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Identification of Pathways Associated with Chemosensitivity through Network Embedding

Sheng Wang, Edward Huang, Junmei Cairns, Jian Peng, Liewei Wang, Saurabh Sinha
doi: https://doi.org/10.1101/168450
Sheng Wang
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Edward Huang
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Junmei Cairns
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Jian Peng
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Liewei Wang
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Saurabh Sinha
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ABSTRACT

Basal gene expression levels have been shown to be predictive of cellular response to cytotoxic treatments. However, such analyses do not fully reveal complex genotype-phenotype relationships, which are partly encoded in highly interconnected molecular networks. Biological pathways provide a complementary way of understanding drug response variation among individuals. In this study, we integrate chemosensitivity data from a recent pharmacogenomics study with basal gene expression data from the CCLE project and prior knowledge of molecular networks to identify specific pathways mediating chemical response. We first develop a computational method called PACER, which ranks pathways for enrichment in a given set of genes using a novel network embedding method. It examines known relationships among genes as encoded in a molecular network along with gene memberships of all pathways to determine a vector representation of each gene and pathway in the same low-dimensional vector space. The relevance of a pathway to the given gene set is then captured by the similarity between the pathway vector and gene vectors. To apply this approach to chemosensitivity data, we identify genes with basal expression levels in a panel of cell lines that are correlated with cytotoxic response to a compound, and then rank pathways for relevance to these response-correlated genes using PACER. Extensive evaluation of this approach on benchmarks constructed from databases of compound target genes, compound chemical structure, as well as large collections of drug response signatures demonstrates its advantages in identifying compound-pathway associations, compared to existing statistical methods of pathway enrichment analysis. The associations identified by PACER can serve as testable hypotheses about chemosensitivity pathways and help further study the mechanism of action of specific cytotoxic drugs. More broadly, PACER represents a novel technique of identifying enriched properties of any gene set of interest while also taking into account networks of known gene-gene relationships and interactions.

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  • Conflict of interest: none.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 25, 2017.
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Identification of Pathways Associated with Chemosensitivity through Network Embedding
Sheng Wang, Edward Huang, Junmei Cairns, Jian Peng, Liewei Wang, Saurabh Sinha
bioRxiv 168450; doi: https://doi.org/10.1101/168450
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Identification of Pathways Associated with Chemosensitivity through Network Embedding
Sheng Wang, Edward Huang, Junmei Cairns, Jian Peng, Liewei Wang, Saurabh Sinha
bioRxiv 168450; doi: https://doi.org/10.1101/168450

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