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1.  High-recall protein entity recognition using a dictionary 
Bioinformatics (Oxford, England)  2005;21(Suppl 1):i266-i273.
Protein name extraction is an important step in mining biological literature. We describe two new methods for this task: semiCRFs and dictionary HMMs. SemiCRFs are a recently-proposed extension to conditional random fields that enables more effective use of dictionary information as features. Dictionary HMMs are a technique in which a dictionary is converted to a large HMM that recognizes phrases from the dictionary, as well as variations of these phrases. Standard training methods for HMMs can be used to learn which variants should be recognized. We compared the performance of our new approaches to that of Maximum Entropy (Max-Ent) and normal CRFs on three datasets, and improvement was obtained for all four methods over the best published results for two of the datasets. CRFs and semiCRFs achieved the highest overall performance according to the widely-used F-measure, while the dictionary HMMs performed the best at finding entities that actually appear in the dictionary—the measure of most interest in our intended application.
PMCID: PMC2857312  PMID: 15961466
Protein Name Extraction; Dictionary HMMs; CRFs; SemiCRFs
2.  Comparative analysis of algorithms for identifying amplifications and deletions in array CGH data 
Array Comparative Genomic Hybridization (CGH) can reveal chromosomal aberrations in the genomic DNA. These amplifications and deletions at the DNA level are important in the pathogenesis of cancer and other diseases. While a large number of approaches have been proposed for analyzing the large array CGH data sets, the relative merits of these methods in practice are not clear.
We compare eleven different algorithms for analyzing array CGH data. These include both segment detection methods and smoothing methods, based on such diverse techniques as mixture models, Hidden Markov Models, maximum likelihood, regression, wavelets, genetic algorithms, and others. We compute the Receiver Operating Characteristic (ROC) curves using simulated data to quantify sensitivity and specificity for various levels of signal-to-noise ratio and different sizes of abnormalities. We also characterize their performance on chromosomal regions of interest in a real data set obtained from patients with Glioblastoma Multiforme. While comparisons of this type are difficult due to possibly sub-optimal choice of parameters in the methods, they nevertheless reveal general characteristics that are helpful to the biological investigator.
PMCID: PMC2819184  PMID: 16081473
3.  CrossChip: a system supporting comparative analysis of different generations of Affymetrix arrays 
To increase compatibility between different generations of Affymetrix GeneChip arrays, we propose a method of filtering probes based on their sequences. Our method is implemented as a web-based service for downloading necessary materials for converting the raw data files (*.CEL) for comparative analysis. The user can specify the appropriate level of filtering by setting the criteria for the minimum overlap length between probe sequences and the minimum number of usable probe pairs per probe set. Our website supports a within-species comparison for human and mouse GeneChip arrays.
PMCID: PMC2819168  PMID: 15684227
4.  MACiE: A Database of Enzyme Reaction Mechanisms 
Bioinformatics (Oxford, England)  2005;21(23):4315-4316.
MACiE (Mechanism, Annotation and Classification in Enzymes) is a publicly available web-based database, held in CMLReact (an XML application), that aims to help our understanding of the evolution of enzyme catalytic mechanisms and also to create a classification system which reflects the actual chemical mechanism (catalytic steps) of an enzyme reaction, not only the overall reaction.
PMCID: PMC2748267  PMID: 16188925
5.  Adding Some SPICE to DAS 
Bioinformatics (Oxford, England)  2005;21(Suppl 2):ii40-ii41.
The distributed annotation system (DAS) defines a communication protocol used to exchange biological annotations. It is motivated by the idea that annotations should not be provided by single centralized databases but instead be spread over multiple sites. Data distribution, performed by DAS servers, is separated from visualization, which is carried out by DAS clients. The original DAS protocol was designed to serve annotation of genomic sequences. We have extended the protocol to be applicable to macromolecular structures. Here we present SPICE, a new DAS client that can be used to visualize protein sequence and structure annotations.
PMCID: PMC2656757  PMID: 16204122
6.  SPLINDID: a semi-parametric, model-based method for obtaining transcription rates and gene regulation parameters from genomic and proteomic expression profiles 
Bioinformatics (Oxford, England)  2005;21(20):3873-3879.
