Using Item Response Theory to Model Multiple Phenotypes and Their Joint Heritability in Family Data

Many important complex diseases are composed of a series of phenotypes, which makes the disease diagnosis and its genetic dissection difficult. The standard procedures to determine heritability in such complex diseases are either applied for single phenotype analyses or to compare findings across phenotypes or multidimensional reduction procedures, such as principal components analysis using all phenotypes. However each method has its own problems and the challenges are even more complex for extended family data and categorical phenotypes. In this paper, we propose a methodology to determine a scale for complex outcomes involving multiple categorical phenotypes in extended pedigrees using item response theory (IRT) models that take all categorical phenotypes into account, allowing informative comparison among individuals. An advantage of the IRT framework is that a straightforward joint heritability parameter can be estimated for categorical phenotypes. Furthermore, our methodology allows many possible extensions such as the inclusion of covariates and multiple variance components. We use Markov Chain Monte Carlo algorithm for the parameter estimation and validate our method through simulated data. As an application we consider the metabolic syndrome as the multiple phenotype disease using data from the Baependi Heart Study consisting of 1,696 individuals in 95 families. We adjust IRT models without covariates and include age and age squared as covariates. The results showed that adjusting for covariates yields a higher joint heritability (h(2)=0.53) than without co variates (h(2)=0.21) indicating that the covariates absorbed some of the error variance.