GAGE: generally applicable gene set enrichment for pathway analysis.
BACKGROUND
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.


RESULTS
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regulatory mechanisms inferred.GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies.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 For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT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.


CONCLUSIONS
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.
Luo
Weijun
W
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. luo@cshl.edu
Friedman
Michael S
MS
Shedden
Kerby
K
Hankenson
Kurt D
KD
Woolf
Peter J
PJ
D000465:Algorithms; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012984:Software
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6