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From Harvard School of Public Health, Boston, Massachusetts, and University Medical Center Utrecht, Utrecht, the Netherlands.
Acknowledgment: The authors thank James Ware for his helpful comments.
Grant Support: By grant R01 ES017876 from the National Institutes of Health and by the Escher Project (T6-202).
Potential Conflicts of Interest: Dr. Knol: Grants received (money to institution): Top Institute Pharma. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2468.
Requests for Single Reprints: Tyler J. VanderWeele, PhD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. VanderWeele: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.
Dr. Knol: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Huispost Str. 6.131Postbus 85500, 3508 GA Utrecht, the Netherlands.
Author Contributions: Conception and design: T.J. VanderWeele, M.J. Knol.
Analysis and interpretation of the data: T.J. VanderWeele.
Drafting of the article: T.J. VanderWeele.
Critical revision of the article for important intellectual content: T.J. VanderWeele, M.J. Knol.
Final approval of the article: M.J. Knol.
Statistical expertise: T.J. VanderWeele.
Obtaining of funding: T.J. VanderWeele.
In randomized trials with subgroup analyses, the primary treatment or intervention of interest is randomized, but the secondary factors defining subgroups are not. This article clarifies when confounding is an issue in subgroup analyses. If investigators are interested simply in targeting subpopulations for intervention, control for confounding is not needed. If investigators are interested in intervening on the secondary factors that define the subgroups to increase the treatment effect or in attributing the subgroup differences to the secondary factors themselves, then confounding is relevant and must be controlled for. The authors demonstrate this point by using examples from published randomized trials.
The estimates of treatment effect in male and female participants are valid, but these differences in treatment effect might be caused by age rather than sex.
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VanderWeele and Knol's attempts to clarify subgroup analyses for randomized trials deserves a strong warning(1).
Subgroup analyses should be viewed with caution and a particular attention must be warranted in industry funded trials when the primary outcome is not statistically significant(2).
Their demonstration using examples from published randomized trials have forgotten Sleigh's post hoc analysis of the ISIS- 2 trial which showed that aspirin therapy was significantly beneficial for all patients except those born under the astrological signs of Gemini or Libra(3).
1 Vanderweele TJ, Knol MJ. Interpretation of subgroup analyses in randomized trials: heterogeneity versus secondary interventions. Ann Intern Med 2011;154:680-3.
2 Sun X, Briel M, Busse JW et al. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review. BMJ 2011 28;342:d1569
3 Sleight P. Subgroup analyses in clinical trials: fun to look at - but don't believe them! Curr Control Trial CardiovascMed 2000;1:125-127.
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