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PubMed2004

mdclust--exploratory microarray analysis by multidimensional clustering.

MOTIVATION: Unsupervised clustering of microarray data may detect potentially important, but not obvious characteristics of samples, for instance subgroups of diagnoses with distinct gene profiles or systematic errors in experimentation. RESULTS: Multidimensional clustering (mdclust) is a method, which identifies sets of sample clusters and associated genes. It applies iteratively two-means clustering and score-based gene selection. For any phenotype variable best matching sets of clusters can be selected. This provides a method to identify gene-phenotype associations, suited even for settings with a large number of phenotype variables. An optional model based discriminant step may reduce further the number of selected genes.

Cluster Analysis↗
PubMed2004

Rapid 3D protein structure database searching using information retrieval techniques.

MOTIVATION: As the sizes of three-dimensional (3D) protein structure databases are growing rapidly nowadays, exhaustive database searching, in which a 3D query structure is compared to each and every structure in the database, becomes inefficient. We propose a rapid 3D protein structure retrieval system named 'ProtDex2', in which we adopt the techniques used in information retrieval systems in order to perform rapid database searching without having access to every 3D structure in the database. The retrieval process is based on the inverted-file index constructed on the feature vectors of the relationships between the secondary structure elements (SSEs) of all the 3D protein structures in the database. ProtDex2 is a significant improvement, both in terms of speed and accuracy, upon its predecessor system, ProtDex. RESULTS: The experimental results show that ProtDex2 is very much faster than two well-known protein structure comparison methods, DALI and CE, yet not sacrificing on the accuracy of the comparison. When comparing with a similar SSE-based method, namely TopScan, ProtDex2 is much faster with comparable degree of accuracy. AVAILABILITY: The software is available at: http://xena1.ddns.comp.nus.edu.sg/~genesis/PD2.htm

Algorithms↗
PubMed2004

Open source clustering software.

SUMMARY: We have implemented k-means clustering, hierarchical clustering and self-organizing maps in a single multipurpose open-source library of C routines, callable from other C and C++ programs. Using this library, we have created an improved version of Michael Eisen's well-known Cluster program for Windows, Mac OS X and Linux/Unix. In addition, we generated a Python and a Perl interface to the C Clustering Library, thereby combining the flexibility of a scripting language with the speed of C. AVAILABILITY: The C Clustering Library and the corresponding Python C extension module Pycluster were released under the Python License, while the Perl module Algorithm::Cluster was released under the Artistic License. The GUI code Cluster 3.0 for Windows, Macintosh and Linux/Unix, as well as the corresponding command-line program, were released under the same license as the original Cluster code. The complete source code is available at http://bonsai.ims.u-tokyo.ac.jp/mdehoon/software/cluster. Alternatively, Algorithm::Cluster can be downloaded from CPAN, while Pycluster is also available as part of the Biopython distribution.

Algorithms↗
PubMed2004

COACH: profile-profile alignment of protein families using hidden Markov models.

MOTIVATION: Alignments of two multiple-sequence alignments, or statistical models of such alignments (profiles), have important applications in computational biology. The increased amount of information in a profile versus a single sequence can lead to more accurate alignments and more sensitive homolog detection in database searches. Several profile-profile alignment methods have been proposed and have been shown to improve sensitivity and alignment quality compared with sequence-sequence methods (such as BLAST) and profile-sequence methods (e.g. PSI-BLAST). Here we present a new approach to profile-profile alignment we call Comparison of Alignments by Constructing Hidden Markov Models (HMMs) (COACH). COACH aligns two multiple sequence alignments by constructing a profile HMM from one alignment and aligning the other to that HMM. RESULTS: We compare the alignment accuracy of COACH with two recently published methods: Yona and Levitt's prof_sim and Sadreyev and Grishin's COMPASS. On two sets of reference alignments selected from the FSSP database, we find that COACH is able, on average, to produce alignments giving the best coverage or the fewest errors, depending on the chosen parameter settings. AVAILABILITY: COACH is freely available from www.drive5.com/lobster

Algorithms↗
PubMed2004

Haplotype reconstruction from genotype data using Imperfect Phylogeny.

