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|Title:||Effect of misreported family history on Mendelian mutation prediction models.|
|Abstract:||People with familial history of disease often consult with genetic counselors about their chance of carrying mutations that increase disease risk. To aid them, genetic counselors use Mendelian models that predict whether the person carries deleterious mutations based on their reported family history. Such models rely on accurate reporting of each member's diagnosis and age of diagnosis, but this information may be inaccurate. Commonly encountered errors in family history can significantly distort predictions, and thus can alter the clinical management of people undergoing counseling, screening, or genetic testing. We derive general results about the distortion in the carrier probability estimate caused by misreported diagnoses in relatives. We show that the Bayes factor that channels all family history information has a convenient and intuitive interpretation. We focus on the ratio of the carrier odds given correct diagnosis versus given misreported diagnosis to measure the impact of errors. We derive the general form of this ratio and approximate it in realistic cases. Misreported age of diagnosis usually causes less distortion than misreported diagnosis. This is the first systematic quantitative assessment of the effect of misreported family history on mutation prediction. We apply the results to the BRCAPRO model, which predicts the risk of carrying a mutation in the breast and ovarian cancer genes BRCA1 and BRCA2.|