ARCAD - A METHOD FOR ESTIMATING AGE-DEPENDENT DISEASE RISK ASSOCIATEDWITH MUTATION CARRIER STATUS FROM FAMILY DATA

We present ARCAD, a method to estimate the disease risk associated wit h mutation carrier status using data on families ascertained by affect ed individuals, in which a germline mutation has been detected. Becaus e the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihoo d. Provided that selection criteria are clearly defined, the ascertain ment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proban d affected before age 17, and at least one or at least two relatives a ffected before age 46. We show that including the correction for the a scertainment provides reliable estimates of the risk, even when many i ndividuals are not tested for the mutation. An application to cancer r isk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pedia tric Oncology at the Institute Gustave Roussy, whose family displays a t least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any ca ncer for a mutation carrier estimated by ARCAD was 42% within the age class 0-16 years, 38% within the age class 17-45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encounte red in the Li-Fraumeni syndrome. (C) 1995 Wiley-Liss, Inc.