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Use of Data-Biased Random Walks on Graphs for the Retrieval of Context-Specific Networks from Genomic Data

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  • Kakajan Komurov
  • Michael A White
  • Prahlad T Ram

Abstract

Extracting network-based functional relationships within genomic datasets is an important challenge in the computational analysis of large-scale data. Although many methods, both public and commercial, have been developed, the problem of identifying networks of interactions that are most relevant to the given input data still remains an open issue. Here, we have leveraged the method of random walks on graphs as a powerful platform for scoring network components based on simultaneous assessment of the experimental data as well as local network connectivity. Using this method, NetWalk, we can calculate distribution of Edge Flux values associated with each interaction in the network, which reflects the relevance of interactions based on the experimental data. We show that network-based analyses of genomic data are simpler and more accurate using NetWalk than with some of the currently employed methods. We also present NetWalk analysis of microarray gene expression data from MCF7 cells exposed to different doses of doxorubicin, which reveals a switch-like pattern in the p53 regulated network in cell cycle arrest and apoptosis. Our analyses demonstrate the use of NetWalk as a valuable tool in generating high-confidence hypotheses from high-content genomic data.Author Summary: Analysis of high-content genomic data within the context of known networks of interactions of genes can lead to a better understanding of the underlying biological processes. However, finding the networks of interactions that are most relevant to the given data is a challenging task. We present a random walk-based algorithm, NetWalk, which integrates genomic data with networks of interactions between genes to score the relevance of each interaction based on both the data values of the genes as well as their local network connectivity. This results in a distribution of Edge Flux values, which can be used for dynamic reconstruction of user-defined networks. Edge Flux values can be further subjected to statistical analyses such as clustering, allowing for direct numerical comparisons of context-specific networks between different conditions. To test NetWalk performance, we carried out microarray gene expression analysis of MCF7 cells subjected to lethal and sublethal doses of a DNA damaging agent. We compared NetWalk to other network-based analysis methods and found that NetWalk was superior in identifying coherently altered sub-networks from the genomic data. Using NetWalk, we further identified p53-regulated networks that are differentially involved in cell cycle arrest and apoptosis, which we experimentally tested.

Suggested Citation

  • Kakajan Komurov & Michael A White & Prahlad T Ram, 2010. "Use of Data-Biased Random Walks on Graphs for the Retrieval of Context-Specific Networks from Genomic Data," PLOS Computational Biology, Public Library of Science, vol. 6(8), pages 1-10, August.
  • Handle: RePEc:plo:pcbi00:1000889
    DOI: 10.1371/journal.pcbi.1000889
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    1. Franz-Josef Müller & Louise C. Laurent & Dennis Kostka & Igor Ulitsky & Roy Williams & Christina Lu & In-Hyun Park & Mahendra S. Rao & Ron Shamir & Philip H. Schwartz & Nils O. Schmidt & Jeanne F. Lor, 2008. "Regulatory networks define phenotypic classes of human stem cell lines," Nature, Nature, vol. 455(7211), pages 401-405, September.
    2. Steve E. Calvano & Wenzhong Xiao & Daniel R. Richards & Ramon M. Felciano & Henry V. Baker & Raymond J. Cho & Richard O. Chen & Bernard H. Brownstein & J. Perren Cobb & S. Kevin Tschoeke & Carol Mille, 2005. "A network-based analysis of systemic inflammation in humans," Nature, Nature, vol. 437(7061), pages 1032-1037, October.
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    1. Elisa Salviato & Vera Djordjilović & Monica Chiogna & Chiara Romualdi, 2019. "SourceSet: A graphical model approach to identify primary genes in perturbed biological pathways," PLOS Computational Biology, Public Library of Science, vol. 15(10), pages 1-28, October.
    2. Aurélien Naldi & Romain M Larive & Urszula Czerwinska & Serge Urbach & Philippe Montcourrier & Christian Roy & Jérôme Solassol & Gilles Freiss & Peter J Coopman & Ovidiu Radulescu, 2017. "Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells," PLOS Computational Biology, Public Library of Science, vol. 13(3), pages 1-27, March.

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