title: Bayesian modeling for genetic anticipation in presence of mutational heterogeneity: a case study in Lynch syndrome.
abstract: Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype. In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect inferential conclusions. We compare the fit of four-candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding effect of changes in secular trends, screening, and medical practices that may affect time to disease detection across birth cohorts. Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts. Our motivating case study comes from a Danish cancer register of 124 families with mutations in mismatch repair (MMR) genes known to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families.
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Boonstra
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Jeremy M G
authors.initials: JM
authors.lastname: Taylor
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020132:Anticipation, Genetic / Q000235:genetics*; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D003198:Computer Simulation; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult