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Keywords:

  • Heterogeneity of treatment effects;
  • HTE analysis;
  • subgroup analysis;
  • individualized care;
  • interaction analysis

Objective. To determine whether investigations of heterogeneity of treatment effects (HTE) in randomized-controlled trials (RCTs) are prespecified and whether authors' interpretations of their analyses are consistent with the objective evidence.

Data Sources/Study Setting. Trials published in Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, and New England Journal of Medicine in 1994, 1999, and 2004.

Study Design. We reviewed 87 RCTs that reported formal tests for statistical interaction or heterogeneity (HTE analyses), derived from a probability sample of 541 articles.

Data Collection/Extraction. We recorded reasons for performing HTE analysis; an objective classification of evidence for HTE (termed “clinicostatistical divergence” [CSD]); and authors' interpretations of findings. Authors' interpretations, compared with CSD, were coded as understated, overstated, or adequately stated.

Principle Findings. Fifty-three RCTs (61 percent) claimed prespecified covariates for HTE analyses. Trials showed strong (6), moderate (11), weak (25), or negligible (16) evidence for CSD (29 could not be classified due to inadequate information). Authors stated that evidence for HTE was sufficient to support differential treatment in subgroups (10); warranted more research (31); was absent (21); or provided no interpretation (25). HTE was overstated in 22 trials, adequately stated in 57 trials, and understated in 8 trials.

Conclusions. Inconsistencies in performance and reporting may limit the potential of HTE analysis as a tool for identifying HTE and individualizing care in diverse populations. Recommendations for future studies on the reporting and interpretation of HTE analyses are provided.