Ezio Bartocci

Model repair for probabilistic systems

We introduce the problem of Model Repair for Probabilistic Systems as follows. Given a probabilistic system M and a probabilistic temporal logic formula φ such that M fails to satisfy φ, the Model Repair problem is to find an M′ that satisfies v and differs from M only in the transition flows of those states in M that are deemed controllable. Moreover, the cost associated with modifying Ms transition flows to obtain M′ should be minimized. Using a new version of parametric probabilistic model checking, we show how the Model Repair problem can be reduced to a nonlinear optimization problem with a minimal-cost objective function, thereby yielding a solution technique. We demonstrate the practical utility of our approach by applying it to a number of significant case studies, including a DTMC reward model of the Zeroconf protocol for assigning IP addresses, and a CTMC model of the highly publicized Kaminsky DNS cache-poisoning attack.

From cardiac cells to genetic regulatory networks

A fundamental question in the treatment of cardiac disorders, such as tachycardia and fibrillation, is under what circumstances does such a disorder arise? To answer to this question, we develop a multiaffine hybrid automaton (MHA) cardiac-cell model, and restate the original question as one of identification of the parameter ranges under which the MHA model accurately reproduces the disorder. The MHA model is obtained from the minimal cardiac model of one of the authors (Fenton) by first bringing it into the form of a canonical, genetic regulatory network, and then linearizing its sigmoidal switches, in an optimal way. By leveraging the Rovergene tool for genetic regulatory networks, we are then able to successfully identify the parameter ranges of interest.

Learning and detecting emergent behavior in networks of cardiac myocytes

We address the problem of specifying and detecting emergent behavior in networks of cardiac myocytes, spiral electric waves in particular, a precursor to atrial and ventricular fibrillation. To solve this problem we: (1) apply discrete mode abstraction to the cycle-linear hybrid automata (CLHA) we have recently developed for modeling the behavior of myocyte networks; (2) introduce the new concept of spatial superposition of CLHA modes; (3) develop a new spatial logic, based on spatial superposition, for specifying emergent behavior; (4) devise a new method for learning the formulae of this logic from the spatial patterns under investigation; and (5) apply bounded model checking to detect the onset of spiral waves. We have implemented our methodology as the EMERALD tool suite, a component of our EHA framework for specification, simulation, analysis, and control of excitable hybrid automata. We illustrate the effectiveness of our approach by applying EMERALD to the scalar electrical fields produced by our CELLEXCITE simulation environment for excitable-cell networks.

On temporal logic and signal processing

We present Time-Frequency Logic (TFL), a new specification formalism for real-valued signals that combines temporal logic properties in the time domain with frequency-domain properties. We provide a property checking framework for this formalism and illustrate its expressive power in defining and recognizing properties of musical pieces. Like hybrid automata and their analysis techniques, the TFL formalism is a contribution to a unified systems theory for hybrid systems.

BioWMS: a web-based Workflow Management System for bioinformatics

BackgroundAn in-silico experiment can be naturally specified as a workflow of activities implementing, in a standardized environment, the process of data and control analysis. A workflow has the advantage to be reproducible, traceable and compositional by reusing other workflows. In order to support the daily work of a bioscientist, several Workflow Management Systems (WMSs) have been proposed in bioinformatics. Generally, these systems centralize the workflow enactment and do not exploit standard process definition languages to describe, in order to be reusable, workflows. While almost all WMSs require heavy stand-alone applications to specify new workflows, only few of them provide a web-based process definition tool.ResultsWe have developed BioWMS, a Workflow Management System that supports, through a web-based interface, the definition, the execution and the results management of an in-silico experiment. BioWMS has been implemented over an agent-based middleware. It dynamically generates, from a user workflow specification, a domain-specific, agent-based workflow engine. Our approach exploits the proactiveness and mobility of the agent-based technology to embed, inside agents behaviour, the application domain features. Agents are workflow executors and the resulting workflow engine is a multiagent system – a distributed, concurrent system – typically open, flexible, and adaptative. A demo is available at http://litbio.unicam.it:8080/biowms.ConclusionBioWMS, supported by Hermes mobile computing middleware, guarantees the flexibility, scalability and fault tolerance required to a workflow enactment over distributed and heterogeneous environment. BioWMS is funded by the FIRB project LITBIO (Laboratory for Interdisciplinary Technologies in Bioinformatics).

Toward real-time simulation of cardiac dynamics

We show that through careful and model-specific optimizations of their GPU implementations, simulations of realistic, detailed cardiac-cell models now can be performed in 2D and 3D in times that are close to real time using a desktop computer. Previously, large-scale simulations of detailed mathematical models of cardiac cells were possible only using supercomputers. In our study, we consider five different models of cardiac electrophysiology that span a broad range of computational complexity: the two-variable Karma model, the four-variable Bueno-Orovio-Cherry-Fenton model, the eight-variable Beeler-Reuter model, the 19-variable Ten Tusscher-Panfilov model, and the 67-variable Iyer-Mazhari-Winslow model. For each of these models, we treat both their single- and double-precision versions and demonstrate linear or even sub-linear growth in simulation times with an increase in the size of the grid used to model cardiac tissue. We also show that our GPU implementations of these models can increase simulation speeds to near real-time for simulations of complex spatial patterns indicative of cardiac arrhythmic disorders, including spiral waves and spiral wave breakup. The achievement of real-time applications without the need for supercomputers may, in the near term, facilitate the adoption of modeling-based clinical diagnostics and treatment planning, including patient-specific electrophysiological studies.

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.

Computational Modeling, Formal Analysis, and Tools for Systems Biology

As the amount of biological data in the public domain grows, so does the range of modeling and analysis techniques employed in systems biology. In recent years, a number of theoretical computer science developments have enabled modeling methodology to keep pace. The growing interest in systems biology in executable models and their analysis has necessitated the borrowing of terms and methods from computer science, such as formal analysis, model checking, static analysis, and runtime verification. Here, we discuss the most important and exciting computational methods and tools currently available to systems biologists. We believe that a deeper understanding of the concepts and theory highlighted in this review will produce better software practice, improved investigation of complex biological processes, and even new ideas and better feedback into computer science.

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.