Computational Methods for Preprocessing and Classifying Gene Expression Data- Survey

Gene Regulatory Networks (GRNs) inference from gene expression data is a hard task and a widely addressed challenge. GRNs can be represented as Boolean models similarly to digital circuits. Cartesian Genetic Programming (CGP), often used for designing circuits, can thus be adopted in the inference of GRNs. The main CGP operator for generating candidate designs is mutation, making its choice important for obtaining good results. Although there are many mutation operators for CGP, to the best of our knowledge, there is no analysis of them in the GRN inference problem. An evaluation of the Single ActiveMutation (SAM) and the Semantically-Oriented Mutation Operator (SOMO)is performed here for GRNs inference. Also, a combination of both operators is proposed. We use a benchmark single-cell RNA-Sequencingtime series data and its evaluation pipeline to measure the performance of the approaches. The experiments indicate that (i) combining SOMOand SAM provides the best results, and (ii) the results obtained by the proposal are competitive with those from state-of-the-art methods.

EnGRNT: Inference of gene regulatory networks using ensemble methods and topological feature extraction

The real-time system of the JT-60 has a cascade structure with the major and the minor control loops. The multi-variable feedback control is adopted in the major control loop in order to adjust non-linear effects which will appear in the high-/beta/region. By applying the concept of 'phase shift control' to the control program of the major control loop, a flexible tokamak discharge control is expected to be performed with taking account of machine protection.

Enabled by recent advances in bioinformatics, the inference of gene regulatory networks (GRNs) from gene expression data has garnered much interest from researchers. This is due to the need of researchers to understand the dynamic behavior and uncover the vast information lay hidden within the networks. In this regard, dynamic Bayesian network (DBN) is extensively used to infer GRNs due to its ability to handle time-series microarray data and modeling feedback loops. However, the efficiency of DBN in inferring GRNs is often hampered by missing values in expression data, and excessive computation time due to the large search space whereby DBN treats all genes as potential regulators for a target gene. In this paper, we proposed a DBN-based model with missing values imputation to improve inference efficiency, and potential regulators detection which aims to lessen computation time by limiting potential regulators based on expression changes. The performance of the proposed model is assessed by using time-series expression data of yeast cell cycle. The experimental results showed reduced computation time and improved efficiency in detecting gene-gene relationships.KeywordsDynamic Bayesian NetworkGene Regulatory NetworksGene Expression DataInference

Inference of gene regulatory network from microarray data is one of the most important issues in bioinformatics. Several algorithms have been introduced for this problem, but they cannot give accurate results in case of time series gene expression data. Here, we propose an algorithm that predicts the gene regulatory network more accurately than the previous methods. A new method finds the relationship between a pair of genes by time-shifting the time series data of one gene against another when we compare the patterns of the gene pair. In addition, we increase the accuracy of the prediction method by filtering out the interactions that cannot exist in real biological network. We tested the algorithm to several simulated data which are based on realistic enzyme kinetics system, and evaluated the effectiveness of our algorithm. Results show that the present algorithm significantly improves the accuracy of the inference of gene regulatory network.

In this study, in order to deal with the noise and uncertainty in gene expression data, learning networks, especially Bayesian networks, that have the ability to use prior knowledge, were used to infer gene regulatory network. Learning networks are methods that have the structure of the network and a learning process to obtain relationships. One of the methods which have been used for measuring the relationship between genes is the correlation metrics, but the high correlated genes not necessarily mean that they have causal effect on each other. Studies on common methods in inference of gene regulatory networks are yet to pay attention to their biological importance and as such, predictions by these methods are less accurate in terms of biological significance. Hence, in the proposed method, genes with high correlation were identified in one cluster using clustering, and the existence of edge between the genes in the cluster was prevented. Finally, after the Bayesian network modeling, based on knowledge gained from clustering, the refining phase and improving regulatory interactions using biological correlation were done. In order to show the efficiency, the proposed method has been compared with several common methods in this area including GENIE3 and BMALR. The results of the evaluation indicate that the proposed method recognized regulatory relations in Bayesian modeling process well, due to using of biological knowledge which is hidden in the data collection, and is able to recognize gene regulatory networks align with important methods in this field.

