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1.  Modeling peptide fragmentation with dynamic Bayesian networks for peptide identification 
Bioinformatics (Oxford, England)  2008;24(13):i348-i356.
Motivation
Tandem mass spectrometry (MS/MS) is an indispensable technology for identification of proteins from complex mixtures. Proteins are digested to peptides that are then identified by their fragmentation patterns in the mass spectrometer. Thus, at its core, MS/MS protein identification relies on the relative predictability of peptide fragmentation. Unfortunately, peptide fragmentation is complex and not fully understood, and what is understood is not always exploited by peptide identification algorithms.
Results
We use a hybrid dynamic Bayesian network (DBN)/support vector machine (SVM) approach to address these two problems. We train a set of DBNs on high-confidence peptide-spectrum matches. These DBNs, known collectively as Riptide, comprise a probabilistic model of peptide fragmentation chemistry. Examination of the distributions learned by Riptide allows identification of new trends, such as prevalent a-ion fragmentation at peptide cleavage sites C-term to hydrophobic residues. In addition, Riptide can be used to produce likelihood scores that indicate whether a given peptide-spectrum match is correct. A vector of such scores is evaluated by an SVM, which produces a final score to be used in peptide identification. Using Riptide in this way yields improved discrimination when compared to other state-of-the-art MS/MS identification algorithms, increasing the number of positive identifications by as much as 12% at a 1% false discovery rate.
Availability
Python and C source code are available upon request from the authors. The curated training sets are available at http://noble.gs.washington.edu/proj/intense/. The Graphical Model Tool Kit (GMTK) is freely available at http://ssli.ee.washington.edu/bilmes/gmtk.
Contact
noble@gs.washington.edu
doi:10.1093/bioinformatics/btn189
PMCID: PMC2665034  PMID: 18586734
2.  Transmembrane Topology and Signal Peptide Prediction Using Dynamic Bayesian Networks 
PLoS Computational Biology  2008;4(11):e1000213.
Hidden Markov models (HMMs) have been successfully applied to the tasks of transmembrane protein topology prediction and signal peptide prediction. In this paper we expand upon this work by making use of the more powerful class of dynamic Bayesian networks (DBNs). Our model, Philius, is inspired by a previously published HMM, Phobius, and combines a signal peptide submodel with a transmembrane submodel. We introduce a two-stage DBN decoder that combines the power of posterior decoding with the grammar constraints of Viterbi-style decoding. Philius also provides protein type, segment, and topology confidence metrics to aid in the interpretation of the predictions. We report a relative improvement of 13% over Phobius in full-topology prediction accuracy on transmembrane proteins, and a sensitivity and specificity of 0.96 in detecting signal peptides. We also show that our confidence metrics correlate well with the observed precision. In addition, we have made predictions on all 6.3 million proteins in the Yeast Resource Center (YRC) database. This large-scale study provides an overall picture of the relative numbers of proteins that include a signal-peptide and/or one or more transmembrane segments as well as a valuable resource for the scientific community. All DBNs are implemented using the Graphical Models Toolkit. Source code for the models described here is available at http://noble.gs.washington.edu/proj/philius. A Philius Web server is available at http://www.yeastrc.org/philius, and the predictions on the YRC database are available at http://www.yeastrc.org/pdr.
Author Summary
Transmembrane proteins control the flow of information and substances into and out of the cell and are involved in a broad range of biological processes. Their interfacing role makes them rewarding drug targets, and it is estimated that more than 50% of recently launched drugs target membrane proteins. However, experimentally determining the three-dimensional structure of a transmembrane protein is still a difficult task, and few of the currently known tertiary structures are of transmembrane proteins despite the fact that as many as one quarter of the proteins in a given organism are transmembrane proteins. Computational methods for predicting the basic topology of a transmembrane protein are therefore of great interest, and these methods must be able to distinguish between mature, membrane-spanning proteins and proteins that, when first synthesized, contain an N-terminal membrane-spanning signal peptide. In this work, we present Philius, a new computational approach that outperforms previous methods in simultaneously detecting signal peptides and correctly predicting the topology of transmembrane proteins. Philius also supplies a set of confidence scores with each prediction. A Philius Web server is available to the public as well as precomputed predictions for over six million proteins in the Yeast Resource Center database.
doi:10.1371/journal.pcbi.1000213
PMCID: PMC2570248  PMID: 18989393
3.  Non-parametric estimation of posterior error probabilities associated with peptides identified by tandem mass spectrometry 
Bioinformatics  2008;24(16):i42-i48.
