title: A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma.
abstract: BACKGROUND
  We propose a 2-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.
  
  
  METHODS
  First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N = 281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N = 74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are reestimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.
  
  
  RESULTS
  Using the best-fitting segregation models in model-based multipoint linkage analysis, we identified 2 separate peaks on chromosome 17; the first agreed with a region identified by Shete and colleagues who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).
  
  
  CONCLUSIONS
  Our approach was able to narrow the linkage peak previously published for glioma.
  
  
  CONCLUSIONS
  We provide a practical solution to model-based linkage analysis for disease affection status with variable age of onset for the kinds of pedigree data often collected for linkage analysis.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Sun
authors.forename: Jaime
authors.initials: J
authors.lastname: Vengoechea
authors.forename: Robert
authors.initials: R
authors.lastname: Elston
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Georgina
authors.initials: G
authors.lastname: Armstrong
authors.forename: Jonine L
authors.initials: JL
authors.lastname: Bernstein
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Claus
authors.forename: Faith
authors.initials: F
authors.lastname: Davis
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Dora
authors.initials: D
authors.lastname: Il'yasova
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Christoffer
authors.initials: C
authors.lastname: Johansen
authors.forename: Rose
authors.initials: R
authors.lastname: Lai
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Bridget J
authors.initials: BJ
authors.lastname: McCarthy
authors.forename: Sara H
authors.initials: SH
authors.lastname: Olson
authors.forename: Siegal
authors.initials: S
authors.lastname: Sadetzki
authors.forename: Joellen
authors.initials: J
authors.lastname: Schildkraut
authors.forename: Sanjay
authors.initials: S
authors.lastname: Shete
authors.forename: Robert
authors.initials: R
authors.lastname: Yu
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Vick
authors.forename: Ryan
authors.initials: R
authors.lastname: Merrell
authors.forename: Margaret
authors.initials: M
authors.lastname: Wrensch
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
mesh_terms: D000328:Adult; D017668:Age of Onset; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005910:Glioma / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010375:Pedigree; D015995:Prevalence; D014481:United States / Q000453:epidemiology