title: A combined functional annotation score for non-synonymous variants.
abstract: OBJECTIVE
  Next-generation sequencing has opened the possibility of large-scale sequence-based disease association studies. A major challenge in interpreting whole-exome data is predicting which of the discovered variants are deleterious or neutral. To address this question in silico, we have developed a score called Combined Annotation scoRing toOL (CAROL), which combines information from 2 bioinformatics tools: PolyPhen-2 and SIFT, in order to improve the prediction of the effect of non-synonymous coding variants.
  
  
  METHODS
  We used a weighted Z method that combines the probabilistic scores of PolyPhen-2 and SIFT. We defined 2 dataset pairs to train and test CAROL using information from the dbSNP: 'HGMD-PUBLIC' and 1000 Genomes Project databases. The training pair comprises a total of 980 positive control (disease-causing) and 4,845 negative control (non-disease-causing) variants. The test pair consists of 1,959 positive and 9,691 negative controls.
  
  
  RESULTS
  CAROL has higher predictive power and accuracy for the effect of non-synonymous variants than each individual annotation tool (PolyPhen-2 and SIFT) and benefits from higher coverage.
  
  
  CONCLUSIONS
  The combination of annotation tools can help improve automated prediction of whole-genome/exome non-synonymous variant functional consequences.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Hinxton, UK. ml10@sanger.ac.uk
authors.forename: Margarida C
authors.initials: MC
authors.lastname: Lopes
authors.forename: Chris
authors.initials: C
authors.lastname: Joyce
authors.forename: Graham R S
authors.initials: GR
authors.lastname: Ritchie
authors.forename: Sally L
authors.initials: SL
authors.lastname: John
authors.forename: Fiona
authors.initials: F
authors.lastname: Cunningham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Asimit
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
mesh_terms: D000465:Algorithms; D023281:Genomics / Q000379:methods*; D006801:Humans; D058977:Molecular Sequence Annotation / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012984:Software