title: A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration.
abstract: Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMD-associated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs.
authors.affiliation: Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Simonett
authors.affiliation: Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Mahsa A
authors.initials: MA
authors.lastname: Sohrab
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pacheco
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Armstrong
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Margarita
authors.initials: M
authors.lastname: Rzhetskaya
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Maureen
authors.initials: M
authors.lastname: Smith
authors.affiliation: 1] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 [2] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 [3] Department of Anthropology, Northwestern University, Evanston, IL [4] Northwestern Comprehensive Center on Obesity, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: M
authors.initials: M
authors.lastname: Geoffrey Hayes
authors.affiliation: Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Amani A
authors.initials: AA
authors.lastname: Fawzi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000483:Alleles; D017242:Complement Factor H / Q000235:genetics; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins; D017242:Complement Factor H