Probabilistic Boolean Networks Research Articles

Controllability of probabilistic Boolean control networks

This paper deals with the controllability of probabilistic Boolean control networks. First, a survey on the semi-tensor product approach to probabilistic Boolean networks is given. Second, the controllability of probabilistic Boolean control networks via two kinds inputs is studied. Finally, examples are given to show the efficiency of the obtained results.

ADAM: analysis of discrete models of biological systems using computer algebra.

BackgroundMany 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.ResultsWe 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.ConclusionsDiscrete 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.

Intervention in Gene Regulatory Networks via Phenotypically Constrained Control Policies Based on Long-Run Behavior

A salient purpose for studying gene regulatory networks is to derive intervention strategies to identify potential drug targets and design gene-based therapeutic intervention. Optimal and approximate intervention strategies based on the transition probability matrix of the underlying Markov chain have been studied extensively for probabilistic Boolean networks. While the key goal of control is to reduce the steady-state probability mass of undesirable network states, in practice it is important to limit collateral damage and this constraint should be taken into account when designing intervention strategies with network models. In this paper, we propose two new phenotypically constrained stationary control policies by directly investigating the effects on the network long-run behavior. They are derived to reduce the risk of visiting undesirable states in conjunction with constraints on the shift of undesirable steady-state mass so that only limited collateral damage can be introduced. We have studied the performance of the new constrained control policies together with the previous greedy control policies to randomly generated probabilistic Boolean networks. A preliminary example for intervening in a metastatic melanoma network is also given to show their potential application in designing genetic therapeutics to reduce the risk of entering both aberrant phenotypes and other ambiguous states corresponding to complications or collateral damage. Experiments on both random network ensembles and the melanoma network demonstrate that, in general, the new proposed control policies exhibit the desired performance. As shown by intervening in the melanoma network, these control policies can potentially serve as future practical gene therapeutic intervention strategies.

Construction of Probabilistic Boolean Networks from a Prescribed Transition Probability Matrix: A Maximum Entropy Rate Approach

AbstractModeling genetic regulatory networks is an important problem in genomic research. Boolean Networks (BNs) and their extensions Probabilistic Boolean Networks (PBNs) have been proposed for modeling genetic regulatory interactions. In a PBN, its steady-state distribution gives very important information about the long-run behavior of the whole network. However, one is also interested in system synthesis which requires the construction of networks. The inverse problem is ill-posed and challenging, as there may be many networks or no network having the given properties, and the size of the problem is huge. The construction of PBNs from a given transition-probability matrix and a given set of BNs is an inverse problem of huge size. We propose a maximum entropy approach for the above problem. Newton's method in conjunction with the Conjugate Gradient (CG) method is then applied to solving the inverse problem. We investigate the convergence rate of the proposed method. Numerical examples are also given to demonstrate the effectiveness of our proposed method.

An integer programming approach to optimal control problems in context-sensitive probabilistic Boolean networks

A Boolean network is one of the models of biological networks such as gene regulatory networks, and has been extensively studied. In particular, a probabilistic Boolean network (PBN) is well known as an extension of Boolean networks, but in the existing methods to solve the optimal control problem of PBNs, it is necessary to compute the state transition diagram with 2 n nodes for a given PBN with n states. To avoid this computation, an integer programming-based approach is proposed for a context-sensitive PBN (CS-PBN), which is a general form of PBNs. In the proposed method, a CS-PBN is transformed into a linear system with binary variables, and the optimal control problem is reduced to an integer linear programming problem. By a numerical example, the effectiveness of the proposed method is shown.

Hybrid Modeling of Cell Signaling and Transcriptional Reprogramming and Its Application in C. elegans Development.

Modeling of signal driven transcriptional reprogramming is critical for understanding of organism development, human disease, and cell biology. Many current modeling techniques discount key features of the biological sub-systems when modeling multiscale, organism-level processes. We present a mechanistic hybrid model, GESSA, which integrates a novel pooled probabilistic Boolean network model of cell signaling and a stochastic simulation of transcription and translation responding to a diffusion model of extracellular signals. We apply the model to simulate the well studied cell fate decision process of the vulval precursor cells (VPCs) in C. elegans, using experimentally derived rate constants wherever possible and shared parameters to avoid overfitting. We demonstrate that GESSA recovers (1) the effects of varying scaffold protein concentration on signal strength, (2) amplification of signals in expression, (3) the relative external ligand concentration in a known geometry, and (4) feedback in biochemical networks. We demonstrate that setting model parameters based on wild-type and LIN-12 loss-of-function mutants in C. elegans leads to correct prediction of a wide variety of mutants including partial penetrance of phenotypes. Moreover, the model is relatively insensitive to parameters, retaining the wild-type phenotype for a wide range of cell signaling rate parameters.

