Validation of the BOADICEA model for epithelial tubo-ovarian cancer risk prediction in UK Biobank

Abstract

Background: The clinical validity of the multifactorial BOADICEA model for epithelial tubo-ovarian cancer (EOC) risk prediction has not been assessed in a large sample size or over a longer term.

Methods: We evaluated the model discrimination and calibration in the UK Biobank cohort comprising 199,429 women (733 incident EOCs) of European ancestry without previous cancer history. We predicted 10-year EOC risk incorporating data on questionnaire-based risk factors (QRFs), family history, a 36-SNP polygenic risk score and pathogenic variants (PV) in six EOC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2).

Results: Discriminative ability was maximised under the multifactorial model that included all risk factors (AUC = 0.68, 95% CI: 0.66-0.70). This model was well calibrated in deciles of predicted risk with calibration slope=0.99 (95% CI: 0.98-1.01). Discriminative ability was similar in women younger or older than 60 years. The AUC was higher when analyses were restricted to PV carriers (0.76, 95% CI: 0.69-0.82). Using relative risk (RR) thresholds, the full model classified 97.7%, 1.7%, 0.4% and 0.2% women in the RR < 2.0, 2.0 ≤ RR < 2.9, 2.9 ≤ RR < 6.0 and RR ≥ 6.0 categories, respectively, identifying 9.1 of incident EOC among those with RR ≥ 2.0.

Discussion: BOADICEA, implemented in CanRisk ( www.canrisk.org ), provides valid 10-year EOC risks and can facilitate clinical decision-making in EOC risk management.

Fig. 1. Observed and predicted 10-year EOC risks under individual or different combinations of risk factors*.

*Women were grouped into deciles based on their predicted risks. Each dot represents the mean observed and predicted risk in the decile and the error bar represents the 95% confidence intervals. The dashed line is the reference line with slope equals to 1, on which the observed risk equals to the predicted risk. When the confidence interval intersects with the reference line, the predicted risk in that decile is not significantly different from the observed risk. If the confidence interval of a decile deviates from the reference line, there is a suggestion of either overprediction (below the line) or underprediction (above the line) of EOC risks by the BOADICEA model. Null age-only model, PRS polygenic risk scores, PV pathogenic variants, QRF questionnaire-based risk factors, FH family history.

Fig. 2. Observed and predicted 10-year EOC risks by age under the full model.

a Age <60 (N = 110,885); b age ≥60 (N = 88,544). Women were grouped into deciles based on their predicted risks. Each dot represents the mean observed and predicted risk in the decile and error bar represents the 95% confidence intervals.

Fig. 3. Observed and predicted 10-year EOC risks in pathogenic variant carriers (N = 1231) under the model considering PV only, PV + PRS + QRF and PV + PRS + QRF + FH.

Women were grouped into deciles based on their predicted risks. Each dot represents the mean observed and predicted risk in the decile, and the error bar represents the 95% CIs.