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Benefits and Challenges of Pre-clustered Network-Based Pathway Analysis
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0002-4665-6537
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0003-2245-7557
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0002-9015-5588
Number of Authors: 32022 (English)In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 13, article id 855766Article in journal (Refereed) Published
Abstract [en]

Functional analysis of gene sets derived from experiments is typically done by pathway annotation. Although many algorithms exist for analyzing the association between a gene set and a pathway, an issue which is generally ignored is that gene sets often represent multiple pathways. In such cases an association to a pathway is weakened by the presence of genes associated with other pathways. A way to counteract this is to cluster the gene set into more homogenous parts before performing pathway analysis on each module. We explored whether network-based pre-clustering of a query gene set can improve pathway analysis. The methods MCL, Infomap, and MGclus were used to cluster the gene set projected onto the FunCoup network. We characterized how well these methods are able to detect individual pathways in multi-pathway gene sets, and applied each of the clustering methods in combination with four pathway analysis methods: Gene Enrichment Analysis, BinoX, NEAT, and ANUBIX. Using benchmarks constructed from the KEGG pathway database we found that clustering can be beneficial by increasing the sensitivity of pathway analysis methods and by providing deeper insights of biological mechanisms related to the phenotype under study. However, keeping a high specificity is a challenge. For ANUBIX, clustering caused a minor loss of specificity, while for BinoX and NEAT it caused an unacceptable loss of specificity. GEA had very low sensitivity both before and after clustering. The choice of clustering method only had a minor effect on the results. We show examples of this approach and conclude that clustering can improve overall pathway annotation performance, but should only be used if the used enrichment method has a low false positive rate.

Place, publisher, year, edition, pages
2022. Vol. 13, article id 855766
Keywords [en]
functional association networks, network clustering, biological mechanisms, pathway enrichment analysis, sensitivity increase
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-207111DOI: 10.3389/fgene.2022.855766ISI: 000802261100001PubMedID: 35620466OAI: oai:DiVA.org:su-207111DiVA, id: diva2:1681387
Available from: 2022-07-06 Created: 2022-07-06 Last updated: 2023-02-23Bibliographically approved

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Castresana-Aguirre, MiguelGuala, DimitriSonnhammer, Erik L. L.

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