2696332
A boosting approach for motif modeling using ChIP-chip data
MOTIVATION
Building an accurate binding model for a transcription factor (TF) is essential to differentiate its true binding targets from those spurious ones. This is an important step toward understanding gene regulation.


RESULTS
This paper describes a boosting approach to modeling TF-DNA binding. Different from the widely used weight matrix model, which predicts TF-DNA binding based on a linear combination of position-specific contributions, our approach builds a TF binding classifier by combining a set of weight matrix based classifiers, thus yielding a non-linear binding decision rule. The proposed approach was applied to the ChIP-chip data of Saccharomyces cerevisiae. When compared with the weight matrix method, our new approach showed significant improvements on the specificity in a majority of cases.
7555324
BioProspector: Discovering Conserved DNA Motifs in Upstream Regulatory Regions of Co-Expressed Genes
The development of genome sequencing and DNA microarray analysis of gene expression gives rise to the demand for data-mining tools. BioProspector, a C program using a Gibbs sampling strategy, examines the upstream region of genes in the same gene expression pattern group and looks for regulatory sequence motifs. BioProspector uses zero to third-order Markov background models whose parameters are either given by the user or estimated from a specified sequence file. The significance of each motif found is judged based on a motif score distribution estimated by a Monte Carlo method. In addition, BioProspector modifies the motif model used in the earlier Gibbs samplers to allow for the modeling of gapped motifs and motifs with palindromic patterns. All these modifications greatly improve the performance of the program. Although testing and development are still in progress, the program has shown preliminary success in finding the binding motifs for Saccharomyces cerevisiae RAP1, Bacillus subtilis RNA polymerase, and Escherichia coli CRP. We are currently working on combining BioProspector with a clustering program to explore gene expression networks and regulatory mechanisms.
5601540
A hidden Markov model for analyzing ChIP-chip experiments on genome tiling arrays and its application to p53 binding sequences
MOTIVATION
Transcription factors (TFs) regulate gene expression by recognizing and binding to specific regulatory regions on the genome, which in higher eukaryotes can occur far away from the regulated genes. Recently, Affymetrix developed the high-density oligonucleotide arrays that tile all the non-repetitive sequences of the human genome at 35 bp resolution. This new array platform allows for the unbiased mapping of in vivo TF binding sequences (TFBSs) using Chromatin ImmunoPrecipitation followed by microarray experiments (ChIP-chip). The massive dataset generated from these experiments pose great challenges for data analysis.


RESULTS
We developed a fast, scalable and sensitive method to extract TFBSs from ChIP-chip experiments on genome tiling arrays. Our method takes advantage of tiling array data from many experiments to normalize and model the behavior of each individual probe, and identifies TFBSs using a hidden Markov model (HMM). When applied to the data of p53 ChIP-chip experiments from an earlier study, our method discovered many new high confidence p53 targets including all the regions verified by quantitative PCR. Using a de novo motif finding algorithm MDscan, we also recovered the p53 motif from our HMM identified p53 target regions. Furthermore, we found substantial p53 motif enrichment in these regions comparing with both genomic background and the TFBSs identified earlier. Several of the newly identified p53 TFBSs are in the promoter region of known genes or associated with previously characterized p53-responsive genes.