Motivation: A mass spectrum produced via tandem mass spectrometry can be tentatively matched to a peptide sequence via database search. Here, we address the problem of assigning a posterior error probability (PEP) to a given peptide-spectrum match (PSM). This problem is considerably more difficult than the related problem of estimating the error rate associated with a large collection of PSMs. Existing methods for estimating PEPs rely on a parametric or semiparametric model of the underlying score distribution.
Results: We demonstrate how to apply non-parametric logistic regression to this problem. The method makes no explicit assumptions about the form of the underlying score distribution; instead, the method relies upon decoy PSMs, produced by searching the spectra against a decoy sequence database, to provide a model of the null score distribution. We show that our non-parametric logistic regression method produces accurate PEP estimates for six different commonly used PSM score functions. In particular, the estimates produced by our method are comparable in accuracy to those of PeptideProphet, which uses a parametric or semiparametric model designed specifically to work with SEQUEST. The advantage of the non-parametric approach is applicability and robustness to new score functions and new types of data.
Availability: C++ code implementing the method as well as supplementary information is available at http://noble.gs.washington.edu/proj/qvality
Contact: noble@gs.washington.edu
doi:10.1093/bioinformatics/btn294
PMCID: PMC2732210  PMID: 18689838
4.  Automated mapping of large-scale chromatin structure in ENCODE 
Bioinformatics  2008;24(17):1911-1916.
Motivation: A recently developed DNaseI assay has given us our first genome-wide view of chromatin structure. In addition to cataloging DNaseI hypersensitive sites, these data allows us to more completely characterize overall features of chromatin accessibility. We employed a Bayesian hierarchical change-point model (CPM), a generalization of a hidden Markov Model (HMM), to characterize tiled microarray DNaseI sensitivity data available from the ENCODE project.
Results: Our analysis shows that the accessibility of chromatin to cleavage by DNaseI is well described by a four state model of local segments with each state described by a continuous mixture of Gaussian variables. The CPM produces a better fit to the observed data than the HMM. The large posterior probability for the four-state CPM suggests that the data falls naturally into four classes of regions, which we call major and minor DNaseI hypersensitive sites (DHSs), regions of intermediate sensitivity, and insensitive regions. These classes agree well with a model of chromatin in which local disruptions (DHSs) are concentrated within larger domains of intermediate sensitivity, the accessibility islands. The CPM assigns 92% of the bases within the ENCODE regions to the insensitive regions. The 5.8% of the bases that are in regions of intermediate sensitivity are clearly enriched in functional elements, including genes and activating histone modifications, while the remaining 2.2% of the bases in hypersensitive regions are very strongly enriched in these elements.
Availability: The CPM software is available upon request from the authors.
Contact: jstam@stamlab.org; noble@gs.washington.edu; Charles_Lawrence@brown.edu
Supplementary information: Supplementary data are available at Bioinformatics online. Source code is available at http://noble.gs.washington.edu/proj/segment.
doi:10.1093/bioinformatics/btn335
PMCID: PMC2519158  PMID: 18591192
5.  Faster Mass Spectrometry-based Protein Inference: Junction Trees are More Efficient than Sampling and Marginalization by Enumeration 
The problem of identifying the proteins in a complex mixture using tandem mass spectrometry can be framed as an inference problem on a graph that connects peptides to proteins. Several existing protein identification methods make use of statistical inference methods for graphical models, including expectation maximization, Markov chain Monte Carlo, and full marginalization coupled with approximation heuristics. We show that, for this problem, the majority of the cost of inference usually comes from a few highly connected subgraphs. Furthermore, we evaluate three different statistical inference methods using a common graphical model, and we demonstrate that junction tree inference substantially improves rates of convergence compared to existing methods. The python code used for this paper is available at http://noble.gs.washington.edu/proj/fido.
doi:10.1109/TCBB.2012.26
PMCID: PMC3389307  PMID: 22331862
Mass spectrometry; protein identification; graphical models; Bayesian inference
6.  Incorporating sequence information into the scoring function: a hidden Markov model for improved peptide identification 
Bioinformatics (Oxford, England)  2008;24(5):674-681.
