Stochastic Hybrid Automata with delayed transitions to model biochemical systems with delays

To study the effects of a delayed immune-response on the growth of an immunogenic neoplasm we introduce Stochastic Hybrid Automata with delayed transitions as a representation of hybrid biochemical systems with delays. These transitions abstractly model unknown dynamics for which a constant duration can be estimated, i.e. a delay. These automata are inspired by standard Stochastic Hybrid Automata, and their semantics is given in terms of Piecewise Deterministic Markov Processes. The approach is general and can be applied to systems where (i) components at low concentrations are modeled discretely (so to retain their intrinsic stochastic fluctuations), (ii) abundant component, e.g., chemical signals, are well approximated by mean-field equations (so to simulate them efficiently) and (iii) missing components are abstracted with delays. Via simulations we show in our application that interesting delay-induced phenomena arise, whose quantification is possible in this new quantitative framework.

[1]  Stephen Gilmore,et al.  Integrated Simulation and Model-Checking for the Analysis of Biochemical Systems , 2009, PASM@EPEW.

[2]  Nikola Burić,et al.  Dynamics of delay-differential equations modelling immunology of tumor growth , 2002 .

[3]  S. Sastry,et al.  Towars a Theory of Stochastic Hybrid Systems , 2000, HSCC.

[4]  D. Kirschner,et al.  Modeling immunotherapy of the tumor – immune interaction , 1998, Journal of mathematical biology.

[5]  Giulio Caravagna,et al.  Bio-PEPAd: A non-Markovian extension of Bio-PEPA , 2012, Theor. Comput. Sci..

[6]  Tianhai Tian,et al.  Oscillatory Regulation of Hes1: Discrete Stochastic Delay Modelling and Simulation , 2006, PLoS Comput. Biol..

[7]  Luca Bortolussi,et al.  Fluid Approximation of CTMC with Deterministic Delays , 2012, 2012 Ninth International Conference on Quantitative Evaluation of Systems.

[8]  D. Gillespie A General Method for Numerically Simulating the Stochastic Time Evolution of Coupled Chemical Reactions , 1976 .

[9]  Yang Cao,et al.  Sensitivity analysis of discrete stochastic systems. , 2005, Biophysical journal.

[10]  Mark H. A. Davis Piecewise‐Deterministic Markov Processes: A General Class of Non‐Diffusion Stochastic Models , 1984 .

[11]  Paola Lecca,et al.  Parameter sensitivity analysis of stochastic models: Application to catalytic reaction networks , 2013, Comput. Biol. Chem..

[12]  John Lygeros,et al.  Toward a General Theory of Stochastic Hybrid Systems , 2006 .

[13]  Robert M. May,et al.  Theoretical Ecology: Principles and Applications , 1977 .

[14]  D. Kirschner,et al.  A mathematical model of tumor-immune evasion and siRNA treatment , 2003 .

[15]  Carlos Gershenson,et al.  Information and Computation , 2013, Handbook of Human Computation.

[16]  Paolo Milazzo,et al.  Delay Stochastic Simulation of Biological Systems: A Purely Delayed Approach , 2011, Trans. Comp. Sys. Biology.

[17]  Alberto Policriti,et al.  (Hybrid) automata and (stochastic) programsThe hybrid automata lattice of a stochastic program , 2013, J. Log. Comput..

[18]  N. Rashevsky,et al.  Mathematical biology , 1961, Connecticut medicine.

[19]  L. Glass,et al.  Oscillation and chaos in physiological control systems. , 1977, Science.

[20]  Giancarlo Mauri,et al.  Effects of delayed immune-response in tumor immune-system interplay , 2012, HSB.

[21]  Ovidiu Radulescu,et al.  Convergence of stochastic gene networks to hybrid piecewise deterministic processes , 2011, 1101.1431.

[22]  D. Pardoll,et al.  Does the immune system see tumors as foreign or self? , 2003, Annual review of immunology.

[23]  Diego Latella,et al.  Continuous approximation of collective system behaviour: A tutorial , 2013, Perform. Evaluation.

[24]  A. Perelson,et al.  Nonlinear dynamics of immunogenic tumors: parameter estimation and global bifurcation analysis. , 1994, Bulletin of mathematical biology.

[25]  Alberto d'Onofrio,et al.  Delay-induced oscillatory dynamics of tumour-immune system interaction , 2010, Math. Comput. Model..

[26]  R. Schreiber,et al.  The three Es of cancer immunoediting. , 2004, Annual review of immunology.

[27]  Giulio Caravagna,et al.  Formal Modeling and Simulation of Biological Systems with Delays , 2011 .

[28]  Wilhelm Huisinga,et al.  ADAPTIVE SIMULATION OF HYBRID STOCHASTIC AND DETERMINISTIC MODELS FOR BIOCHEMICAL SYSTEMS , 2005 .

[29]  Oscar Sotolongo-Costa,et al.  Assessment of cancer immunotherapy outcome in terms of the immune response time features. , 2007, Mathematical medicine and biology : a journal of the IMA.

[30]  Roberto Barbuti,et al.  Tumour suppression by immune system through stochastic oscillations. , 2010, Journal of theoretical biology.

[31]  Luca Bortolussi,et al.  Hybrid behaviour of Markov population models , 2012, Inf. Comput..

[32]  John Lygeros,et al.  Probabilistic reachability and safety for controlled discrete time stochastic hybrid systems , 2008, Autom..

[33]  Alberto Policriti,et al.  The Importance of Being (A Little Bit) Discrete , 2009, Electron. Notes Theor. Comput. Sci..

[34]  Joost-Pieter Katoen,et al.  Approximate Model Checking of Stochastic Hybrid Systems , 2010, Eur. J. Control.

[35]  Ami Radunskaya,et al.  A delay differential equation model for tumor growth , 2003, Journal of mathematical biology.

[36]  Magda Galach,et al.  DYNAMICS OF THE TUMOR—IMMUNE SYSTEM COMPETITION—THE EFFECT OF TIME DELAY , 2003 .

[37]  Peter W. Glynn,et al.  On the role of generalized semi-Markov processes in simulation output analysis , 1983, WSC '83.

[38]  Giancarlo Mauri,et al.  The Interplay of Intrinsic and Extrinsic Bounded Noises in Biomolecular Networks , 2012, PloS one.

[39]  Christos G. Cassandras,et al.  Introduction to Discrete Event Systems, Second Edition , 2008 .

[40]  John Lygeros,et al.  Towars a Theory of Stochastic Hybrid Systems , 2000, HSCC.

[41]  Christos G. Cassandras,et al.  Introduction to Discrete Event Systems , 1999, The Kluwer International Series on Discrete Event Dynamic Systems.

[42]  M. Khammash,et al.  The finite state projection algorithm for the solution of the chemical master equation. , 2006, The Journal of chemical physics.

[43]  Giulio Caravagna,et al.  Distributed delays in a hybrid model of tumor-immune system interplay. , 2012, Mathematical biosciences and engineering : MBE.

[44]  Richard A. Hayden,et al.  Mean Field for Performance Models with Deterministically-Timed Transitions , 2012, 2012 Ninth International Conference on Quantitative Evaluation of Systems.

[45]  P Hogeweg,et al.  Macrophage T lymphocyte interactions in the anti-tumor immune response: a mathematical model. , 1985, Journal of immunology.

[46]  D. Gillespie Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[47]  Alberto d’Onofrio,et al.  Tumor evasion from immune control: Strategies of a MISS to become a MASS , 2007 .

[48]  Roberto Barbuti,et al.  Fine-tuning anti-tumor immunotherapies via stochastic simulations , 2012, BMC Bioinformatics.