Inference of inter-species gene regulatory networks based on gene expression data is an important computational method to predict pathogen-host interactions (PHIs). Both the experimental setup and the nature of PHIs exhibit certain characteristics. First, besides an environmental change, the battle between pathogen and host leads to a constantly changing environment and thus complex gene expression patterns. Second, there might be a delay until one of the organisms reacts. Third, toward later time points only one organism may survive leading to missing gene expression data of the other organism. Here, we account for PHI characteristics by extending NetGenerator, a network inference tool that predicts gene regulatory networks from gene expression time series data. We tested multiple modeling scenarios regarding the stimuli functions of the interaction network based on a benchmark example. We show that modeling perturbation of a PHI network by multiple stimuli better represents the underlying biological phenomena. Furthermore, we utilized the benchmark example to test the influence of missing data points on the inference performance. Our results suggest that PHI network inference with missing data is possible, but we recommend to provide complete time series data. Finally, we extended the NetGenerator tool to incorporate gene- and time point specific variances, because complex PHIs may lead to high variance in expression data. Sample variances are directly considered in the objective function of NetGenerator and indirectly by testing the robustness of interactions based on variance dependent disturbance of gene expression values. We evaluated the method of variance incorporation on dual RNA sequencing (RNA-Seq) data of Mus musculus dendritic cells incubated with Candida albicans and proofed our method by predicting previously verified PHIs as robust interactions.

A survey of the methodological process of modeling, inference, and evaluation of gene regulatory networks using scRNA-Seq data.

The most interesting and challenging gene expression data sets to analyze are large multidimensional data sets that contain expression values for many genes across multiple conditions. In these data sets the use of scientific text can be particularly useful, since there are a myriad of genes examined under vastly different conditions, each of which may induce or repress expression of the same gene for different reasons. There is an enormous complexity to the data that we are examining—each gene is associated with dozens if not hundreds of expression values as well as multiple documents built up from vocabularies consisting of thousands of words. In Section 2.4 we reviewed common gene expression strategies, most of which revolve around defining groups of genes based on common profiles. A limitation of many gene expression analytic approaches is that they do not incorporate comprehensive background knowledge about the genes into the analysis. We present computational methods that leverage the peer-reviewed literature in the automatic analysis of gene expression data sets. Including the literature in gene expression data analysis offers an opportunity to incorporate background functional information about the genes when defining expression clusters. In Chapter 5 we saw how literature- based approaches could help in the analysis of single condition experiments. Here we will apply the strategies introduced in Chapter 6 to assess the coherence of groups of genes to enhance gene expression analysis approaches. The methods proposed here could, in fact, be applied to any multivariate genomics data type. The key concepts discussed in this chapter are listed in the frame box. We begin with a discussion of gene groups and their role in expression analysis; we briefly discuss strategies to assign keywords to groups and strategies to assess their functional coherence. We apply functional coherence measures to gene expression analysis; for examples we focus on a yeast expression data set. We first demonstrate how functional coherence can be used to focus in on the key biologically relevant gene groups derived by clustering methods such as self-organizing maps and k-means clustering.

The inference of gene regulatory networks from expression data is an important area of research that provides insight to the inner workings of a biological system. In this paper we present a new reverse-engineering framework for gene regulatory network reconstruction. It exploits some interesting characteristics of genetic programming, like the ability of solving complex regression problems with little or no information about the underlying data and the ability of performing an automatic selection of features at learning time. Our framework not only reconstructs the topology of the network, but it is also able to simulate its dynamic behaviour, forecasting the gene expression values in the timepoints subsequent to the initial one. In this paper, we test the proposed framework on the well-known IRMA gene regulatory network, and we show that its performances are promising.

The purpose of this paper is to introduce transductive inference with support vector machines (TSVM) as a powerful methodology for classification of gene expression data, using training and prediction data sets. The following classification problems will be considered: determination of cancer diagnosis categories and classification of genes from the budding yeast Saccharomyces cerevisiae in functional groups. In the case of training samples, experts have already classified the samples in their respective classes. So, given each prediction sample, the purpose is to determine its corresponding class. The main aspect of TSVM is that the classification task will be implemented in just one step, improving the generalization capability of the classifier. The TSVM will be compared with the traditional inductive method (SVM) in a series of experiments concerning the two classification problems, with promising results.

