A frailty approach for modelling diseases with variable age of onset in families: The NHLBI family heart study

We use frailty models to analyse the effect of latent genetic and environme ntal risk factors on hazard functions in nuclear families. The approach exp resses latent risk factors (frailties) as functions of the effects of a sin gle major gene and shared familial risk. The latter may result from shared polygenes and/or a common environment. Genetic frailties are modelled using a two-point distribution, and residual frailities (shared environment, pol ygenes) using a gamma distribution. The two-point distribution follows the laws of Mendelian transmission, under either dominant or recessive gene act ion. We describe a robust EM approach for the joint estimation of the magni tude of genetic, covariate, gene by covariate interaction effects while all owing residual familial correlation. We illustrate the method on coronary h eart disease data from the National Heart, Lung, and Blood Institute Family Heart Study. In addition, a simulation study shows that ignoring possible residual correlation in disease status due to a shared familial environment leads to an overestimate of the relative risk associated with a latent gen otype. Copyright (C) 1999 John Wiley & Sons, Ltd.