Fitting ACE structural equation models to case-control family data

Investigators interested in whether a disease aggregates in families often collect case-control family data, which consist of disease status and covariate information for members of families selected via case or control probands. Here, we focus on the use of case-control family data to investigate the relative contributions to the disease of additive genetic effects (A), shared family environment (C), and unique environment (E). We describe an ACE model for binary family data; this structural equation model, which has been described previously, combines a general-family extension of the classic ACE twin model with a (possibly covariate-specific) liability-threshold model for binary outcomes. We then introduce our contribution, a likelihood-based approach to fitting the model to singly ascertained case-control family data. The approach, which involves conditioning on the proband's disease status and also setting prevalence equal to a prespecified value that can be estimated from the data, makes it possible to obtain valid estimates of the A, C, and E variance components from case-control (rather than only from population-based) family data. In fact, simulation experiments suggest that our approach to fitting yields approximately unbiased estimates of the A, C, and E variance components, provided that certain commonly made assumptions hold. Further, when our approach is used to fit the ACE model to Austrian case-control family data on depression, the resulting estimate of heritability is very similar to those from previous analyses of twin data.