The proposed research will develop and apply appropriate methodology for the resolution of major loci, cultural inheritance, and biological inheritance for diseases and their risk factors. Using state-of-the-art models and statistical methods, a number of family studies conducted in many diverse populations will be analyzed on, among other things, idiopathic hemochromatosis, serium iron, immunoglobulins and responses to skin prick tests, asthma, glucose tolerance, insulin independent diabetes, pulmonary function, lipids and lipoproteins. Under the path analytic approach, new methods will be developed and applied for handling non-randomly ascertained family data, for exploring heterogeneity among diverse family studies, for investigating the joint transmission of multiple disease risk-factors, for joint transmission of diseases and risk factors with important application to allergies and immunoglobulins, and for distinguishing between varying gene expression, cohabitational effects, and other transient environmental effects using temporal trend methodology with both cross-sectional and longtitudinal data. Under the segregation analysis approach, powerful methods will be developed and applied for the detection of major genes with pleitropic effects on diseases and risk factors. These will be used extensively to analyze idiopathic hemochromatosis, and to evaluate alternative strategies for early detection of individuals at risk. It is furthermore proposed to undertake a thorough evaluation, through computer simulation, of several methods in genetic epidemiology. These investigations concern the distributional properties of familial correlations estimated from family data, the effects of misspecification of path models, the properties of several statistical methods used in path analysis, and the appropriate degrees of freedom for testing the null hypothesis of no commingling, as relevant to the detection of major loci. They are especially important and timely in view of recent criticisms of such methods. The ultimate goal of genetic epidemiology of human disease is the identification of individual characteristics of the disease associated with genetic and cultural factors, so that efficient individual-specific intervention and counseling strategies can be developed. Therefore, the immediate goal is to elucidate the causes of family resemblance for diseases and their risk factors. The proposed research represents a significant advancement in that direction.