title: Statistical methods for studying disease subtype heterogeneity.
abstract: A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available.
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Department of Biostatistics, National Cancer Center, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, U.S.A.
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, U.S.A.
authors.forename: Sehee
authors.initials: S
authors.lastname: Kim
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.|Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, U.S.A.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Rulla
authors.initials: R
authors.lastname: Tamimi
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
authors.forename: Bernard
authors.identifier: http://orcid.org/0000-0001-6907-0056
authors.initials: B
authors.lastname: Rosner
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.|Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D016022:Case-Control Studies; D004194:Disease / Q000145:classification*; D006801:Humans; D015233:Models, Statistical; D057089:Pathology, Molecular; D011446:Prospective Studies
keywords: heterogeneity test; molecular pathologic epidemiology; omics; pathogenesis; pathology