Robust rank-based methods and detection of GXE in cancer etiology and survival

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DESCRIPTION (provided by applicant): It is now well recognized that both environmental exposures and genetic susceptibility contribute to the development and progression of cancer. In order to identify individuals at a higher risk for developing cancer or with poor prognosis based on their environmental exposures and genetic profiles and to inform potential environmental modifications or behavioral change interventions that can be implemented to prevent or reduce disease burden, it is essential to understand gene-environment (G 4 E) interactions. While considerable effort has been made to study G4E interactions, existing methods suffer serious limitations, which may mask the detection of genetic effects, lead to inconsistent results across studies, and result in suboptimal predictive models. As such, there is an urgent need for novel methodologies that can effectively analyze data and identify important, reproducible G4E interactions for cancer etiology and survival. In this study, we will develop novel rank-based methods for analyzing G4E interactions in cancer etiology and survival studies. The proposed methods have the much desired robustness and consistency properties not shared by existing methods. They can accommodate the joint effects of a large number of markers, conduct both individual marker-level and pathway-level analyses, and are computationally affordable. We will comprehensively evaluate the proposed methods using simulation studies and compare with existing methods. In addition, we will apply the proposed methods and identify G4E interactions in NHL (non-Hodgkin Lymphoma) etiology and survival. Particularly, we will first analyze the Connecticut study. The findings will be comprehensively evaluated and then validated using the NCI-SEER study. The specific aims are as follows. (Aim 1) Develop robust rank-based methods and detect environmental, genetic, and G4E risk factors marginally associated with etiology and survival. (Aim 2) Develop robust rank- based penalization methods and detect environmental, genetic, and G4E risk factors with important joint effects for etiology and survival. (Aim 3) Develop user-friendly software and project website. (Aim 4) Analyze the Connecticut NHL study and identify important G4E interactions. The findings will be comprehensively evaluated and then validated using the NCI-SEER study. The proposed methods will provide a way to more effectively identify G 4 E interactions in the development and prognosis of cancer. They will have superior statistical properties and identify important markers missed by existing methods. The identified markers will provide important insights into the biological mechanisms underlying NHL and serve as basis for future validation studies and clinical practice.