UNLABELLED: Critical to the understanding of the genetic basis for complex diseases is the modeling of human variation. Most of this variation can be characterized by single nucleotide polymorphisms (SNPs) which are mutations at a single nucleotide position. To characterize the genetic variation between different people, we must determine an individual's haplotype or which nucleotide base occurs at each position of these common SNPs for each chromosome. In this paper, we present results for a highly accurate method for haplotype resolution from genotype data. Our method leverages a new insight into the underlying structure of haplotypes that shows that SNPs are organized in highly correlated 'blocks'. In a few recent studies, considerable parts of the human genome were partitioned into blocks, such that the majority of the sequenced genotypes have one of about four common haplotypes in each block. Our method partitions the SNPs into blocks, and for each block, we predict the common haplotypes and each individual's haplotype. We evaluate our method over biological data. Our method predicts the common haplotypes perfectly and has a very low error rate (<2% over the data) when taking into account the predictions for the uncommon haplotypes. Our method is extremely efficient compared with previous methods such as PHASE and HAPLOTYPER. Its efficiency allows us to find the block partition of the haplotypes, to cope with missing data and to work with large datasets. AVAILABILITY: The algorithm is available via a Web server at http://www.calit2.net/compbio/hap/

Algorithms↗
PubMed2004

Robust PCA and classification in biosciences.

MOTIVATION: Principal components analysis (PCA) is a very popular dimension reduction technique that is widely used as a first step in the analysis of high-dimensional microarray data. However, the classical approach that is based on the mean and the sample covariance matrix of the data is very sensitive to outliers. Also, classification methods based on this covariance matrix do not give good results in the presence of outlying measurements. RESULTS: First, we propose a robust PCA (ROBPCA) method for high-dimensional data. It combines projection-pursuit ideas with robust estimation of low-dimensional data. We also propose a diagnostic plot to display and classify the outliers. This ROBPCA method is applied to several bio-chemical datasets. In one example, we also apply a robust discriminant method on the scores obtained with ROBPCA. We show that this combination of robust methods leads to better classifications than classical PCA and quadratic discriminant analysis. AVAILABILITY: All the programs are part of the Matlab Toolbox for Robust Calibration, available at http://www.wis.kuleuven.ac.be/stat/robust.html.

Algorithms↗
PubMed2004

Gene co-expression network topology provides a framework for molecular characterization of cellular state.

MOTIVATION: Gene expression data have become an instrumental resource in describing the molecular state associated with various cellular phenotypes and responses to environmental perturbations. The utility of expression profiling has been demonstrated in partitioning clinical states, predicting the class of unknown samples and in assigning putative functional roles to previously uncharacterized genes based on profile similarity. However, gene expression profiling has had only limited success in identifying therapeutic targets. This is partly due to the fact that current methods based on fold-change focus only on single genes in isolation, and thus cannot convey causal information. In this paper, we present a technique for analysis of expression data in a graph-theoretic framework that relies on associations between genes. We describe the global organization of these networks and biological correlates of their structure. We go on to present a novel technique for the molecular characterization of disparate cellular states that adds a new dimension to the fold-based methods and conclude with an example application to a human medulloblastoma dataset. RESULTS: We have shown that expression networks generated from large model-organism expression datasets are scale-free and that the average clustering coefficient of these networks is several orders of magnitude higher than would be expected for similarly sized scale-free networks, suggesting an inherent hierarchical modularity similar to that previously identified in other biological networks. Furthermore, we have shown that these properties are robust with respect to the parameters of network construction. We have demonstrated an enrichment of genes having lethal knockout phenotypes in the high-degree (i.e. hub) nodes in networks generated from aggregate condition datasets; using process-focused Saccharomyces cerivisiae datasets we have demonstrated additional high-degree enrichments of condition-specific genes encoding proteins known to be involved in or important for the processes interrogated by the microarrays. These results demonstrate the utility of network analysis applied to expression data in identifying genes that are regulated in a state-specific manner. We concluded by showing that a sample application to a human clinical dataset prominently identified a known therapeutic target. AVAILABILITY: Software implementing the methods for network generation presented in this paper is available for academic use by request from the authors in the form of compiled linux binary executables.

Algorithms↗
PubMed2004

A statistical framework for the design of microarray experiments and effective detection of differential gene expression.

