[Bioc-devel] A geneSet data class for facilitating GSEA

[Mark W Kimpel]

I'm going to jump in here on the GSEA direction of change issue as a 
molecular biologist. I can think of examples where it would be relevant, 
and important to test for, and examples where it would be totally 
irrelevant.

I am currently involved in research searching for genes involved with 
preference for alcohol. We may want to use a geneSet that consists of 
all the genes known to be directly involved in dopamine transmission in 
the brain. Because these genes may be up or down regulated in some 
unknown pattern because of feedback loops, direction of change would be 
irrelevant. We just want to know if, on average, dopamine related genes 
are differentially expressed. It may be that one receptor subunit is 
up-regulated and another down-regulated, we wouldn't know any of this a 
priori.

On the other hand, suppose we wanted to construct a geneSet with a set 
of genes found significant in a mouse experiment and then see if this 
geneSet was significant in a GSEA analysis of our rats. Although it may 
not be, here the pattern of up/down may be important if pathways are 
similarly different between preferring and non-preferring lines. In this 
situation it would be nice to be able to test with both options, i.e. 
with directionality taken into account and without it.

One way to do this would be for the geneSet object to contain a slot 
(attribute) that indicates whether the geneSet has directional 
information in it or not. Another slot would be a string describing how 
the phenotypes used to construct the geneSet are related to the 
directionality of individual genes (example: "Direction of change is 
with respect to alcohol preferring vs. non-preferring, with +1 
correlating with increased expression in the preferring phenotype and -1 
to decreased expression.").

To make the use of this directionality optional, the GSEA algorithms 
would look at the slot for directional information (TRUE/FALSE). If 
FALSE, the a non-directional test would be applied, if TRUE, then a 
function argument would have to state whether to use directional 
information or not (TRUE/FALSE).

Certainly you developers would have a better handle than I on how to 
implement this, but I thought I would jump in and give an idea of how an 
end-user might use this information.

And sorry if I messed up the thread on this discussion, I get the digest 
of the developer newsgroup.

Mark

-- 
Mark W. Kimpel MD
Neuroinformatics
Department of Psychiatry
Indiana University School of Medicine