plaque rupture. For immune-mediated disease, where a break in immunological tolerance is the key event at disease initiation, it is expected that other pathways drive disease course, since tolerance can only be broken once to a particular antigen. Also, where developmental mechanisms contribute to predisposition to late-onset disease, the determinants of prognosis may plausibly be independent. Some have argued that independently pleiotropic effects are likely to be typical for complex disease25: for most pairs of traits, the genetic effects on the first are independent of the corresponding effects on the other. However, our independence assumption precludes any meaningful analysis of genetic correlation between incidence and prognosis.
