Are gene-by-environment interactions leveraged in multi-modality neural networks for breast cancer prediction?

Polygenic risk scores (PRSs) can significantly enhance breast cancer risk prediction when combined with clinical risk factor data. While many studies have explored the value-add of PRSs, little is known about the potential impact of gene-by-gene or gene-by-environment interactions towards enhancing the risk discrimination capabilities of multi-modal models combining PRSs with clinical data. In this study, we integrated data on 318 individual genotype variants along with clinical data in a neural network to explore whether gene-by-gene (i.e., between individual variants) and/or gene-by-environment (between clinical risk factors and variants) interactions could be leveraged jointly during training to improve breast cancer risk prediction performance. We benchmarked our approach against a baseline model combining traditional univariate PRSs with clinical data in a logistic regression model and ran an interpretability analysis to identify feature interactions. While our model did not demonstrate improved performance over the baseline, we discovered 248 (<1%) statistically significant gene-by-gene and gene-by-environment interactions out of the ~53.6k possible feature pairs, the most contributory of which included rs6001930 (MKL1) and rs889312 (MAP3K1), with age and menopause being the most heavily interacting non-genetic risk factors. We also modeled the significant interactions as a network of highly connected features, suggesting that potential higher-order interactions are captured by the model. Although gene-by-environment (or gene-by-gene) interactions did not enhance breast cancer risk prediction performance in neural networks, our study provides evidence that these interactions can be leveraged by these models to inform their predictions. This study represents the first application of neural networks to screen for interactions impacting breast cancer risk using real-world data.