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1.  Mining gene functional networks to improve mass-spectrometry-based protein identification 
Bioinformatics  2009;25(22):2955-2961.
Motivation: High-throughput protein identification experiments based on tandem mass spectrometry (MS/MS) often suffer from low sensitivity and low-confidence protein identifications. In a typical shotgun proteomics experiment, it is assumed that all proteins are equally likely to be present. However, there is often other evidence to suggest that a protein is present and confidence in individual protein identification can be updated accordingly.
Results: We develop a method that analyzes MS/MS experiments in the larger context of the biological processes active in a cell. Our method, MSNet, improves protein identification in shotgun proteomics experiments by considering information on functional associations from a gene functional network. MSNet substantially increases the number of proteins identified in the sample at a given error rate. We identify 8–29% more proteins than the original MS experiment when applied to yeast grown in different experimental conditions analyzed on different MS/MS instruments, and 37% more proteins in a human sample. We validate up to 94% of our identifications in yeast by presence in ground-truth reference sets.
Availability and Implementation: Software and datasets are available at http://aug.csres.utexas.edu/msnet
Contact: miranker@cs.utexas.edu, marcotte@icmb.utexas.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btp461
PMCID: PMC2773251  PMID: 19633097
2.  Integrating shotgun proteomics and mRNA expression data to improve protein identification 
Bioinformatics  2009;25(11):1397-1403.
Motivation: Tandem mass spectrometry (MS/MS) offers fast and reliable characterization of complex protein mixtures, but suffers from low sensitivity in protein identification. In a typical shotgun proteomics experiment, it is assumed that all proteins are equally likely to be present. However, there is often other information available, e.g. the probability of a protein's presence is likely to correlate with its mRNA concentration.
Results: We develop a Bayesian score that estimates the posterior probability of a protein's presence in the sample given its identification in an MS/MS experiment and its mRNA concentration measured under similar experimental conditions. Our method, MSpresso, substantially increases the number of proteins identified in an MS/MS experiment at the same error rate, e.g. in yeast, MSpresso increases the number of proteins identified by ∼40%. We apply MSpresso to data from different MS/MS instruments, experimental conditions and organisms (Escherichia coli, human), and predict 19–63% more proteins across the different datasets. MSpresso demonstrates that incorporating prior knowledge of protein presence into shotgun proteomics experiments can substantially improve protein identification scores.
Availability and Implementation: Software is available upon request from the authors. Mass spectrometry datasets and supplementary information are available from http://www.marcottelab.org/MSpresso/.
Contact: marcotte@icmb.utexas.edu; miranker@cs.utexas.edu
Supplementary Information: Supplementary data website: http://www.marcottelab.org/MSpresso/.
doi:10.1093/bioinformatics/btp168
PMCID: PMC2682515  PMID: 19318424
3.  Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer 
Bioinformatics  2016;32(9):1373-1379.
Motivation: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets.
Results: Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel.
Availability and implementation: The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper.
Contact: marcotte@icmb.utexas.edu or jon.young@utexas.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btw010
PMCID: PMC4848405  PMID: 26755624
4.  Revisiting the negative example sampling problem for predicting protein–protein interactions 
Bioinformatics  2011;27(21):3024-3028.
Motivation: A number of computational methods have been proposed that predict protein–protein interactions (PPIs) based on protein sequence features. Since the number of potential non-interacting protein pairs (negative PPIs) is very high both in absolute terms and in comparison to that of interacting protein pairs (positive PPIs), computational prediction methods rely upon subsets of negative PPIs for training and validation. Hence, the need arises for subset sampling for negative PPIs.
Results: We clarify that there are two fundamentally different types of subset sampling for negative PPIs. One is subset sampling for cross-validated testing, where one desires unbiased subsets so that predictive performance estimated with them can be safely assumed to generalize to the population level. The other is subset sampling for training, where one desires the subsets that best train predictive algorithms, even if these subsets are biased. We show that confusion between these two fundamentally different types of subset sampling led one study recently published in Bioinformatics to the erroneous conclusion that predictive algorithms based on protein sequence features are hardly better than random in predicting PPIs. Rather, both protein sequence features and the ‘hubbiness’ of interacting proteins contribute to effective prediction of PPIs. We provide guidance for appropriate use of random versus balanced sampling.
