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Fitting a mixture model by expectation maximization to discover motifs in biopolymers
 Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology
, 1994
"... ABSTRACT: The algorithm described in this paper discovers one or more motifs in a collection of DNA or protein sequences by using the technique of expectation maximization to fit a twocomponent finite mixture model to the set of sequences. Multiple motifs are found by fitting a twocomponent finite ..."
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Cited by 941 (5 self)
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ABSTRACT: The algorithm described in this paper discovers one or more motifs in a collection of DNA or protein sequences by using the technique of expectation maximization to fit a twocomponent finite mixture model to the set of sequences. Multiple motifs are found by fitting a twocomponent finite mixture model to the data, probabilistically erasing the occurrences of the motif thus found, and repeating the process to find successive motifs. The algorithm requires only a set of sequences and a number specifying the width of the motifs as input. It returns a model of each motif and a threshold which together can be used as a Bayesoptimal classifier for searching for occurrences of the motif in other databases. The algorithm estimates how many times each motif occurs in the input dataset and outputs an alignment of the occurrences of the motif. The algorithm is capable of discovering several different motifs with differing numbers of occurrences in a single dataset. Motifs are discovered by treating the set of sequences as though they were created by a stochastic process which can be modelled as a mixture of two densities, one of which generated the occurrences of the motif, and the other the rest of the positions in the sequences. Expectation maximization is used to estimate the parameters of the two densities and the mixing
Computational Identification of Cisregulatory Elements Associated with Groups of Functionally Related Genes in . . .
 J. MOL. BIOL
, 2000
"... ... runs on randomly selected sets of genes and on sets of genes whose upstream regions contain known transcription factor binding sites serve as controls. ..."
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Cited by 331 (15 self)
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... runs on randomly selected sets of genes and on sets of genes whose upstream regions contain known transcription factor binding sites serve as controls.
Finding motifs using random projections
, 2001
"... Pevzner and Sze [23] considered a precise version of the motif discovery problem and simultaneously issued an algorithmic challenge: find a motif Å of length 15, where each planted instance differs from Å in 4 positions. Whereas previous algorithms all failed to solve this (15,4)motif problem, Pevz ..."
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Cited by 287 (6 self)
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Pevzner and Sze [23] considered a precise version of the motif discovery problem and simultaneously issued an algorithmic challenge: find a motif Å of length 15, where each planted instance differs from Å in 4 positions. Whereas previous algorithms all failed to solve this (15,4)motif problem, Pevzner and Sze introduced algorithms that succeeded. However, their algorithms failed to solve the considerably more difficult (14,4), (16,5), and (18,6)motif problems. We introduce a novel motif discovery algorithm based on the use of random projections of the input’s substrings. Experiments on simulated data demonstrate that this algorithm performs better than existing algorithms and, in particular, typically solves the difficult (14,4), (16,5), and (18,6)motif problems quite efficiently. A probabilistic estimate shows that the small values of � for which the algorithm fails to recover the planted Ð � �motif are in all likelihood inherently impossible to solve. We also present experimental results on realistic biological data by identifying ribosome binding sites in prokaryotes as well as a number of known transcriptional regulatory motifs in eukaryotes. 1. CHALLENGING MOTIF PROBLEMS Pevzner and Sze [23] considered a very precise version of the motif discovery problem of computational biology, which had also been considered by Sagot [26]. Based on this formulation, they issued an algorithmic challenge: Planted Ð � �Motif Problem: Suppose there is a fixed but unknown nucleotide sequence Å (the motif) of length Ð. The problem is to determine Å, givenØ nucleotide sequences each of length Ò, and each containing a planted variant of Å. More precisely, each such planted variant is a substring that is Å with exactly � point substitutions. One instantiation that they labeled “The Challenge Problem ” was parameterized as finding a planted (15,4)motif in Ø � sequences each of length Ò � �. These values of Ò, Ø, andÐ are
Unsupervised Learning of Multiple Motifs in Biopolymers Using Expectation Maximization
 Machine Learning
, 1995
"... . The MEME algorithm extends the expectation maximization (EM) algorithm for identifying motifs in unalignedbiopolymer sequences. The aim of MEME is to discover new motifs in a set of biopolymer sequences where little or nothing is known in advance about any motifs that may be present. MEME innovati ..."
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. The MEME algorithm extends the expectation maximization (EM) algorithm for identifying motifs in unalignedbiopolymer sequences. The aim of MEME is to discover new motifs in a set of biopolymer sequences where little or nothing is known in advance about any motifs that may be present. MEME innovations expand the range of problems which can be solved using EM and increase the chance of finding good solutions. First, subsequences which actually occur in the biopolymer sequences are used as starting points for the EM algorithm to increase the probability of finding globally optimal motifs. Second, the assumption that each sequence contains exactly one occurrence of the shared motif is removed. This allows multiple appearances of a motif to occur in any sequence and permits the algorithm to ignore sequences with no appearance of the shared motif, increasing its resistance to noisy data. Third, a method for probabilistically erasing shared motifs after they are found is incorporated so tha...
Polygraph: Automatically generating signatures for polymorphic worms
 In Proceedings of the IEEE Symposium on Security and Privacy
, 2005
"... It is widely believed that contentsignaturebased intrusion detection systems (IDSes) are easily evaded by polymorphic worms, which vary their payload on every infection attempt. In this paper, we present Polygraph, a signature generation system that successfully produces signatures that match poly ..."
