title: Scalable Parameter Estimation for Genome-Scale Biochemical Reaction Networks.
abstract: Mechanistic mathematical modeling of biochemical reaction networks using ordinary differential equation (ODE) models has improved our understanding of small- and medium-scale biological processes. While the same should in principle hold for large- and genome-scale processes, the computational methods for the analysis of ODE models which describe hundreds or thousands of biochemical species and reactions are missing so far. While individual simulations are feasible, the inference of the model parameters from experimental data is computationally too intensive. In this manuscript, we evaluate adjoint sensitivity analysis for parameter estimation in large scale biochemical reaction networks. We present the approach for time-discrete measurement and compare it to state-of-the-art methods used in systems and computational biology. Our comparison reveals a significantly improved computational efficiency and a superior scalability of adjoint sensitivity analysis. The computational complexity is effectively independent of the number of parameters, enabling the analysis of large- and genome-scale models. Our study of a comprehensive kinetic model of ErbB signaling shows that parameter estimation using adjoint sensitivity analysis requires a fraction of the computation time of established methods. The proposed method will facilitate mechanistic modeling of genome-scale cellular processes, as required in the age of omics.
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.|Technische Universität München, Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany.
authors.forename: Fabian
authors.identifier: 0000-0002-5360-4292
authors.initials: F
authors.lastname: Fröhlich
authors.affiliation: University of Klagenfurt, Institute of Mathematics, Klagenfurt, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kaltenbacher
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.|Technische Universität München, Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany.
authors.forename: Fabian J
authors.identifier: 0000-0002-2419-1943
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.|Technische Universität München, Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hasenauer
mesh_terms: D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology*; D016678:Genome / Q000502:physiology*; D008954:Models, Biological; D015233:Models, Statistical; D011381:Programming Languages; D020543:Proteome / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012984:Software
chemical_list: D020543:Proteome