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Comment & Response
May 21, 2020

Stratification Clarification for Methods for Randomized Clinical Trials—Reply

Author Affiliations
  • 1Center for Clinical Trials and Evidence Synthesis, Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 2Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University of Medicine, Baltimore, Maryland
JAMA Ophthalmol. Published online May 21, 2020. doi:10.1001/jamaophthalmol.2020.1864

In Reply Subgroup analyses typically are performed in randomized clinical trials. Proper subgroup analyses are performed on subgroups based on baseline characteristics and may be specified a priori or a posteriori. They are performed to determine if the results of the trial are potentially confounded and the treatment effects vary by subgroup. Subgroup differences in outcomes may be quantitative in nature (in that the effect is in the same direction but different in magnitude) or qualitative in nature (in that the effect is in a different direction than the overall trial results). A major problem with a posteriori–defined subgroup analyses is multiple comparisons. If 20 subgroups are analyzed, one might be expected to be different with a P value less than .05 by chance alone, and most often the number of a posteriori–defined subgroup analyses performed is not specified. This problem can be minimized by limiting the number of subgroups to only a priori–specified subgroups, using corrections for multiple analyses, and including interaction P values. However, despite using these precautions, subgroup results that are qualitatively different from the primary results should be viewed with great caution. This is true especially when the primary results do not show a difference between groups, but even when the primary outcome shows a difference between groups. Biologic plausibility and confirming the results of subgroup analyses in subsequent trials and/or demonstrating a consistent subgroup effect over several trials give confidence that the result is real and not by chance alone.1,2

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