Motivation
The identification of peptides by tandem mass spectrometry (MS/MS) is a central method of proteomics research, but due to the complexity of MS/MS data and the large databases searched, the accuracy of peptide identification algorithms remains limited. To improve the accuracy of identification we applied a machine-learning approach using a hidden Markov model (HMM) to capture the complex and often subtle links between a peptide sequence and its MS/MS spectrum.
Model
Our model, HMM_Score, represents ion types as HMM states and calculates the maximum joint probability for a peptide/spectrum pair using emission probabilities from three factors: the amino acids adjacent to each fragmentation site, the mass dependence of ion types and the intensity dependence of ion types. The Viterbi algorithm is used to calculate the most probable assignment between ion types in a spectrum and a peptide sequence, then a correction factor is added to account for the propensity of the model to favor longer peptides. An expectation value is calculated based on the model score to assess the significance of each peptide/spectrum match.
Results
We trained and tested HMM_Score on three data sets generated by two different mass spectrometer types. For a reference data set recently reported in the literature and validated using seven identification algorithms, HMM_Score produced 43% more positive identification results at a 1% false positive rate than the best of two other commonly used algorithms, Mascot and X!Tandem. HMM_Score is a highly accurate platform for peptide identification that works well for a variety of mass spectrometer and biological sample types.
Availability
The program is freely available on ProteomeCommons via an OpenSource license. See http://bioinfo.unc.edu/downloads/ for the download link.
doi:10.1093/bioinformatics/btn011
PMCID: PMC2699941  PMID: 18187442
7.  Estimating relative abundances of proteins from shotgun proteomics data 
BMC Bioinformatics  2012;13:308.
Background
Spectral counting methods provide an easy means of identifying proteins with differing abundances between complex mixtures using shotgun proteomics data. The crux spectral-counts command, implemented as part of the Crux software toolkit, implements four previously reported spectral counting methods, the spectral index (SIN), the exponentially modified protein abundance index (emPAI), the normalized spectral abundance factor (NSAF), and the distributed normalized spectral abundance factor (dNSAF).
Results
We compared the reproducibility and the linearity relative to each protein’s abundance of the four spectral counting metrics. Our analysis suggests that NSAF yields the most reproducible counts across technical and biological replicates, and both SIN and NSAF achieve the best linearity.
Conclusions
With the crux spectral-counts command, Crux provides open-source modular methods to analyze mass spectrometry data for identifying and now quantifying peptides and proteins. The C++ source code, compiled binaries, spectra and sequence databases are available at http://noble.gs.washington.edu/proj/crux-spectral-counts.
doi:10.1186/1471-2105-13-308
PMCID: PMC3599300  PMID: 23164367
8.  Rankprop: a web server for protein remote homology detection 
Bioinformatics  2008;25(1):121-122.
Summary: We present a large-scale implementation of the Rankprop protein homology ranking algorithm in the form of an openly accessible web server. We use the NRDB40 PSI-BLAST all-versus-all protein similarity network of 1.1 million proteins to construct the graph for the Rankprop algorithm, whereas previously, results were only reported for a database of 108 000 proteins. We also describe two algorithmic improvements to the original algorithm, including propagation from multiple homologs of the query and better normalization of ranking scores, that lead to higher accuracy and to scores with a probabilistic interpretation.
Availability: The Rankprop web server and source code are available at http://rankprop.gs.washington.edu
Contact: iain@nec-labs.com; noble@gs.washington.edu
doi:10.1093/bioinformatics/btn567
PMCID: PMC2638939  PMID: 18990723
9.  Predicting Intensity Ranks of Peptide Fragment Ions 
Journal of proteome research  2009;8(5):2226-2240.
Accurate modeling of peptide fragmentation is necessary for the development of robust scoring functions for peptide-spectrum matches, which are the cornerstone of MS/MS-based identification algorithms. Unfortunately, peptide fragmentation is a complex process that can involve several competing chemical pathways, which makes it difficult to develop generative probabilistic models that describe it accurately. However, the vast amounts of MS/MS data being generated now make it possible to use data-driven machine learning methods to develop discriminative ranking-based models that predict the intensity ranks of a peptide's fragment ions. We use simple sequence-based features that get combined by a boosting algorithm in to models that make peak rank predictions with high accuracy. In an accompanying manuscript, we demonstrate how these prediction models are used to significantly improve the performance of peptide identification algorithms. The models can also be useful in the design of optimal MRM transitions, in cases where there is insufficient experimental data to guide the peak selection process. The prediction algorithm can also be run independently through PepNovo+, which is available for download from http://bix.ucsd.edu/Software/PepNovo.html.
doi:10.1021/pr800677f
PMCID: PMC2738854  PMID: 19256476
MS/MS; peptide; fragmentation; prediction; machine learning; ranking; boosting; MRM
10.  qvality: non-parametric estimation of q-values and posterior error probabilities 
Bioinformatics  2009;25(7):964-966.
