title: Network and data integration for biomarker signature discovery via network smoothed T-statistics.
abstract: Predictive, stable and interpretable gene signatures are generally seen as an important step towards a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinics is the typical low reproducibility of signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. We here propose a technique that integrates network information as well as different kinds of experimental data (here exemplified by mRNA and miRNA expression) into one classifier. This is done by smoothing t-statistics of individual genes or miRNAs over the structure of a combined protein-protein interaction (PPI) and miRNA-target gene network. A permutation test is conducted to select features in a highly consistent manner, and subsequently a Support Vector Machine (SVM) classifier is trained. Compared to several other competing methods our algorithm reveals an overall better prediction performance for early versus late disease relapse and a higher signature stability. Moreover, obtained gene lists can be clearly associated to biological knowledge, such as known disease genes and KEGG pathways. We demonstrate that our data integration strategy can improve classification performance compared to using a single data source only. Our method, called stSVM, is available in R-package netClass on CRAN (http://cran.r-project.org).
authors.affiliation: Algorithmic Bioinformatics, Bonn-Aachen International Center for IT, Bonn, Germany.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Cun
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D003627:Data Interpretation, Statistical
chemical_list: D015415:Biomarkers
references.citation: Br J Cancer. 1998 May;77(9):1460-8
references.pmid: 9652762
references.citation: Prostate. 2009 Jul 1;69(10):1119-27
references.pmid: 19343730
references.citation: Nature. 2011 Jun 29;474(7353):609-15
references.pmid: 21720365
references.citation: Br J Cancer. 2010 Aug 10;103(4):532-41
references.pmid: 20664596
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8
references.pmid: 17991681
references.citation: Biology (Basel). 2012 Feb 27;1(1):5-17
references.pmid: 24832044
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6567-72
references.pmid: 12011421
references.citation: Cancer Res. 2008 Jul 1;68(13):5405-13
references.pmid: 18593943
references.citation: BMC Bioinformatics. 2009 Oct 08;10 Suppl 11:S19
references.pmid: 19811684
references.citation: Cancer Cell Int. 2008 Mar 18;8:3
references.pmid: 18348720
references.citation: BJU Int. 2006 Oct;98(4):719-21
references.pmid: 16978263
references.citation: BMC Bioinformatics. 2005 Mar 17;6:58
references.pmid: 15774002
references.citation: Bioinformatics. 2010 Sep 1;26(17):2136-44
references.pmid: 20591905
references.citation: BMC Genomics. 2009 Jul 07;10 Suppl 1:S6
references.pmid: 19594883
references.citation: Cancer Cell. 2010 Jul 13;18(1):11-22
references.pmid: 20579941
references.citation: PLoS Comput Biol. 2008 Nov;4(11):e1000217
references.pmid: 18989396
references.citation: Cancer Lett. 1999 Aug 3;142(2):207-17
references.pmid: 10463778
references.citation: BMC Bioinformatics. 2005 Sep 21;6:233
references.pmid: 16176585
references.citation: BMC Bioinformatics. 2009 Feb 19;10:62
references.pmid: 19228411
references.citation: Nat Med. 2011 Oct 30;17(11):1498-503
references.pmid: 22037646
references.citation: Nat Rev Genet. 2012 Jul 03;13(8):523-36
references.pmid: 22751426
references.citation: Mol Pain. 2011 Oct 20;7:81
references.pmid: 22014040
references.citation: PLoS One. 2012;7(4):e34796
references.pmid: 22558100
references.citation: Nature. 2010 Apr 15;464(7291):993-8
references.pmid: 20393554
references.citation: Bioinformatics. 2009 Jun 1;25(11):1470-1
references.pmid: 19307239
references.citation: IEEE Trans Inf Technol Biomed. 2011 Jan;15(1):155-63
references.pmid: 20813648
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D685-90
references.pmid: 21071392
references.citation: Cancer Biol Ther. 2004 Jan;3(1):36-41
references.pmid: 14739782
references.citation: Bioinformatics. 2007 Jul 1;23(13):i125-32
references.pmid: 17646288
references.citation: Bioinformatics. 2005 Oct 15;21(20):3940-1
references.pmid: 16096348
references.citation: Genome Biol. 2011 Aug 16;12(8):R77
references.pmid: 21846369
references.citation: Br J Cancer. 1996 Nov;74(10):1592-7
references.pmid: 8932340
references.citation: Int J Cancer. 1999 Jan 18;80(2):250-6
references.pmid: 9935207
references.citation: PLoS One. 2012;7(11):e49634
references.pmid: 23185389
references.citation: BMC Bioinformatics. 2007 Feb 01;8:35
references.pmid: 17270037
references.citation: Leukemia. 2010 Mar;24(3):629-37
references.pmid: 20054351
references.citation: Cancer Res. 2010 Apr 15;70(8):3136-9
references.pmid: 20388772
references.citation: Mol Syst Biol. 2007;3:140
references.pmid: 17940530
references.citation: Bioinformatics. 2004 Jan 1;20(1):93-9
references.pmid: 14693814
references.citation: Nat Biotechnol. 2009 Feb;27(2):199-204
references.pmid: 19182785
references.citation: Gastrointest Cancer Res. 2009 Mar;3(2 Suppl):S19-21
references.pmid: 19461917
references.citation: J Clin Invest. 2008 Sep;118(9):3051-64
references.pmid: 18725989
references.citation: Bioinformatics. 2006 Apr 15;22(8):943-9
references.pmid: 16473874
references.citation: Br J Cancer. 1999 Oct;81(3):503-9
references.pmid: 10507777
references.citation: Prostate Cancer Prostatic Dis. 2005;8(2):119-26
references.pmid: 15809669
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):191-9
references.pmid: 20369376
references.citation: J Clin Pathol. 1998 Nov;51(11):818-24
references.pmid: 10193322
references.citation: PLoS Comput Biol. 2012;8(5):e1002511
references.pmid: 22615549
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
references.pmid: 18077471
references.citation: Genes Dev. 2011 Mar 15;25(6):534-55
references.pmid: 21406553
references.citation: Oncol Rep. 2004 Jan;11(1):219-24
references.pmid: 14654929
references.citation: BMC Bioinformatics. 2009 Jan 13;10:18
references.pmid: 19144132
references.citation: BMC Bioinformatics. 2012 May 01;13:69
references.pmid: 22548963
references.citation: Bioinformatics. 2011 May 15;27(10):1442-3
references.pmid: 21450711
references.citation: BMC Bioinformatics. 2011 Dec 21;12:488
references.pmid: 22188670
references.citation: J Clin Oncol. 2012 Feb 20;30(6):647-60
references.pmid: 22271477
references.citation: Eur J Hum Genet. 1999 Apr;7(3):357-62
references.pmid: 10234512
references.citation: BMC Bioinformatics. 2009 Jan 30;10 Suppl 1:S21
references.pmid: 19208121
references.citation: Nat Genet. 2012 May 20;44(6):685-9
references.pmid: 22610119
references.citation: Bioinformatics. 2007 Oct 1;23(19):2507-17
references.pmid: 17720704