A matrix perturbation method for computing the steady-state probability distributions of probabilistic Boolean networks with gene perturbations

Modeling genetic regulatory interactions is an important issue in systems biology. Probabilistic Boolean networks (PBNs) have been proved to be a useful tool for the task. The steady-state probability distribution of a PBN gives important information about the captured genetic network. The computation of the steady-state probability distribution involves the construction of the transition probability matrix of the PBN. The size of the transition probability matrix is 2 n × 2 n where n is the number of genes. Although given the number of genes and the perturbation probability in a perturbed PBN, the perturbation matrix is the same for different PBNs, the storage requirement for this matrix is huge if the number of genes is large. Thus an important issue is developing computational methods from the perturbation point of view. In this paper, we analyze and estimate the steady-state probability distribution of a PBN with gene perturbations. We first analyze the perturbation matrix. We then give a perturbation matrix analysis for the captured PBN problem and propose a method for computing the steady-state probability distribution. An approximation method with error analysis is then given for further reducing the computational complexity. Numerical experiments are given to demonstrate the efficiency of the proposed methods.

State reduction for network intervention in probabilistic Boolean networks.

A key goal of studying biological systems is to design therapeutic intervention strategies. Probabilistic Boolean networks (PBNs) constitute a mathematical model which enables modeling, predicting and intervening in their long-run behavior using Markov chain theory. The long-run dynamics of a PBN, as represented by its steady-state distribution (SSD), can guide the design of effective intervention strategies for the modeled systems. A major obstacle for its application is the large state space of the underlying Markov chain, which poses a serious computational challenge. Hence, it is critical to reduce the model complexity of PBNs for practical applications. We propose a strategy to reduce the state space of the underlying Markov chain of a PBN based on a criterion that the reduction least distorts the proportional change of stationary masses for critical states, for instance, the network attractors. In comparison to previous reduction methods, we reduce the state space directly, without deleting genes. We then derive stationary control policies on the reduced network that can be naturally induced back to the original network. Computational experiments study the effects of the reduction on model complexity and the performance of designed control policies which is measured by the shift of stationary mass away from undesirable states, those associated with undesirable phenotypes. We consider randomly generated networks as well as a 17-gene gastrointestinal cancer network, which, if not reduced, has a 2(17) × 2(17) transition probability matrix. Such a dimension is too large for direct application of many previously proposed PBN intervention strategies.

Characterizing the Effect of Coarse-Scale PBN Modeling on Dynamics and Intervention Performance of Genetic Regulatory Networks Represented by Stochastic Master Equation Models

Fine-scale models based on stochastic master equations can provide the most detailed description of the dynamics of gene expression and imbed, in principle, all the information about the biochemical reactions involved in gene interactions. However, there is limited time-series experimental data available for inference of such fine-scale models. Furthermore, the computational complexity involved in the design of optimal intervention strategies to favorably effect system dynamics for such detailed models is enormous. Thus, there is a need to design mappings from fine-scale models to coarse-scale models while maintaining sufficient structure for the problem at hand and to study the effect of intervention policies designed using coarse-scale models when applied to fine-scale models. In this paper, we propose a mapping from a fine-scale model represented by a stochastic master equation to a coarse-scale model represented by a probabilistic Boolean network that maintains the collapsed steady state probability distribution of the detailed model. We also derive bounds on the performance of the intervention strategy designed using the coarse-scale model when applied to the fine-scale model.

A CoD-based reduction algorithm for designing stationary control policies on Boolean networks

Gene regulatory networks serve as models from which to derive therapeutic intervention strategies, in particular, stationary control policies over time that shift the probability mass of the steady state distribution (SSD) away from states associated with undesirable phenotypes. Derivation of control policies is hindered by the high-dimensional state spaces associated with gene regulatory networks. Hence, network reduction is a fundamental issue for intervention. The network model that has been most used for the study of intervention in gene regulatory networks is the probabilistic Boolean network (PBN), which is a collection of constituent Boolean networks (BNs) with perturbation. In this article, we propose an algorithm that reduces a BN with perturbation, designs a control policy on the reduced network and then induces that policy to the original network. The coefficient of determination (CoD) is used to choose a gene for deletion, and a reduction mapping is used to rewire the remaining genes. This CoD-reduction procedure is used to construct a reduced network, then either the previously proposed mean first-passage time (MFPT) or SSD stationary control policy is designed on the reduced network, and these policies are induced to the original network. The efficacy of the overall algorithm is demonstrated on networks of 10 genes or less, where it is possible to compare the steady state shifts of the induced and original policies (because the latter can be derived), and by applying it to a 17-gene gastrointestinal network where it is shown that there is substantial beneficial steady state shift. The code for the algorithms is available at: http://gsp.tamu.edu/Publications/supplementary/ghaffari10a/ Please Contact Noushin Ghaffari at nghaffari@tamu.edu for further questions. Supplementary data are available at Bioinformatics online.

