%0 Journal Article %1 Fischer.2013 %A Fischer, Christine %A Kuchenbäcker, Karoline %A Engel, Christoph %A Zachariae, Silke %A Rhiem, Kerstin %A Meindl, Alfons %A Rahner, Nils %A Dikow, Nicola %A Plendl, Hansjörg %A Debatin, Irmgard %A Grimm, Tiemo %A Gadzicki, Dorothea %A Flöttmann, Ricarda %A Horvath, Judit %A Schröck, Evelin %A Stock, Friedrich %A Schäfer, Dieter %A Schwaab, Ira %A Kartsonaki, Christiana %A Mavaddat, Nasim %A Schlegelberger, Brigitte %A Antoniou, Antonis C. %A Schmutzler, Rita %D 2013 %J Journal of medical genetics %K Adult BRCA1_Protein/genetics BRCA2_Protein/genetics Breast_Neoplasms/epidemiology/genetics/pathology European_Continental_Ancestry_Group/genetics Family Female Genes,_BRCA1 Genes,_BRCA2 Genetic_Predisposition_to_Disease Genetic_Testing Germany/epidemiology Heterozygote Humans Male Middle_Aged Models,_Statistical Mutation Ovarian_Neoplasms/epidemiology/genetics Probability Risk_Assessment %N 6 %P 360–367 %T 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 %V 50 %X BACKGROUND\r\nRisk 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.\r\nPATIENTS AND METHODS\r\nUsing 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.\r\nRESULTS\r\nBRCAPRO (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.\r\nCONCLUSIONS\r\nOur 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.

@article{Fischer.2013, abstract = {BACKGROUND\r\nRisk 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.\r\nPATIENTS AND METHODS\r\nUsing 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.\r\nRESULTS\r\nBRCAPRO (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.\r\nCONCLUSIONS\r\nOur 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.}, added-at = {2014-10-13T18:24:46.000+0200}, author = {Fischer, Christine and Kuchenbäcker, Karoline and Engel, Christoph and Zachariae, Silke and Rhiem, Kerstin and Meindl, Alfons and Rahner, Nils and Dikow, Nicola and Plendl, Hansjörg and Debatin, Irmgard and Grimm, Tiemo and Gadzicki, Dorothea and Flöttmann, Ricarda and Horvath, Judit and Schröck, Evelin and Stock, Friedrich and Schäfer, Dieter and Schwaab, Ira and Kartsonaki, Christiana and Mavaddat, Nasim and Schlegelberger, Brigitte and Antoniou, Antonis C. and Schmutzler, Rita}, biburl = {https://www.bibsonomy.org/bibtex/2c1bb645d0543a49b058512e9d5edf8bb/drtester}, interhash = {4db67791dab4d79d08411ded64badbe2}, intrahash = {c1bb645d0543a49b058512e9d5edf8bb}, journal = {Journal of medical genetics}, keywords = {Adult BRCA1_Protein/genetics BRCA2_Protein/genetics Breast_Neoplasms/epidemiology/genetics/pathology European_Continental_Ancestry_Group/genetics Family Female Genes,_BRCA1 Genes,_BRCA2 Genetic_Predisposition_to_Disease Genetic_Testing Germany/epidemiology Heterozygote Humans Male Middle_Aged Models,_Statistical Mutation Ovarian_Neoplasms/epidemiology/genetics Probability Risk_Assessment}, number = 6, pages = {360–367}, timestamp = {2014-10-13T18:24:46.000+0200}, 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}, volume = 50, year = 2013 }