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

A Process Modelling Framework Based on Point Interval Temporal Logic with an Application to Modelling Patient Flows

This thesis considers an application of a temporal theory to describe and model the patient journey in the hospital accident and emergency (A&E) department. The aim is to introduce a generic but dynamic method applied to any setting, including healthcare. Constructing a consistent process model can be instrumental in streamlining healthcare issues. Current process modelling techniques used in healthcare such as flowcharts, unified modelling language activity diagram (UML AD), and business process modelling notation (BPMN) are intuitive and imprecise. They cannot fully capture the complexities of the types of activities and the full extent of temporal constraints to an extent where one could reason about the flows. Formal approaches such as Petri have also been reviewed to investigate their applicability to the healthcare domain to model processes. Additionally, to schedule patient flows, current modelling standards do not offer any formal mechanism, so healthcare relies on critical path method (CPM) and program evaluation review technique (PERT), that also have limitations, i.e. finish-start barrier. It is imperative to specify the temporal constraints between the start and/or end of a process, e.g., the beginning of a process A precedes the start (or end) of a process B. However, these approaches failed to provide us with a mechanism for handling these temporal situations. If provided, a formal representation can assist in effective knowledge representation and quality enhancement concerning a process. Also, it would help in uncovering complexities of a system and assist in modelling it in a consistent way which is not possible with the existing modelling techniques. The above issues are addressed in this thesis by proposing a framework that would provide a knowledge base to model patient flows for accurate representation based on point interval temporal logic (PITL) that treats point and interval as primitives. These objects would constitute the knowledge base for the formal description of a system. With the aid of the inference mechanism of the temporal theory presented here, exhaustive temporal constraints derived from the proposed axiomatic system’ components serves as a knowledge base. The proposed methodological framework would adopt a model-theoretic approach in which a theory is developed and considered as a model while the corresponding instance is considered as its application. Using this approach would assist in identifying core components of the system and their precise operation representing a real-life domain deemed suitable to the process modelling issues specified in this thesis. Thus, I have evaluated the modelling standards for their most-used terminologies and constructs to identify their key components. It will also assist in the generalisation of the critical terms (of process modelling standards) based on their ontology. A set of generalised terms proposed would serve as an enumeration of the theory and subsume the core modelling elements of the process modelling standards. The catalogue presents a knowledge base for the business and healthcare domains, and its components are formally defined (semantics). Furthermore, a resolution theorem-proof is used to show the structural features of the theory (model) to establish it is sound and complete. After establishing that the theory is sound and complete, the next step is to provide the instantiation of the theory. This is achieved by mapping the core components of the theory to their corresponding instances. Additionally, a formal graphical tool termed as point graph (PG) is used to visualise the cases of the proposed axiomatic system. PG facilitates in modelling, and scheduling patient flows and enables analysing existing models for possible inaccuracies and inconsistencies supported by a reasoning mechanism based on PITL. Following that, a transformation is developed to map the core modelling components of the standards into the extended PG (PG*) based on the semantics presented by the axiomatic system. A real-life case (from the King’s College hospital accident and emergency (A&E) department’s trauma patient pathway) is considered to validate the framework. It is divided into three patient flows to depict the journey of a patient with significant trauma, arriving at A&E, undergoing a procedure and subsequently discharged. Their staff relied upon the UML-AD and BPMN to model the patient flows. An evaluation of their representation is presented to show the shortfalls of the modelling standards to model patient flows. The last step is to model these patient flows using the developed approach, which is supported by enhanced reasoning and scheduling

Zero-gravity movement studies

The use of computer graphics to simulate the movement of articulated animals and mechanisms has a number of uses ranging over many fields. Human motion simulation systems can be useful in education, medicine, anatomy, physiology, and dance. In biomechanics, computer displays help to understand and analyze performance. Simulations can be used to help understand the effect of external or internal forces. Similarly, zero-gravity simulation systems should provide a means of designing and exploring the capabilities of hypothetical zero-gravity situations before actually carrying out such actions. The advantage of using a simulation of the motion is that one can experiment with variations of a maneuver before attempting to teach it to an individual. The zero-gravity motion simulation problem can be divided into two broad areas: human movement and behavior in zero-gravity, and simulation of articulated mechanisms

Reasoning about real-time systems with temporal interval logic constraints on multi-state automata

