Incorporating alternative Polygenic Risk Scores into the BOADICEA breast cancer risk prediction model

Abstract

BackgroundThe multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA. MethodsThe mean, standard deviation (SD), and proportion of the overall polygenic component explained by the PRS (2) need to be estimated. was estimated using logistic regression, where the age-specific log-relative risk is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component. ResultsParameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates , as compared with the RL estimates. The RL estimates were very close to those obtained by assuming proportionality to the odds ratio per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean. ConclusionsBOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model. ImpactThe methods described enable comprehensive breast cancer risk assessment.