Context-sensitive Probabilistic Boolean Networks Research Articles

Static output feedback set stabilization for context-sensitive probabilistic Boolean control networks

In this paper, we investigate the static output feedback set stabilization for context-sensitive probabilistic Boolean control networks (CS-PBCNs) via the semi-tensor product of matrices. An algorithm for finding the largest control invariant set with probability one is obtained by the algebraic representations of logical dynamics. Based on the analysis of the set stabilization, necessary and sufficient conditions for S-stabilization are obtained. Static output feedback controllers are designed to achieve S-stabilization for a CS-PBCN. At last, examples to study metastatic melanoma are given to show the effectiveness of our main results.

Model Checking Optimal Infinite-Horizon Control for Probabilistic Gene Regulatory Networks

Genetic regulatory networks (GRNs) are significant fundamental biological networks through which biological system functions can be regulated. A significant challenge in the field of system biology is the construction of a control theory of GRNs through the application of external intervention controls; currently, context-sensitive probabilistic Boolean networks with perturbation (CS-PBNp) are used as an important network model in research on the optimal GRN control problem. This paper proposes an approximate optimal control strategy approach to the infinite-horizon optimal control problem based on probabilistic model checking and genetic algorithms (GAs). The proposed method first reduces the expected cost defined under the infinite-horizon control to a steady-state reward within a discrete-time Markov chain. A CS-PBNp model with a stationary control policy is then constructed to represent the cost of the fixed control strategy based on a temporal logic with a reward property, and calculations are carried out automatically by a PRISM model checker. The stationary control policy is then encoded as an element of the solution space of a GA. Based on the fitness of each control policy element as calculated by PRISM, an optimal solution can be obtained by using a GA to execute genetic operations iteratively. The experimental results generated by applying the proposed approach to the WNT5A network validate the accuracy and effectiveness of the approach.

Stability and stabilisation of context‐sensitive probabilistic Boolean networks

In this study, the authors consider the stability and stabilisation issues of context-sensitive probabilistic Boolean networks. Firstly, the algebraic form of the system is obtained by using the semi-tensor product method. Then, some sufficient conditions for the stability and stabilisation of the system are presented, respectively. At last, an illustrative example is given.

Gene perturbation and intervention in context-sensitive stochastic Boolean networks.

BackgroundIn a gene regulatory network (GRN), gene expressions are affected by noise, and stochastic fluctuations exist in the interactions among genes. These stochastic interactions are context dependent, thus it becomes important to consider noise in a context-sensitive manner in a network model. As a logical model, context-sensitive probabilistic Boolean networks (CSPBNs) account for molecular and genetic noise in the temporal context of gene functions. In a CSPBN with n genes and k contexts, however, a computational complexity of O(nk222n ) (or O(nk2 n )) is required for an accurate (or approximate) computation of the state transition matrix (STM) of the size (2 n ∙ k) × (2 n ∙ k) (or 2 n × 2 n ). The evaluation of a steady state distribution (SSD) is more challenging. Recently, stochastic Boolean networks (SBNs) have been proposed as an efficient implementation of an instantaneous PBN.ResultsThe notion of stochastic Boolean networks (SBNs) is extended for the general model of PBNs, i.e., CSPBNs. This yields a novel structure of context-sensitive SBNs (CSSBNs) for modeling the stochasticity in a GRN. A CSSBN enables an efficient simulation of a CSPBN with a complexity of O(nLk2 n ) for computing the state transition matrix, where L is a factor related to the required sequence length in CSSBN for achieving a desired accuracy. A time-frame expanded CSSBN can further efficiently simulate the stationary behavior of a CSPBN and allow for a tunable tradeoff between accuracy and efficiency. The CSSBN approach is more efficient than an analytical method and more accurate than an approximate analysis.ConclusionsContext-sensitive stochastic Boolean networks (CSSBNs) are proposed as an efficient approach to modeling the effects of gene perturbation and intervention in gene regulatory networks. A CSSBN analysis provides biologically meaningful insights into the oscillatory dynamics of the p53-Mdm2 network in a context-switching environment. It is shown that random gene perturbation has a greater effect on the final distribution of the steady state of a network compared to context switching activities. The CSSBN approach can further predict the steady state distribution of a glioma network under gene intervention. Ultimately, this will help drug discovery and develop effective drug intervention strategies.

Verification and Optimal Control of Context-Sensitive Probabilistic Boolean Networks Using Model Checking and Polynomial Optimization

One of the significant topics in systems biology is to develop control theory of gene regulatory networks (GRNs). In typical control of GRNs, expression of some genes is inhibited (activated) by manipulating external stimuli and expression of other genes. It is expected to apply control theory of GRNs to gene therapy technologies in the future. In this paper, a control method using a Boolean network (BN) is studied. A BN is widely used as a model of GRNs, and gene expression is expressed by a binary value (ON or OFF). In particular, a context-sensitive probabilistic Boolean network (CS-PBN), which is one of the extended models of BNs, is used. For CS-PBNs, the verification problem and the optimal control problem are considered. For the verification problem, a solution method using the probabilistic model checker PRISM is proposed. For the optimal control problem, a solution method using polynomial optimization is proposed. Finally, a numerical example on the WNT5A network, which is related to melanoma, is presented. The proposed methods provide us useful tools in control theory of GRNs.

