Lumpability Abstractions of Rule-based Systems

The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a mathematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the combinatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics. In this paper we prove that this quotienting yields a sufficient condition for weak lumpability and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Syntactic Markovian Bisimulation for Chemical Reaction Networks

In chemical reaction networks (CRNs) with stochastic semantics based on continuous-time Markov chains (CTMCs), the typically large populations of species cause combinatorially large state spaces. This makes the analysis very difficult in practice and represents the major bottleneck for the applicability of minimization techniques based, for instance, on lumpability. In this paper we present syntactic Markovian bisimulation (SMB), a notion of bisimulation developed in the Larsen-Skou style of probabilistic bisimulation, defined over the structure of a CRN rather than over its underlying CTMC. SMB identifies a lumpable partition of the CTMC state space a priori, in the sense that it is an equivalence relation over species implying that two CTMC states are lumpable when they are invariant with respect to the total population of species within the same equivalence class. We develop an efficient partition-refinement algorithm which computes the largest SMB of a CRN in polynomial time in the number of species and reactions. We also provide an algorithm for obtaining a quotient network from an SMB that induces the lumped CTMC directly, thus avoiding the generation of the state space of the original CRN altogether. In practice, we show that SMB allows significant reductions in a number of models from the literature. Finally, we study SMB with respect to the deterministic semantics of CRNs based on ordinary differential equations (ODEs), where each equation gives the time-course evolution of the concentration of a species. SMB implies forward CRN bisimulation, a recently developed behavioral notion of equivalence for the ODE semantics, in an analogous sense: it yields a smaller ODE system that keeps track of the sums of the solutions for equivalent species.Comment: Extended version (with proofs), of the corresponding paper published at KimFest 2017 (http://kimfest.cs.aau.dk/

EPTCS

The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a math- ematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the com- binatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics. In this paper we prove that this quotienting yields a sufficient condition for weak lumpability and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk

Markovian Testing Equivalence and Exponentially Timed Internal Actions

In the theory of testing for Markovian processes developed so far, exponentially timed internal actions are not admitted within processes. When present, these actions cannot be abstracted away, because their execution takes a nonzero amount of time and hence can be observed. On the other hand, they must be carefully taken into account, in order not to equate processes that are distinguishable from a timing viewpoint. In this paper, we recast the definition of Markovian testing equivalence in the framework of a Markovian process calculus including exponentially timed internal actions. Then, we show that the resulting behavioral equivalence is a congruence, has a sound and complete axiomatization, has a modal logic characterization, and can be decided in polynomial time

Minimization of Dynamical Systems over Monoids

Quantitative notions of bisimulation are well-known tools for the minimization of dynamical models such as Markov chains and ordinary differential equations (ODEs). In \emph{forward bisimulations}, each state in the quotient model represents an equivalence class and the dynamical evolution gives the overall sum of its members in the original model. Here we introduce generalized forward bisimulation (GFB) for dynamical systems over commutative monoids and develop a partition refinement algorithm to compute the coarsest one. When the monoid is $(\mathbb{R}, +)$, we recover %our framework recovers probabilistic bisimulation for Markov chains and more recent forward bisimulations for %systems of nonlinear ODEs. %ordinary differential equations. Using $(\mathbb{R}, \cdot)$ we get %When the monoid is $(\mathbb{R}, \cdot)$ we can obtain nonlinear reductions for discrete-time dynamical systems and ODEs %ordinary differential equations where each variable in the quotient model represents the product of original variables in the equivalence class. When the domain is a finite set such as the Booleans $\mathbb{B}$, we can apply GFB to Boolean networks (BN), a widely used dynamical model in computational biology. Using a prototype implementation of our minimization algorithm for GFB, we find disjunction- and conjunction-preserving reductions on 60 BN from two well-known repositories, and demonstrate the obtained analysis speed-ups. We also provide the biological interpretation of the reduction obtained for two selected BN, and we show how GFB enables the analysis of a large one that could not be analyzed otherwise. Using a randomized version of our algorithm we find product-preserving (therefore non-linear) reductions on 21 dynamical weighted networks from the literature that could not be handled by the exact algorithm.Comment: Accepted at Thirty-Eighth Annual ACM/IEEE Symposium on Logic in Computer Science (LICS), 202

