title: cnvOffSeq: detecting intergenic copy number variation using off-target exome sequencing data.
abstract: BACKGROUND
  Exome sequencing technologies have transformed the field of Mendelian genetics and allowed for efficient detection of genomic variants in protein-coding regions. The target enrichment process that is intrinsic to exome sequencing is inherently imperfect, generating large amounts of unintended off-target sequence. Off-target data are characterized by very low and highly heterogeneous coverage and are usually discarded by exome analysis pipelines. We posit that off-target read depth is a rich, but overlooked, source of information that could be mined to detect intergenic copy number variation (CNV). We propose cnvOffseq, a novel normalization framework for off-target read depth that is based on local adaptive singular value decomposition (SVD). This method is designed to address the heterogeneity of the underlying data and allows for accurate and precise CNV detection and genotyping in off-target regions.
  
  
  RESULTS
  cnvOffSeq was benchmarked on whole-exome sequencing samples from the 1000 Genomes Project. In a set of 104 gold standard intergenic deletions, our method achieved a sensitivity of 57.5% and a specificity of 99.2%, while maintaining a low FDR of 5%. For gold standard deletions longer than 5 kb, cnvOffSeq achieves a sensitivity of 90.4% without increasing the FDR. cnvOffSeq outperforms both whole-genome and whole-exome CNV detection methods considerably and is shown to offer a substantial improvement over naïve local SVD.
  
  
  METHODS
  cnvOffSeq is available at http://sourceforge.net/p/cnvoffseq/.
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK and Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Bellos
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK and Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD 4072, Australia Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK and Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
mesh_terms: D000465:Algorithms; D056915:DNA Copy Number Variations; D021901:DNA, Intergenic / Q000737:chemistry*; D059472:Exome; D023281:Genomics; D060005:Genotyping Techniques; D006801:Humans; D017422:Sequence Analysis, DNA / Q000379:methods*; D012984:Software
chemical_list: D021901:DNA, Intergenic