A Monte Carlo model checker for probabilistic LTL with numerical constraints

We define the syntax and semantics of a new temporal logic called probabilistic LTL with numerical constraints (PLTLc). We introduce an efficient model checker for PLTLc properties. The efficiency of the model checker is through approximation using Monte Carlo sampling of finite paths through the model’s state space (simulation outputs) and parallel model checking of the paths. Our model checking method can be applied to any model producing quantitative output – continuous or stochastic, including those with complex dynamics and those with an infinite state space. Furthermore, our offline approach allows the analysis of observed (real-life) behaviour traces. We find in this paper that PLTLc properties with constraints over free variables can replace full model checking experiments, resulting in a significant gain in efficiency. This overcomes one disadvantage of model checking experiments which is that the complexity depends on system granularity and number of variables, and quickly becomes infeasible. We focus on models of biochemical networks, and specifically in this paper on intracellular signalling pathways; however our method can be applied to a wide range of biological as well as technical systems and their models. Our work contributes to the emerging field of synthetic biology by proposing a rigourous approach for the structured formal engineering of biological systems.

[1]  Thomas Hérault,et al.  APMC 3.0: Approximate Verification of Discrete and Continuous Time Markov Chains , 2006, Third International Conference on the Quantitative Evaluation of Systems - (QEST'06).

[2]  Monika Heiner,et al.  A Unifying Framework for Modelling and Analysing Biochemical Pathways Using Petri Nets , 2007, CMSB.

[3]  Alberto Policriti,et al.  Model building and model checking for biochemical processes , 2007, Cell Biochemistry and Biophysics.

[4]  François Fages,et al.  Machine Learning Biochemical Networks from Temporal Logic Properties , 2006, Trans. Comp. Sys. Biology.

[5]  Amir Pnueli The Temporal Semantics of Concurrent Programs , 1981, Theor. Comput. Sci..

[6]  Thomas Hérault,et al.  Approximate Probabilistic Model Checking , 2004, VMCAI.

[7]  Christel Baier,et al.  LiQuor: A tool for Qualitative and Quantitative Linear Time analysis of Reactive Systems , 2006, Third International Conference on the Quantitative Evaluation of Systems - (QEST'06).

[8]  Håkan L. S. Younes,et al.  Numerical vs. statistical probabilistic model checking , 2006, International Journal on Software Tools for Technology Transfer.

[9]  Robert K. Brayton,et al.  Verifying Continuous Time Markov Chains , 1996, CAV.

[10]  Bengt Jonsson,et al.  A logic for reasoning about time and reliability , 1990, Formal Aspects of Computing.

[11]  François Fages,et al.  On the Analysis of Numerical Data Time Series in Temporal Logic , 2007, CMSB.

[12]  Stephan Merz,et al.  Model Checking , 2000 .

[13]  Darren J. Wilkinson,et al.  Tools for the SBML Community , 2006, Bioinform..

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

[15]  Marta Z. Kwiatkowska,et al.  Probabilistic model checking of complex biological pathways , 2008, Theor. Comput. Sci..

[16]  Radu Grosu,et al.  Monte Carlo Model Checking , 2005, TACAS.

[17]  B. Kholodenko,et al.  Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. , 2000, European journal of biochemistry.

[18]  David R. Gilbert,et al.  Analysis of Signalling Pathways Using Continuous Time Markov Chains , 2006, Trans. Comp. Sys. Biology.

[19]  Håkan L. S. Younes,et al.  Probabilistic Verification of Discrete Event Systems Using Acceptance Sampling , 2002, CAV.

[20]  Jehoshua Bruck,et al.  Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Matthias Heinemann,et al.  Synthetic biology - putting engineering into biology , 2006, Bioinform..