Forum: "Separate enrichment analysis of pathways for up- and downregulated genes"
2
gravatar for Woa
2.8 years ago by
Woa2.5k
United States
Woa2.5k wrote:

I recently came across this paper. I wish to know if anybody already following this method or not.

Separate enrichment analysis of pathways for up- and downregulated genes
Guini Hong, Wenjing Zhang, Hongdong Li, Xiaopei Shen and Zheng Guo
J. R. Soc. Interface 6 March 2014 vol. 11 no. 92

http://rsif.royalsocietypublishing.org/content/11/92/20130950.short?rss=1

Abstract:

"Two strategies are often adopted for enrichment analysis of pathways: the analysis of all differentially expressed (DE) genes together or the analysis of up- and downregulated genes separately. However, few studies have examined the rationales of these enrichment analysis strategies. Using both microarray and RNA-seq data, we show that gene pairs with functional links in pathways tended to have positively correlated expression levels, which could result in an imbalance between the up- and downregulated genes in particular pathways. We then show that the imbalance could greatly reduce the statistical power for finding disease-associated pathways through the analysis of all-DE genes. Further, using gene expression profiles from five types of tumours, we illustrate that the separate analysis of up- and downregulated genes could identify more pathways that are really pertinent to phenotypic difference. In conclusion, analysing up- and downregulated genes separately is more powerful than analysing all of the DE genes together."

forum enrichmnet analysis • 1.9k views
ADD COMMENTlink modified 2.8 years ago by Charles Warden4.6k • written 2.8 years ago by Woa2.5k
2
gravatar for mikhail.shugay
2.8 years ago by
mikhail.shugay3.1k
Czech Republic, Brno, CEITEC
mikhail.shugay3.1k wrote:

Interesting, but it's behind the paywall. Hope they've shown that while increasing statistical power thay don't increase false-positive rate. Otherwise seems to be the same as to state "two-tailed P-values tend to be higher than one-tailed" :))

ADD COMMENTlink written 2.8 years ago by mikhail.shugay3.1k
1

PS. There is of course a vast field for debates. For example consider JAK2/STAT5 pathway, known to be involved in ocogenesis. There are both "positive" regulators of pathway activity, like EPOR/JAK2/STAT5 and "negative" ones like SOCS/PIAS genes. So if up-regulated gene group contains "positive" regulators and down-regulated one contains "negative" regulators the pathway is generally regulated. Of course on general basis you usually cluster genes with similar expression profiles and annotate these clusters, but it could be sometimes more wise to take into account positive/negative interactions between genes..

ADD REPLYlink written 2.8 years ago by mikhail.shugay3.1k

or another interpretation could be that by splitting the data they end up making fewer comparisons, thus the correction for multiple testing is smaller.

ADD REPLYlink written 2.8 years ago by Istvan Albert ♦♦ 69k
2
gravatar for Charles Warden
2.8 years ago by
Charles Warden4.6k
Duarte, CA
Charles Warden4.6k wrote:

I always analyze up- and down-regulated gene lists separately: I think that makes the interpretation easier.

That said, there can still be mixed results.  For example, the KEGG Wnt pathway includes both agonists and antagonists, and I did have one circumstance where this was an issue.  This is why I developed BD-Func.

https://peerj.com/articles/159/

However, I admittedly think standard analysis of the up- and down-regulated genes is typically OK.

ADD COMMENTlink modified 2.8 years ago • written 2.8 years ago by Charles Warden4.6k
1
gravatar for Irsan
2.8 years ago by
Irsan6.1k
Amsterdam
Irsan6.1k wrote:
Like many others, I always make a heatmap of the expression estimates of all differentially expressed genes arranged by hierarchical clustering. Then I perform ontology analyses on correlated sets of genes.
ADD COMMENTlink modified 2.8 years ago • written 2.8 years ago by Irsan6.1k
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