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Assessing BRCA Carrier Probabilities in Extended Families

From the Departments of Epidemiology, Breast Medical Oncology, Clinical Cancer Genetics, and Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas; Cancer Therapy and Research Center, San Antonio, TX; and Global Pharmacovigilance and Epidemiology, Aventis Pharmaceuticals Inc, Bridgewater, NJ.

Address reprint requests to Christopher I. Amos, PhD, Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: camos{at}mdanderson.org

Purpose Carrier prediction models estimate the probability that a person has a BRCA mutation. We evaluated the accuracy of the BOADICEA model and compared its performance with that of other models (BRCAPRO, Myriad I and II, Couch, and Manchester Scoring System). We also studied the effect of extended family information on risk estimation using BOADICEA.

Methods We compared the area under receiver operating characteristic curves generated from 472 families with one member tested for BRCA mutations. We calculated sensitivity, specificity, and predictive values at an estimated probability of 10% and explored the biases of carrier prediction.

Results BOADICEA performed better than the other models in Ashkenazi Jewish (AJ) families, BRCAPRO performed slightly better in non-AJ families, and Myriad II performed comparably well in both groups. Including extended family information in BOADICEA yielded slightly better performance than did limiting the information to second-degree relatives. Using a 10% cutoff point, BOADICEA and Myriad II were most sensitive in predicting BRCA1/2 mutations in AJ families, and Myriad II was most sensitive in non-AJ families. The Manchester Scoring System was the most sensitive and least specific in a subgroup of non-AJ families. BOADICEA and BRCAPRO tended to underestimate the observed risk at low estimated probabilities and overestimate it at higher probabilities.

Conclusion The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Supported by National Institutes of Health Grants No. U24 CA78142 and P30 CA 16672.

Presented in part at the 53rd Annual Meeting of the American Society of Human Genetics, Los Angeles, CA, November 4-8, 2003; and the 2005 Annual Meeting of the American College of Medical Genetics, Dallas, TX, March 17-20, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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