Synthetic lethality (SL) is a relationship between two genes, exploited for targeted anti-cancer therapy, whereby functional loss of both genes induces cell death, but the functional loss of either gene alone is non-lethal. Computational prediction of SL gene pairs is sought after because it is expensive to do lab screening for SL. Existing SL labeled pairs from wet- lab experiments often focus on specific genes or pathways, resulting in notable selection bias. Current SL prediction methods ignore this bias when training on available SL labels, and fail to generalize if test sets follow a different selection bias. One way to mitigate bias is to incorporate unlabeled pairs during model learning. However, conventional semi-supervised methods such as self-training can reinforce bias by adding confidently pseudolabeled pairs, which tend to be most similar to previously included samples. We present DBST, a self-training strategy that addresses the issue by promoting diversity in the selection of pseudolabeled samples. This is achieved using metric learning to find a class-contrastive representation of the feature space, based on which DBST selects diverse (or dissimilar) pseudolabeled pairs. In results for five cancer types, semi-supervised models, including DBST, delivered improved SL prediction performance over the supervised model. Additionally, DBST successfully incorporated unlabeled samples that were more dissimilar among them compared to standard self-training. In experiments with differing biases between train and test sets, DBST showed a slight improvement in performance compared to the supervised model.

Motivation: Many tumors show deficiencies in DNA damage repair. These deficiencies can play a role in the disease, but also expose vulnerabilities with therapeutic potential. Targeted treatments exploit specific repair deficiencies, for instance based on synthetic lethality. To decide which patients could benefit from such therapies requires the ability to determine the repair deficiency status of a tumor. It has been suggested that mutational signatures could be better predictors of DNA repair deficiency than loss of function in select genes. However, current models for prediction of repair deficiency rely on mutational signatures extracted using unsupervised learning techniques. As a result, the signatures are not optimized to discriminate between repair deficiency status or pathway. We argue that the supervised learning of mutational signatures guided by repair deficiency status could enable the identification of signatures that are predictive of repair deficiency, and capture underlying mechanisms of DNA repair.
Results: We propose S-NMF, a supervised non-negative matrix factorization method, which jointly optimizes two objectives: (1) learning of signatures shared across tumor samples using NMF, and (2) learning of signatures predictive of repair deficiency using logistic regression. We apply S-NMF to mutation profiles of human induced pluripotent cell lines carrying knockouts of genes involved in three DNA repair pathways: homologous recombination, base excision repair, and mismatch repair. We show that S-NMF achieves high prediction accuracy (0.971) and learns signatures that better distinguish the repair deficiency of a sample. Signatures extracted by S-NMF are similar to cancer-related signatures associated with the same repair deficiency. Additionally, S-NMF can capture signatures of deficiencies affecting distinct subpathways within a main repair pathway (e.g. OGG1 and UNG mechanisms in base excision repair).