title: Large-scale inference of conjunctive Bayesian networks.
abstract: The continuous time conjunctive Bayesian network (CT-CBN) is a graphical model for analyzing the waiting time process of the accumulation of genetic changes (mutations). CT-CBN models have been successfully used in several biological applications such as HIV drug resistance development and genetic progression of cancer. However, current approaches for parameter estimation and network structure learning of CBNs can only deal with a small number of mutations (<20). Here, we address this limitation by presenting an efficient and accurate approximate inference algorithm using a Monte Carlo expectation-maximization algorithm based on importance sampling. The new method can now be used for a large number of mutations, up to one thousand, an increase by two orders of magnitude. In simulation studies, we present the accuracy as well as the running time efficiency of the new inference method and compare it with a MLE method, expectation-maximization, and discrete time CBN model, i.e. a first-order approximation of the CT-CBN model. We also study the application of the new model on HIV drug resistance datasets for the combination therapy with zidovudine plus lamivudine (AZT + 3TC) as well as under no treatment, both extracted from the Swiss HIV Cohort Study database.
  
  
  
  The proposed method is implemented as an R package available at https://github.com/cbg-ethz/MC-CBN CONTACT: niko.beerenwinkel@bsse.ethz.ch
  
  
  
  Supplementary data are available at Bioinformatics online.
authors: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
authors: Hesam
authors: H
authors: Montazeri
authors: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
authors: Jack
authors: J
authors: Kuipers
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland Institute of Medical Virology.
authors: Roger
authors: R
authors: Kouyos
authors: Swiss National Center for Retroviruses, Institute of Medical Virology, University of Zurich, Zurich 8057, Switzerland.
authors: Jürg
authors: J
authors: Böni
authors: Laboratory of Virology, Division of Infectious Diseases, Geneva University Hospital, Geneva, Switzerland.
authors: Sabine
authors: S
authors: Yerly
authors: Department of Biomedicine-Petersplatz, University of Basel, Basel, Switzerland.
authors: Thomas
authors: T
authors: Klimkait
authors: Division of Immunology and Allergy, University Hospital Lausanne, Lausanne, Switzerland.
authors: Vincent
authors: V
authors: Aubert
authors: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland Institute of Medical Virology.
authors: Huldrych F
authors: HF
authors: Günthard
authors: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
authors: Niko
authors: N
authors: Beerenwinkel
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D015331:Cohort Studies; D006801:Humans; D009010:Monte Carlo Method; D009154:Mutation