DEFINING CASENESS FOR PSYCHIATRIC LINKAGE STUDIES

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This is a request for an NIMH Scientist Development Award (K-21) entitled "Defining Caseness for Psychiatric Linkage Studies." The Candidate's primary interest is in the genetic epidemiology of neuropsychiatric disorders. A fundamental problem for psychiatric genetics is the definition of the phenotype. The candidate's training as a psychiatrist and epidemiologist focussed on bipolar disorder drew her attention to this issue, and her recent work on the genetics of Alzheimer's disease put it in a new light. It became clear that her existing skills limited her to a psychiatric, mainly categorical approach to diagnosis, and a mostly conceptual approach to genetics. Thus, support for additional training is requested to allow her to delve much deeper into the diagnosis of Alzheimer's disease and other dementing disorders, and to study psychometric and other techniques for delineating and describing pathology. Support is also requested to allow her to develop a more technical understanding of genetics including modelling, simulations, and linkage analysis. The research project designed to complement this training involves the development of a measure of certainty or caseness for classification of ambiguous phenotypes in psychiatric linkage studies. The project includes constructing a caseness index, cross-validating the index, and testing its ability to improve the power of linkage analysis. It involves work on two different classification problems: differentiating Alzheimer's disease from other dementing illnesses, and delineating which unipolar relatives ought to be considered bipolar for purposes of bipolar linkage studies. In addition to its pedagogic value, work on two disorders side by side may contribute to methods generalizable to other disorders. This integrated combination of training and research will serve to foster the Candidate's development as a clinical investigator interested in the complex relationship of nosology and genetic investigation of psychiatric disorders.