title: Estimation of genotype relative risks from pedigree data by retrospective likelihoods.
abstract: Pedigrees collected for linkage studies are a valuable resource that could be used to estimate genetic relative risks (RRs) for genetic variants recently discovered in case-control genome wide association studies. To estimate RRs from highly ascertained pedigrees, a pedigree "retrospective likelihood" can be used, which adjusts for ascertainment by conditioning on the phenotypes of pedigree members. We explore a variety of approaches to compute the retrospective likelihood, and illustrate a Newton-Raphson method that is computationally efficient particularly for single nucleotide polymorphisms (SNPs) modeled as log-additive effect of alleles on the RR. We also illustrate, by simulations, that a naïve "composite likelihood" method that can lead to biased RR estimates, mainly by not conditioning on the ascertainment process-or as we propose-the disease status of all pedigree members. Applications of the retrospective likelihood to pedigrees collected for a prostate cancer linkage study and recently reported risk-SNPs illustrate the utility of our methods, with results showing that the RRs estimated from the highly ascertained pedigrees are consistent with odds ratios estimated in case-control studies. We also evaluate the potential impact of residual correlations of disease risk among family members due to shared unmeasured risk factors (genetic or environmental) by allowing for a random baseline risk parameter. When modeling only the affected family members in our data, there was little evidence for heterogeneity in baseline risks across families.
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. schaid@mayo.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Riska
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
mesh_terms: D000483:Alleles; D003198:Computer Simulation; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics*; D012189:Retrospective Studies; D012306:Risk; D012307:Risk Factors