Complex event types for agent-based simulation

This thesis presents a novel formal modelling language, complex event types (CETs), to describe behaviours in agent-based simulations. CETs are able to describe behaviours at any computationally represented level of abstraction. Behaviours can be specified both in terms of the state transition rules of the agent-based model that generate them and in terms of the state transition structures themselves. Based on CETs, novel computational statistical methods are introduced which allow statistical dependencies between behaviours at different levels to be established. Different dependencies formalise different probabilistic causal relations and Complex Systems constructs such as ‘emergence’ and ‘autopoiesis’. Explicit links are also made between the different types of CET inter-dependency and the theoretical assumptions they represent. With the novel computational statistical methods, three categories of model can be validated and discovered: (i) inter-level models, which define probabilistic dependencies between behaviours at different levels; (ii) multi-level models, which define the set of simulations for which an inter-level model holds; (iii) inferred predictive models, which define latent relationships between behaviours at different levels. The CET modelling language and computational statistical methods are then applied to a novel agent-based model of Colonic Cancer to demonstrate their applicability to Complex Systems sciences such as Systems Biology. This proof of principle model provides a framework for further development of a detailed integrative model of the system, which can progressively incorporate biological data from different levels and scales as these become available

Advances in Rule-based Modeling: Compartments, Energy, and Hybrid Simulation, with Application to Sepsis and Cell Signaling

Biological systems are commonly modeled as reaction networks, which describe the system at the resolution of biochemical species. Cellular systems, however, are governed by events at a finer scale: local interactions among macromolecular domains. The multi-domain structure of macromolecules, combined with the local nature of interactions, can lead to a combinatorial explosion that pushes reaction network methods to their limits. As an alternative, rule-based models (RBMs) describe the domain-based structure and local interactions found in biological systems. Molecular complexes are represented by graphs: functional domains as vertices, macromolecules as groupings of vertices, and molecular bonding as edges. Reaction rules, which describe classes of reactions, govern local modifications to molecular graphs, such as binding, post-translational modification, and degradation. RBMs can be transformed to equivalent reaction networks and simulated by differential or stochastic methods, or simulated directly with a network-free approach that avoids the problem of combinatorial complexity. Although RBMs and network-free methods resolve many problems in systems modeling, challenges remain. I address three challenges here: (i) managing model complexity due to cooperative interactions, (ii) representing biochemical systems in the compartmental setting of cells and organisms, and (iii) reducing the memory burden of large-scale network-free simulations. First, I present a general theory of energy-based modeling within the BioNetGen framework. Free energy is computed under a pattern-based formalism, and contextual variations within reaction classes are enumerated automatically. Next, I extend the BioNetGen language to permit description of compartmentalized biochemical systems, with treatment of volumes, surfaces and transport. Finally, a hybrid particle/population method is developed to reduce memory requirements of network-free simulations. All methods are implemented and available as part of BioNetGen. The remainder of this work presents an application to sepsis and inflammation. A multi-organ model of peritoneal infection and systemic inflammation is constructed and calibrated to experiment. Extra-corporeal blood purification, a potential treatment for sepsis, is explored in silico. Model simulations demonstrate that removal of blood cytokines and chemokines is a sufficient mechanism for improved survival in sepsis. However, differences between model predictions and the latest experimental data suggest directions for further exploration

Modelling and simulating in systems biology: an approach based on multi-agent systems

Systems Biology is an innovative way of doing biology recently raised in bio-informatics contexts, characterised by the study of biological systems as complex systems with a strong focus on the system level and on the interaction dimension. In other words, the objective is to understand biological systems as a whole, putting on the foreground not only the study of the individual parts as standalone parts, but also of their interaction and of the global properties that emerge at the system level by means of the interaction among the parts. This thesis focuses on the adoption of multi-agent systems (MAS) as a suitable paradigm for Systems Biology, for developing models and simulation of complex biological systems. Multi-agent system have been recently introduced in informatics context as a suitabe paradigm for modelling and engineering complex systems. Roughly speaking, a MAS can be conceived as a set of autonomous and interacting entities, called agents, situated in some kind of nvironment, where they fruitfully interact and coordinate so as to obtain a coherent global system behaviour. The claim of this work is that the general properties of MAS make them an effective approach for modelling and building simulations of complex biological systems, following the methodological principles identified by Systems Biology. In particular, the thesis focuses on cell populations as biological systems. In order to support the claim, the thesis introduces and describes (i) a MAS-based model conceived for modelling the dynamics of systems of cells interacting inside cell environment called niches. (ii) a computational tool, developed for implementing the models and executing the simulations. The tool is meant to work as a kind of virtual laboratory, on top of which kinds of virtual experiments can be performed, characterised by the definition and execution of specific models implemented as MASs, so as to support the validation, falsification and improvement of the models through the observation and analysis of the simulations. A hematopoietic stem cell system is taken as reference case study for formulating a specific model and executing virtual experiments

Toward Accessible Multilevel Modeling in Systems Biology: A Rule-based Language Concept

Promoted by advanced experimental techniques for obtaining high-quality data and the steadily accumulating knowledge about the complexity of life, modeling biological systems at multiple interrelated levels of organization attracts more and more attention recently. Current approaches for modeling multilevel systems typically lack an accessible formal modeling language or have major limitations with respect to expressiveness. The aim of this thesis is to provide a comprehensive discussion on associated problems and needs and to propose a concrete solution addressing them

Spatio-temporal Dynamics of the Wnt/beta-catenin Signaling Pathway: A Computational Systems Biology Approach

The Wnt/β-catenin signaling pathway is involved in human neural progenitor cell differentiation. This dissertation employs the cyclic workflow of computational systems biology to investigate the pathway spatio-temporal dynamics during differentiation. Quantitative in vitro analyses show biphasic kinetics of the pathway proteins. A computational model is developed to investigate in silico these kinetics in correlation with cell cycle and self-induced signaling. We show the importance of stochastic approach and suggest further experiments, hence closing the computational systems biology loop

Automatic Selection of Statistical Model Checkers for Analysis of Biological Models

Statistical Model Checking (SMC) blends the speed of simulation with the rigorous analytical capabilities of model checking, and its success has prompted researchers to implement a number of SMC tools whose availability provides flexibility and fine-tuned control over model analysis. However, each tool has its own practical limitations, and different tools have different requirements and performance characteristics. The performance of different tools may also depend on the specific features of the input model or the type of query to be verified. Consequently, choosing the most suitable tool for verifying any given model requires a significant degree of experience, and in most cases, it is challenging to predict the right one. The aim of our research has been to simplify the model checking process for researchers in biological systems modelling by simplifying and rationalising the model selection process. This has been achieved through delivery of the various key contributions listed below. • We have developed a software component for verification of kernel P (kP) system models, using the NuSMV model checker. We integrated it into a larger software platform (www.kpworkbench.org). • We surveyed five popular SMC tools, comparing their modelling languages, external dependencies, expressibility of specification languages, and performance. To best of our knowledge, this is the first known attempt to categorise the performance of SMC tools based on the commonly used property specifications (property patterns) for model checking. • We have proposed a set of model features which can be used for predicting the fastest SMC for biological model verification, and have shown, moreover, that the proposed features both reduce computation time and increase predictive power. • We used machine learning algorithms for predicting the fastest SMC tool for verification of biological models, and have shown that this approach can successfully predict the fastest SMC tool with over 90% accuracy. • We have developed a software tool, SMC Predictor, that predicts the fastest SMC tool for a given model and property query, and have made this freely available to the wider research community (www.smcpredictor.com). Our results show that using our methodology can generate significant savings in the amount of time and resources required for model verification