BoolNet—an R package for generation, reconstruction and analysis of Boolean networks

As the study of information processing in living cells moves from individual pathways to complex regulatory networks, mathematical models and simulation become indispensable tools for analyzing the complex behavior of such networks and can provide deep insights into the functioning of cells. The dynamics of gene expression, for example, can be modeled with Boolean networks (BNs). These are mathematical models of low complexity, but have the advantage of being able to capture essential properties of gene-regulatory networks. However, current implementations of BNs only focus on different sub-aspects of this model and do not allow for a seamless integration into existing preprocessing pipelines. BoolNet efficiently integrates methods for synchronous, asynchronous and probabilistic BNs. This includes reconstructing networks from time series, generating random networks, robustness analysis via perturbation, Markov chain simulations, and identification and visualization of attractors. The package BoolNet is freely available from the R project at http://cran.r-project.org/ or http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/boolnet/ under Artistic License 2.0. hans.kestler@uni-ulm.de Supplementary data are available at Bioinformatics online.

Generating probabilistic Boolean networks from a prescribed stationary distribution

Modeling gene regulation is an important problem in genomic research. Boolean networks (BN) and its generalization probabilistic Boolean networks (PBNs) have been proposed to model genetic regulatory interactions. BN is a deterministic model while PBN is a stochastic model. In a PBN, on one hand, its stationary distribution gives important information about the long-run behavior of the network. On the other hand, one may be interested in system synthesis which requires the construction of networks from the observed stationary distribution. This results in an inverse problem which is ill-posed and challenging. Because there may be many networks or no network having the given properties and the size of the inverse problem is huge. In this paper, we consider the problem of constructing PBNs from a given stationary distribution and a set of given Boolean Networks (BNs). We first formulate the inverse problem as a constrained least squares problem. We then propose a heuristic method based on Conjugate Gradient (CG) algorithm, an iterative method, to solve the resulting least squares problem. We also introduce an estimation method for the parameters of the PBNs. Numerical examples are then given to demonstrate the effectiveness of the proposed methods.

Optimal control for probabilistic Boolean networks

Aberrant gene functions usually contribute to the pathology or diseases. Avoiding undesirable cellular phenotypes as many as possible is a major purpose of external control for gene regulatory networks. An interesting question is how to control a gene network subjected to the condition that the genes reach some undesirable states with minimal probability during a cell cycle. In this paper, we make use of the theory of the first passage model for discrete-time Markov decision processes to determine the optimal control for a gene intervention model. Specifically, we first use a control model for a probabilistic Boolean network to model interactions among genes and then solve an optimal control problem for maximising the probability of the first arrival time to desirable gene states. In order to illustrate the validity of our approach, examples are also displayed.

Context-Sensitive Probabilistic Boolean Networks: Steady-State Properties, Reduction, and Steady-State Approximation

Context-sensitive probabilistic Boolean networks (PBNs) have been recently introduced as a paradigm for modeling genetic regulatory networks and have served as the main model for the application of intervention methods, including optimal control strategies, to favorably effect system dynamics. Since it is believed that the steady-state behavior of a context-sensitive PBN is indicative of the phenotype, it is important to study the alternation in the steady-state probability distribution due to any variations in the formulations of the context-sensitive PBNs. Furthermore, the huge computational complexity of the context-sensitive PBN model necessitates generation of size-reduction techniques and approximate methods for calculation of the steady-state probability distribution of context-sensitive PBNs. The goal of this paper is threefold: i) to study the effects of the various definitions of context-sensitive PBNs on the steady-state probability distributions and the downstream control policy design; ii) to propose a reduction technique that maintains the steady-state probability distribution; and iii) to provide an approximation method for calculating the steady-state probability distribution of a context-sensitive PBN.

Stationary and structural control in gene regulatory networks: basic concepts

A major reason for constructing gene regulatory networks is to use them as models for determining therapeutic intervention strategies by deriving ways of altering their long-run dynamics in such a way as to reduce the likelihood of entering undesirable states. In general, two paradigms have been taken for gene network intervention: (1) stationary external control is based on optimally altering the status of a control gene (or genes) over time to drive network dynamics; and (2) structural intervention involves an optimal one-time change of the network structure (wiring) to beneficially alter the long-run behaviour of the network. These intervention approaches have mainly been developed within the context of the probabilistic Boolean network model for gene regulation. This article reviews both types of intervention and applies them to reducing the metastatic competence of cells via intervention in a melanoma-related network.