To evaluate a semi-parametric, model-based approach for obtaining transcription rates from mRNA and protein expression.
The transcription profile input was modeled using an exponential function of a cubic spline and the dynamics of translation; mRNA and protein degradation were modeled using the Hargrove–Schmidt model. The transcription rate profile and the translation, and mRNA and protein degradation rate constants were estimated by the maximum likelihood method.
Simulated datasets generated from the stochastic, transit compartment and dispersion signaling models were used to test the approach. The approach satisfactorily fit the mRNA and protein data, and accurately recapitulated the parameter and the normalized transcription rate profile values. The approach was successfully used to model published data on tyrosine aminotransferase pharmacodynamics.
The semi-parametric approach is effective and could be useful for delineating the genomic effects of drugs.
Code suitable for use with the ADAPT software program is available from the corresponding author.
PMCID: PMC2607482  PMID: 16096347
7.  Association mapping and fine mapping with TreeLD 
Bioinformatics (Oxford, England)  2005;21(14):3168-3170.
The program package TreeLD implements a unified approach to association mapping and fine mapping of complex trait loci and a novel approach to visualizing association data, based on an inferred ancestry of the sample. Fundamentally, the TreeLD approach is based on the idea that the evidence for association at a particular position is contained in the ancestral tree relating the sampled chromosomes at that position. TreeLD provides an easy-to-use interface and can be applied to case–control, TDT trio and quantitative trait data.
PMCID: PMC2587010  PMID: 15855250
8.  Differential and trajectory methods for time course gene expression data 
Bioinformatics (Oxford, England)  2005;21(13):3009-3016.
The issue of high dimensionality in microarray data has been, and remains, a hot topic in statistical and computational analysis. Efficient gene filtering and differentiation approaches can reduce the dimensions of data, help to remove redundant genes and noises, and highlight the most relevant genes that are major players in the development of certain diseases or the effect of drug treatment. The purpose of this study is to investigate the efficiency of parametric (including Bayesian and non-Bayesian, linear and non-linear), non-parametric and semi-parametric gene filtering methods through the application of time course microarray data from multiple sclerosis patients being treated with interferon-β-1a. The analysis of variance with bootstrapping (parametric), class dispersion (semi-parametric) and Pareto (non-parametric) with permutation methods are presented and compared for filtering and finding differentially expressed genes. The Bayesian linear correlated model, the Bayesian non-linear model the and non-Bayesian mixed effects model with bootstrap were also developed to characterize the differential expression patterns. Furthermore, trajectory-clustering approaches were developed in order to investigate the dynamic patterns and inter-dependency of drug treatment effects on gene expression.
Results show that the presented methods performed significant differently but all were adequate in capturing a small number of the potentially relevant genes to the disease. The parametric method, such as the mixed model and two Bayesian approaches proved to be more conservative. This may because these methods are based on overall variation in expression across all time points. The semi-parametric (class dispersion) and non-parametric (Pareto) methods were appropriate in capturing variation in expression from time point to time point, thereby making them more suitable for investigating significant monotonic changes and trajectories of changes in gene expressions in time course microarray data. Also, the non-linear Bayesian model proved to be less conservative than linear Bayesian correlated growth models to filter out the redundant genes, although the linear model showed better fit than non-linear model (smaller DIC). We also report the trajectories of significant genes—since we have been able to isolate trajectories of genes whose regulations appear to be inter-dependent.
PMCID: PMC2574001  PMID: 15886280
9.  GOR V server for protein secondary structure prediction 
Bioinformatics (Oxford, England)  2005;21(11):2787-2788.
We have created the GOR V web server for protein secondary structure prediction. The GOR V algorithm combines information theory, Bayesian statistics and evolutionary information. In its fifth version, the GOR method reached (with the full jack-knife procedure) an accuracy of prediction Q3 of 73.5%. Although GOR V has been among the most successful methods, its online unavailability has been a deterrent to its popularity. Here, we remedy this situation by creating the GOR V server.
PMCID: PMC2553678  PMID: 15797907
10.  A semantic analysis of the annotations of the human genome 
Bioinformatics (Oxford, England)  2005;21(16):3416-3421.
