Evaluations of maximization procedures for estimating linkage parameters under heterogeneity.

Locus heterogeneity is a major problem plaguing the mapping of disease genes responsible for complex genetic traits via linkage analysis. A common feature of several available methods to account for heterogeneity is that they involve maximizing a multidimensional likelihood to obtain maximum likelihood estimates. The high dimensionality of the likelihood surface may be due to multiple heterogeneity (mixing) parameters, linkage parameters, and/or regression coefficients corresponding to multiple covariates. Here, we focus on this nontrivial computational aspect of incorporating heterogeneity by considering several likelihood maximization procedures, including the expectation maximization (EM) algorithm and the stochastic expectation maximization (SEM) algorithm. The wide applicability of these procedures is demonstrated first through a general formulation of accounting for heterogeneity, and then by applying them to two specific formulations. Furthermore, our simulation studies as well as an application to the Genetic Analysis Workshop 12 asthma datasets show that, among other observations, SEM performs better than EM. As an aside, we illustrate a limitation of the popular admixture approach for incorporating heterogeneity, proved elsewhere. We also show how to obtain standard errors (SEs) for EM and SEM estimates, using methods available in the literature. These SEs can then be combined with the corresponding estimates to provide confidence intervals of the parameters.