SUPPLEMENTARY INFORMATION
Available at the following URL http://genome.dfci.harvard.edu/~xsliu/HMMTiling/index.html.
16397904
A suite of web-based programs to search for transcriptional regulatory motifs
The identification of regulatory motifs is important for the study of gene expression. Here we present a suite of programs that we have developed to search for regulatory sequence motifs: (i) BioProspector, a Gibbs-sampling-based program for predicting regulatory motifs from co-regulated genes in prokaryotes or lower eukaryotes; (ii) CompareProspector, an extension to BioProspector which incorporates comparative genomics features to be used for higher eukaryotes; (iii) MDscan, a program for finding protein-DNA interaction sites from ChIP-on-chip targets. All three programs examine a group of sequences that may share common regulatory motifs and output a list of putative motifs as position-specific probability matrices, the individual sites used to construct the motifs and the location of each site on the input sequences. The web servers and executables can be accessed at http://seqmotifs.stanford.edu.
353647
On Estimating Tight-Link Bandwidth Characteristics over Multi-Hop Paths
In this paper, we explore multi-hop bandwidth estimation assuming arbitrary cross-traffic at each node and develop a new probing method called Envelope that can asymptotically estimate not only the available bandwidth but also the raw capacity of the tight link. Envelope is based on a multi-link recursive extension of unbiased single-hop estimators proposed in the past (e.g., [14]) and a variation of the packet-cartouche technique [6]. Through extensive simulations, we evaluate Envelope in various network settings and cross-traffic conditions and find that it can measure tight-link bandwidth characteristics with accuracy that significantly surpasses that of the existing methods. We also find that Envelope can measure non-tight links in certain path and cross-traffic configurations.
36065326
Learning short multivariate time series models through evolutionary and sparse matrix computation
Multivariate time series (MTS) data are widely available in different fields including medicine, finance, bioinformatics, science and engineering. Modelling MTS data accurately is important for many decision making activities. One area that has been largely overlooked so far is the particular type of time series where the data set consists of a large number of variables but with a small number of observations. In this paper we describe the development of a novel computational method based on Natural Computation and sparse matrices that bypasses the size restrictions of traditional statistical MTS methods, makes no distribution assumptions, and also locates the associated parameters. Extensive results are presented, where the proposed method is compared with both traditional statistical and heuristic search techniques and evaluated on a number of criteria. The results have implications for a wide range of applications involving the learning of short MTS models.
39184835
Improved Robustness in Time Series Analysis of Gene Expression Data by Polynomial Model Based Clustering
Microarray experiments produce large data sets that often contain noise and considerable missing data. Typical clustering methods such as hierarchical clustering or partitional algorithms can often be adversely affected by such data. This paper introduces a method to overcome such problems associated with noise and missing data by modelling the time series data with polynomials and using these models to cluster the data. Similarity measures for polynomials are given that comply with commonly used standard measures. The polynomial model based clustering is compared with standard clustering methods under different conditions and applied to a real gene expression data set. It shows significantly better results as noise and missing data are increased.
34468051
Approximation Algorithms for Bi-clustering Problems
One of the main goals in the analysis of microarray data is to identify groups of genes and groups of experimental conditions (including environments, individuals and tissues), that exhibit similar expression patterns. This is the so-called bi-clustering problem. In this paper, we consider two variations of the bi-clustering problem: the Consensus Submatrix Problem and the Bottleneck Submatrix Problem. The input of the problems contains a m×n matrix A and integers l and k. The Consensus Submatrix Problem is to find a l×k submatrix with l<m and k<n and a consensus vector such that the sum of distance between all rows in the submatrix and the vector is minimized. The Bottleneck Submatrix Problem is to find a l×k submatrix with l<m and k<n, an integer d and a center vector such that the distance between every row in the submatrix and the vector is at most d and d is minimized. We show that both problems are NP-hard and give randomized approximation algorithms for special cases of the two problems. Using standard techniques, we can derandomize the algorithms to get polynomial time approximation schemes for the two problems. To our knowledge, this is the first time that approximation algorithms with guaranteed ratio are presented for microarray analysis.
23519212
Lower bounds of length of longest cycles in graphs involving neighborhood unions
Let G be a simple graph of order n. Let NC = min {|N(x)∪N(y)|: xy ∉ E(G)}. Denote by c(G), the circumference of G, the length of a longest cycle in G. In this paper we settle a conjecture of Faudree, Gould, Jacobson and Schelp [4], proving that (a) if G is 3-connected, then c(G) ⩾ min {n, 3(NC + 1)/2}; and (b) if G is 4-connected, then c(G) ⩾ min {n, 2NC}. Two examples are given to show that both bounds are sharp.