Project Summary The proposed research will develop novel methods to assess mediation and interaction between genetic and environmental exposures and different disease subtypes so as to better tailor treatments and prevention efforts to individuals' characteristics and so as to better understand the mechanisms governing disease. Methods will be developed for settings in which there are multiple disease subtypes and these disease subtypes may have different prognosis for survival and may be more amenable to different types of treatment and preventive efforts. Methodology for assessing the role of interaction in understanding mechanisms will also be developed. This will include elucidating the role of gene-environment interaction in the heritability of disease, understanding mediating pathways from exposure to disease in the presence of interaction, and identifying sufficient cause interaction for diseases or disease subtypes such that an outcome would occur if two (or more) exposures are present, but not if only one or the other were present. The methodology will be applied to understand prognosis, treatment decisions, preventive interventions, and mechanisms for colorectal cancer, and also for the development of skin lesions; the methodology will also be applied to understand the role of gene-environment interaction in the heritability of numerous traits.