Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug's ...therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment's efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for.
Developing personalized diagnostic strategies and targeted treatments requires a deep understanding of disease biology and the ability to dissect the relationship between molecular and genetic ...factors and their phenotypic consequences. However, such knowledge is fragmented across publications, non-standardized repositories, and evolving ontologies describing various scales of biological organization between genotypes and clinical phenotypes. Here, we present PrimeKG, a multimodal knowledge graph for precision medicine analyses. PrimeKG integrates 20 high-quality resources to describe 17,080 diseases with 4,050,249 relationships representing ten major biological scales, including disease-associated protein perturbations, biological processes and pathways, anatomical and phenotypic scales, and the entire range of approved drugs with their therapeutic action, considerably expanding previous efforts in disease-rooted knowledge graphs. PrimeKG contains an abundance of 'indications', 'contradictions', and 'off-label use' drug-disease edges that lack in other knowledge graphs and can support AI analyses of how drugs affect disease-associated networks. We supplement PrimeKG's graph structure with language descriptions of clinical guidelines to enable multimodal analyses and provide instructions for continual updates of PrimeKG as new data become available.
Molecular interaction networks are powerful resources for molecular discovery. They are increasingly used with machine learning methods to predict biologically meaningful interactions. While deep ...learning on graphs has dramatically advanced the prediction prowess, current graph neural network (GNN) methods are mainly optimized for prediction on the basis of direct similarity between interacting nodes. In biological networks, however, similarity between nodes that do not directly interact has proved incredibly useful in the last decade across a variety of interaction networks. Here, we present SkipGNN, a graph neural network approach for the prediction of molecular interactions. SkipGNN predicts molecular interactions by not only aggregating information from direct interactions but also from second-order interactions, which we call skip similarity. In contrast to existing GNNs, SkipGNN receives neural messages from two-hop neighbors as well as immediate neighbors in the interaction network and non-linearly transforms the messages to obtain useful information for prediction. To inject skip similarity into a GNN, we construct a modified version of the original network, called the skip graph. We then develop an iterative fusion scheme that optimizes a GNN using both the skip graph and the original graph. Experiments on four interaction networks, including drug-drug, drug-target, protein-protein, and gene-disease interactions, show that SkipGNN achieves superior and robust performance. Furthermore, we show that unlike popular GNNs, SkipGNN learns biologically meaningful embeddings and performs especially well on noisy, incomplete interaction networks.
Abstract
Summary
Accurate prediction of drug–target interactions (DTI) is crucial for drug discovery. Recently, deep learning (DL) models for show promising performance for DTI prediction. However, ...these models can be difficult to use for both computer scientists entering the biomedical field and bioinformaticians with limited DL experience. We present DeepPurpose, a comprehensive and easy-to-use DL library for DTI prediction. DeepPurpose supports training of customized DTI prediction models by implementing 15 compound and protein encoders and over 50 neural architectures, along with providing many other useful features. We demonstrate state-of-the-art performance of DeepPurpose on several benchmark datasets.
Availability and implementation
https://github.com/kexinhuang12345/DeepPurpose.
Supplementary information
Supplementary data are available at Bioinformatics online.
There is a need of ensuring that learning (ML) models are interpretable. Higher interpretability of the model means easier comprehension and explanation of future predictions for end‐users. Further, ...interpretable ML models allow healthcare experts to make reasonable and data‐driven decisions to provide personalized decisions that can ultimately lead to higher quality of service in healthcare. Generally, we can classify interpretability approaches in two groups where the first focuses on personalized interpretation (local interpretability) while the second summarizes prediction models on a population level (global interpretability). Alternatively, we can group interpretability methods into model‐specific techniques, which are designed to interpret predictions generated by a specific model, such as a neural network, and model‐agnostic approaches, which provide easy‐to‐understand explanations of predictions made by any ML model. Here, we give an overview of interpretability approaches using structured data and provide examples of practical interpretability of ML in different areas of healthcare, including prediction of health‐related outcomes, optimizing treatments, or improving the efficiency of screening for specific conditions. Further, we outline future directions for interpretable ML and highlight the importance of developing algorithmic solutions that can enable ML driven decision making in high‐stakes healthcare problems.
