might be needed before reaching a conclusion about the absence of statistical inconsistency, particularly in networks with few studies.
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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
                13 October 2015
                March 2016
                : 7
                : 1 ( doiID: 10.1002/jrsm.v7.1 )
                : 80-93
                Affiliations
                [ 1 ] Department of EpidemiologyUniversity of Groningen, University Medical Center Groningen GroningenThe Netherlands
                [ 2 ] School of Social and Community MedicineUniversity of Bristol BristolUK
                Author notes
                [*] [* ] Correspondence to: Gert van Valkenhoef, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

                E‐mail: g.h.m.van.valkenhoef@ 123456rug.nl

                Author information
                http://orcid.org/0000-0002-2172-0221
                Article
                JRSM1167 RSM-03-2014-0012.R3
                10.1002/jrsm.1167
                5057346
                26461181
                33f4f866-7e0a-4197-9fbf-6b56c12181cc
                © 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
                : 12 March 2014
                : 09 July 2015
                : 14 July 2015
                Page count
                Pages: 14
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jrsm1167
                March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.10.2016

                network meta‐analysis,mixed treatment comparisons,meta‐analysis,node splitting,model generation,bayesian modelling

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