FIGURE 2.

Example of a potential surrogate marker that did not perform as expected. (A) Low B-vitamin intakes produce elevated plasma Hcy concentrations. Observational studies showed an association between elevated Hcy concentrations and CVD risk. (B) Therefore, it was hypothesized that low vitamin B intakes would reduce the risk of CVD via a mediating influence of Hcy concentrations. (C) Results from phase III clinical trials showed that B-vitamin supplements reduced Hcy concentrations but had no effect on CVD risk. (D) One possible mechanism is that B-vitamin intake and CVD risk are correlated because of a common relation to Hcy concentrations. However, Hcy is not a mediating factor on a causal pathway between B-vitamin intake and CVD. Thus, elevated Hcy concentrations are a risk factor, but not a surrogate marker, for CVD. CVD, cardiovascular disease; Hcy, homocysteine; ↓, decreased; ↑, increased.