CODEX: a normalization and copy number variation detection method for whole exome sequencing

Nucleic Acids Res. 2015 Mar 31;43(6):e39. doi: 10.1093/nar/gku1363. Epub 2015 Jan 23.


High-throughput sequencing of DNA coding regions has become a common way of assaying genomic variation in the study of human diseases. Copy number variation (CNV) is an important type of genomic variation, but detecting and characterizing CNV from exome sequencing is challenging due to the high level of biases and artifacts. We propose CODEX, a normalization and CNV calling procedure for whole exome sequencing data. The Poisson latent factor model in CODEX includes terms that specifically remove biases due to GC content, exon capture and amplification efficiency, and latent systemic artifacts. CODEX also includes a Poisson likelihood-based recursive segmentation procedure that explicitly models the count-based exome sequencing data. CODEX is compared to existing methods on a population analysis of HapMap samples from the 1000 Genomes Project, and shown to be more accurate on three microarray-based validation data sets. We further evaluate performance on 222 neuroblastoma samples with matched normals and focus on a well-studied rare somatic CNV within the ATRX gene. We show that the cross-sample normalization procedure of CODEX removes more noise than normalizing the tumor against the matched normal and that the segmentation procedure performs well in detecting CNVs with nested structures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Base Composition
  • Bias
  • Case-Control Studies
  • DNA Copy Number Variations*
  • DNA Helicases / genetics
  • DNA, Neoplasm / genetics
  • Databases, Nucleic Acid / statistics & numerical data
  • Exome*
  • Female
  • High-Throughput Nucleotide Sequencing / methods*
  • High-Throughput Nucleotide Sequencing / statistics & numerical data
  • Humans
  • Likelihood Functions
  • Male
  • Neuroblastoma / genetics
  • Nuclear Proteins / genetics
  • Sequence Analysis, DNA / methods*
  • Sequence Analysis, DNA / statistics & numerical data
  • X-linked Nuclear Protein


  • DNA, Neoplasm
  • Nuclear Proteins
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein