title: An optimized algorithm for detecting and annotating regional differential methylation.
abstract: BACKGROUND
  DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data.
  
  
  RESULTS
  Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types.
  
  
  CONCLUSIONS
  Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at http://code.google.com/p/edmr/.
authors.affiliation: Department of Physiology and Biophysics,Weill Cornell Medical College, 1305 York Ave., New York, NY 10065, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Francine E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.forename: Altuna
authors.initials: A
authors.lastname: Akalin
authors.forename: Paul
authors.initials: P
authors.lastname: Zumbo
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.forename: Bik L
authors.initials: BL
authors.lastname: To
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.forename: Anna L
authors.initials: AL
authors.lastname: Brown
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
mesh_terms: D000465:Algorithms; D018899:CpG Islands; D019175:DNA Methylation; D057890:Epigenomics / Q000379:methods; D016678:Genome; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007938:Leukemia / Q000235:genetics; D058977:Molecular Sequence Annotation / Q000379:methods*; D017422:Sequence Analysis, DNA