title: A robust association test for detecting genetic variants with heterogeneous effects.
abstract: One common strategy for detecting disease-associated genetic markers is to compare the genotype distributions between cases and controls, where cases have been diagnosed as having the disease condition. In a study of a complex disease with a heterogeneous etiology, the sampled case group most likely consists of people having different disease subtypes. If we conduct an association test by treating all cases as a single group, we maximize our chance of finding genetic risk factors with a homogeneous effect, regardless of the underlying disease etiology. However, this strategy might diminish the power for detecting risk factors whose effect size varies by disease subtype. We propose a robust statistical procedure to identify genetic risk factors that have either a uniform effect for all disease subtypes or heterogeneous effects across different subtypes, in situations where the subtypes are not predefined but can be characterized roughly by a set of clinical and/or pathologic markers. We demonstrate the advantage of the new procedure through numeric simulation studies and an application to a breast cancer study.
authors: Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD 20850, USA yuka@mail.nih.gov.
authors: Kai
authors: K
authors: Yu
authors: Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD 20850, USA.
authors: Han
authors: H
authors: Zhang
authors: Information Management Services, Inc., Rockville, MD 20892, USA.
authors: William
authors: W
authors: Wheeler
authors: Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD 20850, USA.
authors: Hisani N
authors: HN
authors: Horne
authors: Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Jinbo
authors: J
authors: Chen
authors: Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD 20850, USA.
authors: Jonine D
authors: JD
authors: Figueroa
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008957:Models, Genetic; D012307:Risk Factors
chemical_list: D005819:Genetic Markers
keywords: Breast cancer; Etiology heterogeneity; Genetic association study; Multiple-comparison adjustment; Tree-based model