Reconciling periodic rhythms of large-scale biological networks by optimal control

Periodic rhythms are ubiquitous phenomena that illuminate the underlying mechanism of cyclic activities in biological systems, which can be represented by cyclic attractors of the related biological network. Disorders of periodic rhythms are detrimental to the natural behaviours of living organisms. Previous studies have shown that the state transition from one to another attractor can be accomplished by regulating external signals. However, most of these studies until now have mainly focused on point attractors while ignoring cyclic ones. The aim of this study is to investigate an approach for reconciling abnormal periodic rhythms, such as diminished circadian amplitude and phase delay, to the regular rhythms of complex biological networks. For this purpose, we formulate and solve a mixed-integer nonlinear dynamic optimization problem simultaneously to identify regulation variables and to determine optimal control strategies for state transition and adjustment of periodic rhythms. Numerical experiments are implemented in three examples including a chaotic system, a mammalian circadian rhythm system and a gastric cancer gene regulatory network. The results show that regulating a small number of biochemical molecules in the network is sufficient to successfully drive the system to the target cyclic attractor by implementing an optimal control strategy

Control and Data Analysis of Complex Networks

abstract: This dissertation treats a number of related problems in control and data analysis of complex networks. First, in existing linear controllability frameworks, the ability to steer a network from any initiate state toward any desired state is measured by the minimum number of driver nodes. However, the associated optimal control energy can become unbearably large, preventing actual control from being realized. Here I develop a physical controllability framework and propose strategies to turn physically uncontrollable networks into physically controllable ones. I also discover that although full control can be guaranteed by the prevailing structural controllability theory, it is necessary to balance the number of driver nodes and control energy to achieve actual control, and my work provides a framework to address this issue. Second, in spite of recent progresses in linear controllability, controlling nonlinear dynamical networks remains an outstanding problem. Here I develop an experimentally feasible control framework for nonlinear dynamical networks that exhibit multistability. The control objective is to apply parameter perturbation to drive the system from one attractor to another. I introduce the concept of attractor network and formulate a quantifiable framework: a network is more controllable if the attractor network is more strongly connected. I test the control framework using examples from various models and demonstrate the beneficial role of noise in facilitating control. Third, I analyze large data sets from a diverse online social networking (OSN) systems and find that the growth dynamics of meme popularity exhibit characteristically different behaviors: linear, “S”-shape and exponential growths. Inspired by cell population growth model in microbial ecology, I construct a base growth model for meme popularity in OSNs. Then I incorporate human interest dynamics into the base model and propose a hybrid model which contains a small number of free parameters. The model successfully predicts the various distinct meme growth dynamics. At last, I propose a nonlinear dynamics model to characterize the controlling of WNT signaling pathway in the differentiation of neural progenitor cells. The model is able to predict experiment results and shed light on the understanding of WNT regulation mechanisms.Dissertation/ThesisDoctoral Dissertation Electrical Engineering 201

Reverse Engineering of Biological Systems

Gene regulatory network (GRN) consists of a set of genes and regulatory relationships between the genes. As outputs of the GRN, gene expression data contain important information that can be used to reconstruct the GRN to a certain degree. However, the reverse engineer of GRNs from gene expression data is a challenging problem in systems biology. Conventional methods fail in inferring GRNs from gene expression data because of the relative less number of observations compared with the large number of the genes. The inherent noises in the data make the inference accuracy relatively low and the combinatorial explosion nature of the problem makes the inference task extremely difficult. This study aims at reconstructing the GRNs from time-course gene expression data based on GRN models using system identification and parameter estimation methods. The main content consists of three parts: (1) a review of the methods for reverse engineering of GRNs, (2) reverse engineering of GRNs based on linear models and (3) reverse engineering of GRNs based on a nonlinear model, specifically S-systems. In the first part, after the necessary background and challenges of the problem are introduced, various methods for the inference of GRNs are comprehensively reviewed from two aspects: models and inference algorithms. The advantages and disadvantages of each method are discussed. The second part focus on inferring GRNs from time-course gene expression data based on linear models. First, the statistical properties of two sparse penalties, adaptive LASSO and SCAD, with an autoregressive model are studied. It shows that the proposed methods using these two penalties can asymptotically reconstruct the underlying networks. This provides a solid foundation for these methods and their extensions. Second, the integration of multiple datasets should be able to improve the accuracy of the GRN inference. A novel method, Huber group LASSO, is developed to infer GRNs from multiple time-course data, which is also robust to large noises and outliers that the data may contain. An efficient algorithm is also developed and its convergence analysis is provided. The third part can be further divided into two phases: estimating the parameters of S-systems with system structure known and inferring the S-systems without knowing the system structure. Two methods, alternating weighted least squares (AWLS) and auxiliary function guided coordinate descent (AFGCD), have been developed to estimate the parameters of S-systems from time-course data. AWLS takes advantage of the special structure of S-systems and significantly outperforms one existing method, alternating regression (AR). AFGCD uses the auxiliary function and coordinate descent techniques to get the smart and efficient iteration formula and its convergence is theoretically guaranteed. Without knowing the system structure, taking advantage of the special structure of the S-system model, a novel method, pruning separable parameter estimation algorithm (PSPEA) is developed to locally infer the S-systems. PSPEA is then combined with continuous genetic algorithm (CGA) to form a hybrid algorithm which can globally reconstruct the S-systems

