title: Validity of models for predicting BRCA1 and BRCA2 mutations.
abstract: BACKGROUND
  Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood.
  
  
  OBJECTIVE
  To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University.
  
  
  METHODS
  Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models.
  
  
  METHODS
  Multicenter study across Cancer Genetics Network participating centers.
  
  
  METHODS
  3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics.
  
  
  METHODS
  Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions.
  
  
  RESULTS
  The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing.
  
  
  CONCLUSIONS
  Three recently published models were not included.
  
  
  CONCLUSIONS
  All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21205-2011, USA. gp@jhu.edu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Sining
authors.initials: S
authors.lastname: Chen
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.forename: Tara M
authors.initials: TM
authors.lastname: Friebel
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Weber
authors.forename: Andrea
authors.initials: A
authors.lastname: Eisen
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Malone
authors.forename: Janet R
authors.initials: JR
authors.lastname: Daling
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Camille
authors.initials: C
authors.lastname: Corio
authors.forename: Leoni
authors.initials: L
authors.lastname: Leondaridis
authors.forename: Gail
authors.initials: G
authors.lastname: Tomlinson
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Louise C
authors.initials: LC
authors.lastname: Strong
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Sharon
authors.initials: S
authors.lastname: Sand
authors.forename: Debra
authors.initials: D
authors.lastname: Dutson
authors.forename: Rich
authors.initials: R
authors.lastname: Kerber
authors.forename: Beth N
authors.initials: BN
authors.lastname: Peshkin
authors.forename: David M
authors.initials: DM
authors.lastname: Euhus
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics*; D012680:Sensitivity and Specificity