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Cited by 265 (16 self)
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It is widely believed that contentsignaturebased intrusion detection systems (IDSes) are easily evaded by polymorphic worms, which vary their payload on every infection attempt. In this paper, we present Polygraph, a signature generation system that successfully produces signatures that match polymorphic worms. Polygraph generates signatures that consist of multiple disjoint content substrings. In doing so, Polygraph leverages our insight that for a realworld exploit to function properly, multiple invariant substrings must often be present in all variants of a payload; these substrings typically correspond to protocol framing, return addresses, and in some cases, poorly obfuscated code. We contribute a definition of the polymorphic signature generation problem; propose classes of signature suited for matching polymorphic worm payloads; and present algorithms for automatic generation of signatures in these classes. Our evaluation of these algorithms on a range of polymorphic worms demonstrates that Polygraph produces signatures for polymorphic worms that exhibit low false negatives and false positives. 1.
Hidden Markov models for sequence analysis: extension and analysis of the basic method
, 1996
"... Hidden Markov models (HMMs) are a highly effective means of modeling a family of unaligned sequences or a common motif within a set of unaligned sequences. The trained HMM can then be used for discrimination or multiple alignment. The basic mathematical description of an HMM and its expectationmaxi ..."
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Cited by 219 (23 self)
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Hidden Markov models (HMMs) are a highly effective means of modeling a family of unaligned sequences or a common motif within a set of unaligned sequences. The trained HMM can then be used for discrimination or multiple alignment. The basic mathematical description of an HMM and its expectationmaximization training procedure is relatively straightforward. In this paper, we review the mathematical extensions and heuristics that move the method from the theoretical to the practical. Then, we experimentally analyze the effectiveness of model regularization, dynamic model modification, and optimization strategies. Finally it is demonstrated on the SH2 domain how a domain can be found from unaligned sequences using a special model type. The experimental work was completed with the aid of the Sequence Alignment and Modeling software suite. 1 Introduction Since their introduction to the computational biology community (Haussler et al., 1993; Krogh et al., 1994a), hidden Markov models (HMMs...
Learning Structural SVMs with Latent Variables
"... It is well known in statistics and machine learning that the combination of latent (or hidden) variables and observed variables offer more expressive power than models with observed variables alone. Latent variables ..."
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Cited by 213 (2 self)
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It is well known in statistics and machine learning that the combination of latent (or hidden) variables and observed variables offer more expressive power than models with observed variables alone. Latent variables
Probabilistic discovery of time series motifs
, 2003
"... Several important time series data mining problems reduce to the core task of finding approximately repeated subsequences in a longer time series. In an earlier work, we formalized the idea of approximately repeated subsequences by introducing the notion of time series motifs. Two limitations of thi ..."
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Cited by 179 (24 self)
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Several important time series data mining problems reduce to the core task of finding approximately repeated subsequences in a longer time series. In an earlier work, we formalized the idea of approximately repeated subsequences by introducing the notion of time series motifs. Two limitations of this work were the poor scalability of the motif discovery algorithm, and the inability to discover motifs in the presence of noise. Here we address these limitations by introducing a novel algorithm inspired by recent advances in the problem of pattern discovery in biosequences. Our algorithm is probabilistic in nature, but as we show empirically and theoretically, it can find time series motifs with very high probability even in the presence of noise or “don’t care ” symbols. Not only is the algorithm fast, but it is an anytime algorithm, producing likely candidate motifs almost immediately, and gradually improving the quality of results over time.
Identification of regulatory regions which confer musclespecific gene expression
 J. Mol. Biol
, 1998
"... For many newly sequenced genes, sequence analysis of the putative protein yields no clue on function. It would be bene®cial to be able to identify in the genome the regulatory regions that confer temporal and spatial expression patterns for the uncharacterized genes. Additionally, it would be advant ..."
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Cited by 178 (13 self)
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For many newly sequenced genes, sequence analysis of the putative protein yields no clue on function. It would be bene®cial to be able to identify in the genome the regulatory regions that confer temporal and spatial expression patterns for the uncharacterized genes. Additionally, it would be advantageous to identify regulatory regions within genes of known expression pattern without performing the costly and time consuming laboratory studies now required. To achieve these goals, the wealth of case studies performed over the past 15 years will have to be collected into predictive models of expression. Extensive studies of genes expressed in skeletal muscle have identi®ed speci®c transcription factors which bind to regulatory elements to control gene expression. However, potential binding sites for these factors occur with suf®cient frequency that it is rare for a gene to be found without one. Analysis of experimentally determined muscle regulatory sequences indicates that muscle expression requires multiple elements in close proximity. A model is generated with predictive capability for identifying these musclespeci®c regulatory modules. Phylogenetic footprinting, the identi®cation of sequences conserved between distantly related species, complements the statistical predictions. Through the use of logistic regression analysis, the model promises to be easily modi®ed to take advantage of the elucidation of additional factors, cooperation rules, and spacing constraints.
Approaches to the Automatic Discovery of Patterns in Biosequences
, 1995
"... This paper is a survey of approaches and algorithms used for the automatic discovery of patterns in biosequences. Patterns with the expressive power in the class of regular languages are considered, and a classification of pattern languages in this class is developed, covering those patterns which a ..."
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Cited by 173 (21 self)
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This paper is a survey of approaches and algorithms used for the automatic discovery of patterns in biosequences. Patterns with the expressive power in the class of regular languages are considered, and a classification of pattern languages in this class is developed, covering those patterns which are the most frequently used in molecular bioinformatics. A formulation is given of the problem of the automatic discovery of such patterns from a set of sequences, and an analysis presented of the ways in which an assessment can be made of the significance and usefulness of the discovered patterns. It is shown that this problem is related to problems studied in the field of machine learning. The largest part of this paper comprises a review of a number of existing methods developed to solve this problem and how these relate to each other, focusing on the algorithms underlying the approaches. A comparison is given of the algorithms, and examples are given of patterns that have been discovered...