title: Genetic risk models: Influence of model size on risk estimates and precision.
abstract: Disease risk estimation plays an important role in disease prevention. Many studies have found that the ability to predict risk improves as the number of risk single-nucleotide polymorphisms (SNPs) in the risk model increases. However, the width of the confidence interval of the risk estimate is often not considered in the evaluation of the risk model. Here, we explore how the risk and the confidence interval width change as more SNPs are added to the model in the order of decreasing effect size, using both simulated data and real data from studies of abdominal aortic aneurysms and age-related macular degeneration. Our results show that confidence interval width is positively correlated with model size and the majority of the bigger models have wider confidence interval widths than smaller models. Once the model size is bigger than a certain level, the risk does not shift markedly, as 100% of the risk estimates of the one-SNP-bigger models lie inside the confidence interval of the one-SNP-smaller models. We also created a confidence interval-augmented reclassification table. It shows that both more effective SNPs with larger odds ratios and less effective SNPs with smaller odds ratios contribute to the correct decision of whom to screen. The best screening strategy is selected and evaluated by the net benefit quantity and the reclassification rate. We suggest that individuals whose upper bound of their risk confidence interval is above the screening threshold, which corresponds to the population prevalence of the disease, should be screened.
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shan
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania, United States of America.|Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania, United States of America.|Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Diane T
authors.initials: DT
authors.lastname: Smelser
authors.affiliation: Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, PA.
authors.forename: James R
authors.initials: JR
authors.lastname: Elmore
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.affiliation: Departments of Ophthalmology and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.|Stein Eye Institute, Los Angeles, California, United States of America.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gorin
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
mesh_terms: D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics; D003198:Computer Simulation; D016001:Confidence Intervals; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D018401:Sample Size
keywords: confidence interval; disease risk estimation; model size; reclassification