INFERENCE OF GENE REGULATORY NETWORKS USING BOOLEAN-NETWORK INFERENCE METHODS

The modeling of genetic networks especially from microarray and related data has become an important aspect of the biosciences. This review takes a fresh look at a specific family of models used for constructing genetic networks, the so-called Boolean networks. The review outlines the various different types of Boolean network developed to date, from the original Random Boolean Network to the current Probabilistic Boolean Network. In addition, some of the different inference methods available to infer these genetic networks are also examined. Where possible, particular attention is paid to input requirements as well as the efficiency, advantages and drawbacks of each method. Though the Boolean network model is one of many models available for network inference today, it is well established and remains a topic of considerable interest in the field of genetic network inference. Hybrids of Boolean networks with other approaches may well be the way forward in inferring the most informative networks.

Distribution and enumeration of attractors in probabilistic Boolean networks

Many mathematical models for gene regulatory networks have been proposed. In this study, the authors study attractors in probabilistic Boolean networks (PBNs). They study the expected number of singleton attractors in a PBN and show that it is (2 - (1/2)(L-1))(n), where n is the number of nodes in a PBN and L is the number of Boolean functions assigned to each node. In the case of L=2, this number is simplified into 1.5(n). It is an interesting result because it is known that the expected number of singleton attractors in a Boolean network (BN) is 1. Then, we present algorithms for identifying singleton and small attractors and perform both theoretical and computational analyses on their average case time complexities. For example, the average case time complexities for identifying singleton attractors of a PBN with L=2 and L=3 are O(1.601(n)) and O(1.763(n)), respectively. The results of computational experiments suggest that these algorithms are much more efficient than the naive algorithm that examines all possible 2(n) states.

A Tutorial on Analysis and Simulation of Boolean Gene Regulatory Network Models

Driven by the desire to understand genomic functions through the interactions among genes and gene products, the research in gene regulatory networks has become a heated area in genomic signal processing. Among the most studied mathematical models are Boolean networks and probabilistic Boolean networks, which are rule-based dynamic systems. This tutorial provides an introduction to the essential concepts of these two Boolean models, and presents the up-to-date analysis and simulation methods developed for them. In the Analysis section, we will show that Boolean models are Markov chains, based on which we present a Markovian steady-state analysis on attractors, and also reveal the relationship between probabilistic Boolean networks and dynamic Bayesian networks (another popular genetic network model), again via Markov analysis; we dedicate the last subsection to structural analysis, which opens a door to other topics such as network control. The Simulation section will start from the basic tasks of creating state transition diagrams and finding attractors, proceed to the simulation of network dynamics and obtaining the steady-state distributions, and finally come to an algorithm of generating artificial Boolean networks with prescribed attractors. The contents are arranged in a roughly logical order, such that the Markov chain analysis lays the basis for the most part of Analysis section, and also prepares the readers to the topics in Simulation section.

Generating probabilistic Boolean networks from a prescribed transition probability matrix

Probabilistic Boolean networks (PBNs) have received much attention in modeling genetic regulatory networks. A PBN can be regarded as a Markov chain process and is characterised by a transition probability matrix. In this study, the authors propose efficient algorithms for constructing a PBN when its transition probability matrix is given. The complexities of the algorithms are also analysed. This is an interesting inverse problem in network inference using steady-state data. The problem is important as most microarray data sets are assumed to be obtained from sampling the steady-state.

Boolean Models of Genomic Regulatory Networks: Reduction Mappings, Inference, and External Control

Computational modeling of genomic regulation has become an important focus of systems biology and genomic signal processing for the past several years. It holds the promise to uncover both the structure and dynamical properties of the complex gene, protein or metabolic networks responsible for the cell functioning in various contexts and regimes. This, in turn, will lead to the development of optimal intervention strategies for prevention and control of disease. At the same time, constructing such computational models faces several challenges. High complexity is one of the major impediments for the practical applications of the models. Thus, reducing the size/complexity of a model becomes a critical issue in problems such as model selection, construction of tractable subnetwork models, and control of its dynamical behavior. We focus on the reduction problem in the context of two specific models of genomic regulation: Boolean networks with perturbation (BNP) and probabilistic Boolean networks (PBN). We also compare and draw a parallel between the reduction problem and two other important problems of computational modeling of genomic networks: the problem of network inference and the problem of designing external control policies for intervention/altering the dynamics of the model.