Heterogeneity of the Effect of Vitamin D Supplementation in Randomized Controlled Trials on Cancer Prevention.

D has been suspected to play a role in cancer prevention for the past 4 decades, but definitive proof of benefit has been difficult to determine. In a randomized, double-blind, placebo-controlled trial, Chandler et al found that vitamin D supplementation reduced the incidence of advanced cancer in the Vitamin D and Omega-3 Trial study cohort. The authors found a difference in treatment effects: protective effect was observed among individuals who had normal body mass index (BMI) but not among overweight individuals, most likely because of the simple volumetric dilution of this fat-soluble vitamin in fat tissue. The notion that treatment effect may vary according to BMI indicates the Achilles heel of randomized controlled trials (RCTs). Randomized controlled trials are the criterion standard in evaluating the effects of treatments and are the cornerstone of evidence-based medicine. However, they cannot deal with the heterogeneity of treatment effects. 2 Properly conducted randomization ensures that participants’ characteristics are equally distributed between trial arms and protects against confounding. it does not protect against the issue of heterogeneity of treatment effects because heterogeneity within the treated arm drives a null effect. In an RCT, only group effects are observed, and then compared: if half of the treated group improves but the other half deteriorates, the treatment will be assumed to have no effect. Similarly, if a fraction of the participants who received supplements benefited but there was no effect in others, the effect size will be diluted (and likelihood of reaching a statistically significant finding will be reduced). closely with this: a 17% reduction in advanced cancer risk reported overall (hazard ratio, 0.83; 95% CI, 0.69-0.99) but clear differences in treatment effects emerged after stratification by BMI. A significant 38% risk reduction was observed in normal-weight individuals (hazard ratio, 0.62; 95% CI, 0.45-0.86; BMI, < 25), but there was no effect in overweight (BMI 25-30: hazard ratio, 0.89; 95%