. "16 Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies--George Davey Smith and Shah Ebrahim." Biosocial Surveys. Washington, DC: The National Academies Press, 2007.
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relates to the risk of disease. Why, then, should an alternative approach be advanced? The impetus for thinking of new approaches is that conventional observational study designs have yielded findings that have failed to be confirmed by randomized controlled trials (Davey Smith and Ebrahim, 2002). Observational studies demonstrated that beta carotene intake was associated with a lower risk of lung cancer mortality, and this stimulated an already active market for vitamin supplements that was based on the notion that they substantially influence chronic disease risk (Figure 16-1). The scientists involved in conducting the observational studies advocated taking supplements in material intended for the public (Willett, 2001) and also, relying on observational data, concluded “Available data thus strongly support the hypothesis that dietary carotenoids reduce the risk of lung cancer” (Willett, 1990). However large-scale randomized controlled trials reported disappointing findings: beta carotene supplementation produced no reduction in risk of lung cancer (AlphaTocopherol and Beta-Carotene Cancer Prevention Study Group, 1994).
With respect to cardiovascular disease, observational studies suggesting that beta carotene (Manson et al., 1991), vitamin E supplements (Rimm et al., 1993; Stampfer et al., 1993), vitamin C supplements (Osganian et al., 2003), and hormone replacement therapy (Stampfer and Colditz, 1991) were protective were followed by large trials showing no such protection (Omenn et al., 1996; Alpha-Tocopherol and Beta-Carotene Cancer Prevention Study Group, 1994; Lancet, 1999; Heart Protection Study Collaborative Group, 2002; Beral, Banks, and Reeves, 2002). In each case special pleading was advanced to explain the discrepancy: Were the doses of vitamins given in the trials too high or too low to be comparable to the observational studies? Did hormone replacement therapy use start too late in the trials? Were differences explained by the duration of followup or other design aspects? Were interactions with other factors, such as smoking or alcohol consumption, key? Rather than such particular explanations being true (with the happy consequence that both the observational studies and the trials had got the right answers, but to different questions), it is likely that a general problem of confounding—by lifestyle and socioeconomic factors, or by baseline health status and prescription policies—is responsible. Indeed, in the vitamin E supplements example, the observational studies and the trials tested precisely the same thing. Figures 16-2a and 16-2b show the findings from observational studies of taking vitamin E supplements (Rimm et al., 1993; Stampfer et al., 1993) and a meta-analysis of trials of supplements (Eidelman, Hollar, Hebert, Lamas, and Hennekens, 2004). The point here is that the observational studies specifically investigated the effect of taking supplements for a short period (2-5 years) and found an apparent, robust, and large protective effect, even after adjustment for confounders. The trials tested ran-