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Journal of Computational Biology
Multiple Testing Methods For ChIP–Chip High Density Oligonucleotide Array Data
To cite this article:
Sündüz Keleş, Mark J. Van Der Laan, Sandrine Dudoit, Simon E. Cawley.
Journal of Computational Biology.
April 2006,
13(3): 579-613.
doi:10.1089/cmb.2006.13.579.
Published in Volume: 13 Issue 3: May 17, 2006
Sündüz Keleş Departments of Statistics and Biostatistics and Medical Informatics, University of Wisconsin, Madison, Madison, WI 53706. Mark J. Van Der Laan Division of Biostatistics, University of California, Berkeley, CA 94720-7360. Sandrine Dudoit Division of Biostatistics, University of California, Berkeley, CA 94720-7360. Simon E. Cawley Affymetrix, 3380 Central Expressway, Santa Clara, CA 95051. Cawley et al. (2004) have recently mapped the locations of binding sites for three transcription factors along human chromosomes 21 and 22 using ChIP–Chip experiments. ChIP–Chip experiments are a new approach to the genomewide identification of transcription factor binding sites and consist of chromatin (Ch) immunoprecipitation (IP) of transcription factorbound genomic DNA followed by high density oligonucleotide hybridization (Chip) of the IP-enriched DNA. We investigate the ChIP–Chip data structure and propose methods for inferring the location of transcription factor binding sites from these data. The proposed methods involve testing for each probe whether it is part of a bound sequence using a scan statistic that takes into account the spatial structure of the data. Different multiple testing procedures are considered for controlling the familywise error rate and false discovery rate. A nested-Bonferroni adjustment, which is more powerful than the traditional Bonferroni adjustment when the test statistics are dependent, is discussed. Simulation studies show that taking into account the spatial structure of the data substantially improves the sensitivity of the multiple testing procedures. Application of the proposed methods to ChIP–Chip data for transcription factor p53 identified many potential target binding regions along human chromosomes 21 and 22. Among these identified regions, 18% fall within a 3 kb vicinity of the 5′UTR of a known gene or CpG island and 31% fall between the codon start site and the codon end site of a known gene but not inside an exon. More than half of these potential target sequences contain the p53 consensus binding site or very close matches to it. Moreover, these target segments include the 13 experimentally verified p53 binding regions of Cawley et al. (2004), as well as 49 additional regions that show higher hybridization signal than these 13 experimentally verified regions.  This paper was cited by:TileProbe: modeling tiling array probe effects using publicly available data J. T. Judy, H. Ji Bioinformatics. Oct 2009, Vol. 25, No. 18: 2369-2375 CrossRef SWI/SNF-Brg1 Regulates Self-Renewal and Occupies Core Pluripotency-Related Genes in Embryonic Stem Cells Benjamin L. Kidder, Stephen Palmer, Jason G. Knott Stem Cells. Mar 2009, Vol. 27, No. 2: 317-328 CrossRef A Bayesian Hidden Markov Model for Motif Discovery Through Joint Modeling of Genomic Sequence and ChIP-Chip Data Jonathan A. L. Gelfond, Mayetri Gupta, Joseph G. Ibrahim Biometrics. Mar 2009 CrossRef ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes A. A. Margolin, T. Palomero, P. Sumazin, A. Califano, A. A. Ferrando, G. Stolovitzky Proceedings of the National Academy of Sciences. Feb 2009, Vol. 106, No. 1: 244-249 CrossRef Poisson approximation for significance in genome-wide ChIP-chip tiling arrays Y. Zhang Bioinformatics. Nov 2008, Vol. 24, No. 24: 2825-2831 CrossRef Mixture Modeling for Genome-Wide Localization of Transcription Factors Sündüz Keleş Biometrics. Apr 2007, Vol. 63, No. 1: 10-21 CrossRef Novel TRF1/BRF target genes revealed by genome-wide analysis of Drosophila Pol III transcription Yoh Isogai, Shinako Takada, Robert Tjian, Sündüz Keleş The EMBO Journal. Feb 2007, Vol. 26, No. 1: 79-89 CrossRef
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