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Drug2ways: Reasoning over causal paths in biological networks for drug discovery.

ABSTRACT: Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.

SUBMITTER: Rivas-Barragan D

PROVIDER: S-EPMC7735677 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Drug2ways: Reasoning over causal paths in biological networks for drug discovery.

Rivas-Barragan Daniel D Mubeen Sarah S Guim Bernat Francesc F Hofmann-Apitius Martin M Domingo-Fernández Daniel D

PLoS computational biology 20201202 12

Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity ...[more]

PMID: 33264280

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Project description:BACKGROUND: We recently published in BMC Systems Biology an approach for calculating the perturbation amplitudes of causal network models by integrating gene differential expression data. This approach relies on the process of score aggregation, which combines the perturbations at the level of the individual network nodes into a global measure that quantifies the perturbation of the network as a whole. Such "bottom-up" aggregation relates the changes in molecular entities measured by omics technologies to systems-level phenotypes. However, the aggregation method we used is limited to a specific class of causal network models called "causally consistent", which is equivalent to the notion of balance of a signed graph used in graph theory. As a consequence of this limitation, our aggregation method cannot be used in the many relevant cases involving "causally inconsistent" network models such as those containing negative feedbacks. FINDINGS: In this note, we propose an algorithm called "sampling of spanning trees" (SST) that extends our published aggregation method to causally inconsistent network models by replacing the signed relationships between the network nodes by an appropriate continuous measure. The SST algorithm is based on spanning trees, which are a particular class of subgraphs used in graph theory, and on a sampling procedure leveraging the properties of specific random walks on the graph. This algorithm is applied to several cases of biological interest. CONCLUSIONS: The SST algorithm provides a practical means of aggregating nodal values over causally inconsistent network models based on solid mathematical foundations. We showed its utility in systems biology, where the nodal values can be perturbation amplitudes of protein activities or gene differential expressions, while the networks can be models of cellular signaling or expression regulation. Since the SST algorithm is based on general graph-theoretical considerations, it is scalable to arbitrary graph sizes and can potentially be used for performing quantitative analyses in any context involving signed graphs.

Project description:Training of elite athletes requires regular physiological and medical monitoring to plan the schedule, intensity and volume of training, and subsequent recovery. In sports medicine, ECG-based analyses are well-established. However, they rarely consider the correspondence of respiratory and cardiac activity. Given such mutual influence, we hypothesize that athlete monitoring might be developed with causal inference and that detailed, time-related techniques should be preceded by a more general, time-independent approach that considers the whole group of participants and parameters describing whole signals. The aim of this study was to discover general causal paths among cardiac and respiratory variables in elite athletes in two body positions (supine and standing), at rest. ECG and impedance pneumography signals were obtained from 100 elite athletes. The mean heart rate, the root-mean-square difference of successive RR intervals (RMSSD), its natural logarithm (lnRMSSD), the mean respiratory rate (RR), the breathing activity coefficients, and the resulting breathing regularity (BR) were estimated. Several causal discovery frameworks were applied, comprising Generalized Correlations (GC), Causal Additive Modeling (CAM), Fast Greedy Equivalence Search (FGES), Greedy Fast Causal Inference (GFCI), and two score-based Bayesian network learning algorithms: Hill-Climbing (HC) and Tabu Search. The discovery of cardiorespiratory paths appears ambiguous. The main, still mild, rules best supported by data are: for supine - tidal volume causes heart activity variation, which causes average heart activity, which causes respiratory timing; and for standing - normalized respiratory activity variation causes average heart activity. The presented approach allows data-driven and time-independent analysis of elite athletes as a particular population, without considering prior knowledge. However, the results seem to be consistent with the medical background. Causality inference is an interesting mathematical approach to the analysis of biological responses, which are complex. One can use it to profile athletes and plan appropriate training. In the next step, we plan to expand the study using time-related causality analyses.

Dataset Information

Drug2ways: Reasoning over causal paths in biological networks for drug discovery.

Publications

Drug2ways: Reasoning over causal paths in biological networks for drug discovery.

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