Benchmarking Machine Learning Methods for Synthetic Lethality Prediction in Cancer

Synthetic lethality (SL) is a type of genetic interaction that occurs when defects in two genes cause cell death, while a defect in a single gene does not. Targeting an SL partner of a gene mutated in cancer can selectively kill tumor cells. Traditional wet-lab experiments for SL screening are resource-intensive. Hence, many computational methods have been developed for virtual screening of SL gene pairs. This study benchmarks recent machine learning methods for SL prediction, including three matrix factorization and eight deep learning models. We scrutinize model performance using various data splitting scenarios, negative sample ratios, and negative sampling methods on both classification and ranking tasks to assess the models’ generalizability and robustness. Our benchmark analyzed performance differences among the models and emphasized the importance of data and real-world scenarios. Finally, we suggest future directions to improve machine learning methods for SL discovery in terms of predictive power and interpretability. ### Competing Interest Statement The authors have declared no competing interest.