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178 The road travelledalso to help increase awareness about the issues by sharing the deeply personalstory with the general public. At the same time, a debate is also raging aboutwhether she got the right estimates of her risks and whether she could havemade alternative, less drastic choices, to minimize and manage her long-termrisks of these two cancers. And of course, all of these are embedded in a muchbroader debate in the community about the appropriate use of comprehensivegenome sequencing information for personalized medicine (treatment andprevention) in the future.17.2 Kin-cohort study: My gateway to geneticsThis debate about Angelina Jolie’s decision is taking me back through thememory lane to May of 1999 when I joined the Division of Cancer Epidemiologyand Genetics of the National Cancer Institute as a post-doctoral fellowafter finishing my PhD in Statistics from the University of Washington,Seattle. The very first project my mentor, Sholom Wacholder, introduced meto involved estimation of risk of certain cancers, including those of breastand ovary, associated with mutations in genes BRCA1 and BRCA2 from theWashington Ashkenazi Study (WAS) (Struewing et al., 1997). My mentorand his colleagues had previously developed the novel “kin-cohort” approachthat allowed estimation of age-specific cumulative risk of a disease associatedwith a genetic mutation based on the disease history of the set of relatives ofgenotyped study participants (Wacholder et al., 1998). This approach, whenapplied to the WAS study, estimated the lifetime risk or penetrance of breastcancer to be between 50–60%, substantially lower than the estimates of penetrancearound 90–100% that have been previously obtained from analysisof highly disease enriched families. It was thought that WAS, which werevolunteer-based and not as prone to ascertainment bias as family-studies, providedmore unbiased estimate of risk for BRCA1/2 mutation carriers in thegeneral population. Other studies, that have employed “un-selected” designs,have estimated the penetrance to be even lower.The approach my mentor and colleagues had previously developed wasvery simple and elegant. It relied on the observation that since approximatelyhalf of the first-degree relatives of BRCA1/2 mutation carriers are expectedto be carriers by themselves due to Mendelian laws of transmission, the risksof the disease in this group of relatives should be approximately 50:50 mixtureof the risk of the disease associated with carriers and non-carriers. Further, forararemutation,sinceveryfewofthefirstdegreerelativesofthenon-carriersare expected to be carriers themselves, the risk of the disease in the group ofrelatives should be approximately the same as that for non-carriers themselves.Thus they employed a simple method-of-moment approach to estimate theage-specific cumulative risks associated with carriers and non-carriers using