FG Datenstrukturen und Softwarezuverlässigkeit
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Institute
BTU
Snoopy is a powerful modelling and simulation tool for various types of Petri nets, which have been applied to a wide range of biochemical reaction networks. We present an enhanced version of Snoopy, now supporting coloured and uncoloured stochastic, continuous and hybrid Petri Nets with fuzzy kinetic parameters. Colour helps to cope with modelling challenges imposed by larger and more complex networks. Fuzzy parameters are specifically useful when kinetic parameter values can not be precisely measured or estimated. By running fuzzy simulation we obtain output bands of the variables of interest induced by the effect of the fuzzy kinetic parameters. Simulation is always done on the uncoloured level. For this purpose, coloured fuzzy Petri nets are automatically unfolded to their corresponding uncoloured counterparts. Combining the power of fuzzy kinetic parameters with the modelling convenience of coloured Petri nets provides a new quality in user support with sophisticated modelling and analysis features.
We present a methodology for systematically extending epidemic models to multilevel and multiscale spatio-temporal pandemic ones. Our approach builds on the use of coloured stochastic and continuous Petri nets facilitating the sound component-based extension of basic SIR models to include population stratification and also spatio-geographic information and travel connections, represented as graphs, resulting in robust stratified pandemic metapopulation models. The epidemic components and the spatial and stratification data are combined together in these coloured models and built in to the underlying expanded models. As a consequence this method is inherently easy to use, producing scalable and reusable models with a high degree of clarity and accessibility which can be read either in a deterministic or stochastic paradigm. Our method is supported by a publicly available platform PetriNuts; it enables the visual construction and editing of models; deterministic, stochastic and hybrid simulation as well as structural and behavioural analysis. All models are available as Supplementary Material, ensuring reproducibility. All uncoloured Petri nets can be animated within a web browser at https://www-dssz.informatik.tu-cottbus.de/DSSZ/Research/ModellingEpidemics, assisting the comprehension of those models. We aim to enable modellers and planners to construct clear and robust models by themselves.
We present a methodology for systematically extending epidemic models to multilevel and multiscale spatio-temporal pandemic ones. Our approach builds on the use of coloured stochastic and continuous Petri nets facilitating the sound component-based extension of basic SIR models to include population stratification and also spatio-geographic information and travel connections, represented as graphs, resulting in robust stratified pandemic metapopulation models. This method is inherently easy to use, producing scalable and reusable models with a high degree of clarity and accessibility which can be read either in a deterministic or stochastic paradigm. Our method is supported by a publicly available platform PetriNuts; it enables the visual construction and editing of models; deterministic, stochastic and hybrid simulation as well as structural and behavioural analysis. All the models are available as supplementary material, ensuring reproducibility.
Over the last twenty years, Petri nets have been increasingly adopted for modelling and simulating biological systems, as they offer an intuitive and graphical approach for this purpose. Their usability convenience comes from the fact that they offer many types of elements to describe systems in a qualitative and quantitative way. Coloured Petri nets are particularly useful to model systems with repeated components in a compact fashion. Our tool Snoopy for modelling and simulating Petri nets is one of the most well-known tools supporting a family of related Petri net classes comprising stochastic, continuous and hybrid Petri nets, and covering uncoloured and coloured Petri nets alike. However, kinetic information of a biological system, i.e. kinetic parameters may be uncertain, due to many reasons, e.g. environmental factors. Besides, coloured Petri nets as they were previously supported in Snoopy suffered from some inconsistencies. Due to these inconsistencies, exploring the model behaviour using different sizes (scaleability) was not feasible. Both challenges call for a new and more powerful approach integrating the modelling of uncertainties together with modelling features supporting repeated structures in a compact and scalable way.
This thesis comprises two major contributions: Firstly, we introduce the definition and present the simulation algorithm for both uncoloured and coloured fuzzy Petri nets, by extending the existing quantitative uncoloured and coloured Petri nets in Snoopy. This includes discretising the uncertain kinetic parameters to crisp values by using sampling strategies. Secondly, we harmonise coloured Petri nets in Snoopy with their uncoloured counterparts and we extend the Snoopy’s coloured Petri nets by all the features, which are supported by the coloured abstract net description language - an exchange format of coloured Petri nets in our PetriNuts tool family.
By performing fuzzy simulation, one can obtain two kinds of output: fuzzy bands of each output variable and their corresponding timed-membership functions. Each fuzzy band describes the uncertainties associated with the input, whereas membership functions give more accurate information about the associated uncertainties. The most important features that we obtain by harmonising coloured Petri nets are to develop scaleable models, by defining scaling factors as constants and unifying the usage of coloured Petri nets with the other tools in our PetriNuts tool family.