A control theoretic perspective on social networks

This thesis discusses the application of control theory to the study of complex networks, drawing inspiration from the behavior of social networks. There are three topic areas covered by the thesis. The first area considers the ability to control a dynamical system which evolves over a network. Specifically, this thesis introduces a network controllability notion known as herdability. Herdability quantifies the ability to encourage general behavioral change in a system via a set-based reachability condition, which describes a class of desirable behaviors for the application of control in a social network setting. The notion is closely related to the classical notion of controllability, however ensuring complete controllability of large complex networks is often unnecessary for certain beneficial behaviors to be achieved. The basic theory of herdability is developed in this thesis. The second area of study, which builds directly on the first, is the application of herdability to the study of complex networks. Specifically, this thesis explores how to make a network herdable, an extension of the input selection problem which is often discussed in the context of controllability. The input selection problem in this case considers which nodes to select to ensure the maximal number of nodes in the system are herdable. When there are multiple single node sets which can be used to make a system completely herdable, a herdability centrality measure is introduced to differentiate between them. The herdability centrality measure, a measure of importance with respect to the ability to herd the network with minimum energy, is compared to existing centrality measures. The third area explores modeling the spread of the adoption of a beneficial behavior or an idea, in which the spread is encouraged by the action of a social network. A novel model of awareness-coupled epidemic spread is introduced, where agents in a network are aware of a virus (here representing something which should be spread) moving through the network. If the agents have a high opinion of the virus, they are more likely to adopt it. The behavior of this viral model is considered both analytically and in simulation.Ph.D

A multi-objective mathematical model for the optimization of the transittability of complex biomolecular networks

International audienceThe fundamental goal of systems biology is to understand the dynamic aspects of cells and their behaviour. This organism is represented by a network so-called complex biomolecular network in which the nodes represent the different cellular components and the edges represent the interactions occurring among them. Through this network, it is easy to study the transition states and the dynamic behaviour of cells. Indeed, perturbing some nodes of the biomolecular network induce the transition of all the network. This process, known as the ”transittability”, expresses the idea of steering the complex biomolecular network from an unexpected state to a desired state.In this context, we are thus interested in how to use the transittability of biomolecular networks to increase the efficiency of translational medicine for improving human health and disease, including genetic and environmental factors of of patient’s well-being. This is a great opportunity to understand diseases, and find new diagnoses and treatments.Due to its complexity, the transittability of complex biomolecular networks can be considered as an optimization problem. Up to a recent date only few studies have been carried out in this problem. Most of them focused only on the minimization of the required nodes to steer the entire network, and others considered the minimization of the number of stimuli to be applied on the network. However, this assumption is not always realistic, because steering complex biomolecular networks is in general a multi-objective optimization problem. It requires finding appropriate trade-offs among various objectives, for example between the appropriate nodes to be stimulated and the number of external stimuli to be used and their cost, and the impact on patient’s well-being.In this paper, the optimization of the transittability of complex biomolecular networks is investigated from the multi-objective perspective. In the mathematical model four criteria are considered simultaneously: the minimization of the number of external stimuli, the minimization of their total cost, the minimization of the number of target nodes, and the minimization of the patient discomfort. All these objectives are described theoretically and mathematically in detail