This is the second revision to the proposal that was submitted in response to RFA MH-98-017. The overall objective of the proposed research is to develop novel methodologies for dissecting complex diseases such as cancer. The presence of one or more complexities is likely invalidating several distributional assumptions, potentially misleading the LOD score analysis. Without requiring strong assumptions, IBD based methods are robust, but have been found to be inefficient for mapping complex traits. To retain the efficiency of discovering disease genes and the robustness of statistical analysis, the investigators are developing a set of semiparametric methods for linkage/linkage disequilibrium/association studies on complex traits. In this proposal, they are going to develop new methods, based on this semiparametric framework, while implementing established methods and some of these new methods. Specifically, the investigators propose: (1) to extend their current method for linkage-disequilibrium to incorporate models motivated by evolutionary process as well as to allow multiple markers, to develop and evaluate semi-parametric methods for continuous and censored phenotypes, and to study issues in assessing genome-wide significance; (2) to develop semi-parametric methods for association analysis within pedigree mixtures for age-at-onset data; and (3) to modify existing programs by extending them to handle a variety of pedigree structures, ascertainment criteria, genetic markers, and continuous and censored phenotypes, and to make programs more user-friendly and computationally efficient. Through simulation studies, they will evaluate performance of the new methods and compare them with other established methods in mapping complex traits. While developing methods has a high priority, they intend to implement all of the new methods and to release """"""""working"""""""" programs to colleagues as soon as methods are accepted through the peer review process. After quality control checks, many of these working programs will be integrated into a software package and will be made available to the community.
