Abstract
BackgroundSome patients will experience more or less benefit from treatment than the averages reported from clinical trials; such variation in therapeutic outcome is termed heterogeneity of treatment effects (HTE). Identifying HTE is necessary to individualize treatment. The degree to which heterogeneity is sought and analyzed correctly in the general medical literature is unknown. We undertook this literature sample to track the use of HTE analyses over time, examine the appropriateness of the statistical methods used, and explore the predictors of such analyses.MethodsArticles were selected through a probability sample of randomized controlled trials (RCTs) published in Annals of Internal Medicine, BMJ, JAMA, The Lancet, and NEJM during odd numbered months of 1994, 1999, and 2004. RCTs were independently reviewed and coded by two abstractors, with adjudication by a third. Studies were classified as reporting: (1) HTE analysis, utilizing a formal test for heterogeneity or treatment-by-covariate interaction, (2) subgroup analysis only, involving no formal test for heterogeneity or interaction; or (3) neither. Chi-square tests and multiple logistic regression were used to identify variables associated with HTE reporting.Results319 studies were included. Ninety-two (29%) reported HTE analysis; another 88 (28%) reported subgroup analysis only, without examining HTE formally. Major covariates examined included individual risk factors associated with prognosis, responsiveness to treatment, or vulnerability to adverse effects of treatment (56%); gender (30%); age (29%); study site or center (29%); and race/ethnicity (7%). Journal of publication and sample size were significant independent predictors of HTE analysis (p < 0.05 and p < 0.001, respectively).ConclusionHTE is frequently ignored or incorrectly analyzed. An iterative process of exploratory analysis followed by confirmatory HTE analysis will generate the data needed to facilitate an individualized approach to evidence-based medicine.
Highlights
Some patients will experience more or less benefit from treatment than the averages reported from clinical trials; such variation in therapeutic outcome is termed heterogeneity of treatment effects (HTE)
To further explore HTE reporting characteristics, we separately examined the association between study characteristics and HTE reporting in articles above and below the median sample size (262 subjects)
This review of 319 Randomized controlled trials (RCTs) published in five prominent general medical journals is the most comprehensive to date, and the only one that examines trends of HTE reporting over time
Summary
Some patients will experience more or less benefit from treatment than the averages reported from clinical trials; such variation in therapeutic outcome is termed heterogeneity of treatment effects (HTE). The degree to which heterogeneity is sought and analyzed correctly in the general medical literature is unknown We undertook this literature sample to track the use of HTE analyses over time, examine the appropriateness of the statistical methods used, and explore the predictors of such analyses. While estimates of the average treatment effect are generally useful, some treated individuals, both within and outside of clinical trials, will experience more or less benefit than the reported average. Such variation in treatment effect is termed heterogeneity of treatment effects (HTE) [1,2]. While qualitative HTE may be uncommon, quantitative HTE should not be dismissed, because even modest variations in the magnitude of net treatment benefits may have important implications for patient care and cost-effectiveness
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