Forward and Backward Bisimulations for Chemical Reaction Networks

We present two quantitative behavioral equivalences over species of a chemical reaction network (CRN) with semantics based on ordinary differential equations. Forward CRN bisimulation identifies a partition where each equivalence class represents the exact sum of the concentrations of the species belonging to that class. Backward CRN bisimulation relates species that have the identical solutions at all time points when starting from the same initial conditions. Both notions can be checked using only CRN syntactical information, i.e., by inspection of the set of reactions. We provide a unified algorithm that computes the coarsest refinement up to our bisimulations in polynomial time. Further, we give algorithms to compute quotient CRNs induced by a bisimulation. As an application, we find significant reductions in a number of models of biological processes from the literature. In two cases we allow the analysis of benchmark models which would be otherwise intractable due to their memory requirements.Comment: Extended version of the CONCUR 2015 pape

Language-based Abstractions for Dynamical Systems

Ordinary differential equations (ODEs) are the primary means to modelling dynamical systems in many natural and engineering sciences. The number of equations required to describe a system with high heterogeneity limits our capability of effectively performing analyses. This has motivated a large body of research, across many disciplines, into abstraction techniques that provide smaller ODE systems while preserving the original dynamics in some appropriate sense. In this paper we give an overview of a recently proposed computer-science perspective to this problem, where ODE reduction is recast to finding an appropriate equivalence relation over ODE variables, akin to classical models of computation based on labelled transition systems.Comment: In Proceedings QAPL 2017, arXiv:1707.0366

Challenges in Quantitative Abstractions for Collective Adaptive Systems

Like with most large-scale systems, the evaluation of quantitative properties of collective adaptive systems is an important issue that crosscuts all its development stages, from design (in the case of engineered systems) to runtime monitoring and control. Unfortunately it is a difficult problem to tackle in general, due to the typically high computational cost involved in the analysis. This calls for the development of appropriate quantitative abstraction techniques that preserve most of the system's dynamical behaviour using a more compact representation. This paper focuses on models based on ordinary differential equations and reviews recent results where abstraction is achieved by aggregation of variables, reflecting on the shortcomings in the state of the art and setting out challenges for future research.Comment: In Proceedings FORECAST 2016, arXiv:1607.0200

Efficient Syntax-Driven Lumping of Differential Equations

We present an algorithm to compute exact aggregations of a class of systems of ordinary differential equations (ODEs). Our approach consists in an extension of Paige and Tarjan’s seminal solution to the coarsest refinement problem by encoding an ODE system into a suitable discrete-state representation. In particular, we consider a simple extension of the syntax of elementary chemical reaction networks because (i) it can express ODEs with derivatives given by polynomials of degree at most two, which are relevant in many applications in natural sciences and engineering; and (ii) we can build on two recently introduced bisimulations, which yield two complementary notions of ODE lumping. Our algorithm computes the largest bisimulations in O(r⋅s⋅logs)O(r⋅s⋅log⁡s) time, where r is the number of monomials and s is the number of variables in the ODEs. Numerical experiments on real-world models from biochemistry, electrical engineering, and structural mechanics show that our prototype is able to handle ODEs with millions of variables and monomials, providing significant model reductions

Efficient Local Computation of Differential Bisimulations via Coupling and Up-to Methods

We introduce polynomial couplings, a generalization of probabilistic couplings, to develop an algorithm for the computation of equivalence relations which can be interpreted as a lifting of probabilistic bisimulation to polynomial differential equations, a ubiquitous model of dynamical systems across science and engineering. The algorithm enjoys polynomial time complexity and complements classical partition-refinement approaches because: (a) it implements a local exploration of the system, possibly yielding equivalences that do not necessarily involve the inspection of the whole system of differential equations; (b) it can be enhanced by up-to techniques; and (c) it allows the specification of pairs which ought not be included in the output. Using a prototype, these advantages are demonstrated on case studies from systems biology for applications to model reduction and comparison. Notably, we report four orders of magnitude smaller runtimes than partition-refinement approaches when disproving equivalences between Markov chains

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

Symbolic Computation of Differential Equivalences

Ordinary differential equations (ODEs) are widespread in manynatural sciences including chemistry, ecology, and systems biology,and in disciplines such as control theory and electrical engineering. Building on the celebrated molecules-as-processes paradigm, they have become increasingly popular in computer science, with high-level languages and formal methods such as Petri nets, process algebra, and rule-based systems that are interpreted as ODEs. We consider the problem of comparing and minimizing ODEs automatically. Influenced by traditional approaches in the theory of programming, we propose differential equivalence relations. We study them for a basic intermediate language, for which we have decidability results, that can be targeted by a class of high-level specifications. An ODE implicitly represents an uncountable state space, hence reasoning techniques cannot be borrowed from established domains such as probabilistic programs with finite-state Markov chain semantics. We provide novel symbolic procedures to check an equivalence and compute the largest one via partition refinement algorithms that use satisfiability modulo theories. We illustrate the generality of our framework by showing that differential equivalences include (i) well-known notions for the minimization of continuous-time Markov chains (lumpability),(ii) bisimulations for chemical reaction networks recently proposedby Cardelli et al., and (iii) behavioral relations for process algebra with ODE semantics. With a prototype implementation we are able to detect equivalences in biochemical models from the literature thatcannot be reduced using competing automatic techniques

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

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