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.

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.

Adaptive intervention in probabilistic boolean networks

A basic problem of translational systems biology is to utilize gene regulatory networks as a vehicle to design therapeutic intervention strategies to beneficially alter network and, therefore, cellular dynamics. One strain of research has this problem from the perspective of control theory via the design of optimal Markov chain decision processes, mainly in the framework of probabilistic Boolean networks (PBNs). Full optimization assumes that the network is accurately modeled and, to the extent that model inference is inaccurate, which can be expected for gene regulatory networks owing to the combination of model complexity and a paucity of time-course data, the designed intervention strategy may perform poorly. We desire intervention strategies that do not assume accurate full-model inference. This article demonstrates the feasibility of applying on-line adaptive control to improve intervention performance in genetic regulatory networks modeled by PBNs. It shows via simulations that when the network is modeled by a member of a known family of PBNs, an adaptive design can yield improved performance in terms of the average cost. Two algorithms are presented, one better suited for instantaneously random PBNs and the other better suited for context-sensitive PBNs with low switching probability between the constituent BNs.

Inferring context-sensitive Probabilistic Boolean Networks from gene expression data under multi-biological conditions

In recent years biological microarrays have emerged as a high-throughput data acquisition technology in bioinformatics. In conjunction with this, there is an increasing need to develop frameworks for the formal analysis of biological pathways. A modeling approach defined as Probabilistic Boolean Networks (PBNs) was proposed for inferring genetic regulatory networks [1]. This technology, an extension of Boolean Networks [2], is able to capture the time-varying dependencies with deterministic probabilities for a series of sets of predictor functions.

Optimal infinite-horizon control for probabilistic Boolean networks

External control of a genetic regulatory network is used for the purpose of avoiding undesirable states, such as those associated with disease. Heretofore, intervention has focused on finite-horizon control, i.e., control over a small number of stages. This paper considers the design of optimal infinite-horizon control for context-sensitive probabilistic Boolean networks (PBNs). It can also be applied to instantaneously random PBNs. The stationary policy obtained is independent of time and dependent on the current state. This paper concentrates on discounted problems with bounded cost per stage and on average-cost-per-stage problems. These formulations are used to generate stationary policies for a PBN constructed from melanoma gene-expression data. The results show that the stationary policies obtained by the two different formulations are capable of shifting the probability mass of the stationary distribution from undesirable states to desirable ones.

A Method of Gene Expression Data Partitioning for the Construction of Context-Sensitive PBNs

Bioinformatics and systems Biology Conference. The accompanying paper presents a new method of fitting probabilistic Boolean networks (PBN) to gene expression data sequences.

Intervention in context-sensitive probabilistic Boolean networks

Intervention in a gene regulatory network is used to help it avoid undesirable states, such as those associated with a disease. Several types of intervention have been studied in the framework of a probabilistic Boolean network (PBN), which is essentially a finite collection of Boolean networks in which at any discrete time point the gene state vector transitions according to the rules of one of the constituent networks. For an instantaneously random PBN, the governing Boolean network is randomly chosen at each time point. For a context-sensitive PBN, the governing Boolean network remains fixed for an interval of time until a binary random variable determines a switch. The theory of automatic control has been previously applied to find optimal strategies for manipulating external (control) variables that affect the transition probabilities of an instantaneously random PBN to desirably affect its dynamic evolution over a finite time horizon. This paper extends the methods of external control to context-sensitive PBNs. This paper treats intervention via external control variables in context-sensitive PBNs by extending the results for instantaneously random PBNs in several directions. First, and most importantly, whereas an instantaneously random PBN yields a Markov chain whose state space is composed of gene vectors, each state of the Markov chain corresponding to a context-sensitive PBN is composed of a pair, the current gene vector occupied by the network and the current constituent Boolean network. Second, the analysis is applied to PBNs with perturbation, meaning that random gene perturbation is permitted at each instant with some probability. Third, the (mathematical) influence of genes within the network is used to choose the particular gene with which to intervene. Lastly, PBNs are designed from data using a recently proposed inference procedure that takes steady-state considerations into account. The results are applied to a context-sensitive PBN derived from gene-expression data collected in a study of metastatic melanoma, the intent being to devise a control strategy that reduces the WNT5A gene's action in affecting biological regulation, since the available data suggest that disruption of this influence could reduce the chance of a melanoma metastasizing.