Reproducibility of simulation experiments is still a significant challenge and has attracted considerable attention in recent years. One cause of this situation is bad habits of the scientific community. Many results are published without data or source code, and only a textual description of the simulation set-up is provided. Other causes are: no complete simulation set-up, no proper output data analysis and inconsistency of published data, which makes it impossible to compare results.
The progress of computational modelling, amount of data and complexity of models requires designing experiments in such a way that ensures reproducibility. A textual description does not provide all the needed details. A computer code is more reliable than a textual description. It is the precise specification that describes a simulation configuration, model, etc. When computer code, data, models and all parameters are provided, the simulation results become reproducible.
The main goal of this thesis is to develop a tool that ensures reproducibility and efficient execution of simulation experiments, often involving many individual simulation runs. The tool should support a wide range of application scenarios, where the typical scenario is simulation of biochemical reaction networks, which are represented as (coloured) Petri nets interpreted in the stochastic, continuous or hybrid paradigm. The model to be simulated can be given in various formats, including SBML.
The result is a command line tool called Spike, which can be used for various scenarios, including benchmarking, simulation of adaptive models and parameter optimization. It builds on a human-readable configuration script SPC, supporting the efficient specification of multiple model configurations as well as multiple simulator configurations in a single configuration file.
Integrated modelling of biological systems is becoming a necessity for constructing models containing the major biochemical processes of such systems in order to obtain a holistic understanding of their dynamics and to elucidate emergent behaviours. Hybrid modelling methods are crucial to achieve integrated modelling of biological systems. This paper reviews currently popular hybrid modelling methods, developed for systems biology, mainly revealing why they are proposed, how they are formed from single modelling formalisms and how to simulate them. By doing this, we identify future research requirements regarding hybrid approaches for further promoting integrated modelling of biological systems.
Membrane systems are a very powerful computational modelling formalism inspired by the internal organisation of living cells. Modelling of membrane systems is challenged by composing many structurally similar components, which may result in very large models. Furthermore, some components may suffer from a lack of precise kinetic parameters. Coloured fuzzy Petri nets combine coloured Petri nets with fuzzy kinetic parameters, and thus offer an approach to address these challenges. In this paper, we use coloured fuzzy Petri nets to model and simulate membrane systems which are enriched by fuzzy kinetic parameters. We also introduce a methodology and workflow utilising coloured fuzzy Petri nets for modelling and simulating general biological systems which have to cope with incomplete knowledge of their kinetic data.
Whole-cell modeling aims to incorporate all main genes and processes, and their interactions of a cell in one model. Whole-cell modeling has been regarded as the central aim of systems biology but also as a grand challenge, which plays essential roles in current and future systems biology. In this paper, we analyze whole-cell modeling challenges and requirements and classify them into three aspects (or dimensions): heterogeneous biochemical networks, uncertainties in components, and representation of cell structure. We then explore how to use different Petri net classes to address different aspects of whole-cell modeling requirements. Based on these analyses, we present a Petri nets-based framework for whole-cell modeling, which not only addresses many whole-cell modeling requirements, but also offers a graphical, modular, and hierarchical modeling tool. We think this framework can offer a feasible modeling approach for whole-cell model construction.
Fuzzy Petri nets
(2021)
This document explains the procedure of modelling and simulating FPN
and FPNC in Snoopy; please compare Figure 1 . Please note that the same
steps for one net class can be equally applied to the other classes, just differentiate between uncoloured Petri nets (PN) and coloured Petri nets (PNC).
Furthermore, we give more details about Latin Hybercube Sampling strategies supported by Snoopy's FPN.
Dynamics of cell fate decisions are commonly investigated by inferring temporal sequences of gene expression states by assembling snapshots of individual cells where each cell is measured once. Ordering cells according to minimal differences in expression patterns and assuming that differentiation occurs by a sequence of irreversible steps, yields unidirectional, eventually branching Markov chains with a single source node. In an alternative approach, we used multi-nucleate cells to follow gene expression taking true time series. Assembling state machines, each made from single-cell trajectories, gives a network of highly structured Markov chains of states with different source and sink nodes including cycles, revealing essential information on the dynamics of regulatory events. We argue that the obtained networks depict aspects of the Waddington landscape of cell differentiation and characterize them as reachability graphs that provide the basis for the reconstruction of the underlying gene regulatory network.