The correct interpretation of any biological experiment depends in an essential way on the accuracy and consistency of the existing annotation databases. Such databases are ubiquitous and used by all life scientists in most experiments. However, it is well known that such databases are incomplete and many annotations may also be incorrect. In this paper we describe a technique that can be used to analyze the semantic content of such annotation databases. Our approach is able to extract implicit semantic relationships between genes and functions. This ability allows us to discover novel functions for known genes. This approach is able to identify missing and inaccurate annotations in existing annotation databases, and thus help improve their accuracy. We used our technique to analyze the current annotations of the human genome. From this body of annotations, we were able to predict 212 additional gene–function assignments. A subsequent literature search found that 138 of these gene–functions assignments are supported by existing peer-reviewed papers. An additional 23 assignments have been confirmed in the meantime by the addition of the respective annotations in later releases of the Gene Ontology database. Overall, the 161 confirmed assignments represent 75.95% of the proposed gene–function assignments. Only one of our predictions (0.4%) was contradicted by the existing literature. We could not find any relevant articles for 50 of our predictions (23.58%). The method is independent of the organism and can be used to analyze and improve the quality of the data of any public or private annotation database.
PMCID: PMC2435251  PMID: 15955782
11.  Ontological analysis of gene expression data: current tools, limitations, and open problems 
Bioinformatics (Oxford, England)  2005;21(18):3587-3595.
Independent of the platform and the analysis methods used, the result of a microarray experiment is, in most cases, a list of differentially expressed genes. An automatic ontological analysis approach has been recently proposed to help with the biological interpretation of such results. Currently, this approach is the de facto standard for the secondary analysis of high throughput experiments and a large number of tools have been developed for this purpose. We present a detailed comparison of 14 such tools using the following criteria: scope of the analysis, visualization capabilities, statistical model(s) used, correction for multiple comparisons, reference microar-rays available, installation issues and sources of annotation data. This detailed analysis of the capabilities of these tools will help researchers choose the most appropriate tool for a given type of analysis. More importantly, in spite of the fact that this type of analysis has been generally adopted, this approach has several important intrinsic drawbacks. These drawbacks are associated with all tools discussed and represent conceptual limitations of the current state-of-the-art in ontological analysis. We propose these as challenges for the next generation of secondary data analysis tools.
PMCID: PMC2435250  PMID: 15994189
12.  Simple decision rules for classifying human cancers from gene expression profiles 
Bioinformatics (Oxford, England)  2005;21(20):3896-3904.
Various studies have shown that cancer tissue samples can be successfully detected and classified by their gene expression patterns using machine learning approaches. One of the challenges in applying these techniques for classifying gene expression data is to extract accurate, readily interpretable rules providing biological insight as to how classification is performed. Current methods generate classifiers that are accurate but difficult to interpret. This is the trade-off between credibility and comprehensibility of the classifiers. Here, we introduce a new classifier in order to address these problems. It is referred to as k-TSP (k–Top Scoring Pairs) and is based on the concept of ‘relative expression reversals’. This method generates simple and accurate decision rules that only involve a small number of gene-to-gene expression comparisons, thereby facilitating follow-up studies.
In this study, we have compared our approach to other machine learning techniques for class prediction in 19 binary and multi-class gene expression datasets involving human cancers. The k-TSP classifier performs as efficiently as Prediction Analysis of Microarray and support vector machine, and outperforms other learning methods (decision trees, k-nearest neighbour and naïve Bayes). Our approach is easy to interpret as the classifier involves only a small number of informative genes. For these reasons, we consider the k-TSP method to be a useful tool for cancer classification from micro-array gene expression data.
The software and datasets are available at
PMCID: PMC1987374  PMID: 16105897
13.  iGNM: a database of protein functional motions based on Gaussian Network Model 
Bioinformatics (Oxford, England)  2005;21(13):2978-2987.
The knowledge of protein structure is not sufficient for understanding and controlling its function. Function is a dynamic property. Although protein structural information has been rapidly accumulating in databases, little effort has been invested to date toward systematically characterizing protein dynamics. The recent success of analytical methods based on elastic network models, and in particular the Gaussian Network Model (GNM), permits us to perform a high-throughput analysis of the collective dynamics of proteins.
