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GAGE: generally applicable gene set enrichment for pathway analysis.

ABSTRACT: Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs.To address these limitations, we present a new GSA method called Generally Applicable Gene-set Enrichment (GAGE). We successfully apply GAGE to multiple microarray datasets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better results when compared to two other commonly used GSA methods of GSEA and PAGE. We demonstrate this improvement in the following three aspects: (1) consistency across repeated studies/experiments; (2) sensitivity and specificity; (3) biological relevance of the regulatory mechanisms inferred.GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies. From two published lung cancer data sets, GAGE derived a more cohesive and predictive mechanistic scheme underlying lung cancer progress and metastasis. For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT signaling, Wnt signaling, and estrogen signaling pathways-all of which are supported by the experimental literature.GAGE is generally applicable to gene expression datasets with different sample sizes and experimental designs. GAGE consistently outperformed two most frequently used GSA methods and inferred statistically and biologically more relevant regulatory pathways. The GAGE method is implemented in R in the "gage" package, available under the GNU GPL from http://sysbio.engin.umich.edu/~luow/downloads.php.

SUBMITTER: Luo W

PROVIDER: S-EPMC2696452 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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GAGE: generally applicable gene set enrichment for pathway analysis.

Luo Weijun W Friedman Michael S MS Shedden Kerby K Hankenson Kurt D KD Woolf Peter J PJ

BMC bioinformatics 20090527

<h4>Background</h4>Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs.<h4>Results</h4>To address these limitations, we present a new GSA ...[more]

PMID: 19473525

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Project description:BackgroundGene Set Enrichment Analysis (GSEA) is a powerful tool to identify enriched functional categories of informative biomarkers. Canonical GSEA takes one-dimensional feature scores derived from the data of one platform as inputs. Numerous extensions of GSEA handling multimodal OMIC data are proposed, yet none of them explicitly captures combinatorial relations of feature scores from multiple platforms.ResultsWe propose multivariate GSEA (MGSEA) to capture combinatorial relations of gene set enrichment among multiple platform features. MGSEA successfully captures designed feature relations from simulated data. By applying it to the scores of delineating breast cancer and glioblastoma multiforme (GBM) subtypes from The Cancer Genome Atlas (TCGA) datasets of CNV, DNA methylation and mRNA expressions, we find that breast cancer and GBM data yield both similar and distinct outcomes. Among the enriched functional categories, subtype-specific biomarkers are dominated by mRNA expression in many functional categories in both cancer types and also by CNV in many functional categories in breast cancer. The enriched functional categories belonging to distinct combinatorial patterns are involved different oncogenic processes: cell proliferation (such as cell cycle control, estrogen responses, MYC and E2F targets) for mRNA expression in breast cancer, invasion and metastasis (such as cell adhesion and epithelial-mesenchymal transition (EMT)) for CNV in breast cancer, and diverse processes (such as immune and inflammatory responses, cell adhesion, angiogenesis, and EMT) for mRNA expression in GBM. These observations persist in two external datasets (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) for breast cancer and Repository for Molecular Brain Neoplasia Data (REMBRANDT) for GBM) and are consistent with knowledge of cancer subtypes. We further compare the characteristics of MGSEA with several extensions of GSEA and point out the pros and cons of each method.ConclusionsWe demonstrated the utility of MGSEA by inferring the combinatorial relations of multiple platforms for cancer subtype delineation in three multi-OMIC datasets: TCGA, METABRIC and REMBRANDT. The inferred combinatorial patterns are consistent with the current knowledge and also reveal novel insights about cancer subtypes. MGSEA can be further applied to any genotype-phenotype association problems with multimodal OMIC data.

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GAGE: generally applicable gene set enrichment for pathway analysis.

Publications

GAGE: generally applicable gene set enrichment for pathway analysis.

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