Transfer learning of condition-specific perturbation in gene interactions improves drug response prediction.

SUMMARY: Drug response is conventionally measured at the cell level, often quantified by metrics like IC50. However, to gain a deeper understanding of drug response, cellular outcomes need to be understood in terms of pathway perturbation. This perspective leads us to recognize a challenge posed by the gap between two widely used large-scale databases, LINCS L1000 and GDSC, measuring drug response at different levels-L1000 captures information at the gene expression level, while GDSC operates at the cell line level. Our study aims to bridge this gap by integrating the two databases through transfer learning, focusing on condition-specific perturbations in gene interactions from L1000 to interpret drug response integrating both gene and cell levels in GDSC. This transfer learning strategy involves pretraining on the transcriptomic-level L1000 dataset, with parameter-frozen fine-tuning to cell line-level drug response. Our novel condition-specific gene-gene attention (CSG2A) mechanism dynamically learns gene interactions specific to input conditions, guided by both data and biological network priors. The CSG2A network, equipped with transfer learning strategy, achieves state-of-the-art performance in cell line-level drug response prediction. In two case studies, well-known mechanisms of drugs are well represented in both the learned gene-gene attention and the predicted transcriptomic profiles. This alignment supports the modeling power in terms of interpretability and biological relevance. Furthermore, our model's unique capacity to capture drug response in terms of both pathway perturbation and cell viability extends predictions to the patient level using TCGA data, demonstrating its expressive power obtained from both gene and cell levels. AVAILABILITY AND IMPLEMENTATION: The source code for the CSG2A network is available at https://github.com/eugenebang/CSG2A.

A model-agnostic framework to enhance knowledge graph-based drug combination prediction with drug-drug interaction data and supervised contrastive learning.

Combination therapies have brought significant advancements to the treatment of various diseases in the medical field. However, searching for effective drug combinations remains a major challenge due to the vast number of possible combinations. Biomedical knowledge graph (KG)-based methods have shown potential in predicting effective combinations for wide spectrum of diseases, but the lack of credible negative samples has limited the prediction performance of machine learning models. To address this issue, we propose a novel model-agnostic framework that leverages existing drug-drug interaction (DDI) data as a reliable negative dataset and employs supervised contrastive learning (SCL) to transform drug embedding vectors to be more suitable for drug combination prediction. We conducted extensive experiments using various network embedding algorithms, including random walk and graph neural networks, on a biomedical KG. Our framework significantly improved performance metrics compared to the baseline framework. We also provide embedding space visualizations and case studies that demonstrate the effectiveness of our approach. This work highlights the potential of using DDI data and SCL in finding tighter decision boundaries for predicting effective drug combinations.

Biomedical knowledge graph learning for drug repurposing by extending guilt-by-association to multiple layers.

Computational drug repurposing aims to identify new indications for existing drugs by utilizing high-throughput data, often in the form of biomedical knowledge graphs. However, learning on biomedical knowledge graphs can be challenging due to the dominance of genes and a small number of drug and disease entities, resulting in less effective representations. To overcome this challenge, we propose a "semantic multi-layer guilt-by-association" approach that leverages the principle of guilt-by-association - "similar genes share similar functions", at the drug-gene-disease level. Using this approach, our model DREAMwalk: Drug Repurposing through Exploring Associations using Multi-layer random walk uses our semantic information-guided random walk to generate drug and disease-populated node sequences, allowing for effective mapping of both drugs and diseases in a unified embedding space. Compared to state-of-the-art link prediction models, our approach improves drug-disease association prediction accuracy by up to 16.8%. Moreover, exploration of the embedding space reveals a well-aligned harmony between biological and semantic contexts. We demonstrate the effectiveness of our approach through repurposing case studies for breast carcinoma and Alzheimer's disease, highlighting the potential of multi-layer guilt-by-association perspective for drug repurposing on biomedical knowledge graphs.

DRPreter: Interpretable Anticancer Drug Response Prediction Using Knowledge-Guided Graph Neural Networks and Transformer.

Some of the recent studies on drug sensitivity prediction have applied graph neural networks to leverage prior knowledge on the drug structure or gene network, and other studies have focused on the interpretability of the model to delineate the mechanism governing the drug response. However, it is crucial to make a prediction model that is both knowledge-guided and interpretable, so that the prediction accuracy is improved and practical use of the model can be enhanced. We propose an interpretable model called DRPreter (drug response predictor and interpreter) that predicts the anticancer drug response. DRPreter learns cell line and drug information with graph neural networks; the cell-line graph is further divided into multiple subgraphs with domain knowledge on biological pathways. A type-aware transformer in DRPreter helps detect relationships between pathways and a drug, highlighting important pathways that are involved in the drug response. Extensive experiments on the GDSC (Genomics of Drug Sensitivity and Cancer) dataset demonstrate that the proposed method outperforms state-of-the-art graph-based models for drug response prediction. In addition, DRPreter detected putative key genes and pathways for specific drug-cell-line pairs with supporting evidence in the literature, implying that our model can help interpret the mechanism of action of the drug.

A Survey on Computational Methods for Investigation on ncRNA-Disease Association through the Mode of Action Perspective.

Molecular and sequencing technologies have been successfully used in decoding biological mechanisms of various diseases. As revealed by many novel discoveries, the role of non-coding RNAs (ncRNAs) in understanding disease mechanisms is becoming increasingly important. Since ncRNAs primarily act as regulators of transcription, associating ncRNAs with diseases involves multiple inference steps. Leveraging the fast-accumulating high-throughput screening results, a number of computational models predicting ncRNA-disease associations have been developed. These tools suggest novel disease-related biomarkers or therapeutic targetable ncRNAs, contributing to the realization of precision medicine. In this survey, we first introduce the biological roles of different ncRNAs and summarize the databases containing ncRNA-disease associations. Then, we suggest a new trend in recent computational prediction of ncRNA-disease association, which is the mode of action (MoA) network perspective. This perspective includes integrating ncRNAs with mRNA, pathway and phenotype information. In the next section, we describe computational methodologies widely used in this research domain. Existing computational studies are then summarized in terms of their coverage of the MoA network. Lastly, we discuss the potential applications and future roles of the MoA network in terms of integrating biological mechanisms for ncRNA-disease associations.

On modeling and utilizing chemical compound information with deep learning technologies: A task-oriented approach.

A large number of chemical compounds are available in databases such as PubChem and ZINC. However, currently known compounds, though large, represent only a fraction of possible compounds, which is known as chemical space. Many of these compounds in the databases are annotated with properties and assay data that can be used for drug discovery efforts. For this goal, a number of machine learning algorithms have been developed and recent deep learning technologies can be effectively used to navigate chemical space, especially for unknown chemical compounds, in terms of drug-related tasks. In this article, we survey how deep learning technologies can model and utilize chemical compound information in a task-oriented way by exploiting annotated properties and assay data in the chemical compounds databases. We first compile what kind of tasks are trying to be accomplished by machine learning methods. Then, we survey deep learning technologies to show their modeling power and current applications for accomplishing drug related tasks. Next, we survey deep learning techniques to address the insufficiency issue of annotated data for more effective navigation of chemical space. Chemical compound information alone may not be powerful enough for drug related tasks, thus we survey what kind of information, such as assay and gene expression data, can be used to improve the prediction power of deep learning models. Finally, we conclude this survey with four important newly developed technologies that are yet to be fully incorporated into computational analysis of chemical information.