Summary: Qvality is a C++ program for estimating two types of standard statistical confidence measures: the q-value, which is an analog of the p-value that incorporates multiple testing correction, and the posterior error probability (PEP, also known as the local false discovery rate), which corresponds to the probability that a given observation is drawn from the null distribution. In computing q-values, qvality employs a standard bootstrap procedure to estimate the prior probability of a score being from the null distribution; for PEP estimation, qvality relies upon non-parametric logistic regression. Relative to other tools for estimating statistical confidence measures, qvality is unique in its ability to estimate both types of scores directly from a null distribution, without requiring the user to calculate p-values.
Availability: A web server, C++ source code and binaries are available under MIT license at http://noble.gs.washington.edu/proj/qvality
Contact: lukas.kall@cbr.su.se
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btp021
PMCID: PMC2660870  PMID: 19193729
11.  The Genomedata format for storing large-scale functional genomics data 
Bioinformatics  2010;26(11):1458-1459.
Summary: We present a format for efficient storage of multiple tracks of numeric data anchored to a genome. The format allows fast random access to hundreds of gigabytes of data, while retaining a small disk space footprint. We have also developed utilities to load data into this format. We show that retrieving data from this format is more than 2900 times faster than a naive approach using wiggle files.
Availability and Implementation: Reference implementation in Python and C components available at http://noble.gs.washington.edu/proj/genomedata/ under the GNU General Public License.
Contact: william-noble@uw.edu
doi:10.1093/bioinformatics/btq164
PMCID: PMC2872006  PMID: 20435580
12.  Multi-spectra peptide sequencing and its applications to multistage mass spectrometry 
Bioinformatics  2008;24(13):i416-i423.
Despite a recent surge of interest in database-independent peptide identifications, accurate de novo peptide sequencing remains an elusive goal. While the recently introduced spectral network approach resulted in accurate peptide sequencing in low-complexity samples, its success depends on the chance of presence of spectra from overlapping peptides. On the other hand, while multistage mass spectrometry (collecting multiple MS 3 spectra from each MS 2 spectrum) can be applied to all spectra in a complex sample, there are currently no software tools for de novo peptide sequencing by multistage mass spectrometry. We describe a rigorous probabilistic framework for analyzing spectra of overlapping peptides and show how to apply it for multistage mass spectrometry. Our software results in both accurate de novo peptide sequencing from multistage mass spectra (despite the inferior quality of MS 3 spectra) and improved interpretation of spectral networks. We further study the problem of de novo peptide sequencing with accurate parent mass (but inaccurate fragment masses), the protocol that may soon become the dominant mode of spectral acquisition. Most existing peptide sequencing algorithms (based on the spectrum graph approach) do not track the accurate parent mass and are thus not equipped for solving this problem. We describe a de novo peptide sequencing algorithm aimed at this experimental protocol and show that it improves the sequencing accuracy on both tandem and multistage mass spectrometry.
Availability: The open-source implementation of our software is available at http://proteomics.bioprojects.org.
Contact: bandeira@ucsd.edu
Supplementary information:: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btn184
PMCID: PMC2718660  PMID: 18785330
13.  SQID: An intensity-incorporated protein identification algorithm for tandem mass spectrometry 
Journal of proteome research  2011;10(4):1593-1602.
To interpret LC-MS/MS data in proteomics, most popular protein identification algorithms primarily use predicted fragment m/z values to assign peptide sequences to fragmentation spectra. The intensity information is often undervalued, since it is not as easy to predict and incorporate into algorithms. Nevertheless, the use of intensity to assist peptide identification is an attractive prospect and can potentially improve the confidence of matches and generate more identifications. Based on our previously reported study of fragmentation intensity patterns, we developed a protein identification algorithm, SeQuence IDentfication (SQID), which makes use of the coarse intensity from a statistical analysis. The scoring scheme was validated by comparing with Sequest and X!Tandem using three datasets, and the results indicate an improvement in the number of identified peptides, including unique peptides that are not identified by Sequest or X!Tandem. The software and source code are available under the GNU GPL license at: http://quiz2.chem.arizona.edu/wysocki/bioinformatics.htm.
doi:10.1021/pr100959y
PMCID: PMC3477243  PMID: 21204564
protein identification algorithm; intensity; tandem mass spectrometry; database search
14.  MyriMatch: highly accurate tandem mass spectral peptide identification by multivariate hypergeometric analysis 
Journal of proteome research  2007;6(2):654-661.
