Identification of pathways associated with chemosensitivity through network embedding.
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 comple...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-03-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC6443184?pdf=render |
| _version_ | 1811306248718516224 |
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| author | Sheng Wang Edward Huang Junmei Cairns Jian Peng Liewei Wang Saurabh Sinha |
| author_facet | Sheng Wang Edward Huang Junmei Cairns Jian Peng Liewei Wang Saurabh Sinha |
| author_sort | Sheng Wang |
| collection | DOAJ |
| description | 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 large-scale 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 a molecular network that encodes known gene-gene as well as gene-pathway relationships, and determines 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 whose basal expression levels in a panel of cell lines 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 and 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 on chemosensitivity pathways and help further study the mechanisms 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. |
| first_indexed | 2024-04-13T08:41:00Z |
| format | Article |
| id | doaj.art-4d3a51362fba4ccbb532e020e5bcd89d |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-13T08:41:00Z |
| publishDate | 2019-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-4d3a51362fba4ccbb532e020e5bcd89d2022-12-22T02:53:53ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582019-03-01153e100686410.1371/journal.pcbi.1006864Identification of pathways associated with chemosensitivity through network embedding.Sheng WangEdward HuangJunmei CairnsJian PengLiewei WangSaurabh SinhaBasal 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 large-scale 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 a molecular network that encodes known gene-gene as well as gene-pathway relationships, and determines 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 whose basal expression levels in a panel of cell lines 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 and 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 on chemosensitivity pathways and help further study the mechanisms 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.http://europepmc.org/articles/PMC6443184?pdf=render |
| spellingShingle | Sheng Wang Edward Huang Junmei Cairns Jian Peng Liewei Wang Saurabh Sinha Identification of pathways associated with chemosensitivity through network embedding. PLoS Computational Biology |
| title | Identification of pathways associated with chemosensitivity through network embedding. |
| title_full | Identification of pathways associated with chemosensitivity through network embedding. |
| title_fullStr | Identification of pathways associated with chemosensitivity through network embedding. |
| title_full_unstemmed | Identification of pathways associated with chemosensitivity through network embedding. |
| title_short | Identification of pathways associated with chemosensitivity through network embedding. |
| title_sort | identification of pathways associated with chemosensitivity through network embedding |
| url | http://europepmc.org/articles/PMC6443184?pdf=render |
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