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      Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics

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          Abstract

          Background

          Clinical researchers have often preferred to use a fixed effects model for the primary interpretation of a meta-analysis. Heterogeneity is usually assessed via the well known Q and I 2 statistics, along with the random effects estimate they imply. In recent years, alternative methods for quantifying heterogeneity have been proposed, that are based on a 'generalised' Q statistic.

          Methods

          We review 18 IPD meta-analyses of RCTs into treatments for cancer, in order to quantify the amount of heterogeneity present and also to discuss practical methods for explaining heterogeneity.

          Results

          Differing results were obtained when the standard Q and I 2 statistics were used to test for the presence of heterogeneity. The two meta-analyses with the largest amount of heterogeneity were investigated further, and on inspection the straightforward application of a random effects model was not deemed appropriate. Compared to the standard Q statistic, the generalised Q statistic provided a more accurate platform for estimating the amount of heterogeneity in the 18 meta-analyses.

          Conclusions

          Explaining heterogeneity via the pre-specification of trial subgroups, graphical diagnostic tools and sensitivity analyses produced a more desirable outcome than an automatic application of the random effects model. Generalised Q statistic methods for quantifying and adjusting for heterogeneity should be incorporated as standard into statistical software. Software is provided to help achieve this aim.

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          Most cited references27

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          A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials.

          Heterogeneity can be a major component of meta-analyses and by virtue of that fact warrants investigation. Classic analysis methods, such as meta-regression, are used to explore the sources of heterogeneity. However, it may be difficult to apply such a method in complex cases or in the absence of an a priori hypothesis. This paper presents a graphical method to identify trials, groups of trials or groups of patients that are sources of heterogeneity. The contribution of these trials to the overall result can also be evaluated with this method. Each trial is represented by a dot on a 2D graph. The X-axis represents the contribution of the trial to the overall Cochran Q-test for heterogeneity. The Y-axis represents the influence of the trial, defined as the standardized squared difference between the treatment effects estimated with and without the trial. This approach has been applied to data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) comprising 10,850 patients in 65 randomized trials. The graphical method allowed us to identify trials that contributed considerably to the overall heterogeneity and had a strong influence on the overall result. It also provided useful information for the interpretation of heterogeneity in this meta-analysis. The proposed graphical method identifies trials that account for most of the heterogeneity without having to explore all possible sources of heterogeneity by subgroup analyses. This method can also be applied to identify types of patients that explain heterogeneity in the treatment effect. Copyright 2002 John Wiley & Sons, Ltd.
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            Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group.

            To evaluate the effect of cytotoxic chemotherapy on survival in patients with non-small cell lung cancer. Meta-analysis using updated data on individual patients from all available randomised trials, both published and unpublished. 9387 patients (7151 deaths) from 52 randomised clinical trials. Survival. The results for modern regimens containing cisplatin favoured chemotherapy in all comparisons and reached conventional levels of significance when used with radical radiotherapy and with supportive care. Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at five years). Trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death; absolute benefit of 4% at two years), and trials comparing supportive care with supportive care plus chemotherapy 0.73 (27% reduction in the risk of death; 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size of effect was seen in any subgroup of patients. In all but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.
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              Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.

              L. Stewart (2002)
              Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence. We did a systematic review and meta-analysis using updated data on individual patients from all available randomised trials that compared radiotherapy alone with radiotherapy plus chemotherapy. Data for 3004 patients from 12 randomised controlled trials were included (11 published and one unpublished). Overall, the results showed significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI 0.78-0.91, p<0.0001) or a 15% relative decrease in the risk of death. This effect is equivalent to an absolute increase in 1-year survival of 6% (95% CI 3-9) from 40% to 46% and a 2-month increase in median survival time (1-3). There was no evidence that the effect of chemotherapy differed in any group of patients defined by age, sex, histology, performance status, or extent of resection. This small but clear improvement in survival from chemotherapy encourages further study of drug treatment of these tumours.
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                Author and article information

                Journal
                BMC Med Res Methodol
                BMC Medical Research Methodology
                BioMed Central
                1471-2288
                2011
                7 April 2011
                : 11
                : 41
                Affiliations
                [1 ]MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK
                [2 ]MRC Biostatistics Unit, Robinson Way, Cambridge, CB2 0SR, UK
                Article
                1471-2288-11-41
                10.1186/1471-2288-11-41
                3102034
                21473747
                2a63c68a-e5f7-4d7c-a198-7b54ad051e76
                Copyright ©2011 Bowden et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 November 2010
                : 7 April 2011
                Categories
                Research Article

                Medicine
                Medicine

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