Markov chain aggregation for agent-based models

Banisch S. Markov chain aggregation for agent-based models. Bielefeld: Universitätsbibliothek Bielefeld; 2014.This thesis introduces a Markov chain approach that allows a rigorous analysis of a class of agent-based models (ABMs). It provides a general framework of aggregation in agent-based and related computational models by making use of Markov chain aggregation and lumpability theory in order to link between the micro and the macro level of observation. The starting point is a microscopic Markov chain description of the dynamical process in complete correspondence with the dynamical behavior of the agent model, which is obtained by considering the set of all possible agent configurations as the state space of a huge Markov chain. This is referred to as micro chain, and an explicit formal representation including microscopic transition rates can be derived for a class of models by using the random mapping representation of a Markov process. The explicit micro formulation enables the application of the theory of Markov chain aggregation -- namely, lumpability -- in order to reduce the state space of the micro chain and relate microscopic descriptions to a macroscopic formulation of interest. Well-known conditions for lumpability make it possible to establish the cases where the macro model is still Markov, and in this case we obtain a complete picture of the dynamics including the transient stage, the most interesting phase in applications. For such a purpose a crucial role is played by the type of probability distribution used to implement the stochastic part of the model which defines the updating rule and governs the dynamics. Namely, if we decide to remain at a Markovian level, then the partition, or equivalently, the collective variables used to build the macro model must be compatible with the symmetries of the probability distribution ω. This underlines the theoretical importance of homogeneous or complete mixing in the analysis of »voter-like« models at use in population genetics, evolutionary game theory and social dynamics. On the other hand, if a favored level of observation is not compatible with the symmetries in ω, a certain amount of memory is introduced by the transition from the micro level to such a macro description, and this is the fingerprint of emergence in ABMs. The resulting divergence from Markovianity can be quantified using information-theoretic measures and the thesis presents a scenario in which these measures can be explicitly computed. Two simple models are used to illustrate these theoretical ideas: the voter model (VM) and an extension of it called contrarian voter model (CVM). Using these examples, the thesis shows that Markov chain theory allows for a rather precise understanding of the model dynamics in case of »simple« population structures where a tractable macro chain can be derived. Constraining the system by interaction networks with a strong local structure leads to the emergence of meta-stable states in the transient of the model. Constraints on the interaction behavior such as bounded confidence or assortative mating lead to the emergence of new absorbing states in the associated macro chain and are related to stable patterns of polarization (stable co-existence of different opinions or species). Constraints and heterogeneities in the microscopic system and complex social interactions are the basic characteristics of ABMs, and the Markov chain approach to link the micro chain to a macro level description (and likewise the failure of a Markovian link) highlights the crucial role played by those ingredients in the generation of complex macroscopic outcomes

Unwinding biological systems

Unwinding conditions have been fruitfully exploited in Information Flow Security to define persistent security properties. In this paper we investigate their meaning and possible uses in the analysis of biological systems. In particular, we elaborate on the notion of robustness and propose some instances of unwinding over the process algebra Bio-PEPA and over hybrid automata. We exploit such instances to analyse two case-studies: Neurospora crassa circadian system and Influenza kinetics models

Combinatorial Conversion and Moment Bisimulation for Stochastic Rewriting Systems

We develop a novel method to analyze the dynamics of stochastic rewriting systems evolving over finitary adhesive, extensive categories. Our formalism is based on the so-called rule algebra framework and exhibits an intimate relationship between the combinatorics of the rewriting rules (as encoded in the rule algebra) and the dynamics which these rules generate on observables (as encoded in the stochastic mechanics formalism). We introduce the concept of combinatorial conversion, whereby under certain technical conditions the evolution equation for (the exponential generating function of) the statistical moments of observables can be expressed as the action of certain differential operators on formal power series. This permits us to formulate the novel concept of moment-bisimulation, whereby two dynamical systems are compared in terms of their evolution of sets of observables that are in bijection. In particular, we exhibit non-trivial examples of graphical rewriting systems that are moment-bisimilar to certain discrete rewriting systems (such as branching processes or the larger class of stochastic chemical reaction systems). Our results point towards applications of a vast number of existing well-established exact and approximate analysis techniques developed for chemical reaction systems to the far richer class of general stochastic rewriting systems