Browsing by Author "Hinkelmann, Franziska"
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- ADAM: Analysis of Discrete Models of Biological Systems Using Computer AlgebraHinkelmann, Franziska; Brandon, Madison; Guang, Bonny; McNeill, Rustin; Blekherman, Grigoriy; Veliz-Cuba, Alan; Laubenbacher, Reinhard C. (2011-07-20)Background Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, to gain a better understanding of them. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. There exist software tools to analyze discrete models, but they either lack the algorithmic functionality to analyze complex models deterministically or they are inaccessible to many users as they require understanding the underlying algorithm and implementation, do not have a graphical user interface, or are hard to install. Efficient analysis methods that are accessible to modelers and easy to use are needed. Results We propose a method for efficiently identifying attractors and introduce the web-based tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness and robustness. For a large set of published complex discrete models, ADAM identified the attractors in less than one second. Conclusions Discrete modeling techniques are a useful tool for analyzing complex biological systems and there is a need in the biological community for accessible efficient analysis tools. ADAM provides analysis methods based on mathematical algorithms as a web-based tool for several different input formats, and it makes analysis of complex models accessible to a larger community, as it is platform independent as a web-service and does not require understanding of the underlying mathematics.
- Algebraic theory for discrete models in systems biologyHinkelmann, Franziska (Virginia Tech, 2011-08-01)This dissertation develops algebraic theory for discrete models in systems biology. Many discrete model types can be translated into the framework of polynomial dynamical systems (PDS), that is, time- and state-discrete dynamical systems over a finite field where the transition function for each variable is given as a polynomial. This allows for using a range of theoretical and computational tools from computer algebra, which results in a powerful computational engine for model construction, parameter estimation, and analysis methods. Formal definitions and theorems for PDS and the concept of PDS as models of biological systems are introduced in section 1.3. Constructing a model for given time-course data is a challenging problem. Several methods for reverse-engineering, the process of inferring a model solely based on experimental data, are described briefly in section 1.3. If the underlying dependencies of the model components are known in addition to experimental data, inferring a "good" model amounts to parameter estimation. Chapter 2 describes a parameter estimation algorithm that infers a special class of polynomials, so called nested canalyzing functions. Models consisting of nested canalyzing functions have been shown to exhibit desirable biological properties, namely robustness and stability. The algorithm is based on the parametrization of nested canalyzing functions. To demonstrate the feasibility of the method, it is applied to the cell-cycle network of budding yeast. Several discrete model types, such as Boolean networks, logical models, and bounded Petri nets, can be translated into the framework of PDS. Section 3 describes how to translate agent-based models into polynomial dynamical systems. Chapter 4, 5, and 6 are concerned with analysis of complex models. Section 4 proposes a new method to identify steady states and limit cycles. The method relies on the fact that attractors correspond to the solutions of a system of polynomials over a finite field, a long-studied problem in algebraic geometry which can be efficiently solved by computing Gröbner bases. Section 5 introduces a bit-wise implementation of a Gröbner basis algorithm for Boolean polynomials. This implementation has been incorporated into the core engine of Macaulay 2. Chapter 6 discusses bistability for Boolean models formulated as polynomial dynamical systems.
- Steady state analysis of Boolean molecular network models via model reduction and computational algebraVeliz-Cuba, Alan; Aguilar, Boris; Hinkelmann, Franziska; Laubenbacher, Reinhard C. (2014-06-26)Background A key problem in the analysis of mathematical models of molecular networks is the determination of their steady states. The present paper addresses this problem for Boolean network models, an increasingly popular modeling paradigm for networks lacking detailed kinetic information. For small models, the problem can be solved by exhaustive enumeration of all state transitions. But for larger models this is not feasible, since the size of the phase space grows exponentially with the dimension of the network. The dimension of published models is growing to over 100, so that efficient methods for steady state determination are essential. Several methods have been proposed for large networks, some of them heuristic. While these methods represent a substantial improvement in scalability over exhaustive enumeration, the problem for large networks is still unsolved in general. Results This paper presents an algorithm that consists of two main parts. The first is a graph theoretic reduction of the wiring diagram of the network, while preserving all information about steady states. The second part formulates the determination of all steady states of a Boolean network as a problem of finding all solutions to a system of polynomial equations over the finite number system with two elements. This problem can be solved with existing computer algebra software. This algorithm compares favorably with several existing algorithms for steady state determination. One advantage is that it is not heuristic or reliant on sampling, but rather determines algorithmically and exactly all steady states of a Boolean network. The code for the algorithm, as well as the test suite of benchmark networks, is available upon request from the corresponding author. Conclusions The algorithm presented in this paper reliably determines all steady states of sparse Boolean networks with up to 1000 nodes. The algorithm is effective at analyzing virtually all published models even those of moderate connectivity. The problem for large Boolean networks with high average connectivity remains an open problem.