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Primer: the fallacy of subgroup analysis

Nature Clinical Practice Rheumatology volume 3, pages 407–413 (2007)Cite this article

Abstract

The identification of subgroups of patients from randomized clinical trials that are of specific interest for guiding clinical decisions can be an attractive idea; however, since such trials are designed for the comparison of groups of patients, performing subgroup analyses can result in misinterpretation of the data. Such analyses must, therefore, be performed and evaluated with caution: these should be pre-planned and included in the design of a suitably powered trial. Data obtained should be analyzed using formal statistical tests of interaction on proper subgroups rather than improper subgroups of patients, the results obtained should be delineated carefully, and details of how these analyses were performed, and how the data should be interpreted, should be reported in the trial paper. The caveats associated with this approach, such as the occurrence of false positive or false negative effects, chance differences in observed effects, lack of power to perform the analysis, floor or ceiling effects, issues relating to multiple statistical testing, and over-reporting and under-reporting are discussed in this review. Subgroup analyses can, however, provide valuable, albeit predominantly exploratory, information on which to base clinical decisions if they are performed in accordance with recommendations and guidelines, and do, therefore, have a legitimate place in rheumatology clinical trials.

Key Points

  • Subgroup analyses do have a place in the interpretation of data from randomized controlled trials in the field of rheumatology, but there are many pitfalls associated with this approach

  • Specific guidelines as to how to perform these analyses should be followed to ensure accurate conclusions are drawn

  • In subgroup analyses, only formal tests of interaction should be performed on proper subgroups that were defined in the design of the trial; subgroup-specific tests should not be carried out

  • Any lack of differential effect should be interpreted with caution unless the trial was specifically powered to include subgroup analyses

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Figure 1: A theoretical example of data that illustrates the regression to the mean phenomenon

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Acknowledgements

I wish to thank the anonymous peer-reviewers for their helpful and constructive comments on a previous version of this manuscript.

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Author notes

  1. Ecole de santé Publique, Faculté de Médecine, 9 avenue de la Forêt de Haye, B.P. 184, 54505 Vandoeuvre-les-Nancy Cedex, France francis.guillemin@medecine.uhp-nancy.fr

Authors and Affiliations

  1. F Guillemin is Professor of Epidemiology and Public Health at the School of Public Health, Nancy University, and Head of the Clinical Epidemiology Centre Inserm CIE6 at Nancy-University Hospital, France.,

    Francis Guillemin

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  1. Francis Guillemin
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Guillemin, F. Primer: the fallacy of subgroup analysis. Nat Rev Rheumatol 3, 407–413 (2007). https://doi.org/10.1038/ncprheum0528

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