title: Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
abstract: BACKGROUND
  Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated.
  
  
  METHODS
  Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2.
  
  
  RESULTS
  BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed.
  
  
  CONCLUSIONS
  Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg 69120, Germany. cfischer@uni-hd.de
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Karoline
authors.initials: K
authors.lastname: Kuchenbäcker
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Silke
authors.initials: S
authors.lastname: Zachariae
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rhiem
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Plendl
authors.forename: Irmgard
authors.initials: I
authors.lastname: Debatin
authors.forename: Tiemo
authors.initials: T
authors.lastname: Grimm
authors.forename: Dorothea
authors.initials: D
authors.lastname: Gadzicki
authors.forename: Ricarda
authors.initials: R
authors.lastname: Flöttmann
authors.forename: Judit
authors.initials: J
authors.lastname: Horvath
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stock
authors.forename: Dieter
authors.initials: D
authors.lastname: Schäfer
authors.forename: Ira
authors.initials: I
authors.lastname: Schwaab
authors.forename: Christiana
authors.initials: C
authors.lastname: Kartsonaki
authors.forename: Nasim
authors.initials: N
authors.lastname: Mavaddat
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Rita
authors.initials: R
authors.lastname: Schmutzler
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics; D011336:Probability; D018570:Risk Assessment; D044465:White People / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: Cancer: breast; Clinical genetics; Genetic screening/counselling; Prevention; Screening