MOTIVATION: Microarray experiments generate a high data volume. However, often due to financial or experimental considerations, e.g. lack of sample, there is little or no replication of the experiments or hybridizations. These factors combined with the intrinsic variability associated with the measurement of gene expression can result in an unsatisfactory detection rate of differential gene expression (DGE). Our motivation was to provide an easy to use measure of the success rate of DGE detection that could find routine use in the design of microarray experiments or in post-experiment assessment. RESULTS: In this study, we address the problem of both random errors and systematic biases in microarray experimentation. We propose a mathematical model for the measured data in microarray experiments and on the basis of this model present a t-based statistical procedure to determine DGE. We have derived a formula to determine the success rate of DGE detection that takes into account the number of microarrays, the number of genes, the magnitude of DGE, and the variance from biological and technical sources. The formula and look-up tables based on the formula, can be used to assist in the design of microarray experiments. We also propose an ad hoc method for estimating the fraction of non-differentially expressed genes within a set of genes being tested. This will help to increase the power of DGE detection. AVAILABILITY: The functions to calculate the success rate of DGE detection have been implemented as a Java application, which is accessible at http://www.le.ac.uk/mrctox/microarray_lab/Microarray_Softwares/Microarray_Softwares.htm

Algorithms↗
PubMed2004

The 'subsequent artificial neural network' (SANN) approach might bring more classificatory power to ANN-based DNA microarray analyses.

MOTIVATION: Human decisions often proceed in two steps. Initially those most preferred are chosen followed by a subsequent choice of these preferences. Applying one artificial neural network (ANN), a classification is limited to the preselection process. The final categorization is only possible by a subsequent ANN that distinguishes the pre-chosen classes. Existing strategies using coupled ANNs are discussed and a new approach particularly suited for multiclass classification problems is introduced ('Subsequent ANN', SANN). RESULTS: Evaluating a simulated data base comprising 3 classes, classification results of SANN were obviously superior to those achieved by ANN. To evaluate a real-world data base the microarray benchmark GCM (14 classes) was chosen. The ANN results reached 72%, comparable to previous results. Using SANN, up to 81% of the tumors were correctly classified. AVAILABILITY: Programs used in this work and numerical results are available upon request.

Algorithms↗
PubMed2004

The Baumgartner-Weiss-Schindler test for the detection of differentially expressed genes in replicated microarray experiments.

MOTIVATION: An important application of microarray experiments is to identify differentially expressed genes. Because microarray data are often not distributed according to a normal distribution nonparametric methods were suggested for their statistical analysis. Here, the Baumgartner-Weiss-Schindler test, a novel and powerful test based on ranks, is investigated and compared with the parametric t-test as well as with two other nonparametric tests (Wilcoxon rank sum test, Fisher-Pitman permutation test) recently recommended for the analysis of gene expression data. RESULTS: Simulation studies show that an exact permutation test based on the Baumgartner-Weiss-Schindler statistic B is preferable to the other three tests. It is less conservative than the Wilcoxon test and more powerful, in particular in case of asymmetric or heavily tailed distributions. When the underlying distribution is symmetric the differences in power between the tests are relatively small. Thus, the Baumgartner-Weiss-Schindler is recommended for the usual situation that the underlying distribution is a priori unknown. AVAILABILITY: SAS code available on request from the authors.

Algorithms↗
PubMed2004

BagBoosting for tumor classification with gene expression data.

MOTIVATION: Microarray experiments are expected to contribute significantly to the progress in cancer treatment by enabling a precise and early diagnosis. They create a need for class prediction tools, which can deal with a large number of highly correlated input variables, perform feature selection and provide class probability estimates that serve as a quantification of the predictive uncertainty. A very promising solution is to combine the two ensemble schemes bagging and boosting to a novel algorithm called BagBoosting. RESULTS: When bagging is used as a module in boosting, the resulting classifier consistently improves the predictive performance and the probability estimates of both bagging and boosting on real and simulated gene expression data. This quasi-guaranteed improvement can be obtained by simply making a bigger computing effort. The advantageous predictive potential is also confirmed by comparing BagBoosting to several established class prediction tools for microarray data. AVAILABILITY: Software for the modified boosting algorithms, for benchmark studies and for the simulation of microarray data are available as an R package under GNU public license at http://stat.ethz.ch/~dettling/bagboost.html.

Algorithms↗
PubMed2004

A simple and fast secondary structure prediction method using hidden neural networks.

