Table 1.

Computational tools for performing functional enrichment analysis using omics datasets.

Tool	Yeara	Description and last updateb	No. of citationsc	Type of omics		References/URLd
				RNA	Protein
DAVID	2003	Free webserver that performs enrichment analysis using various databases (including Biocarta, KEGG, Reactome, GO) based on a modified Fisher's exact test. Last update: 2018	15,954	√	√	Huang da et al., 2009a http://david.ncifcrf.gov/
GSEA	2005	Free multi-platform software. Performs rank-based enrichment using annotated gene sets from MSigDB or custom annotations. Calculates an enrichment score based on weighted Kolmogorov-Smirnov-like statistics. Last update (MSigDB): 2017	13,892	√	√	Subramanian et al., 2005
Ingenuity Pathway Analysis (IPA)	2004*	A paid alternative that combines various analyses tools including functional enrichment (of diseases and biological functions), that is performed based on Fisher's exact test using a manually curated ontology and a continuously updated knowledgebase	1,767$	√	√	http://www.ingenuity.com
Panther	2003	Allows the performance of binomial and Fisher's exact test using information from GO, Panther pathways and Reactome	1,732	√	√	Thomas et al., 2003; Mi et al., 2013 http://pantherdb.org
ClueGO	2009	A plugin for Cytoscape that performs enrichment analysis using Gene Ontology, Reactome, and KEGG, also creating network-based visualizations of gene functions. Supports many organisms, and others can be added upon request. Performs enrichment analysis based on the hypergeometric distribution. The most recent database annotations can be retrieved automatically	1,338	√	√	Bindea et al., 2009 http://apps.cytoscape.org/apps/cluego
WebGestalt	2005	Free webserver supporting 12 model organisms including human and mouse, and performs both list- (Fisher's exact test) and rank-based enrichment of various databases including GO, KEGG, Reactome, Panther, and WikiPathways. Last update: 2017	1,265	√	√	Zhang et al., 2005; Wang et al., 2017 http://www.webgestalt.org
Reactome	2005	Offers a module for enrichment analysis based on a hypergeometric test using curated information from the Reactome Knowledgebase	1,124	√	√	Joshi-Tope et al., 2005; Fabregat et al., 2018; http://www.reactome.org
Enrichr	2013	Free webserver that performs enrichment analysis of >40 databases taking as input a list of mammalian genes. Allows various types of visualizations and programmatic access via API. Employs a modified Fisher's exact test to perform enrichment analysis	736	√	√	Chen et al., 2013; Kuleshov et al., 2016 http://amp.pharm.mssm.edu/Enrichr
g:Profiler	2007	Free webserver supporting >200 organisms and performing both list- and rank-based enrichment (hypergeometric distribution-based) of various databases including GO, KEGG, Reactome, BioGRID (protein-protein interaction), OMIM, TRANSFAC (regulatory), and Human Protein Atlas. Updated quarterly following Ensembl's releases	447	√	√	Reimand et al., 2007 https://biit.cs.ut.ee/gprofiler/
GAGE	2009	A methodological framework that uses a two-sample t-test to test whether a specific gene-set is enriched relative to a background set	379	√	√	Luo et al., 2009
ConsensusPathDB	2009	Free webserver integrating information from 32 human-related biological databases and allowing enrichment analysis using a hypergeometric distribution. Supports only human identifiers (from UniProt, HGNC, Ensembl, Entrez or RefSeq). Last update: 2018 for most databases	240	√	√	Kamburov et al., 2009
ROAST	2010	R function within the limma package that performs individual gene set testing based on multivariate regression. The user should select pathways of interest based on a priori knowledge. RNA-seq data should be processed using the voom/limma pipeline to use the package	208	√		Wu et al., 2010

^aYear of original publication.

^bDate of last update relevant only to tools that rely on embedded or external databases.

^cNumber of citations of the original publication retrieved from Google Scholar, current as of May 2018.

^dIf more than one, the original work and the most recent update are cited.

^$Based on PubMed all-time search using “Ingenuity Pathway Analysis” as a query.

^*Based on PubMed searches for the first usage of the tool published in the literature.