Qualitatively modelling genetic regulatory networks : Petri net techniques and tools

The development of post-genomic technologies has led to a paradigm shift in the way we study genetic regulatory networks (GRNs) - the underlying systems which mediate cell function. To complement this, the focus is on devising scalable, unambiguous and automated formal techniques for holistically modelling and analysing these complex systems. Quantitative approaches offer one possible solution, but do not appear to be commensurate with currently available data. This motivates qualitative approaches such as Boolean networks (BNs) , which abstractly model the system without requiring such a high level of data completeness. Qualitative approaches enable fundamental dynamical properties to be studied, and are well-suited to initial investigations. However, strengthened formal techniques and tool support are required if they are to meet the demands of the biological community. This thesis aims to investigate, develop and evaluate the application of Petri nets (PNs) for qualitatively modelling and analysing GRNs. PNs are well-established in the field of computer science, and enjoy a number of attractive benefits, such a wide range of techniques and tools, which make them ideal for studying biological systems. We take an existing qualitative PN approach for modelling GRNs based on BNs, and extend it to more general models based on multi-valued networks (MVNs). Importantly, we develop tool support to automate model construction. We illustrate our approach with two detailed case studies on Boolean models for carbon stress in Escherichia coli and sporulation in Bacillus subtilis, and then consider a multi-valued model of the former. These case studies explore the analysis power of PN s by exploiting a range of techniques and tools. A number of behavioural differences are identified between the two E. coli models which lead us to question their formal relationship. We investigate this by proposing a framework for reasoning about the behaviour of MVNs at different levels of abstraction. We develop tool support for practical models, and show a number of important results which motivate the need for multi-valued modelling. Asynchronous BN s can be seen to be more biologically realistic than their synchronous counterparts. However, they have the drawback of capturing behaviour which is unrealisable in practice. We propose a novel approach for refining such behaviour using signal transition graphs, a PN formalism from asynchronous circuit design. We automate our approach, and demonstrate it using a BN of the lysis-lysogeny switch in phage A. Our results show that a more realistic asynchronous model can be derived which preserves the stochastic switch.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A High Level Net Approach For Discovering Potential Incosistencies In Fuzzy Knowledge Bases

The problem of verifying the integrity of fuzzy knowledge bases is discussed. An approach to find potential inconsistencies in fuzzy rule based systems is described. The approach models the knowledge base as a High Level Fuzzy Petri Net and uses the structural properties of the net for verification. Basic notions on approximate reasoning, regular and hierarchical High Level Fuzzy Petri Nets are also given. The method used for consistency checking is reviewed through the analysis of several cases including simple and chaining rules. Procedures for discovering potential inconsistencies at both local and global levels are described. © 1994.642175193Agarwal, Tanniru, A Petri-Net based approach for verifying the integrity of production systems (1992) Int. J. Man-Machine Studies, 36, pp. 447-468Chang, Hall, The validation of fuzzy knowledge-based systems (1992) Fuzzy Logic and the Management of Uncertainty, pp. 589-604. , L. Zadeh, J. Kacprzyk, John Wiley & Sons, New YorkChen, Ke, Chang, Knowledge representation using fuzzy Petri nets (1990) IEEE Trans. Knowledge and Data Engineering, 2, pp. 311-319Dubois, Prade, Fuzzy sets in approximate reasoning, part 1: inference with possibility distributions (1991) Fuzzy Sets and Systems, 40, pp. 143-202Genrich, Predicate/Transition nets (1986) Petri Nets: Central Models and their Properties, 254, pp. 207-247. , W. Brauer, W. Reisig, G. Rozenberg, 2nd edition, Lecture Notes in Computer Science, Springer-Verlag, BerlinGiordana, Saitta, Modeling production rules by means of predicate transition networks (1985) Information Sciences, 35, pp. 1-41Gupta, Qi, Theory of T-norms and fuzzy inference methods (1991) Fuzzy Sets and Systems, 40, pp. 431-450Leung, So, Inconsistency in fuzzy rule-based expert systems (1990) Proceedings of the International Conference on Fuzzy Logic & Neural Networks, pp. 849-852. , JapanMizumoto, Zimmermann, Comparison of fuzzy reasoning methods (1982) Fuzzy Sets and Systems, 8, pp. 253-283Murata, Petri nets: properties, analysis and applications (1989) Proceedings IEEE, 77, pp. 541-580. , 2nd editionNazareth, Issues in the verification of knowledge in rule-based systems (1989) Int. J. Man-Machine Studies, 30, pp. 255-271Pedrycz, (1989) Fuzzy Control and Fuzzy Systems, , Wiley, New YorkScarpelli, Gomide, Modeling fuzzy reasoning using fuzzy Petri nets (1992) Tech. Rep. RT-DCA 020/92, , 2nd edition, DCA/FEE/UNICAMP, Campinas, SPScarpelli, Gomide, Pedrycz, Modeling fuzzy reasoning using high level fuzzy Petri nets (1992) Tech. Rep. RT-DCA 023/92, , 2nd edition, DCA/FEE/UNICAMP, Campinas, SP, (submitted)Scarpelli, Gomide, Yager, A backward reasoning algorithm for high level fuzzy Petri nets (1993) Tech. Rep. RT-DCA 004/93, , 2nd edition, DCA/FEE/UNICAMP, Campinas, SP, (submitted)Scarpelli, Gomide, Fuzzy reasoning and fuzzy Petri nets (1993) Proc. Fifth IFSA World Congress, pp. 1326-1329. , Seoul, KoreaScarpelli, Gomide, Fuzzy reasoning and fuzzy Petri nets in manufacturing systems modeling (1993) Journal of Intelligent and Fuzzy Systems, 1, pp. 225-241Scarpelli, Gomide, Discovering potential inconsistencies in fuzzy knowledge bases using high level nets (1993) Tech. Rep. RT-DCA 006/93, , 2nd edition, DCA/FEE/UNICAMP, Campinas, SPScarpelli, Modeling, design and verification of fuzzy rule bases using net theory (1993) Doctoral Thesis, , 2nd edition, DCA/FEE/UNICAMP, Campinas, SP, (in Portuguese)Scarpelli, Gomide, Fuzzy reasoning and high level fuzzy Petri nets (1993) Proc. First European Congress on Fuzzy and Intelligent Technologies, , Aachen, GermanyYager, Larsen, On discovering potential inconsistencies in validating uncertain knowledge bases by reflecting on the input (1991) IEEE Trans. on Systems, Man and Cybernetics, 21, pp. 790-801Yager, Connectives and quantifiers in fuzzy sets (1991) Fuzzy Sets and Systems, 40, pp. 39-75Zadeh, Fuzzy sets as a basis for a theory of possibility (1978) Fuzzy Sets and Systems, 1, pp. 3-20Zadeh, A theory of approximate reasoning (1979) Machine Inteligence, 9, pp. 149-194. , 2nd edition, Hayes, Michie, Kulich, John Wiley & Sons, New Yor