MOTIVATION: In this paper, we present a secondary structure prediction method YASPIN that unlike the current state-of-the-art methods utilizes a single neural network for predicting the secondary structure elements in a 7-state local structure scheme and then optimizes the output using a hidden Markov model, which results in providing more information for the prediction. RESULTS: YASPIN was compared with the current top-performing secondary structure prediction methods, such as PHDpsi, PROFsec, SSPro2, JNET and PSIPRED. The overall prediction accuracy on the independent EVA5 sequence set is comparable with that of the top performers, according to the Q3, SOV and Matthew's correlations accuracy measures. YASPIN shows the highest accuracy in terms of Q3 and SOV scores for strand prediction. AVAILABILITY: YASPIN is available on-line at the Centre for Integrative Bioinformatics website (http://ibivu.cs.vu.nl/programs/yaspinwww/) at the Vrije University in Amsterdam and will soon be mirrored on the Mathematical Biology website (http://www.mathbio.nimr.mrc.ac.uk) at the NIMR in London. CONTACT: kxlin@nimr.mrc.ac.uk

Algorithms↗
PubMed2004

A new algorithm for detecting low-complexity regions in protein sequences.

MOTIVATION: Pair-wise alignment of protein sequences and local similarity searches produce many false positives because of compositionally biased regions, also called low-complexity regions (LCRs), of amino acid residues. Masking and filtering such regions significantly improves the reliability of homology searches and, consequently, functional predictions. Most of the available algorithms are based on a statistical approach. We wished to investigate the structural properties of LCRs in biological sequences and develop an algorithm for filtering them. RESULTS: We present an algorithm for detecting and masking LCRs in protein sequences to improve the quality of database searches. We developed the algorithm based on the complexity analysis of subsequences delimited by a pair of identical, repeating subsequences. Given a protein sequence, the algorithm first computes the suffix tree of the sequence. It then collects repeating subsequences from the tree. Finally, the algorithm iteratively tests whether each subsequence delimited by a pair of repeating subsequences meets a given criteria. Test results with 1000 proteins from 20 families in Pfam show that the repeating subsequences are a good indicator for the low-complexity regions, and the algorithm based on such structural information strongly compete with others. AVAILABILITY: http://bioinfo.knu.ac.kr/research/CARD/ CONTACT: swshin@bioinfo.knu.ac.kr

Algorithms↗
PubMed2004

Filtering of ineffective siRNAs and improved siRNA design tool.

MOTIVATION: Short interfering RNAs (siRNAs) can be used to suppress gene expression and possess many potential applications in therapy, but how to design an effective siRNA is still not clear. Based on the MPI (Max-Planck-Institute) basic principles, a number of siRNA design tools have been developed recently. The set of candidates reported by these tools is usually large and often contains ineffective siRNAs. In view of this, we initiate the study of filtering ineffective siRNAs. RESULTS: The contribution of this paper is 2-fold. First, we propose a fair scheme to compare existing design tools based on real data in the literature. Second, we attempt to improve the MPI principles and existing tools by an algorithm that can filter ineffective siRNAs. The algorithm is based on some new observations on the secondary structure, which we have verified by AI techniques (decision trees and support vector machines). We have tested our algorithm together with the MPI principles and the existing tools. The results show that our filtering algorithm is effective. AVAILABILITY: The siRNA design software tool can be found in the website http://www.cs.hku.hk/~sirna/ CONTACT: smyiu@cs.hku.hk

Algorithms↗
PubMed2004

Protein homology detection by HMM-HMM comparison.

MOTIVATION: Protein homology detection and sequence alignment are at the basis of protein structure prediction, function prediction and evolution. RESULTS: We have generalized the alignment of protein sequences with a profile hidden Markov model (HMM) to the case of pairwise alignment of profile HMMs. We present a method for detecting distant homologous relationships between proteins based on this approach. The method (HHsearch) is benchmarked together with BLAST, PSI-BLAST, HMMER and the profile-profile comparison tools PROF_SIM and COMPASS, in an all-against-all comparison of a database of 3691 protein domains from SCOP 1.63 with pairwise sequence identities below 20%.Sensitivity: When the predicted secondary structure is included in the HMMs, HHsearch is able to detect between 2.7 and 4.2 times more homologs than PSI-BLAST or HMMER and between 1.44 and 1.9 times more than COMPASS or PROF_SIM for a rate of false positives of 10%. Approximately half of the improvement over the profile-profile comparison methods is attributable to the use of profile HMMs in place of simple profiles. Alignment quality: Higher sensitivity is mirrored by an increased alignment quality. HHsearch produced 1.2, 1.7 and 3.3 times more good alignments ('balanced' score >0.3) than the next best method (COMPASS), and 1.6, 2.9 and 9.4 times more than PSI-BLAST, at the family, superfamily and fold level, respectively.Speed: HHsearch scans a query of 200 residues against 3691 domains in 33 s on an AMD64 2GHz PC. This is 10 times faster than PROF_SIM and 17 times faster than COMPASS.