Models of real-time systems using a single paradigm often turn out to be inadequate, whether the paradigm is based on states, rules, event sequences, or logic. A model-based approach to reasoning about real-time systems is presented in which a temporal interval logic called TIL is employed to define constraints on a new type of high level automata. The combination, called hierarchical multi-state (HMS) machines, can be used to model formally a real-time system, a dynamic set of requirements, the environment, heuristic knowledge about planning-related problem solving, and the computational states of the reasoning mechanism. In this framework, mathematical techniques were developed for: (1) proving the correctness of a representation; (2) planning of concurrent tasks to achieve goals; and (3) scheduling of plans to satisfy complex temporal constraints. HMS machines allow reasoning about a real-time system from a model of how truth arises instead of merely depending of what is true in a system

Encoding Higher Level Extensions of Petri Nets in Answer Set Programming

Answering realistic questions about biological systems and pathways similar to the ones used by text books to test understanding of students about biological systems is one of our long term research goals. Often these questions require simulation based reasoning. To answer such questions, we need formalisms to build pathway models, add extensions, simulate, and reason with them. We chose Petri Nets and Answer Set Programming (ASP) as suitable formalisms, since Petri Net models are similar to biological pathway diagrams; and ASP provides easy extension and strong reasoning abilities. We found that certain aspects of biological pathways, such as locations and substance types, cannot be represented succinctly using regular Petri Nets. As a result, we need higher level constructs like colored tokens. In this paper, we show how Petri Nets with colored tokens can be encoded in ASP in an intuitive manner, how additional Petri Net extensions can be added by making small code changes, and how this work furthers our long term research goals. Our approach can be adapted to other domains with similar modeling needs

The uses of process modeling : a framework for understanding modeling formalisms

There is wide-spread recognition of the urgent need to improve software processes in order to improve the performance of software organizations. Process models are essential in achieving understanding and visibility of processes and are important for other uses including the analysis of processes for improvement. It has been increasingly difficult to compare and evaluate the variety of process modeling formalisms that have appeared in recent years without a clear understanding of precisely for what they will be used. The contribution of this paper is to provide an understanding and a fairly comprehensive catalog of the applications of process modeling for which formalisms may be used. The primary mechanism for doing this is a guided tour of the literature on process modeling supplemented by recent industrial experience. In the paper, basic definitions concerning processes, process descriptions and process modeling are reviewed and then uses of process modeling are surveyed under the following headings: communication among process participants, construction of new processes, control of processes, process· analysis, and process support by automation. Comments are offered on paradigms for process modeling formalisms and directions for future work to permit evolution of a discipline of process engineering are given

Representing Conversations for Scalable Overhearing

Open distributed multi-agent systems are gaining interest in the academic community and in industry. In such open settings, agents are often coordinated using standardized agent conversation protocols. The representation of such protocols (for analysis, validation, monitoring, etc) is an important aspect of multi-agent applications. Recently, Petri nets have been shown to be an interesting approach to such representation, and radically different approaches using Petri nets have been proposed. However, their relative strengths and weaknesses have not been examined. Moreover, their scalability and suitability for different tasks have not been addressed. This paper addresses both these challenges. First, we analyze existing Petri net representations in terms of their scalability and appropriateness for overhearing, an important task in monitoring open multi-agent systems. Then, building on the insights gained, we introduce a novel representation using Colored Petri nets that explicitly represent legal joint conversation states and messages. This representation approach offers significant improvements in scalability and is particularly suitable for overhearing. Furthermore, we show that this new representation offers a comprehensive coverage of all conversation features of FIPA conversation standards. We also present a procedure for transforming AUML conversation protocol diagrams (a standard human-readable representation), to our Colored Petri net representation

An introduction to Biomodel engineering, illustrated for signal transduction pathways

BioModel Engineering is the science of designing, constructing and analyzing computational models of biological systems. It is inspired by concepts from software engineering and computing science. This paper illustrates a major theme in BioModel Engineering, namely that identifying a quantitative model of a dynamic system means building the structure, finding an initial state, and parameter fitting. In our approach, the structure is obtained by piecewise construction of models from modular parts, the initial state is obtained by analysis of the structure and parameter fitting comprises determining the rate parameters of the kinetic equations. We illustrate this with an example in the area of intracellular signalling pathways