title: Dissecting trait heterogeneity: a comparison of three clustering methods applied to genotypic data.
abstract: BACKGROUND
  Trait heterogeneity, which exists when a trait has been defined with insufficient specificity such that it is actually two or more distinct traits, has been implicated as a confounding factor in traditional statistical genetics of complex human disease. In the absence of detailed phenotypic data collected consistently in combination with genetic data, unsupervised computational methodologies offer the potential for discovering underlying trait heterogeneity. The performance of three such methods--Bayesian Classification, Hypergraph-Based Clustering, and Fuzzy k-Modes Clustering--appropriate for categorical data were compared. Also tested was the ability of these methods to detect trait heterogeneity in the presence of locus heterogeneity and/or gene-gene interaction, which are two other complicating factors in discovering genetic models of complex human disease. To determine the efficacy of applying the Bayesian Classification method to real data, the reliability of its internal clustering metrics at finding good clusterings was evaluated using permutation testing.
  
  
  RESULTS
  Bayesian Classification outperformed the other two methods, with the exception that the Fuzzy k-Modes Clustering performed best on the most complex genetic model. Bayesian Classification achieved excellent recovery for 75% of the datasets simulated under the simplest genetic model, while it achieved moderate recovery for 56% of datasets with a sample size of 500 or more (across all simulated models) and for 86% of datasets with 10 or fewer nonfunctional loci (across all simulated models). Neither Hypergraph Clustering nor Fuzzy k-Modes Clustering achieved good or excellent cluster recovery for a majority of datasets even under a restricted set of conditions. When using the average log of class strength as the internal clustering metric, the false positive rate was controlled very well, at three percent or less for all three significance levels (0.01, 0.05, 0.10), and the false negative rate was acceptably low (18 percent) for the least stringent significance level of 0.10.
  
  
  CONCLUSIONS
  Bayesian Classification shows promise as an unsupervised computational method for dissecting trait heterogeneity in genotypic data. Its control of false positive and false negative rates lends confidence to the validity of its results. Further investigation of how different parameter settings may improve the performance of Bayesian Classification, especially under more complex genetic models, is ongoing.
authors.affiliation: Neuroscience Graduate Program, Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA. t.thornton-wells@vanderbilt.edu
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D016000:Cluster Analysis; D003198:Computer Simulation; D017143:Fuzzy Logic; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci