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First, an observational study can suffer from confounding or reverse causality. Ill health may both lower circulating vitamin D and raise mortality, while lifestyle, socioeconomic status, and comorbidity may affect both variables. Randomization breaks these baseline associations in expectation.

Second, the interventions answer different questions. Supplementation may be too small, too late, too short, or poorly adhered to, and an average effect can be nearly zero when benefit is confined to people with severe deficiency. Such heterogeneous treatment effects can coexist with a strong observational gradient.