title: High-dimensional Bayesian parameter estimation: case study for a model of JAK2/STAT5 signaling.
abstract: In this work we present results of a detailed Bayesian parameter estimation for an analysis of ordinary differential equation models. These depend on many unknown parameters that have to be inferred from experimental data. The statistical inference in a high-dimensional parameter space is however conceptually and computationally challenging. To ensure rigorous assessment of model and prediction uncertainties we take advantage of both a profile posterior approach and Markov chain Monte Carlo sampling. We analyzed a dynamical model of the JAK2/STAT5 signal transduction pathway that contains more than one hundred parameters. Using the profile posterior we found that the corresponding posterior distribution is bimodal. To guarantee efficient mixing in the presence of multimodal posterior distributions we applied a multi-chain sampling approach. The Bayesian parameter estimation enables the assessment of prediction uncertainties and the design of additional experiments that enhance the explanatory power of the model. This study represents a proof of principle that detailed statistical analysis for quantitative dynamical modeling used in systems biology is feasible also in high-dimensional parameter spaces.
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Germany; Department of Mathematics, Technische Universität München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hug
authors.forename: A
authors.initials: A
authors.lastname: Raue
authors.forename: J
authors.initials: J
authors.lastname: Hasenauer
authors.forename: J
authors.initials: J
authors.lastname: Bachmann
authors.forename: U
authors.initials: U
authors.lastname: Klingmüller
authors.forename: J
authors.initials: J
authors.lastname: Timmer
authors.forename: F J
authors.initials: FJ
authors.lastname: Theis
mesh_terms: D001499:Bayes Theorem; D053614:Janus Kinase 2 / Q000502:physiology; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D050791:STAT Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology / Q000379:methods
chemical_list: D050791:STAT Transcription Factors; D053614:Janus Kinase 2
keywords: Bayesian inference; Cellular signal transduction pathways; Ordinary differential equation models; Parameter estimation; Profile likelihood