A generic approach to behaviour-driven biochemical model construction

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Modelling of biochemical systems has received considerable attention over the last decade from bioengineering, biochemistry, computer science, and mathematics. This thesis investigates the applications of computational techniques to computational systems biology, for the construction of biochemical models in terms of topology and kinetic rates. Due to the complexity of biochemical systems, it is natural to construct models representing the biochemical systems incrementally in a piecewise manner. Syntax and semantics of two patterns are defined for the instantiation of components which are extendable, reusable and fundamental building blocks for models composition. We propose and implement a set of genetic operators and composition rules to tackle issues of piecewise composing models from scratch. Quantitative Petri nets are evolved by the genetic operators, and evolutionary process of modelling are guided by the composition rules. Metaheuristic algorithms are widely applied in BioModel Engineering to support intelligent and heuristic analysis of biochemical systems in terms of structure and kinetic rates. We illustrate parameters of biochemical models based on Biochemical Systems Theory, and then the topology and kinetic rates of the models are manipulated by employing evolution strategy and simulated annealing respectively. A new hybrid modelling framework is proposed and implemented for the models construction. Two heuristic algorithms are performed on two embedded layers in the hybrid framework: an outer layer for topology mutation and an inner layer for rates optimization. Moreover, variants of the hybrid piecewise modelling framework are investigated. Regarding flexibility of these variants, various combinations of evolutionary operators, evaluation criteria and design principles can be taken into account. We examine performance of five sets of the variants on specific aspects of modelling. The comparison of variants is not to explicitly show that one variant clearly outperforms the others, but it provides an indication of considering important features for various aspects of the modelling. Because of the very heavy computational demands, the process of modelling is paralleled by employing a grid environment, GridGain. Application of the GridGain and heuristic algorithms to analyze biological processes can support modelling of biochemical systems in a computational manner, which can also benefit mathematical modelling in computer science and bioengineering. We apply our proposed modelling framework to model biochemical systems in a hybrid piecewise manner. Modelling variants of the framework are comparatively studied on specific aims of modelling. Simulation results show that our modelling framework can compose synthetic models exhibiting similar species behaviour, generate models with alternative topologies and obtain general knowledge about key modelling features

Improving Software Model Inference by Combining State Merging and Markov Models

Labelled-transition systems (LTS) are widely used by developers and testers to model software systems in terms of their sequential behaviour. They provide an overview of the behaviour of the system and their reaction to different inputs. LTS models are the foundation for various automated verification techniques such as model-checking and model-based testing. These techniques require up-to-date models to be meaningful. Unfortunately, software models are rare in practice. Due to the effort and time required to build these models manually, a software engineer would want to infer them automatically from traces (sequences of events or function calls). Many techniques have focused on inferring LTS models from given traces of system execution, where these traces are produced by running a system on a series of tests. State-merging is the foundation of some of the most successful LTS inference techniques to construct LTS models. Passive inference approaches such as k-tail and Evidence-Driven State Merging (EDSM) can infer LTS models from these traces. Moreover, the best-performing methods of inferring LTS models rely on the availability of negatives, i.e. traces that are not permitted from specific states and such information is not usually available. The long-standing challenge for such inference approaches is constructing models well from very few traces and without negatives. Active inference techniques such as Query-driven State Merging (QSM) can learn LTSs from traces by asking queries as tests to a system being learnt. It may lead to infer inaccurate LTSs since the performance of QSM relies on the availability of traces. The challenge for such inference approaches is inferring LTSs well from very few traces and with fewer queries asked. In this thesis, investigations of the existing techniques are presented to the challenge of inferring LTS models from few positive traces. These techniques fail to find correct LTS models in cases of insufficient training data. This thesis focuses on finding better solutions to this problem by using evidence obtained from the Markov models to bias the EDSM learner towards merging states that are more likely to correspond to the same state in a model. Markov models are used to capture the dependencies between event sequences in the collected traces. Those dependencies rely on whether elements of event permitted or prohibited to follow short sequences appear in the traces. This thesis proposed EDSM-Markov a passive inference technique that aimed to improve the existing ones in the absence of negative traces and to prevent the over-generalization problem. In this thesis, improvements obtained by the proposed learners are demonstrated by a series of experiments using randomly-generated labelled-transition systems and case studies. The results obtained from the conducted experiments showed that EDSM-Markov can infer better LTSs compared to other techniques. This thesis also proposes modifications to the QSM learner to improve the accuracy of the inferred LTSs. This results in a new learner, which is named ModifiedQSM. This includes considering more tests to the system being inferred in order to avoid the over-generalization problem. It includes investigations of using Markov models to reduce the number of queries consumed by the ModifiedQSM learner. Hence, this thesis introduces a new LTS inference technique, which is called MarkovQSM. Moreover, enhancements of LTSs inferred by ModifiedQSM and MarkovQSM learners are demonstrated by a series of experiments. The results from the experiments demonstrate that ModifiedQSM can infer better LTSs compared to other techniques. Moreover, MarkovQSM has proven to significantly reduce the number of membership queries consumed compared to ModifiedQSM with a very small loss of accuracy