Shotgun proteomics experiments are dependent upon database search engines to identify peptides from tandem mass spectra. Many of these algorithms score potential identifications by evaluating the number of fragment ions matched between each peptide sequence and an observed spectrum. These systems, however, generally do not distinguish between matching an intense peak and matching a minor peak. We have developed a statistical model to score peptide matches that is based upon the multivariate hypergeometric distribution. This scorer, part of the “MyriMatch” database search engine, places greater emphasis on matching intense peaks. The probability that the best match for each spectrum has occurred by random chance can be employed to separate correct matches from random ones. We evaluated this software on data sets from three different laboratories employing three different ion trap instruments. Employing a novel system for testing discrimination, we demonstrate that stratifying peaks into multiple intensity classes improves the discrimination of scoring. We compare MyriMatch results to those of Sequest and X!Tandem, revealing that it is capable of higher discrimination than either of these algorithms. When minimal peak filtering is employed, performance plummets for a scoring model that does not stratify matched peaks by intensity. On the other hand, we find that MyriMatch discrimination improves as more peaks are retained in each spectrum. MyriMatch also scales well to tandem mass spectra from high-resolution mass analyzers. These findings may indicate limitations for existing database search scorers that count matched peaks without differentiating them by intensity. This software and source code is available under Mozilla Public License at this URL: http://www.mc.vanderbilt.edu/msrc/bioinformatics/.
doi:10.1021/pr0604054
PMCID: PMC2525619  PMID: 17269722
Proteomics; Identification; Statistical Distribution; Reversed Database; Peak Filtering
15.  Unsupervised pattern discovery in human chromatin structure through genomic segmentation 
Nature methods  2012;9(5):473-476.
We applied a dynamic Bayesian network method that identifies joint patterns from multiple functional genomics experiments to ChIP-seq histone modification and transcription factor data, and DNaseI-seq and FAIRE-seq open chromatin readouts from the human cell line K562. In an unsupervised fashion, we identified patterns associated with transcription start sites, gene ends, enhancers, CTCF elements, and repressed regions. Software and genome browser tracks are at http://noble.gs.washington.edu/proj/segway/.
doi:10.1038/nmeth.1937
PMCID: PMC3340533  PMID: 22426492
16.  Context-Sensitive Markov Models for Peptide Scoring and Identification from Tandem Mass Spectrometry 
Abstract
Peptide and protein identification via tandem mass spectrometry (MS/MS) lies at the heart of proteomic characterization of biological samples. Several algorithms are able to search, score, and assign peptides to large MS/MS datasets. Most popular methods, however, underutilize the intensity information available in the tandem mass spectrum due to the complex nature of the peptide fragmentation process, thus contributing to loss of potential identifications. We present a novel probabilistic scoring algorithm called Context-Sensitive Peptide Identification (CSPI) based on highly flexible Input-Output Hidden Markov Models (IO-HMM) that capture the influence of peptide physicochemical properties on their observed MS/MS spectra. We use several local and global properties of peptides and their fragment ions from literature. Comparison with two popular algorithms, Crux (re-implementation of SEQUEST) and X!Tandem, on multiple datasets of varying complexity, shows that peptide identification scores from our models are able to achieve greater discrimination between true and false peptides, identifying up to ∼25% more peptides at a False Discovery Rate (FDR) of 1%. We evaluated two alternative normalization schemes for fragment ion-intensities, a global rank-based and a local window-based. Our results indicate the importance of appropriate normalization methods for learning superior models. Further, combining our scores with Crux using a state-of-the-art procedure, Percolator, we demonstrate the utility of using scoring features from intensity-based models, identifying ∼4-8 % additional identifications over Percolator at 1% FDR. IO-HMMs offer a scalable and flexible framework with several modeling choices to learn complex patterns embedded in MS/MS data.
doi:10.1089/omi.2012.0073
PMCID: PMC3567622  PMID: 23289783
17.  Dispec: A Novel Peptide Scoring Algorithm Based on Peptide Matching Discriminability 
PLoS ONE  2013;8(5):e62724.
