title: Estimating the dynamics and dependencies of accumulating mutations with applications to HIV drug resistance.
abstract: We introduce a new model called the observed time conjunctive Bayesian network (OT-CBN) that describes the accumulation of genetic events (mutations) under partial temporal ordering constraints. Unlike other CBN models, the OT-CBN model uses sampling time points of genotypes in addition to genotypes themselves to estimate model parameters. We developed an expectation-maximization algorithm to obtain approximate maximum likelihood estimates by accounting for this additional information. In a simulation study, we show that the OT-CBN model outperforms the continuous time CBN (CT-CBN) (Beerenwinkel and Sullivant, 2009. Markov models for accumulating mutations. Biometrika 96: (3), 645-661), which does not take into account individual sampling times for parameter estimation. We also show superiority of the OT-CBN model on several datasets of HIV drug resistance mutations extracted from the Swiss HIV Cohort Study database.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland and SIB Swiss Institute of Bioinformatics, Basel 4058, Switzerland.
authors.forename: Hesam
authors.initials: H
authors.lastname: Montazeri
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland Institute of Medical Virology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland Institute of Medical Virology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland Institute of Medical Virology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Kouyos
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland and SIB Swiss Institute of Bioinformatics, Basel, Switzerland niko.beerenwinkel@bsse.ethz.ch.
authors.forename: Niko
authors.initials: N
authors.lastname: Beerenwinkel
mesh_terms: D001499:Bayes Theorem; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D015233:Models, Statistical; D000067552:Mutation Accumulation
keywords: Conjunctive Bayesian networks; Expectation–maximization algorithm; Genetic progression; HIV drug resistance; Maximum likelihood estimation