We computed the GNM dynamics for 20 058 structures from the Protein Data Bank, and generated information on the equilibrium dynamics at the level of individual residues. The results are stored on a web-based system called i GNM and configured so as to permit the users to visualize or download the results through a standard web browser using a simple search engine. Static and animated images for describing the conformational mobility of proteins over a broad range of normal modes are accessible, along with an online calculation engine available for newly deposited structures. A case study of the dynamics of 20 non-homologous hydrolases is presented to illustrate the utility of the iGNM database for identifying key residues that control the cooperative motions and revealing the connection between collective dynamics and catalytic activity.
PMCID: PMC1752228  PMID: 15860562
14.  Predicting protein–protein interaction by searching evolutionary tree automorphism space 
Bioinformatics (Oxford, England)  2005;21(Suppl 1):i241-i250.
Uncovering the protein–protein interaction network is a fundamental step in the quest to understand the molecular machinery of a cell. This motivates the search for efficient computational methods for predicting such interactions. Among the available predictors are those that are based on the co-evolution hypothesis “evolutionary trees of protein families (that are known to interact) are expected to have similar topologies”. Many of these methods are limited by the fact that they can handle only a small number of protein sequences. Also, details on evolutionary tree topology are missing as they use similarity matrices in lieu of the trees.
We introduce MORPH, a new algorithm for predicting protein interaction partners between members of two protein families that are known to interact. Our approach can also be seen as a new method for searching the best superposition of the corresponding evolutionary trees based on tree automorphism group. We discuss relevant facts related to the predictability of protein–protein interaction based on their co-evolution. When compared with related computational approaches, our method reduces the search space by ~3 × 105-fold and at the same time increases the accuracy of predicting correct binding partners.
PMCID: PMC1618802  PMID: 15961463
15.  Nexplorer: Phylogeny-based exploration of sequence family data 
Bioinformatics (Oxford, England)  2005;22(1):120-121.
Nexplorer is a web-based program for interactive browsing and manipulation of character data in NEXUS format, well suited for use with alignments and trees representing families of homologous genes or proteins. Users may upload a sequence family data set, or choose from one of several thousand already available. Nexplorer provides a flexible means to develop customized views that combine a tree and a data matrix or alignment, to create subsets of data, and to output data files or publication-quality graphics.
Web access is from
PMCID: PMC1615790  PMID: 16267087
16.  Automated interpretation of MS/MS spectra of oligosaccharides 
Bioinformatics (Oxford, England)  2005;21(Suppl 1):i431-i439.
Motivation: The emerging glycomics and glycoproteomics projects aim to characterize all forms of glycoproteins in different tissues and organisms. Tandem mass spectrometry (MS/MS) is the key experimental methodology for high-throughput glycan identification and characterization. Fragmentation of glycans from high energy collision-induced dissociation generates ions from glycosidic as well as internal cleavages. The cross-ring ions resulting from internal cleavages provide additional information that is important to reveal the type of linkage between monosaccharides. This information, however, is not incorporated into the current programs for analyzing glycan mass spectra. As a result, they can rarely distinguish from the mass spectra isomeric oligosaccharides, which have the same saccharide composition but different types of sequences, branches or linkages.
Results: In this paper, we describe a novel algorithm for glycan characterization using MS/MS. This algorithm consists of three steps. First, we develop a scoring scheme to identify potential bond linkages between monosaccharides, based on the appearance pattern of cross-ring ions. Next, we use a dynamic programming algorithm to determine the most probable oligosaccharide structures from the mass spectrum. Finally, we re-evaluate these oligosaccharide structures, taking into account the double fragmentation ions. We also show the preliminary results of testing our algorithm on several MS/MS spectra of oligosaccharides.
Availability: The program GLYCH is available upon request from the authors.
PMCID: PMC1513159  PMID: 15961488
17.  Querying and Computing with BioCyc Databases 
Bioinformatics (Oxford, England)  2005;21(16):3454-3455.
