Dataset Information

Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer.

ABSTRACT: To better understand the molecular features of cancers, a comprehensive analysis using multiomics data has been conducted. Additionally, a pathway activity inference method has been developed to facilitate the integrative effects of multiple genes. In this respect, we have recently proposed a novel integrative pathway activity inference approach, iDRW, and demonstrated the effectiveness of the method with respect to dichotomizing two survival groups. However, there were several limitations, such as a lack of generality. In this study, we designed a directed gene-gene graph using pathway information by assigning interactions between genes in multiple layers of networks. : As a proof-of-concept study, it was evaluated using three genomic profiles of urologic cancer patients. The proposed integrative approach achieved improved outcome prediction performances compared with a single genomic profile alone and other existing pathway activity inference methods. The integrative approach also identified common/cancer-specific candidate driver pathways as predictive prognostic features in urologic cancers. Furthermore, it provides better biological insights into the prioritized pathways and genes in an integrated view using a multi-layered gene-gene network. Our framework is not specifically designed for urologic cancers and can be generally applicable for various datasets. iDRW is implemented as the R software package. The source codes are available at https://github.com/sykim122/iDRW. Supplementary data are available at Bioinformatics online.

SUBMITTER: Yeon Kim S

PROVIDER: S-EPMC8388033 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer.

Kim So Yeon SY Choe Eun Kyung EK Shivakumar Manu M Kim Dokyoon D Sohn Kyung-Ah KA

Bioinformatics (Oxford, England) 20210801 16

<h4>Motivation</h4>To better understand the molecular features of cancers, a comprehensive analysis using multi-omics data has been conducted. In addition, a pathway activity inference method has been developed to facilitate the integrative effects of multiple genes. In this respect, we have recently proposed a novel integrative pathway activity inference approach, iDRW and demonstrated the effectiveness of the method with respect to dichotomizing two survival groups. However, there were several ...[more]

PMID: 33543748

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Project description:BackgroundSeveral studies have demonstrated that synthetic lethal genetic interactions between gene mutations provide an indication of functional redundancy between molecular complexes and pathways. These observations help explain the finding that organisms are able to tolerate single gene deletions for a large majority of genes. For example, system-wide gene knockout/knockdown studies in S. cerevisiae and C. elegans revealed non-viable phenotypes for a mere 18% and 10% of the genome, respectively. It has been postulated that the low percentage of essential genes reflects the extensive amount of genetic buffering that occurs within genomes. Consistent with this hypothesis, systematic double-knockout screens in S. cerevisiae and C. elegans show that, on average, 0.5% of tested gene pairs are synthetic sick or synthetic lethal. While knowledge of synthetic lethal interactions provides valuable insight into molecular functionality, testing all combinations of gene pairs represents a daunting task for molecular biologists, as the combinatorial nature of these relationships imposes a large experimental burden. Still, the task of mapping pairwise interactions between genes is essential to discovering functional relationships between molecular complexes and pathways, as they form the basis of genetic robustness. Towards the goal of alleviating the experimental workload, computational techniques that accurately predict genetic interactions can potentially aid in targeting the most likely candidate interactions. Building on previous studies that analyzed properties of network topology to predict genetic interactions, we apply random walks on biological networks to accurately predict pairwise genetic interactions. Furthermore, we incorporate all published non-interactions into our algorithm for measuring the topological relatedness between two genes. We apply our method to S. cerevisiae and C. elegans datasets and, using a decision tree classifier, integrate diverse biological networks and show that our method outperforms established methods.ResultsBy applying random walks on biological networks, we were able to predict synthetic lethal interactions at a true positive rate of 95 percent against a false positive rate of 10 percent in S. cerevisiae. Similarly, in C. elegans, we achieved a true positive rate of 95 against a false positive rate of 7 percent. Furthermore, we demonstrate that the inclusion of non-interacting gene pairs results in a considerable performance improvement.ConclusionWe presented a method based on random walks that accurately captures aspects of network topology towards the goal of classifying potential genetic interactions as either synthetic lethal or non-interacting. Our method, which is generalizable to all types of biological networks, is likely to perform well with limited information, as estimated by holding out large portions of the synthetic lethal interactions and non-interactions.

Project description:Large-scale network mining and analysis is key to revealing the underlying dynamics of networks, not easily observable before. Lately, there is a fast-growing interest in learning low-dimensional continuous representations of networks that can be utilized to perform highly accurate and scalable graph mining tasks. A family of these methods is based on performing random walks on a network to learn its structural features and providing the sequence of random walks as input to a deep learning architecture to learn a network embedding. While these methods perform well, they can only operate on static networks. However, in real-world, networks are evolving, as nodes and edges are continuously added or deleted. As a result, any previously obtained network representation will now be outdated having an adverse effect on the accuracy of the network mining task at stake. The naive approach to address this problem is to re-apply the embedding method of choice every time there is an update to the network. But this approach has serious drawbacks. First, it is inefficient, because the embedding method itself is computationally expensive. Then, the network mining task outcome obtained by the subsequent network representations are not directly comparable to each other, due to the randomness involved in the new set of random walks involved each time. In this paper, we propose EvoNRL, a random-walk based method for learning representations of evolving networks. The key idea of our approach is to first obtain a set of random walks on the current state of network. Then, while changes occur in the evolving network's topology, to dynamically update the random walks in reserve, so they do not introduce any bias. That way we are in position of utilizing the updated set of random walks to continuously learn accurate mappings from the evolving network to a low-dimension network representation. Moreover, we present an analytical method for determining the right time to obtain a new representation of the evolving network that balances accuracy and time performance. A thorough experimental evaluation is performed that demonstrates the effectiveness of our method against sensible baselines and varying conditions.

Dataset Information

Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer.

Publications

Multi-layered network-based pathway activity inference using directed random walks: application to predicting clinical outcomes in urologic cancer.

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