Reconstruction of gene regulatory networks (GRNs), which explicitly represent the causality of developmental or regulatory process, is of utmost interest and has become a challenging computational problem for understanding the complex regulatory mechanisms in cellular systems. However, all existing methods of inferring GRNs from gene expression profiles have their strengths and weaknesses. In particular, many properties of GRNs, such as topology sparseness and non-linear dependence, are generally in regulation mechanism but seldom are taken into account simultaneously in one computational method. In this work, we present a novel method for inferring GRNs from gene expression data considering the non-linear dependence and topological structure of GRNs by employing path consistency algorithm (PCA) based on conditional mutual information (CMI). In this algorithm, the conditional dependence between a pair of genes is represented by the CMI between them. With the general hypothesis of Gaussian distribution underlying gene expression data, CMI between a pair of genes is computed by a concise formula involving the covariance matrices of the related gene expression profiles. The method is validated on the benchmark GRNs from the DREAM challenge and the widely used SOS DNA repair network in Escherichia coli. The cross-validation results confirmed the effectiveness of our method (PCA-CMI), which outperforms significantly other previous methods. Besides its high accuracy, our method is able to distinguish direct (or causal) interactions from indirect associations. All the source data and code are available at: http://csb.shu.edu.cn/subweb/grn.htm. lnchen@sibs.ac.cn; zpliu@sibs.ac.cn Supplementary data are available at Bioinformatics online.

To address one of the most challenging ecosystems issues at the cellular level, this paper surveys the fuzzy methods used in gene regulatory networks (GRNs) inference. GRNs represent causal relationships between genes that have a direct influence on the life and the development of living organisms, and provide a useful contribution to the understanding of the cellular functions as well as the mechanisms of diseases. The ecosystems impacted by GRN inference span various levels from cell to society -- globally.

MotivationDeciphering gene interaction networks (GINs) from time-course gene expression (TCGx) data is highly valuable to understand gene behaviors (e.g., activation, inhibition, time-lagged causality) at the system level. Existing methods usually use a global or local proximity measure to infer GINs from a single dataset. As the noise contained in a single data set is hardly self-resolved, the results are sometimes not reliable. Also, these proximity measurements cannot handle the co-existence of the various in vivo positive, negative and time-lagged gene interactions.Methods and resultsWe propose to infer reliable GINs from multiple TCGx datasets using a novel conserved subsequential pattern of gene expression. A subsequential pattern is a maximal subset of genes sharing positive, negative or time-lagged correlations of one expression template on their own subsets of time points. Based on these patterns, a GIN can be built from each of the datasets. It is assumed that reliable gene interactions would be detected repeatedly. We thus use conserved gene pairs from the individual GINs of the multiple TCGx datasets to construct a reliable GIN for a species. We apply our method on six TCGx datasets related to yeast cell cycle, and validate the reliable GINs using protein interaction networks, biopathways and transcription factor-gene regulations. We also compare the reliable GINs with those GINs reconstructed by a global proximity measure Pearson correlation coefficient method from single datasets. It has been demonstrated that our reliable GINs achieve much better prediction performance especially with much higher precision. The functional enrichment analysis also suggests that gene sets in a reliable GIN are more functionally significant. Our method is especially useful to decipher GINs from multiple TCGx datasets related to less studied organisms where little knowledge is available except gene expression data.

Modulators (Ms) are proteins that modify the activity of transcription factors (TFs) and influence expression of their target genes (TGs). To discover modulators of NF-κB/RelA, we first identified 365 NF-κB/RelA-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used a probabilistic model to infer 8349 (M, NF-κB/RelA, TG) triplets and their modes of modulatory action from our combined LC-MS/MS and ChIP-Seq (ChIP followed by next generation sequencing) data, published RelA modulators and TGs, and a compendium of gene expression profiles. Hierarchical clustering of the derived modulatory network revealed functional subnetworks and suggested new pathways modulating RelA transcriptional activity. The modulators with the highest number of TGs and most non-random distribution of action modes (measured by Shannon entropy) are consistent with published reports. Our results provide a repertoire of testable hypotheses for experimental validation. One of the NF-κB/RelA modulators we identified is STAT1. The inferred (STAT1, NF-κB/RelA, TG) triplets were validated by LC-selected reaction monitoring-MS and the results of STAT1 deletion in human fibrosarcoma cells. Overall, we have identified 562 NF-κB/RelA modulators, which are potential drug targets, and clarified mechanisms of achieving NF-κB/RelA multiple functions through modulators. Our approach can be readily applied to other TFs.