This project is primarily concerned with gene characterization for censored age-at-onset disease traits like cancer. During previous cycles, we have investigated a number of design issues for family-based studies, such as those arising in the context of our work on the NCI's Cooperative Family Registries for Breast and Colorectal Cancer Studies (CFRBCCS) as well as methods for modeling penetrance in relation to age and multiple genetic and environmental factors. The present proposal represents a continuation of work on these major themes. We propose to continue our efforts on methodologic issues in gene characterization, with the following aims: (i) Development of a unified likelihood framework for family-based association studies, including creation of a likelihood for segregation, linkage, direct association, and linkage disequilibrium for candidate genes, non-random ascertainment of families, censored age-at-onset phenotypes, estimation of penetrance from ascertained families with only some members genotyped, robust tests and variance estimators allowing for residual familial aggregation, multistage sampling of pedigrees, uncertainties in reported phenotype information in genetic analyses, implementation of these methods in the research version of the Genetic Analysis Package (GAP-A), and investigation of the relative efficiency of alternative study designs; (ii) Approaches to modeling complex disease traits, including methods for analysis of multiple phenotypes (e.g., multiple sites of cancer, such as the HNPCC syndrome), toxicokinetic models for complex metabolic pathways involving multiple genes and environmental exposures, and penetrance models incorporating genomic instability; (iii) Methods for characterizing the phenotypic effect of highly polymorphic genes; (iv) Methods for allowing for population stratification in case-control and cohort gene-association studies of unrelated individuals. To illustrate our methodologic work, we will draw examples from the CFRBCCS and other studies the genetic epidemiology of cancer in the USC Department of Preventive Medicine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052862-12
Application #
6743186
Study Section
Special Emphasis Panel (ZRG1-SNEM-5 (01))
Program Officer
Seminara, Daniela
Project Start
1991-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
12
Fiscal Year
2004
Total Cost
$325,406
Indirect Cost
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Choong, Eva; Quteineh, Lina; Cardinaux, Jean-René et al. (2013) Influence of CRTC1 polymorphisms on body mass index and fat mass in psychiatric patients and the general adult population. JAMA Psychiatry 70:1011-9
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Millstein, Joshua; Siegmund, Kimberly D; Conti, David V et al. (2005) Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis. BMC Genet 6 Suppl 1:S147

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