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Bioinformatics Advance Access originally published online on March 28, 2007
Bioinformatics 2007 23(11):1356-1362; doi:10.1093/bioinformatics/btm116
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Extending the pathway analysis framework with a test for transcriptional variance implicates novel pathway modulation during myogenic differentiation

Daniel M. Kemp 1, N. R. Nirmala 2 and Joseph D. Szustakowski 2,*

1Diabetes and Metabolism Disease Area and 2Genome and Proteome Sciences, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA

*To whom correspondence should be addressed.


  Abstract

Motivation: We describe an extension of the pathway-based enrichment approach for analyzing microarray data via a robust test for transcriptional variance. The use of a variance test is intended to identify additional patterns of transcriptional regulation in which many genes in a pathway are up- and down-regulated. Such patterns may be indicative of the reciprocal regulation of pathway activators and inhibitors or of the differential regulation of separate biological sub-processes and should extend the number of detectable patterns of transcriptional modulation.

Results: We validated this new statistical approach on a microarray experiment that captures the temporal transcriptional profile of muscle differentiation in mouse C2C12 cells. Comparisons of the transcriptional state of myoblasts and differentiated myotubes via a robust variance test implicated several novel pathways in muscle cell differentiation previously overlooked by a standard enrichment analysis. Specifically, pathways involved in cell structure, calcium-mediated signaling and muscle-specific signaling were identified as differentially modulated based on their increased transcriptional variance. These biologically relevant results validate this approach and demonstrate the flexible nature of pathway-based methods of data analysis.

Availability: The software is available as Supplementary Material.

Contact: joseph.szustakowski{at}novartis.com

Supplementary information: Supplementary data are available at Bioinformatics online.

Associate Editor: Martin Bishop

Received on October 30, 2006; revised on March 7, 2007; accepted on March 16, 2007

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