Algorithms↗
PubMed2005

Dynamic model based algorithms for screening and genotyping over 100 K SNPs on oligonucleotide microarrays.

MOTIVATION: A high density of single nucleotide polymorphism (SNP) coverage on the genome is desirable and often an essential requirement for population genetics studies. Region-specific or chromosome-specific linkage studies also benefit from the availability of as many high quality SNPs as possible. The availability of millions of SNPs from both Perlegen and the public domain and the development of an efficient microarray-based assay for genotyping SNPs has brought up some interesting analytical challenges. Effective methods for the selection of optimal subsets of SNPs spanning the genome and methods for accurately calling genotypes from probe hybridization patterns have enabled the development of a new microarray-based system for robustly genotyping over 100,000 SNPs per sample. RESULTS: We introduce a new dynamic model-based algorithm (DM) for screening over 3 million SNPs and genotyping over 100,000 SNPs. The model is based on four possible underlying states: Null, A, AB and B for each probe quartet. We calculate a probe-level log likelihood for each model and then select between the four competing models with an SNP-level statistical aggregation across multiple probe quartets to provide a high-quality genotype call along with a quality measure of the call. We assess performance with HapMap reference genotypes, informative Mendelian inheritance relationship in families, and consistency between DM and another genotype classification method. At a call rate of 95.91% the concordance with reference genotypes from the HapMap Project is 99.81% based on over 1.5 million genotypes, the Mendelian error rate is 0.018% based on 10 trios, and the consistency between DM and MPAM is 99.90% at a comparable rate of 97.18%. We also develop methods for SNP selection and optimal probe selection. AVAILABILITY: The DM algorithm is available in Affymetrix's Genotyping Tools software package and in Affymetrix's GDAS software package. See http://www.affymetrix.com for further information. 10 K and 100 K mapping array data are available on the Affymetrix website.

Algorithms↗
PubMed2006

Comparative genomics reveals unusually long motifs in mammalian genomes.

MOTIVATION: The recent discovery of the first small modulatory RNA (smRNA) presents the challenge of finding other molecules of similar length and conservation level. Unlike short interfering RNA (siRNA) and micro-RNA (miRNA), effective computational and experimental screening methods are not currently known for this species of RNA molecule, and the discovery of the one known example was partly fortuitous because it happened to be complementary to a well-studied DNA binding motif (the Neuron Restrictive Silencer Element). RESULTS: The existing comparative genomics approaches (e.g., phylogenetic footprinting) rely on alignments of orthologous regions across multiple genomes. This approach, while extremely valuable, is not suitable for finding motifs with highly diverged "non-alignable" flanking regions. Here we show that several unusually long and well conserved motifs can be discovered de novo through a comparative genomics approach that does not require an alignment of orthologous upstream regions. These motifs, including Neuron Restrictive Silencer Element, were missed in recent comparative genomics studies that rely on phylogenetic footprinting. While the functions of these motifs remain unknown, we argue that some may represent biologically important sites. AVAILABILITY: Our comparative genomics software, a web-accessible database of our results and a compilation of experimentally validated binding sites for NRSE can be found at http://www.cse.ucsd.edu/groups/bioinformatics.

Algorithms↗
PubMed2003

Dose assessment of aircraft crew in The Netherlands.

As the operator of the National Dose Registration and Information System, NRG has implemented a system for radiation exposure monitoring for the Dutch airlines. The system is based on the use of computer generated flight plans together with dose calculations using the CARI-6M program. Before installing the system a study was performed to estimate the uncertainty in the assessment of the annual dose of the crew members. It was concluded that the proposed system complies with international recommendations on the uncertainty in dose assessments in individual monitoring and that the operational costs of the system are low.

Aircraft↗