Reverse engineering of genetic networks with time delayed recurrent neural networks and clustering techniques

In the iterative process of experimentally probing biological networks and computationally inferring models for the networks, fast, accurate and flexible computational frameworks are needed for modeling and reverse engineering biological networks. In this dissertation, I propose a novel model to simulate gene regulatory networks using a specific type of time delayed recurrent neural networks. Also, I introduce a parameter clustering method to select groups of parameter sets from the simulations representing biologically reasonable networks. Additionally, a general purpose adaptive function is used here to decrease and study the connectivity of small gene regulatory networks modules. In this dissertation, the performance of this novel model is shown to simulate the dynamics and to infer the topology of gene regulatory networks derived from synthetic and experimental time series gene expression data. Here, I assess the quality of the inferred networks by the use of graph edit distance measurements in comparison to the synthetic and experimental benchmarks. Additionally, I compare between edition costs of the inferred networks obtained with the time delay recurrent networks and other previously described reverse engineering methods based on continuous time recurrent neural and dynamic Bayesian networks. Furthermore, I address questions of network connectivity and correlation between data fitting and inference power by simulating common experimental limitations of the reverse engineering process as incomplete and highly noisy data. The novel specific type of time delay recurrent neural networks model in combination with parameter clustering substantially improves the inference power of reverse engineered networks. Additionally, some suggestions for future improvements are discussed, particularly under the data driven perspective as the solution for modeling complex biological systems

Time-delayed models of gene regulatory networks

We discuss different mathematical models of gene regulatory networks as relevant to the onset and development of cancer. After discussion of alternativemodelling approaches, we use a paradigmatic two-gene network to focus on the role played by time delays in the dynamics of gene regulatory networks. We contrast the dynamics of the reduced model arising in the limit of fast mRNA dynamics with that of the full model. The review concludes with the discussion of some open problems

On delayed genetic regulatory networks with polytopic uncertainties: Robust stability analysis

Copyright [2008] IEEE. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of Brunel University's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to [email protected]. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.In this paper, we investigate the robust asymptotic stability problem of genetic regulatory networks with time-varying delays and polytopic parameter uncertainties. Both cases of differentiable and nondifferentiable time-delays are considered, and the convex polytopic description is utilized to characterize the genetic network model uncertainties. By using a Lyapunov functional approach and linear matrix inequality (LMI) techniques, the stability criteria for the uncertain delayed genetic networks are established in the form of LMIs, which can be readily verified by using standard numerical software. An important feature of the results reported here is that all the stability conditions are dependent on the upper and lower bounds of the delays, which is made possible by using up-to-date techniques for achieving delay dependence. Another feature of the results lies in that a novel Lyapunov functional dependent on the uncertain parameters is utilized, which renders the results to be potentially less conservative than those obtained via a fixed Lyapunov functional for the entire uncertainty domain. A genetic network example is employed to illustrate the applicability and usefulness of the developed theoretical results

On robust stability of stochastic genetic regulatory networks with time delays: A delay fractioning approach

Copyright [2009] IEEE. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of Brunel University's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to [email protected]. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.Robust stability serves as an important regulation mechanism in system biology and synthetic biology. In this paper, the robust stability analysis problem is investigated for a class of nonlinear delayed genetic regulatory networks with parameter uncertainties and stochastic perturbations. The nonlinear function describing the feedback regulation satisfies the sector condition, the time delays exist in both translation and feedback regulation processes, and the state-dependent Brownian motions are introduced to reflect the inherent intrinsic and extrinsic noise perturbations. The purpose of the addressed stability analysis problem is to establish some easy-to-verify conditions under which the dynamics of the true concentrations of the messenger ribonucleic acid (mRNA) and protein is asymptotically stable irrespective of the norm-bounded modeling errors. By utilizing a new Lyapunov functional based on the idea of “delay fractioning”, we employ the linear matrix inequality (LMI) technique to derive delay-dependent sufficient conditions ensuring the robust stability of the gene regulatory networks. Note that the obtained results are formulated in terms of LMIs that can easily be solved using standard software packages. Simulation examples are exploited to illustrate the effectiveness of the proposed design procedures

A Method to Identify and Analyze Biological Programs through Automated Reasoning.

Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich but often lack explanatory and predictive power, or dynamic models that can be simulated to reproduce known behavior. However, in such approaches implicit assumptions are introduced as typically only one mechanism is considered, and exhaustively investigating all scenarios is impractical using simulation. To address these limitations, we present a methodology based on automated formal reasoning, which permits the synthesis and analysis of the complete set of logical models consistent with experimental observations. We test hypotheses against all candidate models, and remove the need for simulation by characterizing and simultaneously analyzing all mechanistic explanations of observed behavior. Our methodology transforms knowledge of complex biological processes from sets of possible interactions and experimental observations to precise, predictive biological programs governing cell function

An extended Kalman filtering approach to modeling nonlinear dynamic gene regulatory networks via short gene expression time series

Copyright [2009] IEEE. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of Brunel University's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to [email protected]. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.In this paper, the extended Kalman filter (EKF) algorithm is applied to model the gene regulatory network from gene time series data. The gene regulatory network is considered as a nonlinear dynamic stochastic model that consists of the gene measurement equation and the gene regulation equation. After specifying the model structure, we apply the EKF algorithm for identifying both the model parameters and the actual value of gene expression levels. It is shown that the EKF algorithm is an online estimation algorithm that can identify a large number of parameters (including parameters of nonlinear functions) through iterative procedure by using a small number of observations. Four real-world gene expression data sets are employed to demonstrate the effectiveness of the EKF algorithm, and the obtained models are evaluated from the viewpoint of bioinformatics

Introduction to Focus Issue : Dynamics in Systems Biology

Peer reviewedPublisher PD

Robust H∞ feedback control for uncertain stochastic delayed genetic regulatory networks with additive and multiplicative noise

The official published version can found at the link below.Noises are ubiquitous in genetic regulatory networks (GRNs). Gene regulation is inherently a stochastic process because of intrinsic and extrinsic noises that cause kinetic parameter variations and basal rate disturbance. Time delays are usually inevitable due to different biochemical reactions in such GRNs. In this paper, a delayed stochastic model with additive and multiplicative noises is utilized to describe stochastic GRNs. A feedback gene controller design scheme is proposed to guarantee that the GRN is mean-square asymptotically stable with noise attenuation, where the structure of the controllers can be specified according to engineering requirements. By applying control theory and mathematical tools, the analytical solution to the control design problem is given, which helps to provide some insight into synthetic biology and systems biology. The control scheme is employed in a three-gene network to illustrate the applicability and usefulness of the design.This work was funded by Royal Society of the U.K.; Foundation for the Author of National Excellent Doctoral Dissertation of China. Grant Number: 2007E4; Heilongjiang Outstanding Youth Science Fund of China. Grant Number: JC200809; Fok Ying Tung Education Foundation. Grant Number: 111064; International Science and Technology Cooperation Project of China. Grant Number: 2009DFA32050; University of Science and Technology of China Graduate Innovative Foundation

Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways