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A methodology for the analysis of differential coexpression across the human lifespan.

ABSTRACT: BACKGROUND:Differential coexpression is a change in coexpression between genes that may reflect 'rewiring' of transcriptional networks. It has previously been hypothesized that such changes might be occurring over time in the lifespan of an organism. While both coexpression and differential expression of genes have been previously studied in life stage change or aging, differential coexpression has not. Generalizing differential coexpression analysis to many time points presents a methodological challenge. Here we introduce a method for analyzing changes in coexpression across multiple ordered groups (e.g., over time) and extensively test its validity and usefulness. RESULTS:Our method is based on the use of the Haar basis set to efficiently represent changes in coexpression at multiple time scales, and thus represents a principled and generalizable extension of the idea of differential coexpression to life stage data. We used published microarray studies categorized by age to test the methodology. We validated the methodology by testing our ability to reconstruct Gene Ontology (GO) categories using our measure of differential coexpression and compared this result to using coexpression alone. Our method allows significant improvement in characterizing these groups of genes. Further, we examine the statistical properties of our measure of differential coexpression and establish that the results are significant both statistically and by an improvement in semantic similarity. In addition, we found that our method finds more significant changes in gene relationships compared to several other methods of expressing temporal relationships between genes, such as coexpression over time. CONCLUSION:Differential coexpression over age generates significant and biologically relevant information about the genes producing it. Our Haar basis methodology for determining age-related differential coexpression performs better than other tested methods. The Haar basis set also lends itself to ready interpretation in terms of both evolutionary and physiological mechanisms of aging and can be seen as a natural generalization of two-category differential coexpression. CONTACT:paul@bioinformatics.ubc.ca.

SUBMITTER: Gillis J

PROVIDER: S-EPMC2761903 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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A methodology for the analysis of differential coexpression across the human lifespan.

Gillis Jesse J Pavlidis Paul P

BMC bioinformatics 20090922

<h4>Background</h4>Differential coexpression is a change in coexpression between genes that may reflect 'rewiring' of transcriptional networks. It has previously been hypothesized that such changes might be occurring over time in the lifespan of an organism. While both coexpression and differential expression of genes have been previously studied in life stage change or aging, differential coexpression has not. Generalizing differential coexpression analysis to many time points presents a method ...[more]

PMID: 19772654

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Project description:Analyses of gene set differential coexpression may shed light on molecular mechanisms underlying phenotypes and diseases. However, differential coexpression analyses of conceptually similar individual studies are often inconsistent and underpowered to provide definitive results. Researchers can greatly benefit from an open-source application facilitating the aggregation of evidence of differential coexpression across studies and the estimation of more robust common effects. We developed Meta Gene Set Coexpression Analysis (MetaGSCA), an analytical tool to systematically assess differential coexpression of an a priori defined gene set by aggregating evidence across studies to provide a definitive result. In the kernel, a nonparametric approach that accounts for the gene-gene correlation structure is used to test whether the gene set is differentially coexpressed between two comparative conditions, from which a permutation test p-statistic is computed for each individual study. A meta-analysis is then performed to combine individual study results with one of two options: a random-intercept logistic regression model or the inverse variance method. We demonstrated MetaGSCA in case studies investigating two human diseases and identified pathways highly relevant to each disease across studies. We further applied MetaGSCA in a pan-cancer analysis with hundreds of major cellular pathways in 11 cancer types. The results indicated that a majority of the pathways identified were dysregulated in the pan-cancer scenario, many of which have been previously reported in the cancer literature. Our analysis with randomly generated gene sets showed excellent specificity, indicating that the significant pathways/gene sets identified by MetaGSCA are unlikely false positives. MetaGSCA is a user-friendly tool implemented in both forms of a Web-based application and an R package "MetaGSCA". It enables comprehensive meta-analyses of gene set differential coexpression data, with an optional module of post hoc pathway crosstalk network analysis to identify and visualize pathways having similar coexpression profiles.

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A methodology for the analysis of differential coexpression across the human lifespan.

Publications

A methodology for the analysis of differential coexpression across the human lifespan.

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