This article is categorized under:
Application Areas > Health Care
Four groups of machine learning models for prediction in healthcare based on their interpretability characteristics
As explanations are increasingly used to understand the behavior of graph neural networks (GNNs), evaluating the quality and reliability of GNN explanations is crucial. However, assessing the quality ...of GNN explanations is challenging as existing graph datasets have no or unreliable ground-truth explanations. Here, we introduce a synthetic graph data generator, SHAPEGGEN, which can generate a variety of benchmark datasets (e.g., varying graph sizes, degree distributions, homophilic vs. heterophilic graphs) accompanied by ground-truth explanations. The flexibility to generate diverse synthetic datasets and corresponding ground-truth explanations allows SHAPEGGEN to mimic the data in various real-world areas. We include SHAPEGGEN and several real-world graph datasets in a graph explainability library, GRAPHXAI. In addition to synthetic and real-world graph datasets with ground-truth explanations, GRAPHXAI provides data loaders, data processing functions, visualizers, GNN model implementations, and evaluation metrics to benchmark GNN explainability methods.
Uncovering modular structure in networks is fundamental for systems in biology, physics, and engineering. Community detection identifies candidate modules as hypotheses, which then need to be ...validated through experiments, such as mutagenesis in a biological laboratory. Only a few communities can typically be validated, and it is thus important to prioritize which communities to select for downstream experimentation. Here we develop CRANK, a mathematically principled approach for prioritizing network communities. CRANK efficiently evaluates robustness and magnitude of structural features of each community and then combines these features into the community prioritization. CRANK can be used with any community detection method. It needs only information provided by the network structure and does not require any additional metadata or labels. However, when available, CRANK can incorporate domain-specific information to further boost performance. Experiments on many large networks show that CRANK effectively prioritizes communities, yielding a nearly 50-fold improvement in community prioritization.
Phenotype robustness to environmental fluctuations is a common biological phenomenon. Although most phenotypes involve multiple proteins that interact with each other, the basic principles of how ...such interactome networks respond to environmental unpredictability and change during evolution are largely unknown. Here we study interactomes of 1,840 species across the tree of life involving a total of 8,762,166 protein–protein interactions. Our study focuses on the resilience of interactomes to network failures and finds that interactomes become more resilient during evolution, meaning that interactomes become more robust to network failures over time. In bacteria, we find that a more resilient interactome is in turn associated with the greater ability of the organism to survive in a more complex, variable, and competitive environment. We find that at the protein family level proteins exhibit a coordinated rewiring of interactions over time and that a resilient interactome arises through gradual change of the network topology. Our findings have implications for understanding molecular network structure in the context of both evolution and environment.
Although tremendous effort has been put into cell-type annotation, identification of previously uncharacterized cell types in heterogeneous single-cell RNA-seq data remains a challenge. Here we ...present MARS, a meta-learning approach for identifying and annotating known as well as new cell types. MARS overcomes the heterogeneity of cell types by transferring latent cell representations across multiple datasets. MARS uses deep learning to learn a cell embedding function as well as a set of landmarks in the cell embedding space. The method has a unique ability to discover cell types that have never been seen before and annotate experiments that are as yet unannotated. We apply MARS to a large mouse cell atlas and show its ability to accurately identify cell types, even when it has never seen them before. Further, MARS automatically generates interpretable names for new cell types by probabilistically defining a cell type in the embedding space.
Networks are ubiquitous in biology where they encode connectivity patterns at all scales of organization, from molecular to the biome. However, biological networks are noisy due to the limitations of ...measurement technology and inherent natural variation, which can hamper discovery of network patterns and dynamics. We propose Network Enhancement (NE), a method for improving the signal-to-noise ratio of undirected, weighted networks. NE uses a doubly stochastic matrix operator that induces sparsity and provides a closed-form solution that increases spectral eigengap of the input network. As a result, NE removes weak edges, enhances real connections, and leads to better downstream performance. Experiments show that NE improves gene-function prediction by denoising tissue-specific interaction networks, alleviates interpretation of noisy Hi-C contact maps from the human genome, and boosts fine-grained identification accuracy of species. Our results indicate that NE is widely applicable for denoising biological networks.
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