Identifying peptides from the fragmentation spectra is a fundamental step in mass spectrometry (MS) data processing. The significance (discriminability) of every peak varies, providing additional information for potentially enhancing the identification sensitivity and the correct match rate. However this important information was not considered in previous algorithms. Here we presented a novel method based on Peptide Matching Discriminability (PMD), in which the PMD information of every peak reflects the discriminability of candidate peptides. In addition, we developed a novel peptide scoring algorithm Dispec based on PMD, by taking three aspects of discriminability into consideration: PMD, intensity discriminability and m/z error discriminability. Compared with Mascot and Sequest, Dispec identified remarkably more peptides from three experimental datasets with the same confidence at 1% PSM-level FDR. Dispec is also robust and versatile for various datasets obtained on different instruments. The concept of discriminability enhances the peptide identification and thus may contribute largely to the proteome studies. As an open-source program, Dispec is freely available at http://bioinformatics.jnu.edu.cn/software/dispec/.
doi:10.1371/journal.pone.0062724
PMCID: PMC3652849  PMID: 23675420
18.  IDPicker 2.0: Improved Protein Assembly with High Discrimination Peptide Identification Filtering 
Journal of proteome research  2009;8(8):3872-3881.
Tandem mass spectrometry-based shotgun proteomics has become a widespread technology for analyzing complex protein mixtures. A number of database searching algorithms have been developed to assign peptide sequences to tandem mass spectra. Assembling the peptide identifications to proteins, however, is a challenging issue because many peptides are shared among multiple proteins. IDPicker is an open-source protein assembly tool that derives a minimum protein list from peptide identifications filtered to a specified False Discovery Rate. Here, we update IDPicker to increase confident peptide identifications by combining multiple scores produced by database search tools. By segregating peptide identifications for thresholding using both the precursor charge state and the number of tryptic termini, IDPicker retrieves more peptides for protein assembly. The new version is more robust against false positive proteins, especially in searches using multispecies databases, by requiring additional novel peptides in the parsimony process. IDPicker has been designed for incorporation in many identification workflows by the addition of a graphical user interface and the ability to read identifications from the pepXML format. These advances position IDPicker for high peptide discrimination and reliable protein assembly in large-scale proteomics studies. The source code and binaries for the latest version of IDPicker are available from http://fenchurch.mc.vanderbilt.edu/.
doi:10.1021/pr900360j
PMCID: PMC2810655  PMID: 19522537
bioinformatics; parsimony; protein assembly; protein inference; false discovery rate
19.  Open MS/MS spectral library search to identify unanticipated post-translational modifications and increase spectral identification rate 
Bioinformatics  2010;26(12):i399-i406.
Motivation: Identification of post-translationally modified proteins has become one of the central issues of current proteomics. Spectral library search is a new and promising computational approach to mass spectrometry-based protein identification. However, its potential in identification of unanticipated post-translational modifications has rarely been explored. The existing spectral library search tools are designed to match the query spectrum to the reference library spectra with the same peptide mass. Thus, spectra of peptides with unanticipated modifications cannot be identified.
Results: In this article, we present an open spectral library search tool, named pMatch. It extends the existing library search algorithms in at least three aspects to support the identification of unanticipated modifications. First, the spectra in library are optimized with the full peptide sequence information to better tolerate the peptide fragmentation pattern variations caused by some modification(s). Second, a new scoring system is devised, which uses charge-dependent mass shifts for peak matching and combines a probability-based model with the general spectral dot-product for scoring. Third, a target-decoy strategy is used for false discovery rate control. To demonstrate the effectiveness of pMatch, a library search experiment was conducted on a public dataset with over 40 000 spectra in comparison with SpectraST, the most popular library search engine. Additional validations were done on four published datasets including over 150 000 spectra. The results showed that pMatch can effectively identify unanticipated modifications and significantly increase spectral identification rate.
Availability: http://pfind.ict.ac.cn/pmatch/
Contact: yfu@ict.ac.cn; rxsun@ict.ac.cn
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq185
PMCID: PMC2881370  PMID: 20529934
20.  Learning the structure of gene regulatory networks from time series gene expression data 
BMC Genomics  2011;12(Suppl 5):S13.
