Luca Bortolussi

Modeling Biological Systems in Stochastic Concurrent Constraint Programming

We present an application of stochastic Concurrent Constraint Programming (sCCP) for modeling biological systems. We provide a library of sCCP processes that can be used to describe straightforwardly biological networks. In the meanwhile, we show that sCCP proves to be a general and extensible framework, allowing to describe a wide class of dynamical behaviours and kinetic laws.

Fluid model checking

In this paper we investigate a potential use of fluid approximation techniques in the context of stochastic model checking of CSL formulae. We focus on properties describing the behaviour of a single agent in a (large) population of agents, exploiting a limit result known also as fast simulation. In particular, we will approximate the behaviour of a single agent with a time-inhomogeneous CTMC which depends on the environment and on the other agents only through the solution of the fluid differential equation. We will prove the asymptotic correctness of our approach in terms of satisfiability of CSL formulae and of reachability probabilities. We will also present a procedure to model check time-inhomogeneous CTMC against CSL formulae.

Stochastic Concurrent Constraint Programming and Differential Equations

Abstract We tackle the problem of relating models of systems (mainly biological systems) based on stochastic process algebras (SPA) with models based on differential equations. We define a syntactic procedure that translates programs written in stochastic Concurrent Constraint Programming (sCCP) into a set of Ordinary Differential Equations (ODE), and also the inverse procedure translating ODEs into sCCP programs. For the class of biochemical reactions, we show that the translation is correct w.r.t. the intended rate semantics of the models. Finally, we show that the translation does not generally preserve the dynamical behavior, giving a list of open research problems in this direction.

System design of stochastic models using robustness of temporal properties

Abstract Stochastic models such as Continuous-Time Markov Chains (CTMC) and Stochastic Hybrid Automata (SHA) are powerful formalisms to model and to reason about the dynamics of biological systems, due to their ability to capture the stochasticity inherent in biological processes. A classical question in formal modelling with clear relevance to biological modelling is the model checking problem, i.e. calculate the probability that a behaviour, expressed for instance in terms of a certain temporal logic formula, may occur in a given stochastic process. However, one may not only be interested in the notion of satisfiability, but also in the capacity of a system to maintain a particular emergent behaviour unaffected by the perturbations, caused e.g. from extrinsic noise, or by possible small changes in the model parameters. To address this issue, researchers from the verification community have recently proposed several notions of robustness for temporal logic providing suitable definitions of distance between a trajectory of a (deterministic) dynamical system and the boundaries of the set of trajectories satisfying the property of interest. The contributions of this paper are twofold. First, we extend the notion of robustness to stochastic systems, showing that this naturally leads to a distribution of robustness degrees. By discussing three examples, we show how to approximate the distribution of the robustness degree and the average robustness . Secondly, we show how to exploit this notion to address the system design problem , where the goal is to optimise some control parameters of a stochastic model in order to maximise robustness of the desired specifications.

Data-driven statistical learning of temporal logic properties

We present a novel approach to learn logical formulae characterising the emergent behaviour of a dynamical system from system observations. At a high level, the approach starts by devising a data-driven statistical abstraction of the system. We then propose general optimisation strategies for selecting formulae with high satisfaction probability, either within a discrete set of formulae of bounded complexity, or a parametric family of formulae. We illustrate and apply the methodology on two real world case studies: characterising the dynamics of a biological circadian oscillator, and discriminating different types of cardiac malfunction from electro-cardiogram data. Our results demonstrate that this approach provides a statistically principled and generally usable tool to logically characterise dynamical systems in terms of temporal logic formulae.

Stochastic Concurrent Constraint Programming

Abstract We present a stochastic version of Concurrent Constraint Programming (CCP), where we associate a rate to each basic instruction that interacts with the constraint store. We give an operational semantic that can be provided either with a discrete or a continuous model of time. The notion of observables is discussed, both for the discrete and the continuous version, and a connection between the two is given. Finally, a possible application for modeling biological networks is presented.

Smoothed model checking for uncertain Continuous-Time Markov Chains

We consider the problem of computing the satisfaction probability of a formula for stochastic models with parametric uncertainty. We show that this satisfaction probability is a smooth function of the model parameters under mild conditions. This enables us to devise a novel Bayesian statistical algorithm which performs model checking simultaneously for all values of the model parameters from observations of truth values of the formula over individual runs of the model at isolated parameter values. This is achieved by exploiting the smoothness of the satisfaction function: by modelling explicitly correlations through a prior distribution over a space of smooth functions (a Gaussian Process), we can condition on observations at individual parameter values to construct an analytical approximation of the function itself. Extensive experiments on non-trivial case studies show that the approach is accurate and considerably faster than naive parameter exploration with standard statistical model checking methods.

On the Robustness of Temporal Properties for Stochastic Models

Stochastic models such as Continuous-Time Markov Chains (CTMC) and Stochastic Hybrid Automata (SHA) are powerful formalisms to model and to reason about the dynamics of biological systems, due to their ability to capture the stochasticity inherent in biological processes. A classical question in formal modelling with clear relevance to biological modelling is the model checking problem, i.e. calculate the probability that a behaviour, expressed for instance in terms of a certain temporal logic formula, may occur in a given stochastic process. However, one may not only be interested in the notion of satisfiability, but also in the capacity of a system to mantain a particular emergent behaviour unaffected by the perturbations, caused e.g. from extrinsic noise, or by possible small changes in the model parameters. To address this issue, researchers from the verification community have recently proposed several notions of robustness for temporal logic providing suitable definitions of distance between a trajectory of a (deterministic) dynamical system and the boundaries of the set of trajectories satisfying the property of interest. The contributions of this paper are twofold. First, we extend the notion of robustness to stochastic systems, showing that this naturally leads to a distribution of robustness scores. By discussing two examples, we show how to approximate the distribution of the robustness score and its key indicators: the average robustness and the conditional average robustness. Secondly, we show how to combine these indicators with the satisfaction probability to address the system design problem, where the goal is to optimize some control parameters of a stochastic model in order to best maximize robustness of the desired specifications.

Hybrid dynamics of stochastic programs

We provide Stochastic Concurrent Constraint Programming (sCCP), a stochastic process algebra based on CCP, with a semantics in terms of hybrid automata. We associate with each sCCP program both a stochastic and a non-deterministic hybrid automaton. Then, we compare such automata with the standard stochastic semantics (given by a Continuous Time Markov Chain) and the one based on ordinary differential equations, obtained by a fluid-flow approximation technique. We discuss in detail two case studies: Repressilator and the Circadian Clock, with particular regard to the robustness exhibited by the different semantic models and to the effect of discreteness in dynamical evolution of such systems.

Learning and designing stochastic processes from logical constraints

Continuous time Markov Chains (CTMCs) are a convenient mathematical model for a broad range of natural and computer systems. As a result, they have received considerable attention in the theoretical computer science community, with many important techniques such as model checking being now mainstream. However, most methodologies start with an assumption of complete specification of the CTMC, in terms of both initial conditions and parameters. While this may be plausible in some cases (e.g. small scale engineered systems) it is certainly not valid nor desirable in many cases (e.g. biological systems), and it does not lead to a constructive approach to rational design of systems based on specific requirements. Here we consider the problems of learning and designing CTMCs from observations/ requirements formulated in terms of satisfaction of temporal logic formulae. We recast the problem in terms of learning and maximising an unknown function (the likelihood of the parameters) which can be numerically estimated at any value of the parameter space (at a non-negligible computational cost). We adapt a recently proposed, provably convergent global optimisation algorithm developed in the machine learning community, and demonstrate its efficacy on a number of non-trivial test cases.