title: Cladograms with Path to Event (ClaPTE): a novel algorithm to detect associations between genotypes or phenotypes using phylogenies.
abstract: BACKGROUND
  Associations between genotype and phenotype provide insight into the evolution of pathogenesis, drug resistance, and the spread of pathogens between hosts. However, common ancestry can lead to apparent associations between biologically unrelated features. The novel method Cladograms with Path to Event (ClaPTE) detects associations between character-pairs (either a pair of mutations or a mutation paired with a phenotype) while adjusting for common ancestry, using phylogenetic trees.
  
  
  METHODS
  ClaPTE tests for character-pairs changing close together on the phylogenetic tree, consistent with an associated character-pair. ClaPTE is compared to three existing methods (independent contrasts, mixed model, and likelihood ratio) to detect character-pair associations adjusted for common ancestry. Comparisons utilize simulations on gene trees for: HIV Env, HIV promoter, and bacterial DnaJ and GuaB; and case studies for Oseltamavir resistance in Influenza, and for DnaJ and GuaB. Simulated data include both true-positive/associated character-pairs, and true-negative/not-associated character-pairs, used to assess type I (frequency of p-values in true-negatives) and type II (sensitivity to true-positives) error control.
  
  
  CONCLUSIONS
  ClaPTE has competitive sensitivity and better type I error control than existing methods. In the Influenza/Oseltamavir case study, ClaPTE reports no new permissive mutations but detects associations between adjacent (in primary sequence) amino acid positions which other methods miss. In the DnaJ and GuaB case study, ClaPTE reports more frequent associations between positions both from the same protein family than between positions from different families, in contrast to other methods. In both case studies, the results from ClaPTE are biologically plausible.
authors.affiliation: Department of Pharmacology, Ohio State University College of Medicine, 5072 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, United States; Mathematical Biosciences Institute, The Ohio State University, Jennings Hall 3rd Floor, 1735 Neil Avenue, Columbus, OH 43210, United States. Electronic address: handelman.9@osu.edu.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Handelman
authors.affiliation: Department of Biomedical Informatics, Ohio State University College of Medicine, 3190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, United States.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Aaronson
authors.affiliation: Mathematical Biosciences Institute, The Ohio State University, Jennings Hall 3rd Floor, 1735 Neil Avenue, Columbus, OH 43210, United States.
authors.forename: Michal
authors.initials: M
authors.lastname: Seweryn
authors.affiliation: Department of Biomedical Informatics, Ohio State University College of Medicine, 3190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Voronkin
authors.affiliation: Department of Microbial Infection & Immunity and Department of Microbiology, The Ohio State University, 788 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210, United States.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Kwiek
authors.affiliation: Department of Pharmacology, Ohio State University College of Medicine, 5072 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, United States.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.affiliation: Department of Statistics, The Ohio State University, 404 Cockins Hall, 1958 Neil Avenue, Columbus, OH 43210-1247, United States.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Verducci
authors.affiliation: Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223-0001, United States.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Janies
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D005838:Genotype; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics; D008957:Models, Genetic; D010641:Phenotype; D010802:Phylogeny; D011506:Proteins / Q000235:genetics
chemical_list: D011506:Proteins
keywords: Correlated evolution; Drug resistance; Genetic simulation; Genotype-phenotype association; HIV evolution; Influenza evolution; Phylogenetics; Protein evolution