Background
Dynamic Bayesian Network (DBN) is an approach widely used for reconstruction of gene regulatory networks from time-series microarray data. Its performance in network reconstruction depends on a structure learning algorithm. REVEAL (REVerse Engineering ALgorithm) is one of the algorithms implemented for learning DBN structure and used to reconstruct gene regulatory networks (GRN). However, the two-stage temporal Bayes network (2TBN) structure of DBN that specifies correlation between time slices cannot be obtained by score metrics used in REVEAL.
Methods
In this paper, we study a more sophisticated score function for DBN first proposed by Nir Friedman for stationary DBNs structure learning of both initial and transition networks but has not yet been used for reconstruction of GRNs. We implemented Friedman's Bayesian Information Criterion (BIC) score function, modified K2 algorithm to learn Dynamic Bayesian Network structure with the score function and tested the performance of the algorithm for GRN reconstruction with synthetic time series gene expression data generated by GeneNetWeaver and real yeast benchmark experiment data.
Results
We implemented an algorithm for DBN structure learning with Friedman's score function, tested it on reconstruction of both synthetic networks and real yeast networks and compared it with REVEAL in the absence or presence of preprocessed network generated by Zou&Conzen's algorithm. By introducing a stationary correlation between two consecutive time slices, Friedman's score function showed a higher precision and recall than the naive REVEAL algorithm.
Conclusions
Friedman's score metrics for DBN can be used to reconstruct transition networks and has a great potential to improve the accuracy of gene regulatory network structure prediction with time series gene expression datasets.
doi:10.1186/1471-2164-12-S5-S13
PMCID: PMC3287495  PMID: 22369588
21.  TAP Hunter: a SVM-based system for predicting TAP ligands using local description of amino acid sequence 
Immunome Research  2010;6(Suppl 1):S6.
Background
Selective peptide transport by the transporter associated with antigen processing (TAP) represents one of the main candidate mechanisms that may regulate the presentation of antigenic peptides to HLA class I molecules. Because TAP-binding preferences may significant impact T-cell epitope selection, there is great interest in applying computational techniques to systematically discover these elements.
Results
We describe TAP Hunter, a web-based computational system for predicting TAP-binding peptides. A novel encoding scheme, based on representations of TAP peptide fragments and composition effects, allows the identification of variable-length TAP ligands using SVM as the prediction engine. The system was rigorously trained and tested using 613 experimentally verified peptide sequences. The results showed that the system has good predictive ability with area under the receiver operating characteristics curve (AROC) ≥0.88. In addition, TAP Hunter is compared against several existing public available TAP predictors and has showed either superior or comparable performance.
Conclusions
TAP Hunter provides a reliable platform for predicting variable length peptides binding onto the TAP transporter. To facilitate the usage of TAP Hunter to the scientific community, a simple, flexible and user-friendly web-server is developed and freely available at http://datam.i2r.a-star.edu.sg/taphunter/.
doi:10.1186/1745-7580-6-S1-S6
PMCID: PMC2946784  PMID: 20875157
22.  A dynamic Bayesian network for identifying protein-binding footprints from single molecule-based sequencing data 
Bioinformatics  2010;26(12):i334-i342.
Motivation: A global map of transcription factor binding sites (TFBSs) is critical to understanding gene regulation and genome function. DNaseI digestion of chromatin coupled with massively parallel sequencing (digital genomic footprinting) enables the identification of protein-binding footprints with high resolution on a genome-wide scale. However, accurately inferring the locations of these footprints remains a challenging computational problem.
Results: We present a dynamic Bayesian network-based approach for the identification and assignment of statistical confidence estimates to protein-binding footprints from digital genomic footprinting data. The method, DBFP, allows footprints to be identified in a probabilistic framework and outperforms our previously described algorithm in terms of precision at a fixed recall. Applied to a digital footprinting data set from Saccharomyces cerevisiae, DBFP identifies 4679 statistically significant footprints within intergenic regions. These footprints are mainly located near transcription start sites and are strongly enriched for known TFBSs. Footprints containing no known motif are preferentially located proximal to other footprints, consistent with cooperative binding of these footprints. DBFP also identifies a set of statistically significant footprints in the yeast coding regions. Many of these footprints coincide with the boundaries of antisense transcripts, and the most significant footprints are enriched for binding sites of the chromatin-associated factors Abf1 and Rap1.
Contact: jay.hesselberth@ucdenver.edu; william-noble@u.washington.edu
Supplementary information: Supplementary material is available at Bioinformatics online.
doi:10.1093/bioinformatics/btq175
PMCID: PMC2881360  PMID: 20529925
23.  A dynamic Bayesian network approach to protein secondary structure prediction 
BMC Bioinformatics  2008;9:49.