A treatment of stereochemistry in computer aided organic synthesis

This thesis describes the author’s contributions to a new stereochemical processing module constructed for the ARChem retrosynthesis program. The purpose of the module is to add the ability to perform enantioselective and diastereoselective retrosynthetic disconnections and generate appropriate precursor molecules. The module uses evidence based rules generated from a large database of literature reactions. Chapter 1 provides an introduction and critical review of the published body of work for computer aided synthesis design. The role of computer perception of key structural features (rings, functions groups etc.) and the construction and use of reaction transforms for generating precursors is discussed. Emphasis is also given to the application of strategies in retrosynthetic analysis. The availability of large reaction databases has enabled a new generation of retrosynthesis design programs to be developed that use automatically generated transforms assembled from published reactions. A brief description of the transform generation method employed by ARChem is given. Chapter 2 describes the algorithms devised by the author for handling the computer recognition and representation of the stereochemical features found in molecule and reaction scheme diagrams. The approach is generalised and uses flexible recognition patterns to transform information found in chemical diagrams into concise stereo descriptors for computer processing. An algorithm for efficiently comparing and classifying pairs of stereo descriptors is described. This algorithm is central for solving the stereochemical constraints in a variety of substructure matching problems addressed in chapter 3. The concise representation of reactions and transform rules as hyperstructure graphs is described. Chapter 3 is concerned with the efficient and reliable detection of stereochemical symmetry in both molecules, reactions and rules. A novel symmetry perception algorithm, based on a constraints satisfaction problem (CSP) solver, is described. The use of a CSP solver to implement an isomorph‐free matching algorithm for stereochemical substructure matching is detailed. The prime function of this algorithm is to seek out unique retron locations in target molecules and then to generate precursor molecules without duplications due to symmetry. Novel algorithms for classifying asymmetric, pseudo‐asymmetric and symmetric stereocentres; meso, centro, and C2 symmetric molecules; and the stereotopicity of trigonal (sp2) centres are described. Chapter 4 introduces and formalises the annotated structural language used to create both retrosynthetic rules and the patterns used for functional group recognition. A novel functional group recognition package is described along with its use to detect important electronic features such as electron‐withdrawing or donating groups and leaving groups. The functional groups and electronic features are used as constraints in retron rules to improve transform relevance. Chapter 5 details the approach taken to design detailed stereoselective and substrate controlled transforms from organised hierarchies of rules. The rules employ a rich set of constraints annotations that concisely describe the keying retrons. The application of the transforms for collating evidence based scoring parameters from published reaction examples is described. A survey of available reaction databases and the techniques for mining stereoselective reactions is demonstrated. A data mining tool was developed for finding the best reputable stereoselective reaction types for coding as transforms. For various reasons it was not possible during the research period to fully integrate this work with the ARChem program. Instead, Chapter 6 introduces a novel one‐step retrosynthesis module to test the developed transforms. The retrosynthesis algorithms use the organisation of the transform rule hierarchy to efficiently locate the best retron matches using all applicable stereoselective transforms. This module was tested using a small set of selected target molecules and the generated routes were ranked using a series of measured parameters including: stereocentre clearance and bond cleavage; example reputation; estimated stereoselectivity with reliability; and evidence of tolerated functional groups. In addition a method for detecting regioselectivity issues is presented. This work presents a number of algorithms using common set and graph theory operations and notations. Appendix A lists the set theory symbols and meanings. Appendix B summarises and defines the common graph theory terminology used throughout this thesis

Network communities and the foreign exchange market

Many systems studied in the biological, physical, and social sciences are composed of multiple interacting components. Often the number of components and interactions is so large that attaining an understanding of the system necessitates some form of simplication. A common representation that captures the key connection patterns is a network in which the nodes correspond to system components and the edges represent interactions. In this thesis we use network techniques and more traditional clustering methods to coarse-grain systems composed of many interacting components and to identify the most important interactions.\ud \ud This thesis focuses on two main themes: the analysis of financial systems and the study of network communities, an important mesoscopic feature of many networks. In the first part of the thesis, we discuss some of the issues associated with the analysis of financial data and investigate the potential for risk-free profit in the foreign exchange market. We then use principal component analysis (PCA) to identify common features in the correlation structure of different financial markets. In the second part of the thesis, we focus on network communities. We investigate the evolving structure of foreign exchange (FX) market correlations by representing the correlations as time-dependent networks and investigating the evolution of network communities. We employ a node-centric approach that allows us to track the effects of the community evolution on the functional roles of individual nodes and uncovers major trading changes that occurred in the market. Finally, we consider the community structure of networks from a wide variety of different disciplines. We introduce a framework for comparing network communities and use this technique to identify networks with similar mesoscopic structures. Based on this similarity, we create taxonomies of a large set of networks from different fields and individual families of networks from the same field

High Performance Computing Based Methods for Simulation and Optimisation of Flow Problems

The thesis is concerned with the study of methods in high-performance computing for simulation and optimisation of flow problems that occur in the framework of microflows. We consider the adequate use of techniques in parallel computing by means of finite element based solvers for partial differential equations and by means of sensitivity- and adjoint-based optimisation methods. The main focus is on three-dimensional, low Reynolds number flows described by the instationary Navier-Stokes equations

Biological image analysis

In biological research images are extensively used to monitor growth, dynamics and changes in biological specimen, such as cells or plants. Many of these images are used solely for observation or are manually annotated by an expert. In this dissertation we discuss several methods to automate the annotating and analysis of bio-images. Two large clusters of methods have been investigated and developed. A first set of methods focuses on the automatic delineation of relevant objects in bio-images, such as individual cells in microscopic images. Since these methods should be useful for many different applications, e.g. to detect and delineate different objects (cells, plants, leafs, ...) in different types of images (different types of microscopes, regular colour photographs, ...), the methods should be easy to adjust. Therefore we developed a methodology relying on probability theory, where all required parameters can easily be estimated by a biologist, without requiring any knowledge on the techniques used in the actual software. A second cluster of investigated techniques focuses on the analysis of shapes. By defining new features that describe shapes, we are able to automatically classify shapes, retrieve similar shapes from a database and even analyse how an object deforms through time