title: CSAX: Characterizing Systematic Anomalies in eXpression Data.
abstract: Methods for translating gene expression signatures into clinically relevant information have typically relied upon having many samples from patients with similar molecular phenotypes. Here, we address the question of what can be done when it is relatively easy to obtain healthy patient samples, but when abnormalities corresponding to disease states may be rare and one-of-a-kind. The associated computational challenge, anomaly detection, is a well-studied machine-learning problem. However, due to the dimensionality and variability of expression data, existing methods based on feature space analysis or individual anomalously expressed genes are insufficient. We present a novel approach, CSAX, that identifies pathways in an individual sample in which the normal expression relationships are disrupted. To evaluate our approach, we have compiled and released a compendium of public expression data sets, reformulated to create a test bed for anomaly detection. We demonstrate the accuracy of CSAX on the data sets in our compendium, compare it to other leading methods, and show that CSAX aids in both identifying anomalies and explaining their underlying biology. We describe an approach to characterizing the difficulty of specific expression anomaly detection tasks. We then illustrate CSAX's value in two developmental case studies. Confirming prior hypotheses, CSAX highlights disruption of platelet activation pathways in a neonate with retinopathy of prematurity and identifies, for the first time, dysregulated oxidative stress response in second trimester amniotic fluid of fetuses with obese mothers. Our approach provides an important step toward identification of individual disease patterns in the era of precision medicine.
authors: 1 AncestryDNA , San Francisco, California.
authors: Keith
authors: K
authors: Noto
authors: Saeed
authors: S
authors: Majidi
authors: Andrea G
authors: AG
authors: Edlow
authors: Heather C
authors: HC
authors: Wick
authors: Diana W
authors: DW
authors: Bianchi
authors: Donna K
authors: DK
authors: Slonim
mesh_terms: D000328:Adult; D000465:Algorithms; D000653:Amniotic Fluid / Q000737:chemistry; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D030541:Databases, Genetic; D066264:Datasets as Topic; D005260:Female; D005333:Fetus; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D009765:Obesity / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D015539:Platelet Activation / Q000235:genetics; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D012178:Retinopathy of Prematurity / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012984:Software; D059467:Transcriptome
keywords: anomaly detection; expression analysis; gene sets; maternal obesity; retinopathy of prematurity
references: BMC Genomics. 2006 Oct 30;7:278
references: 17074082
references: Physiol Genomics. 2007 Dec 19;32(1):154-9
references: 17925482
references: Int J Dev Neurosci. 2009 Nov;27(7):627-33
references: 19695321
references: Am J Med Genet A. 2006 Aug 15;140(16):1749-56
references: 16835915
references: Nutr Neurosci. 2013 May;16(3):96-103
references: 23006985
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Glia. 2006 Nov 15;54(7):666-675
references: 17006895
references: Bioinformatics. 2005 Feb 15;21(4):464-70
references: 15374867
references: J Neurosci. 2008 Oct 8;28(41):10330-8
references: 18842892
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D559-64
references: 22102568
references: J Nutr Biochem. 2014 Feb;25(2):227-31
references: 24445048
references: J Biopharm Stat. 2010 Mar;20(2):193-208
references: 20309754
references: Neurosci Lett. 2009 May 22;455(3):183-6
references: 19429117
references: J Neurochem. 1999 Oct;73(4):1615-25
references: 10501208
references: Hum Genet. 2011 Mar;129(3):295-305
references: 21152935
references: Hum Genet. 2014 Sep;133(9):1075-82
references: 24850140
references: J Cell Biol. 2009 Dec 28;187(7):1101-16
references: 20038681
references: Am J Med Genet Suppl. 1990;7:91-7
references: 2149983
references: BMC Genomics. 2009 Dec 03;10 Suppl 3:S26
references: 19958490
references: Bioinformatics. 2009 Sep 1;25(17):2222-8
references: 19549629
references: PLoS One. 2011 Feb 18;6(2):e17259
references: 21365010
references: Comp Funct Genomics. 2001;2(1):28-34
references: 18628896
references: Data Min Knowl Discov. 2012;25(1):109-133
references: 22639542
references: BMC Bioinformatics. 2014 Feb 07;15:45
references: 24507166
references: J AAPOS. 2011 Feb 1;15(1):e3-e4
references: 22025899
references: PLoS One. 2014 Feb 18;9(2):e88661
references: 24558408
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D691-7
references: 21067998
references: Neural Comput. 2000 May;12(5):1207-45
references: 10905814
references: Obstet Gynecol. 1984 Mar;63(3 Suppl):84S-85S
references: 6700888
references: Clin Breast Cancer. 2011 Mar;11(1):20-6
references: 21421518
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9425-9
references: 19474297
references: J Neurosci. 2004 May 5;24(18):4412-20
references: 15128855
references: Cancer Res. 2010 Jun 15;70(12):4789-94
references: 20501843
references: Nat Genet. 2003 Jul;34(3):267-73
references: 12808457
references: J Neurochem. 2011 Jun;117(6):949-60
references: 21463325
references: Obstet Gynecol. 2012 Jan;119(1):111-8
references: 22183218
references: Proc IEEE Int Conf Data Min. 2010 Dec 13;:953-958
references: 22020249
references: Cancer Inform. 2011 Apr 18;10:109-20
references: 21584264
references: EMBO Rep. 2007 Dec;8(12):1162-9
references: 17975556
references: PLoS One. 2013 Oct 23;8(10):e78585
references: 24194948
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Biol Reprod. 2014 Jun;90(6):129
references: 24759787
references: Prenat Diagn. 2013 Sep;33(9):873-83
references: 23640821
references: Pediatrics. 1990 May;85(5):753-9
references: 2330236
references: Science. 2005 Oct 28;310(5748):644-8
references: 16254181
references: Retina. 2010 Apr;30(4 Suppl):S20-3
references: 20224477
references: Genome Res. 1996 Jul;6(7):639-45
references: 8796352
references: Nat Genet. 2002 Dec;32 Suppl:502-8
references: 12454645
references: Nat Biotechnol. 1996 Dec;14(13):1675-80
references: 9634850
references: Bioinformatics. 2005 Apr 15;21(8):1572-8
references: 15615693
references: Ann N Y Acad Sci. 2000 Jun;908:244-54
references: 10911963
references: Invest Ophthalmol Vis Sci. 2013 Feb 28;54(2):1527-35
references: 23361511