In recent years, psychiatric genetics has eagerly appropriated the techniques of mathematical and statistical analysis. But methods are not static, and understanding of their strengths and weaknesses keeps evolving. Investigators are wrestling with issues of robustness, power, and appropriateness of new complex analysis methods. The human gene map is here, and scientists working in psychiatric genetics are ready to use the map, but it is not always clear how best to take advantage of this new information. Past work supported by this grant has not only developed new methods for genetic analysis but has tested and characterized those methods in rigorous theoretical analyses, supplemented by realistic computer simulations. The research focuses on linkage and segregation analysis, two of the major tools available for understanding complex diseases. Problems and complications will be quantified, and new methods to solve these problems will be developed. Results from this project will assist the genetic analysis of common psychiatric diseases with genetic components, such as autism, bipolar affective disorder, schizophrenia, Alzheimer's disease, and panic disorder.Greater understanding of the genetic contributions to psychiatric disease will lead, in turn, to improved counseling, treatment, and prevention. Research will proceed in four areas: I. Power and robustness of parametric and nonparametric linkage methods: Rigorously compare competing methods in this controversial area. II. Sex differences and linkage analysis: Quantify effects of sex differences in recombination fraction and/or in penetrance on a linkage analysis, as well as how imprinting will influence a linkage analysis. 111. Ascertainment: Develop and test good approximations for intractable ascertainment problems, particularly in the context of sequential sampling. IV. Anticipation: Develop and test accurate statistical methods for circumventing ascertainment and other biases. The project will not be restricted to the problems detailed above but is designed to be flexible and move rapidly to address new problems of pressing importance as they arise during the grant period.
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