Probabilities of spurious connections in gene networks: application to expression time series

MOTIVATION: The reconstruction of gene networks from gene-expression microarrays is gaining popularity as methods improve and as more data become available. The reliability of such networks could be judged by the probability that a connection between genes is spurious, resulting from chance fluctuations rather than from a true biological relationship. RESULTS: Unlike the false discovery rate and positive false discovery rate, the decisive false discovery rate (dFDR) is exactly equal to a conditional probability without assuming independence or the randomness of hypothesis truth values. This property is useful not only in the common application to the detection of differential gene expression, but also in determining the probability of a spurious connection in a reconstructed gene network. Estimators of the dFDR can estimate each of three probabilities: (1) The probability that two genes that appear to be associated with each other lack such association. (2) The probability that a time ordering observed for two associated genes is misleading. (3) The probability that a time ordering observed for two genes is misleading, either because they are not associated or because they are associated without a lag in time. The first probability applies to both static and dynamic gene networks, and the other two only apply to dynamic gene networks.     

Inference of scale-free networks from gene expression time series

Quantitative time-series observation of gene expression is becoming possible, for example by cell array technology. However, there are no practical methods with which to infer network structures using only observed time-series data. As most computational models of biological networks for continuous time-series data have a high degree of freedom, it is almost impossible to infer the correct structures. On the other hand, it has been reported that some kinds of biological networks, such as gene networks and metabolic pathways, may have scale-free properties. We hypothesize that the architecture of inferred biological network models can be restricted to scale-free networks. We developed an inference algorithm for biological networks using only time-series data by introducing such a restriction. We adopt the S-system as the network model, and a distributed genetic algorithm to optimize models to fit its simulated results to observed time series data. We have tested our algorithm on a case study (simulated data). We compared optimization under no restriction, which allows for a fully connected network, and under the restriction that the total number of links must equal that expected from a scale free network. The restriction reduced both false positive and false negative estimation of the links and also the differences between model simulation and the given time-series data.     

STEM: a tool for the analysis of short time series gene expression data

Background  

Time series microarray experiments are widely used to study dynamical biological processes. Due to the cost of microarray experiments, and also in some cases the limited availability of biological material, about 80% of microarray time series experiments are short (3–8 time points). Previously short time series gene expression data has been mainly analyzed using more general gene expression analysis tools not designed for the unique challenges and opportunities inherent in short time series gene expression data.     

A new measure for functional similarity of gene products based on Gene Ontology

Background  

Gene Ontology (GO) is a standard vocabulary of functional terms and allows for coherent annotation of gene products. These annotations provide a basis for new methods that compare gene products regarding their molecular function and biological role.     

Extracting biologically significant patterns from short time series gene expression data

Background  

Time series gene expression data analysis is used widely to study the dynamics of various cell processes. Most of the time series data available today consist of few time points only, thus making the application of standard clustering techniques difficult.     

Indirect two-sided relative ranking: a robust similarity measure for gene expression data

Background  

There is a large amount of gene expression data that exists in the public domain. This data has been generated under a variety of experimental conditions. Unfortunately, these experimental variations have generally prevented researchers from accurately comparing and combining this wealth of data, which still hides many novel insights.     

A polynomial time biclustering algorithm for finding approximate expression patterns in gene expression time series

Background  

The ability to monitor the change in expression patterns over time, and to observe the emergence of coherent temporal responses using gene expression time series, obtained from microarray experiments, is critical to advance our understanding of complex biological processes. In this context, biclustering algorithms have been recognized as an important tool for the discovery of local expression patterns, which are crucial to unravel potential regulatory mechanisms. Although most formulations of the biclustering problem are NP-hard, when working with time series expression data the interesting biclusters can be restricted to those with contiguous columns. This restriction leads to a tractable problem and enables the design of efficient biclustering algorithms able to identify all maximal contiguous column coherent biclusters.     

A multi-step approach to time series analysis and gene expression clustering

MOTIVATION: The huge growth in gene expression data calls for the implementation of automatic tools for data processing and interpretation. RESULTS: We present a new and comprehensive machine learning data mining framework consisting in a non-linear PCA neural network for feature extraction, and probabilistic principal surfaces combined with an agglomerative approach based on Negentropy aimed at clustering gene microarray data. The method, which provides a user-friendly visualization interface, can work on noisy data with missing points and represents an automatic procedure to get, with no a priori assumptions, the number of clusters present in the data. Cell-cycle dataset and a detailed analysis confirm the biological nature of the most significant clusters. AVAILABILITY: The software described here is a subpackage part of the ASTRONEURAL package and is available upon request from the corresponding author. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

TimeClust: a clustering tool for gene expression time series

TimeClust is a user-friendly software package to cluster genes according to their temporal expression profiles. It can be conveniently used to analyze data obtained from DNA microarray time-course experiments. It implements two original algorithms specifically designed for clustering short time series together with hierarchical clustering and self-organizing maps. AVAILABILITY: TimeClust executable files for Windows and LINUX platforms can be downloaded free of charge for non-profit institutions from the following web site: http://aimed11.unipv.it/TimeClust.     

A graph-based semantic similarity measure for the gene ontology

Existing methods for calculating semantic similarities between pairs of Gene Ontology (GO) terms and gene products often rely on external databases like Gene Ontology Annotation (GOA) that annotate gene products using the GO terms. This dependency leads to some limitations in real applications. Here, we present a semantic similarity algorithm (SSA), that relies exclusively on the GO. When calculating the semantic similarity between a pair of input GO terms, SSA takes into account the shortest path between them, the depth of their nearest common ancestor, and a novel similarity score calculated between the definitions of the involved GO terms. In our work, we use SSA to calculate semantic similarities between pairs of proteins by combining pairwise semantic similarities between the GO terms that annotate the involved proteins. The reliability of SSA was evaluated by comparing the resulting semantic similarities between proteins with the functional similarities between proteins derived from expert annotations or sequence similarity. Comparisons with existing state-of-the-art methods showed that SSA is highly competitive with the other methods. SSA provides a reliable measure for semantics similarity independent of external databases of functional-annotation observations.     

An effective data mining technique for reconstructing gene regulatory networks from time series expression data

Recent development in DNA microarray technologies has made the reconstruction of gene regulatory networks (GRNs) feasible. To infer the overall structure of a GRN, there is a need to find out how the expression of each gene can be affected by the others. Many existing approaches to reconstructing GRNs are developed to generate hypotheses about the presence or absence of interactions between genes so that laboratory experiments can be performed afterwards for verification. Since, they are not intended to be used to predict if a gene in an unseen sample has any interactions with other genes, statistical verification of the reliability of the discovered interactions can be difficult. Furthermore, since the temporal ordering of the data is not taken into consideration, the directionality of regulation cannot be established using these existing techniques. To tackle these problems, we propose a data mining technique here. This technique makes use of a probabilistic inference approach to uncover interesting dependency relationships in noisy, high-dimensional time series expression data. It is not only able to determine if a gene is dependent on another but also whether or not it is activated or inhibited. In addition, it can predict how a gene would be affected by other genes even in unseen samples. For performance evaluation, the proposed technique has been tested with real expression data. Experimental results show that it can be very effective. The discovered dependency relationships can reveal gene regulatory relationships that could be used to infer the structures of GRNs.     

Dynamic Bayesian network and nonparametric regression for nonlinear modeling of gene networks from time series gene expression data

We propose a dynamic Bayesian network and nonparametric regression model for constructing a gene network from time series microarray gene expression data. The proposed method can overcome a shortcoming of the Bayesian network model in the sense of the construction of cyclic regulations. The proposed method can analyze the microarray data as a continuous data and can capture even nonlinear relations among genes. It can be expected that this model will give a deeper insight into complicated biological systems. We also derive a new criterion for evaluating an estimated network from Bayes approach. We conduct Monte Carlo experiments to examine the effectiveness of the proposed method. We also demonstrate the proposed method through the analysis of the Saccharomyces cerevisiae gene expression data.     

一种新的基因注释语义相似度计算方法

基因本体(GO)数据库为基因提供了统一的注释,有效地解决了不同数据库描述相同基因的不一致问题。但是,根据基因注释如何比较基因的功能相似性,这个问题仍然没有得到有效解决。本文提出一种新的基因注释语义相似度计算方法,这种方法在本质上是基于基因的生物学特性,其特点在于结点的语义相似度与结点所在集合无关,只与结点在GO图的位置有关,语义相似度可被重复利用。它既考虑了基因所映射的GO结点深度,又考虑了两GO结点之间所有路径对结点语义相似度的影响。文中以酵母菌的异亮氨酸降解代谢通路和谷氨酸合成代谢通路为实验,实验结果表明这种算法能准确地计算基因注释语义相似度。     

Clustering of gene expression data using a local shape-based similarity measure

MOTIVATION: Microarray technology enables the study of gene expression in large scale. The application of methods for data analysis then allows for grouping genes that show a similar expression profile and that are thus likely to be co-regulated. A relationship among genes at the biological level often presents itself by locally similar and potentially time-shifted patterns in their expression profiles. RESULTS: Here, we propose a new method (CLARITY; Clustering with Local shApe-based similaRITY) for the analysis of microarray time course experiments that uses a local shape-based similarity measure based on Spearman rank correlation. This measure does not require a normalization of the expression data and is comparably robust towards noise. It is also able to detect similar and even time-shifted sub-profiles. To this end, we implemented an approach motivated by the BLAST algorithm for sequence alignment.We used CLARITY to cluster the times series of gene expression data during the mitotic cell cycle of the yeast Saccharomyces cerevisiae. The obtained clusters were related to the MIPS functional classification to assess their biological significance. We found that several clusters were significantly enriched with genes that share similar or related functions.     

Detecting determinism in short time series, with an application to the analysis of a stationary EEG recording

We have developed a new method for detecting determinism in a short time series and used this method to examine whether a stationary EEG is deterministic or stochastic. The method is based on the observation that the trajectory of a time series generated from a differentiable dynamical system behaves smoothly in an embedded phase space. The angles between two successive directional vectors in the trajectory reconstructed from a time series at a minimum embedding dimension were calculated as a function of time. We measured the irregularity of the angle variations obtained from the time series using second-order difference plots and central tendency measures, and compared these values with those from surrogate data. The ability of the proposed method to distinguish between chaotic and stochastic dynamics is demonstrated through a number of simulated time series, including data from Lorenz, R?ssler, and Van der Pol attractors, high-dimensional equations, and 1/f noise. We then applied this method to the analysis of stationary segments of EEG recordings consisting of 750 data points (6-s segments) from five normal subjects. The stationary EEG segments were not found to exhibit deterministic components. This method can be used to analyze determinism in short time series, such as those from physiological recordings, that can be modeled using differentiable dynamical processes.