Modular Verification of Biological Systems

Systems of interest in systems biology (such as metabolic pathways, signalling pathways and gene regulatory networks) often consist of a huge number of components interacting in different ways, thus exhibiting very complex behaviours. In biology, such behaviours are usually explored by means of simulation techniques applied to models defined on the basis of system observation and of hypotheses on its functioning. Model checking has also been recently applied to the analysis of biological systems. This analysis technique typically relies on a state space representation whose size, unfortunately, makes the analysis often intractable for realistic models. A method for trying to avoid the state space explosion problem is to consider a decomposition of the system, and to apply a modular verification technique. In particular, properties to be verified often concern only a small portion of the modelled system rather than the system as a whole. Hence, for each property it would be useful to be able to isolate a minimal fragment of the model that is necessary to verify such a property. In this thesis we introduce a modular verification technique in which the system of interest is described by means of an automata-based formalism, called sync-programs, that supports modular construction. Our modular verification technique is based on results of Grumberg et al.~and on their application to the theory of concurrent systems proposed by Attie and Emerson. In particular, we adapt Attie and Emerson's approach to deal with biological systems by allowing automata to synchronise by performing transitions simultaneously. Modular verification allows qualitative aspects of systems to be analysed with the guarantee that properties proved to hold in a suitable model fragment also hold in the whole model. The correctness of the verification technique is proved. The class of properties preserved is ACTL$^{-}$, the universal fragment of temporal logic CTL. The preservation holds only for positive answers and negative answers are not necessarily preserved. In order to verify properties we use the NuSMV model checker, which is a well-established and efficient instrument. We provide a formal translation of sync-programs to simpler automata, which can be given as input to NuSMV. We prove the correspondence of the verification problems. We show the application of our verification technique in some biological case studies. We compare the time required to verify the property on the whole model with the time needed to verify the same property by only considering those modules which are involved in the behaviour of the system related to the property. In order to handle modelling and verification of more realistic biological scenarios, we propose also a dynamic version of our formalism. It allows entities to be created dynamically, in particular by other already running entities, as it often happens in biological systems. Moreover, multiple copies of the same entities can be present at the same time in a system. We show a correspondence of our model with Petri Nets. This has a consequence that tools developed for Petri Nets could be used also for dynamic sync-programs. Modular verification allows properties expressed as DACTL- formulae (dynamic version of ACTL-) to be verified on a portion of the model. The results of analysis of the case study of the MAP kinase cascade activated by surface and internalised EGF receptors, which consists of 143 species and 80 reactions, suggest applicability and scalability of the approach. The results raise the prospect of rendering tractable problems that are currently intractable in the verification of biological systems. In addition, we expect that the techniques developed in the thesis could be applied with profit not only to models of biological systems, but more generally to models of concurrent systems

Supporting user-oriented analysis for multi-view domain-specific visual languages

This is the post-print version of the final paper published in Information and Software Technology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2008 Elsevier B.V.The integration of usable and flexible analysis support in modelling environments is a key success factor in Model-Driven Development. In this paradigm, models are the core asset from which code is automatically generated, and thus ensuring model correctness is a fundamental quality control activity. For this purpose, a common approach is to transform the system models into formal semantic domains for verification. However, if the analysis results are not shown in a proper way to the end-user (e.g. in terms of the original language) they may become useless. In this paper we present a novel DSVL called BaVeL that facilitates the flexible annotation of verification results obtained in semantic domains to different formats, including the context of the original language. BaVeL is used in combination with a consistency framework, providing support for all steps in a verification process: acquisition of additional input data, transformation of the system models into semantic domains, verification, and flexible annotation of analysis results. The approach has been validated analytically by the cognitive dimensions framework, and empirically by its implementation and application to several DSVLs. Here we present a case study of a notation in the area of Digital Libraries, where the analysis is performed by transformations into Petri nets and a process algebra.Spanish Ministry of Education and Science and MODUWEB

Model-based dependability analysis : state-of-the-art, challenges and future outlook

Abstract: Over the past two decades, the study of model-based dependability analysis has gathered significant research interest. Different approaches have been developed to automate and address various limitations of classical dependability techniques to contend with the increasing complexity and challenges of modern safety-critical system. Two leading paradigms have emerged, one which constructs predictive system failure models from component failure models compositionally using the topology of the system. The other utilizes design models - typically state automata - to explore system behaviour through fault injection. This paper reviews a number of prominent techniques under these two paradigms, and provides an insight into their working mechanism, applicability, strengths and challenges, as well as recent developments within these fields. We also discuss the emerging trends on integrated approaches and advanced analysis capabilities. Lastly, we outline the future outlook for model-based dependability analysis

On Modelling and Analysis of Dynamic Reconfiguration of Dependable Real-Time Systems

This paper motivates the need for a formalism for the modelling and analysis of dynamic reconfiguration of dependable real-time systems. We present requirements that the formalism must meet, and use these to evaluate well established formalisms and two process algebras that we have been developing, namely, Webpi and CCSdp. A simple case study is developed to illustrate the modelling power of these two formalisms. The paper shows how Webpi and CCSdp represent a significant step forward in modelling adaptive and dependable real-time systems.Comment: Presented and published at DEPEND 201

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

Automating the transformation-based analysis of visual languages

The final publication is available at Springer via http://dx.doi.org/10.1007/s00165-009-0114-yWe present a novel approach for the automatic generation of model-to-model transformations given a description of the operational semantics of the source language in the form of graph transformation rules. The approach is geared to the generation of transformations from Domain-Specific Visual Languages (DSVLs) into semantic domains with an explicit notion of transition, like for example Petri nets. The generated transformation is expressed in the form of operational triple graph grammar rules that transform the static information (initial model) and the dynamics (source rules and their execution control structure). We illustrate these techniques with a DSVL in the domain of production systems, for which we generate a transformation into Petri nets. We also tackle the description of timing aspects in graph transformation rules, and its analysis through their automatic translation into Time Petri netsWork sponsored by the Spanish Ministry of Science and Innovation, project METEORIC (TIN2008-02081/TIN) and by the Canadian Natural Sciences and Engineering Research Council (NSERC)

From RT-LOTOS to Time Petri Nets new foundations for a verification platform

The formal description technique RT-LOTOS has been selected as intermediate language to add formality to a real-time UML profile named TURTLE. For this sake, an RT-LOTOS verification platform has been developed for early detection of design errors in real-time system models. The paper discusses an extension of the platform by inclusion of verification tools developed for Time Petri Nets. The starting point is the definition of RT-LOTOS to TPN translation patterns. In particular, we introduce the concept of components embedding Time Petri Nets. The translation patterns are implemented in a prototype tool which takes as input an RT-LOTOS specification and outputs a TPN in the format admitted by the TINA tool. The efficiency of the proposed solution has been demonstrated on various case studies