We describe multiple methods for accessing and querying the complex and integrated cellular data in the BioCyc family of databases: access through multiple file formats, access through Application Program Interfaces (APIs) for LISP, Perl and Java, and SQL access through the BioWarehouse relational database.
The Pathway Tools software and 20 BioCyc DBs in Tiers 1 and 2 are freely available to academic users; fees apply to some types of commercial use. For download instructions see
PMCID: PMC1450015  PMID: 15961440
18.  SNPselector: a web tool for selecting SNPs for genetic association studies 
Bioinformatics (Oxford, England)  2005;21(22):4181-4186.
Summary: Single nucleotide polymorphisms (SNPs) are commonly used for association studies to find genes responsible for complex genetic diseases. With the recent advance of SNP technology, researchers are able to assay thousands of SNPs in a single experiment. But the process of manually choosing thousands of genotyping SNPs for tens or hundreds of genes is time consuming. We have developed a web-based program, SNPselector, to automate the process. SNPselector takes a list of gene names or a list of genomic regions as input and searches the Ensembl genes or genomic regions for available SNPs. It prioritizes these SNPs on their tagging for linkage disequilibrium, SNP allele frequencies and source, function, regulatory potential, and repeat status. SNPselector outputs result in compressed Excel spreadsheet files for review by the user.
Availability: SNPselector is freely available at
PMCID: PMC1361283  PMID: 16179360
19.  Alignments anchored on genomic landmarks can aid in the identification of regulatory elements 
Bioinformatics (Oxford, England)  2005;21(Suppl 1):i440-i448.
The transcription start site (TSS) has been located for an increasing number of genes across several organisms. Statistical tests have shown that some cis-acting regulatory elements have positional preferences with respect to the TSS, but few strategies have emerged for locating elements by their positional preferences. This paper elaborates such a strategy. First, we align promoter regions without gaps, anchoring the alignment on each promoter’s TSS. Second, we apply a novel word-specific mask. Third, we apply a clustering test related to gapless BLAST statistics. The test examines whether any specific word is placed unusually consistently with respect to the TSS. Finally, our program A-GLAM, an extension of the GLAM program, uses significant word positions as new ‘anchors’ to realign the sequences. A Gibbs sampling algorithm then locates putative cis-acting regulatory elements. Usually, Gibbs sampling requires a preliminary masking step, to avoid convergence onto a dominant but uninteresting signal from a DNA repeat. However, since the positional anchors focus A-GLAM on the motif of interest, masking DNA repeats during Gibbs sampling becomes unnecessary.
In a set of human DNA sequences with experimentally characterized TSSs, the placement of 791 octonucleotide words was unusually consistent (multiple test corrected P < 0.05). Alignments anchored on these words sometimes located statistically significant motifs inaccessible to GLAM or AlignACE.
The A-GLAM program and a list of statistically significant words are available at
PMCID: PMC1317086  PMID: 15961489
20.  Mining genetic epidemiology data with Bayesian networks I: Bayesian networks and example application (plasma apoE levels) 
Bioinformatics (Oxford, England)  2005;21(15):3273-3278.
The wealth of single nucleotide polymorphism (SNP) data within candidate genes and anticipated across the genome poses enormous analytical problems for studies of genotype-to-phenotype relationships, and modern data mining methods may be particularly well suited to meet the swelling challenges. In this paper, we introduce the method of Belief (Bayesian) networks to the domain of genotype-to-phenotype analyses and provide an example application.
A Belief network is a graphical model of a probabilistic nature that represents a joint multivariate probability distribution and reflects conditional independences between variables. Given the data, optimal network topology can be estimated with the assistance of heuristic search algorithms and scoring criteria. Statistical significance of edge strengths can be evaluated using Bayesian methods and bootstrapping. As an example application, the method of Belief networks was applied to 20 SNPs in the apolipoprotein (apo) E gene and plasma apoE levels in a sample of 702 individuals from Jackson, MS. Plasma apoE level was the primary target variable. These analyses indicate that the edge between SNP 4075, coding for the well-known ɛ2 allele, and plasma apoE level was strong. Belief networks can effectively describe complex uncertain processes and can both learn from data and incorporate prior knowledge.
PMCID: PMC1201438  PMID: 15914545

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