We consider coloured Petri nets, qualitative and quantitative ones alike, as supported by our PetriNuts tool family, comprising, among others, Snoopy, Marcie and Spike. Currently, most analysis and simulation techniques require to unfold the given coloured Petri net into its corresponding plain, uncoloured Petri net representation. This unfolding step is rather straightforward for finite discrete colour sets, but tends to be time-consuming due to the potentially huge number of possible transition bindings. We present an unfolding approach building on a special type of symbolic data structures, called Interval Decision Diagram, and compare its runtime performance with an unfolding engine employing an off-the-shelf library to solve constraint satisfaction problems. For this comparison we use the 22 scalable coloured models from the MCC benchmark suite, complemented by a few from our own collection.
A Graphical Approach for Hybrid Simulation of 3D Diffusion Bio-Models via Coloured Hybrid Petri Nets
(2020)
Three-dimensional modelling of biological systems is imperative to study the behaviour of dynamic systems that require the analysis of how their components interact in space. However, there are only a few formal tools that offer a convenient modelling of such systems. The traditional approach to construct and simulate 3D models is to build a system of partial differential equations (PDEs). Although this approach may be computationally efficient and has been employed by many researchers over the years, it is not always intuitive since it does not provide a visual depiction of the modelled systems. Indeed, a visual modelling can help to conceive a mental image which eventually contributes to the understanding of the problem under study. Coloured Hybrid Petri Nets () are a high-level representation of classical Petri nets that offer hybrid as well as spatial modelling of biological systems. In addition to their graphical representations, models are also scalable. This paper shows how can be used to construct and simulate systems that require three-dimensional as well as hybrid (stochastic/continuous) modelling. We use calcium diffusion in three dimensions to illustrate our main ideas. More specifically, we show that creating 3D models using can yield more flexible models as the structure can be easily scaled up and down by just modifying a few parameters. This advantage of convenient model configuration facilitates the design of different experiments without the need to alter the model structure.
Integrated modelling of biological systems is challenged by composing components with sufficient kinetic data and components with insufficient kinetic data or components built only using experts’ experience and knowledge. Fuzzy continuous Petri nets (FCPNs) combine continuous Petri nets with fuzzy inference systems, and thus offer an hybrid uncertain/certain approach to integrated modelling of such biological systems with uncertainties. In this paper, we give a formal definition and a corresponding simulation algorithm of FCPNs, and briefly introduce the FCPN tool that we have developed for implementing FCPNs. We then present a methodology and workflow utilizing FCPNs to achieve hybrid (uncertain/certain) modelling of biological systems illustrated with a case study of the Mercaptopurine metabolic pathway. We hope this research will promote the wider application of FCPNs and address the uncertain/certain integrated modelling challenge in the systems biology area.
Spatial quorum sensing modelling using coloured hybrid Petri nets and simulative model checking
(2019)
Spike - a command line tool for continuous, stochastic & hybrid simulation of (coloured) Petri nets
(2018)
Coloured Hybrid Petri Nets: an Adaptable Modelling Approach for Multi-scale Biological Networks
(2018)
BioModelKit: Spatial Modelling of Complex Multiscale Molecular Biosystems based on Modular Models
(2018)
A Case Study in Design and Verification of Manufacturing Systems with Hierarchical Petri Nets
(1999)
A Case Study in Developing Control Software of Manufacturing Systems with Hierarchical Petri Nets
(1996)
Combining structural properties and symbolic representation for efficient analysis of Petri nets
(1998)
On Integration of Qualitative and Quantitative Analysis of Manufacturing Systems Using Petri Nets
(1997)
Coloured Petri nets for multilevel, multiscale and multidimensional modelling of biological systems
(2019)
Modeling biological gradient formation: combining partial differential equations and Petri nets
(2016)
Fuzzy stochastic Petri nets for modeling biological systems with uncertain kinetic parameters
(2016)
Modeling and Simulation of Multi-scale Environmental Systems with Generalized Hybrid Petri Nets
(2015)
This report documents the program and the outcomes of Dagstuhl Seminar 14481 "Multiscale Spatial Computational Systems Biology". This seminar explored challenges arising from the need to model and analyse complex biological systems at multiple scales (spatial and temporal), which falls within the general remit of Computational Systems Biology. A distinguishing factor of the seminar was the modelling exercise -- where teams explored different modelling paradigms, in order to better understand the details of the approaches, their challenges, potential applications, and their pros and cons. This activity was carried out in a collaborative and self-directed manner using the Open Space Technology approach as evidenced by a high degree of communication both within and between the teams. Eight teams were formed, and reports from five of them are included in this document.