Effective treatment of cancer is a major challenge faced by healthcare providers, due to the highly individualized nature of patient responses to treatment. This is caused by the heterogeneity seen in cancer-causing alterations (mutations) across patient genomes. Limited availability of response data in patients makes it difficult to train personalized treatment recommendation models on mutations from clinical genomic sequencing reports. Prior methods tackle this by utilising larger, labelled pre-clinical laboratory datasets (‘cell lines’), via transfer learning. These methods augment patient data by learning a shared, domain-invariant representation, between the cell line and patient domains, which is then used to train a downstream drug response prediction (DRP) model. This approach augments data in the shared space but fails to model patient-specific characteristics, which have a strong influence on their drug response. We propose a novel generative attention-based data augmentation and predictive modeling framework, GANDALF, to tackle this crucial shortcoming of prior methods. GANDALF not only augments patient genomic data directly, but also accounts for its domain-specific characteristics. GANDALF outperforms state-of-the-art DRP models on publicly available patient datasets and emerges as the front-runner amongst SOTA cancer DRP models.

Cancer, a leading cause of death globally, occurs due to genomic changes and manifests heterogeneously across patients. To advance research on personalized treatment strategies, the effectiveness of various drugs on cells derived from cancers (’cell lines’) is experimentally determined in laboratory settings. Nevertheless, variations in the distribution of genomic data and drug responses between cell lines and humans arise due to biological and environmental differences. Moreover, while genomic profiles of many cancer patients are readily available, the scarcity of corresponding drug response data limits the ability to train machine learning models that can predict drug response in patients effectively. Recent cancer drug response prediction methods have largely followed the paradigm of unsupervised domain-invariant representation learning followed by a downstream drug response classification step. Introducing supervision in both stages is challenging due to heterogeneous patient response to drugs and limited drug response data. This paper addresses these challenges through a novel representation learning method in the first phase and weak supervision in the second. Experimental results on real patient data demonstrate the efficacy of our method WISER (Weak supervISion and supErvised Representation learning) over state-of-the-art alternatives on predicting personalized drug response. Our implementation is available at https://github.com/kyrs/WISER

Cancer remains a global challenge due to its growing clinical and economic burden. Its uniquely personal manifestation, which makes treatment difficult, has fuelled the quest for personalized treatment strategies. Thus, genomic profiling is increasingly becoming part of clinical diagnostic panels. Effective use of such panels requires accurate drug response prediction (DRP) models, which are challenging to build due to limited labelled patient data. Previous methods to address this problem have used various forms of transfer learning. However, they do not explicitly model the variable length sequential structure of the list of mutations in such diagnostic panels. Further, they do not utilize auxiliary information (like patient survival) for model training. We address these limitations through a novel transformer-based method, which surpasses the performance of state-of-the-art DRP models on benchmark data. Code for our method is available at https://github.com/CDAL-SOC/PREDICT-AI.

A Synthetic Lethal (SL) interaction is a functional relationship between two genes or functional entities where the loss of either entity is viable but the loss of both is lethal. Such pairs can be used to develop targeted anticancer therapies with fewer side effects and reduced overtreatment. However, finding clinically relevant SL interactions remains challenging. Leveraging unified gene expression data of both disease-free and cancerous samples, we design a new technique based on statistical hypothesis testing, called ASTER, to identify SL pairs. We empirically find that the patterns of mutually exclusivity ASTER finds using genomic and transcriptomic data provides a strong signal of synthetic lethality. For large-scale multiple hypothesis testing, we develop an extension called ASTER++ that can utilize additional input gene features within the hypothesis testing framework. Our computational and functional experiments demonstrate the efficacy of ASTER in identifying SL pairs with potential therapeutic benefits.

MOTIVATION: In many biomedical studies, there arises the need to integrate data from multiple directly or indirectly related sources. Collective matrix factorization (CMF) and its variants are models designed to collectively learn from arbitrary collections of matrices. The latent factors learnt are rich integrative representations that can be used in downstream tasks, such as clustering or relation prediction with standard machine-learning models. Previous CMF-based methods have numerous modeling limitations. They do not adequately capture complex non-linear interactions and do not explicitly model varying sparsity and noise levels in the inputs, and some cannot model inputs with multiple datatypes. These inadequacies limit their use on many biomedical datasets. RESULTS: To address these limitations, we develop Neural Collective Matrix Factorization (NCMF), the first fully neural approach to CMF. We evaluate NCMF on relation prediction tasks of gene-disease association prediction and adverse drug event prediction, using multiple datasets. In each case, data are obtained from heterogeneous publicly available databases and used to learn representations to build predictive models. NCMF is found to outperform previous CMF-based methods and several state-of-the-art graph embedding methods for representation learning in our experiments. Our experiments illustrate the versatility and efficacy of NCMF in representation learning for seamless integration of heterogeneous data. AVAILABILITY AND IMPLEMENTATION: https://github.com/ajayago/NCMF_bioinformatics. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.