Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women

LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve ( a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77 - 0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75 - 0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed ( p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve ( 0.78; 95% CI 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed ( p, 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than BRCAPRO which substantially overpredicts carriers in this population.