Biomedical subjects

Ziv Bar-Joseph

Publications and source records attributed to Ziv Bar-Joseph.

9 recordsLinked to original sources

PubMed2005

Clustering short time series gene expression data.

MOTIVATION: Time series expression experiments are used to study a wide range of biological systems. More than 80% of all time series expression datasets are short (8 time points or fewer). These datasets present unique challenges. On account of the large number of genes profiled (often tens of thousands) and the small number of time points many patterns are expected to arise at random. Most clustering algorithms are unable to distinguish between real and random patterns. RESULTS: We present an algorithm specifically designed for clustering short time series expression data. Our algorithm works by assigning genes to a predefined set of model profiles that capture the potential distinct patterns that can be expected from the experiment. We discuss how to obtain such a set of profiles and how to determine the significance of each of these profiles. Significant profiles are retained for further analysis and can be combined to form clusters. We tested our method on both simulated and real biological data. Using immune response data we show that our algorithm can correctly detect the temporal profile of relevant functional categories. Using Gene Ontology analysis we show that our algorithm outperforms both general clustering algorithms and algorithms designed specifically for clustering time series gene expression data. AVAILABILITY: Information on obtaining a Java implementation with a graphical user interface (GUI) is available from http://www.cs.cmu.edu/~jernst/st/ SUPPLEMENTARY INFORMATION: Available at http://www.cs.cmu.edu/~jernst/st/

Algorithms↗

PubMed2005

Random forest similarity for protein-protein interaction prediction from multiple sources.

One of the most important, but often ignored, parts of any clustering and classification algorithm is the computation of the similarity matrix. This is especially important when integrating high throughput biological data sources because of the high noise rates and the many missing values. In this paper we present a new method to compute such similarities for the task of classifying pairs of proteins as interacting or not. Our method uses direct and indirect information about interaction pairs to constructs a random forest (a collection of decision tress) from a training set. The resulting forest is used to determine the similarity between protein pairs and this similarity is used by a classification algorithm (a modified kNN) to classify protein pairs. Testing the algorithm on yeast data indicates that it is able to improve coverage to 20% of interacting pairs with a false positive rate of 50%. These results compare favorably with all previously suggested methods for this task indicating the importance of robust similarity estimates.

Algorithms↗

PubMed2004

Deconvolving cell cycle expression data with complementary information.

MOTIVATION: In the study of many systems, cells are first synchronized so that a large population of cells exhibit similar behavior. While synchronization can usually be achieved for a short duration, after a while cells begin to lose their synchronization. Synchronization loss is a continuous process and so the observed value in a population of cells for a gene at time t is actually a convolution of its values in an interval around t. Deconvolving the observed values from a mixed population will allow us to obtain better models for these systems and to accurately detect the genes that participate in these systems. RESULTS: We present an algorithm which combines budding index and gene expression data to deconvolve expression profiles. Using the budding index data we first fit a synchronization loss model for the cell cycle system. Our deconvolution algorithm uses this loss model and can also use information from co-expressed genes, making it more robust against noise and missing values. Using expression and budding data for yeast we show that our algorithm is able to reconstruct a more accurate representation when compared with the observed values. In addition, using the deconvolved profiles we are able to correctly identify 15% more cycling genes when compared to a set identified using the observed values. AVAILABILITY: Matlab implementation can be downloaded from the supporting website http://www.cs.cmu.edu/~zivbj/decon/decon.html

Biological Clocks↗

PubMed2004

Analyzing time series gene expression data.

MOTIVATION: Time series expression experiments are an increasingly popular method for studying a wide range of biological systems. However, when analyzing these experiments researchers face many new computational challenges. Algorithms that are specifically designed for time series experiments are required so that we can take advantage of their unique features (such as the ability to infer causality from the temporal response pattern) and address the unique problems they raise (e.g. handling the different non-uniform sampling rates). RESULTS: We present a comprehensive review of the current research in time series expression data analysis. We divide the computational challenges into four analysis levels: experimental design, data analysis, pattern recognition and networks. For each of these levels, we discuss computational and biological problems at that level and point out some of the methods that have been proposed to deal with these issues. Many open problems in all these levels are discussed. This review is intended to serve as both, a point of reference for experimental biologists looking for practical solutions for analyzing their data, and a starting point for computer scientists interested in working on the computational problems related to time series expression analysis.

Adaptation, Physiological↗

PubMed2003

Computational discovery of gene modules and regulatory networks.

We describe an algorithm for discovering regulatory networks of gene modules, GRAM (Genetic Regulatory Modules), that combines information from genome-wide location and expression data sets. A gene module is defined as a set of coexpressed genes to which the same set of transcription factors binds. Unlike previous approaches that relied primarily on functional information from expression data, the GRAM algorithm explicitly links genes to the factors that regulate them by incorporating DNA binding data, which provide direct physical evidence of regulatory interactions. We use the GRAM algorithm to describe a genome-wide regulatory network in Saccharomyces cerevisiae using binding information for 106 transcription factors profiled in rich medium conditions data from over 500 expression experiments. We also present a genome-wide location analysis data set for regulators in yeast cells treated with rapamycin, and use the GRAM algorithm to provide biological insights into this regulatory network

Algorithms↗

PubMed2003

Comparing the continuous representation of time-series expression profiles to identify differentially expressed genes.

We present a general algorithm to detect genes differentially expressed between two nonhomogeneous time-series data sets. As increasing amounts of high-throughput biological data become available, a major challenge in genomic and computational biology is to develop methods for comparing data from different experimental sources. Time-series whole-genome expression data are a particularly valuable source of information because they can describe an unfolding biological process such as the cell cycle or immune response. However, comparisons of time-series expression data sets are hindered by biological and experimental inconsistencies such as differences in sampling rate, variations in the timing of biological processes, and the lack of repeats. Our algorithm overcomes these difficulties by using a continuous representation for time-series data and combining a noise model for individual samples with a global difference measure. We introduce a corresponding statistical method for computing the significance of this differential expression measure. We used our algorithm to compare cell-cycle-dependent gene expression in wild-type and knockout yeast strains. Our algorithm identified a set of 56 differentially expressed genes, and these results were validated by using independent protein-DNA-binding data. Unlike previous methods, our algorithm was also able to identify 22 non-cell-cycle-regulated genes as differentially expressed. This set of genes is significantly correlated in a set of independent expression experiments, suggesting additional roles for the transcription factors Fkh1 and Fkh2 in controlling cellular activity in yeast.

Algorithms↗

PubMed2003

K-ary clustering with optimal leaf ordering for gene expression data.

MOTIVATION: A major challenge in gene expression analysis is effective data organization and visualization. One of the most popular tools for this task is hierarchical clustering. Hierarchical clustering allows a user to view relationships in scales ranging from single genes to large sets of genes, while at the same time providing a global view of the expression data. However, hierarchical clustering is very sensitive to noise, it usually lacks of a method to actually identify distinct clusters, and produces a large number of possible leaf orderings of the hierarchical clustering tree. In this paper we propose a new hierarchical clustering algorithm which reduces susceptibility to noise, permits up to k siblings to be directly related, and provides a single optimal order for the resulting tree. RESULTS: We present an algorithm that efficiently constructs a k-ary tree, where each node can have up to k children, and then optimally orders the leaves of that tree. By combining k clusters at each step our algorithm becomes more robust against noise and missing values. By optimally ordering the leaves of the resulting tree we maintain the pairwise relationships that appear in the original method, without sacrificing the robustness. Our k-ary construction algorithm runs in O(n(3)) regardless of k and our ordering algorithm runs in O(4(k)n(3)). We present several examples that show that our k-ary clustering algorithm achieves results that are superior to the binary tree results in both global presentation and cluster identification. AVAILABILITY: We have implemented the above algorithms in C++ on the Linux operating system.

Algorithms↗

PubMed2003

Continuous representations of time-series gene expression data.

We present algorithms for time-series gene expression analysis that permit the principled estimation of unobserved time points, clustering, and dataset alignment. Each expression profile is modeled as a cubic spline (piecewise polynomial) that is estimated from the observed data and every time point influences the overall smooth expression curve. We constrain the spline coefficients of genes in the same class to have similar expression patterns, while also allowing for gene specific parameters. We show that unobserved time points can be reconstructed using our method with 10-15% less error when compared to previous best methods. Our clustering algorithm operates directly on the continuous representations of gene expression profiles, and we demonstrate that this is particularly effective when applied to nonuniformly sampled data. Our continuous alignment algorithm also avoids difficulties encountered by discrete approaches. In particular, our method allows for control of the number of degrees of freedom of the warp through the specification of parameterized functions, which helps to avoid overfitting. We demonstrate that our algorithm produces stable low-error alignments on real expression data and further show a specific application to yeast knock-out data that produces biologically meaningful results.

Algorithms↗

PubMed2002

Transcriptional regulatory networks in Saccharomyces cerevisiae.

We have determined how most of the transcriptional regulators encoded in the eukaryote Saccharomyces cerevisiae associate with genes across the genome in living cells. Just as maps of metabolic networks describe the potential pathways that may be used by a cell to accomplish metabolic processes, this network of regulator-gene interactions describes potential pathways yeast cells can use to regulate global gene expression programs. We use this information to identify network motifs, the simplest units of network architecture, and demonstrate that an automated process can use motifs to assemble a transcriptional regulatory network structure. Our results reveal that eukaryotic cellular functions are highly connected through networks of transcriptional regulators that regulate other transcriptional regulators.

Algorithms↗