title: Ranking non-synonymous single nucleotide polymorphisms based on disease concepts.
abstract: As the number of non-synonymous single nucleotide polymorphisms (nsSNPs) identified through whole-exome/whole-genome sequencing programs increases, researchers and clinicians are becoming increasingly reliant upon computational prediction algorithms designed to prioritize potential functional variants for further study. A large proportion of existing prediction algorithms are 'disease agnostic' but are nevertheless quite capable of predicting when a mutation is likely to be deleterious. However, most clinical and research applications of these algorithms relate to specific diseases and would therefore benefit from an approach that discriminates between functional variants specifically related to that disease from those which are not. In a whole-exome/whole-genome sequencing context, such an approach could substantially reduce the number of false positive candidate mutations. Here, we test this postulate by incorporating a disease-specific weighting scheme into the Functional Analysis through Hidden Markov Models (FATHMM) algorithm. When compared to traditional prediction algorithms, we observed an overall reduction in the number of false positives identified using a disease-specific approach to functional prediction across 17 distinct disease concepts/categories. Our results illustrate the potential benefits of making disease-specific predictions when prioritizing candidate variants in relation to specific diseases. A web-based implementation of our algorithm is available at http://fathmm.biocompute.org.uk.
authors: Hashem A
authors: HA
authors: Shihab
authors: Julian
authors: J
authors: Gough
authors: Matthew
authors: M
authors: Mort
authors: David N
authors: DN
authors: Cooper
authors: Ian N M
authors: IN
authors: Day
authors: Bristol Centre for Systems Biomedicine and MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Tom.Gaunt@bristol.ac.uk.
authors: Tom R
authors: TR
authors: Gaunt
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D019295:Computational Biology; D006801:Humans; D020407:Internet; D008390:Markov Chains; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012984:Software