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BMJ. 2016 Nov 24;355:i5826. doi: 10.1136/bmj.i5826.

Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses.

Author information

Department of Health Research and Policy, and Meta-Research Innovation Center at Stanford (METRICS), Stanford, CA, USA.
Stanford Prevention Research Center, Stanford University, Stanford, CA, USA.
Department of Public Health, Erasmus MC, Rotterdam, Netherlands.
Departments of Medicine, Health Research and Policy, and Statistics, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, CA 94305, USA



 To evaluate the frequency, validity, and relevance of statistically significant (P<0.05) sex-treatment interactions in randomized controlled trials in Cochrane meta-analyses.


 Meta-epidemiological study.


 Cochrane Database of Systematic Reviews (CDSR) and PubMed.


 Reviews published in the CDSR with sex-treatment subgroup analyses in the forest plots, using data from randomized controlled trials.


 Information on the study design and sex subgroup data were extracted from reviews and forest plots that met inclusion criteria. For each statistically significant sex-treatment interaction, the potential for biological plausibility and clinical significance was considered.


 Among the 41 reviews with relevant data, there were 109 separate treatment-outcome analyses ("topics"). Among the 109 topics, eight (7%) had a statistically significant sex-treatment interaction. The 109 topics included 311 randomized controlled trials (162 with both sexes, 46 with males only, 103 with females only). Of the 162 individual randomized controlled trials that included both sexes, 15 (9%) had a statistically significant sex-treatment interaction. Of four topics where the first published randomized controlled trial had a statistically significant sex-treatment interaction, no meta-analyses that included other randomized controlled trials retained the statistical significance and no meta-analyses showed statistical significance when data from the first published randomized controlled trial were excluded. Of the eight statistically significant sex-treatment interactions from the overall analyses, only three were discussed by the CDSR reviewers for a potential impact on different clinical management for males compared with females. None of these topics had a sex-treatment interaction that influenced treatment recommendations in recent guidelines. UpToDate, an online physician-authored clinical decision support resource, suggested differential management of men and women for one of these sex-treatment interactions.


 Statistically significant sex-treatment interactions are only slightly more frequent than what would be expected by chance and there is little evidence of subsequent corroboration or clinical relevance of sex-treatment interactions.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

All authors have completed the ICMJE uniform disclosure form at and declare: METRICS (Meta-Research Innovation Center at Stanford) is supported by a grant from the Laura and John Arnold Foundation, PGS received support from the Stanford Clinical and Translational Science Award to Spectrum (NIH UL1 TR 001085), JFT is supported by the NIH (T32 HL007034), EWS is partly supported by the NIH (PRICES project, U01 NS086294), and JPAI is supported by an unrestricted gift by Sue and Bob O’Donnell to Stanford Prevention Research Center; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

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