Description:
Background In any gene regulatory network (GRN), the complex interactions occurring amongst transcription factors and target genes can be either instantaneous or time-delayed. However, many existing modeling approaches currently applied for inferring GRNs are unable to represent both these interactions simultaneously. As a result, all these approaches cannot detect important interactions of the other type. S-System model, a differential equation based approach which has been increasingly applied for modeling GRNs, also suffers from this limitation. In fact, all S-System based existing modeling approaches have been designed to capture only instantaneous interactions, and are unable to infer time-delayed interactions. Results In this paper, we propose a novel Time-Delayed S-System (TDSS) model which uses a set of delay differential equations to represent the system dynamics. The ability to incorporate time-delay parameters in the proposed S-System model enables simultaneous modeling of both instantaneous and time-delayed interactions. Furthermore, the delay parameters are not limited to just positive integer values (corresponding to time stamps in the data), but can also take fractional values. Moreover, we also propose a new criterion for model evaluation exploiting the sparse and scale-free nature of GRNs to effectively narrow down the search space, which not only reduces the computation time significantly but also improves model accuracy. The evaluation criterion systematically adapts the max-min in-degrees and also systematically balances the effect of network accuracy and complexity during optimization. Conclusion The four well-known performance measures applied to the experimental studies on synthetic networks with various time-delayed regulations clearly demonstrate that the proposed method can capture both instantaneous and delayed interactions correctly with high precision. The experiments carried out on two well-known real-life networks, namely IRMA and SOS DNA repair network in Escherichia coli show a significant improvement compared with other state-of-the-art approaches for GRN modeling.
Description:
Background In any gene regulatory network (GRN), the complex interactions occurring amongst transcription factors and target genes can be either instantaneous or time-delayed. However, many existing modeling approaches currently applied for inferring GRNs are unable to represent both these interactions simultaneously. As a result, all these approaches cannot detect important interactions of the other type. S-System model, a differential equation based approach which has been increasingly applied for modeling GRNs, also suffers from this limitation. In fact, all S-System based existing modeling approaches have been designed to capture only instantaneous interactions, and are unable to infer time-delayed interactions. Results In this paper, we propose a novel Time-Delayed S-System (TDSS) model which uses a set of delay differential equations to represent the system dynamics. The ability to incorporate time-delay parameters in the proposed S-System model enables simultaneous modeling of both instantaneous and time-delayed interactions. Furthermore, the delay parameters are not limited to just positive integer values (corresponding to time stamps in the data), but can also take fractional values. Moreover, we also propose a new criterion for model evaluation exploiting the sparse and scale-free nature of GRNs to effectively narrow down the search space, which not only reduces the computation time significantly but also improves model accuracy. The evaluation criterion systematically adapts the max-min in-degrees and also systematically balances the effect of network accuracy and complexity during optimization. Conclusion The four well-known performance measures applied to the experimental studies on synthetic networks with various time-delayed regulations clearly demonstrate that the proposed method can capture both instantaneous and delayed interactions correctly with high precision. The experiments carried out on two well-known real-life networks, namely IRMA and SOS DNA repair network in Escherichia coli show a significant improvement compared with other state-of-the-art approaches for GRN modeling.
Description:
Abstract—Gene Regulatory Network (GRN) plays an important role in the understanding of complex biological systems. In most cases, high throughput microarray gene expression data is used for finding these regulatory relationships among genes. In this paper, we present a novel approach, based on decoupled SSystem model, for reverse engineering GRNs. In the proposed method, the genetic algorithm used for scoring the networks contains several useful features for accurate network inference, namely a Prediction Initialization (PI) algorithm to initialize the individuals, a Flip Operation (FO) for better mating of values and a restricted execution of Hill Climbing Local Search over few individuals. It also includes a novel refinement technique which utilizes the fit solutions of the genetic algorithm for optimizing sensitivity and specificity of the inferred network. Comparative studies and robustness analysis using standard benchmark data set show the superiority of the proposed method.
Description:
With the advent of microarray technology, researchers are able to determine cellular dynamics for thousands of genes simultaneously, thereby enabling reverse engineering of the gene regulatory network (GRN) from high-throughput time-series gene expression data. Amongst the various currently available models for inferring GRN, the S-System formalism is often considered as an excellent compromise between accuracy and mathematical tractability. In this paper, a novel approach for inferring GRN based on the decoupled S-System model, incorporating the new concept of adaptive regulatory genes cardinality, is proposed. Parameter learning for the S-System is carried out in an evolving manner using a versatile and robust Trigonometric Evolutionary Algorithm. The applicability and efficiency of the proposed method is studied using a well-known and widely studied synthetic network with various levels of noise, and excellent performance observed. Further, investigations of a 5 gene in-vivo synthetic biological network of Saccharomyces cerevisiae called IRMA, has succeeded in detecting higher number of correct regulations compared to other approaches reported earlier.
Description:
A Gene Regulatory Network (GRN) is the functional circuitry of a living organism that exhibits the regulatory relationships among genes of a cellular system at the gene level. In real-life biological networks, the number of genes present are very large exhibiting both, the instantaneous and time-delayed regulations. While our recent technique [1] addresses the modeling of time-delays occurring in genetic interactions, the issue of large-scale GRN modeling still remains. In this paper, we propose a novel methodology for large-scale modeling of GRNs by decomposing the GRN into two independent sub-networks utilizing its biological traits. Using the time-delayed S-system model [1], these two sub-networks are learnt separately and then combined to get the entire GRN. To speed up the inference mechanism, a cardinality-based fitness function, especially developed for inferring large-scale GRNs is proposed to allow incorporation of knowledge of maximum in-degree. A novel local-search method is also proposed to further facilitate the incorporation of biological knowledge by gene clustering and gene ranking. Experimental studies demonstrate that the proposed approach is successful in learning large genetic networks, currently not achievable with existing S-system based modeling approaches.
Description:
Gene regulatory network (GRN) reconstruction from high-throughput microarray data is an important problem in systems biology. The S-System model, a differential equation based approach, is among the mainstream approaches for modeling GRNs
Description:
Gene Regulatory Network (GRN) contains interactions occurring between transcription factors (TF) and target genes which are captured during the microarray creation. However, information about the interactions among microRNAs (miRNA) and target genes can not be captured by current microarray technology. To overcome this limitation, we propose a new technique to reverse engineer GRN from partial microarray data which represent target genes' interactions only. Using S-System model, the approach is modified to incorporate the unavailability of information about miRNA-target genes interactions. The most versatile Differential Evolutionary algorithm is used for optimization and parameter learning. Experimental studies on three newly created synthetic networks, and one real network of Saccharomycescerevisiae called IRMA network, show significant improvement compared to traditional S-System based approach.
Description:
Gene regulatory network (GRN) consists of interactions between transcription factors (TFs) and target genes (TGs). Recently, it has been observed that micro RNAs (miRNAs) play a significant part in genetic interactions. However, current microarray technologies do not capture miRNA expression levels. To overcome this, we propose a new technique to reverse engineer GRN from the available partial microarray data which contains expression levels of TFs and TGs only. Using S-System model, the approach is adapted to cope with the unavailability of information about the expression levels of miRNAs. The versatile Differential Evolutionary algorithm is used for optimization and parameter estimation. Experimental studies on four in silico networks, and a real network of Saccharomyces cerevisiae called IRMA network, show significant improvement compared to traditional S-System approach.