title: A scan statistic to extract causal gene clusters from case-control genome-wide rare CNV data.
abstract: BACKGROUND
  Several statistical tests have been developed for analyzing genome-wide association data by incorporating gene pathway information in terms of gene sets. Using these methods, hundreds of gene sets are typically tested, and the tested gene sets often overlap. This overlapping greatly increases the probability of generating false positives, and the results obtained are difficult to interpret, particularly when many gene sets show statistical significance.
  
  
  RESULTS
  We propose a flexible statistical framework to circumvent these problems. Inspired by spatial scan statistics for detecting clustering of disease occurrence in the field of epidemiology, we developed a scan statistic to extract disease-associated gene clusters from a whole gene pathway. Extracting one or a few significant gene clusters from a global pathway limits the overall false positive probability, which results in increased statistical power, and facilitates the interpretation of test results. In the present study, we applied our method to genome-wide association data for rare copy-number variations, which have been strongly implicated in common diseases. Application of our method to a simulated dataset demonstrated the high accuracy of this method in detecting disease-associated gene clusters in a whole gene pathway.
  
  
  CONCLUSIONS
  The scan statistic approach proposed here shows a high level of accuracy in detecting gene clusters in a whole gene pathway. This study has provided a sound statistical framework for analyzing genome-wide rare CNV data by incorporating topological information on the gene pathway.
authors: National Institute of Public Health, Wako, Saitama 351-0197, Japan. nishiyama@minos.ocn.ne.jp
authors: Takeshi
authors: T
authors: Nishiyama
authors: Kunihiko
authors: K
authors: Takahashi
authors: Toshiro
authors: T
authors: Tango
authors: Dalila
authors: D
authors: Pinto
authors: Stephen W
authors: SW
authors: Scherer
authors: Satoshi
authors: S
authors: Takami
authors: Hirohisa
authors: H
authors: Kishino
references: Am J Hum Genet. 2008 Sep;83(3):311-21
references: 18691683
references: Am J Hum Genet. 2010 Jun 11;86(6):832-8
references: 20471002
references: Am J Hum Genet. 2010 Nov 12;87(5):604-17
references: 21070896
references: Am J Hum Genet. 2006 Jun;78(6):1011-25
references: 16685651
references: Int J Health Geogr. 2008 Apr 11;7:14
references: 18402711
references: Science. 2008 Apr 25;320(5875):539-43
references: 18369103
references: PLoS Genet. 2009 Feb;5(2):e1000384
references: 19214210
references: Expert Rev Proteomics. 2010 Feb;7(1):55-63
references: 20121476
references: Nature. 2010 Jul 15;466(7304):368-72
references: 20531469
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Genomics. 2001 Sep;77(1-2):105-13
references: 11543639
references: Nat Genet. 2005 Apr;37(4):333-4
references: 15800641
references: N Engl J Med. 2008 Feb 14;358(7):667-75
references: 18184952
references: Annu Rev Public Health. 2007;28:235-58
references: 17367287
references: Nature. 2008 Sep 11;455(7210):232-6
references: 18668039
references: Hum Mol Genet. 2008 Feb 15;17(4):628-38
references: 18156158
references: Science. 2007 Apr 20;316(5823):445-9
references: 17363630
references: Nature. 2010 Apr 1;464(7289):713-20
references: 20360734
references: Nature. 2008 Sep 11;455(7210):237-41
references: 18668038
references: Annu Rev Med. 2010;61:437-55
references: 20059347
references: PLoS Genet. 2009 Jun;5(6):e1000536
references: 19557195
references: Hum Mol Genet. 2005 Feb 15;14(4):483-92
references: 15615769
references: Nature. 2009 May 28;459(7246):569-73
references: 19404257
references: Nature. 2010 Apr 1;464(7289):704-12
references: 19812545
references: Curr Opin Genet Dev. 2007 Jun;17(3):182-92
references: 17467974
references: Nat Genet. 2007 Jul;39(7 Suppl):S43-7
references: 17597781
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D685-90
references: 21071392
references: Genet Epidemiol. 2010 Feb;34(2):188-93
references: 19810025
references: Int J Health Geogr. 2005 May 18;4:11
references: 15904524
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
references: 18077471
references: Neuron. 2005 Sep 1;47(5):629-32
references: 16129392
references: Bioinformatics. 2007 Oct 1;23(19):2581-8
references: 17785348
references: Bioinformatics. 2005 Jan 1;21(1):135-6
references: 15297301
references: Nature. 2009 Oct 8;461(7265):747-53
references: 19812666
references: Nat Rev Genet. 2010 Jun;11(6):415-25
references: 20479773
references: Lancet. 2006 Jul 15;368(9531):210-5
references: 16844490
references: PLoS Genet. 2009 Feb;5(2):e1000373
references: 19197363