Background
Protein secondary structure prediction method based on probabilistic models such as hidden Markov model (HMM) appeals to many because it provides meaningful information relevant to sequence-structure relationship. However, at present, the prediction accuracy of pure HMM-type methods is much lower than that of machine learning-based methods such as neural networks (NN) or support vector machines (SVM).
Results
In this paper, we report a new method of probabilistic nature for protein secondary structure prediction, based on dynamic Bayesian networks (DBN). The new method models the PSI-BLAST profile of a protein sequence using a multivariate Gaussian distribution, and simultaneously takes into account the dependency between the profile and secondary structure and the dependency between profiles of neighboring residues. In addition, a segment length distribution is introduced for each secondary structure state. Tests show that the DBN method has made a significant improvement in the accuracy compared to other pure HMM-type methods. Further improvement is achieved by combining the DBN with an NN, a method called DBNN, which shows better Q3 accuracy than many popular methods and is competitive to the current state-of-the-arts. The most interesting feature of DBN/DBNN is that a significant improvement in the prediction accuracy is achieved when combined with other methods by a simple consensus.
Conclusion
The DBN method using a Gaussian distribution for the PSI-BLAST profile and a high-ordered dependency between profiles of neighboring residues produces significantly better prediction accuracy than other HMM-type probabilistic methods. Owing to their different nature, the DBN and NN combine to form a more accurate method DBNN. Future improvement may be achieved by combining DBNN with a method of SVM type.
doi:10.1186/1471-2105-9-49
PMCID: PMC2266706  PMID: 18218144
24.  Score regularization for peptide identification 
BMC Bioinformatics  2011;12(Suppl 1):S2.
Background
Peptide identification from tandem mass spectrometry (MS/MS) data is one of the most important problems in computational proteomics. This technique relies heavily on the accurate assessment of the quality of peptide-spectrum matches (PSMs). However, current MS technology and PSM scoring algorithm are far from perfect, leading to the generation of incorrect peptide-spectrum pairs. Thus, it is critical to develop new post-processing techniques that can distinguish true identifications from false identifications effectively.
Results
In this paper, we present a consistency-based PSM re-ranking method to improve the initial identification results. This method uses one additional assumption that two peptides belonging to the same protein should be correlated to each other. We formulate an optimization problem that embraces two objectives through regularization: the smoothing consistency among scores of correlated peptides and the fitting consistency between new scores and initial scores. This optimization problem can be solved analytically. The experimental study on several real MS/MS data sets shows that this re-ranking method improves the identification performance.
Conclusions
The score regularization method can be used as a general post-processing step for improving peptide identifications. Source codes and data sets are available at: http://bioinformatics.ust.hk/SRPI.rar.
doi:10.1186/1471-2105-12-S1-S2
PMCID: PMC3044274  PMID: 21342549
25.  A machine learning approach to explore the spectra intensity pattern of peptides using tandem mass spectrometry data 
BMC Bioinformatics  2008;9:325.
Background
A better understanding of the mechanisms involved in gas-phase fragmentation of peptides is essential for the development of more reliable algorithms for high-throughput protein identification using mass spectrometry (MS). Current methodologies depend predominantly on the use of derived m/z values of fragment ions, and, the knowledge provided by the intensity information present in MS/MS spectra has not been fully exploited. Indeed spectrum intensity information is very rarely utilized in the algorithms currently in use for high-throughput protein identification.
Results
In this work, a Bayesian neural network approach is employed to analyze ion intensity information present in 13878 different MS/MS spectra. The influence of a library of 35 features on peptide fragmentation is examined under different proton mobility conditions. Useful rules involved in peptide fragmentation are found and subsets of features which have significant influence on fragmentation pathway of peptides are characterised. An intensity model is built based on the selected features and the model can make an accurate prediction of the intensity patterns for given MS/MS spectra. The predictions include not only the mean values of spectra intensity but also the variances that can be used to tolerate noises and system biases within experimental MS/MS spectra.
Conclusion
The intensity patterns of fragmentation spectra are informative and can be used to analyze the influence of various characteristics of fragmented peptides on their fragmentation pathway. The features with significant influence can be used in turn to predict spectra intensities. Such information can help develop more reliable algorithms for peptide and protein identification.
doi:10.1186/1471-2105-9-325
PMCID: PMC2529326  PMID: 18664292

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