Availability: The datasets used for this study are available at http://www.marcottelab.org/PPINegativeDataSampling.
Contact: yungki@mail.utexas.edu; marcotte@icmb.utexas.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr514
PMCID: PMC3198576  PMID: 21908540
5.  An automated proteomic data analysis workflow for mass spectrometry 
BMC Bioinformatics  2009;10(Suppl 11):S17.
Background
Mass spectrometry-based protein identification methods are fundamental to proteomics. Biological experiments are usually performed in replicates and proteomic analyses generate huge datasets which need to be integrated and quantitatively analyzed. The Sequest™ search algorithm is a commonly used algorithm for identifying peptides and proteins from two dimensional liquid chromatography electrospray ionization tandem mass spectrometry (2-D LC ESI MS2) data. A number of proteomic pipelines that facilitate high throughput 'post data acquisition analysis' are described in the literature. However, these pipelines need to be updated to accommodate the rapidly evolving data analysis methods. Here, we describe a proteomic data analysis pipeline that specifically addresses two main issues pertinent to protein identification and differential expression analysis: 1) estimation of the probability of peptide and protein identifications and 2) non-parametric statistics for protein differential expression analysis. Our proteomic analysis workflow analyzes replicate datasets from a single experimental paradigm to generate a list of identified proteins with their probabilities and significant changes in protein expression using parametric and non-parametric statistics.
Results
The input for our workflow is Bioworks™ 3.2 Sequest (or a later version, including cluster) output in XML format. We use a decoy database approach to assign probability to peptide identifications. The user has the option to select "quality thresholds" on peptide identifications based on the P value. We also estimate probability for protein identification. Proteins identified with peptides at a user-specified threshold value from biological experiments are grouped as either control or treatment for further analysis in ProtQuant. ProtQuant utilizes a parametric (ANOVA) method, for calculating differences in protein expression based on the quantitative measure ΣXcorr. Alternatively ProtQuant output can be further processed using non-parametric Monte-Carlo resampling statistics to calculate P values for differential expression. Correction for multiple testing of ANOVA and resampling P values is done using Benjamini and Hochberg's method. The results of these statistical analyses are then combined into a single output file containing a comprehensive protein list with probabilities and differential expression analysis, associated P values, and resampling statistics.
Conclusion
For biologists carrying out proteomics by mass spectrometry, our workflow facilitates automated, easy to use analyses of Bioworks (3.2 or later versions) data. All the methods used in the workflow are peer-reviewed and as such the results of our workflow are compliant with proteomic data submission guidelines to public proteomic data repositories including PRIDE. Our workflow is a necessary intermediate step that is required to link proteomics data to biological knowledge for generating testable hypotheses.
doi:10.1186/1471-2105-10-S11-S17
PMCID: PMC3226188  PMID: 19811682
6.  The Comparative RNA Web (CRW) Site: an online database of comparative sequence and structure information for ribosomal, intron, and other RNAs 
BMC Bioinformatics  2002;3:2.
Background
Comparative analysis of RNA sequences is the basis for the detailed and accurate predictions of RNA structure and the determination of phylogenetic relationships for organisms that span the entire phylogenetic tree. Underlying these accomplishments are very large, well-organized, and processed collections of RNA sequences. This data, starting with the sequences organized into a database management system and aligned to reveal their higher-order structure, and patterns of conservation and variation for organisms that span the phylogenetic tree, has been collected and analyzed. This type of information can be fundamental for and have an influence on the study of phylogenetic relationships, RNA structure, and the melding of these two fields.
Results
We have prepared a large web site that disseminates our comparative sequence and structure models and data. The four major types of comparative information and systems available for the three ribosomal RNAs (5S, 16S, and 23S rRNA), transfer RNA (tRNA), and two of the catalytic intron RNAs (group I and group II) are: (1) Current Comparative Structure Models; (2) Nucleotide Frequency and Conservation Information; (3) Sequence and Structure Data; and (4) Data Access Systems.
Conclusions
This online RNA sequence and structure information, the result of extensive analysis, interpretation, data collection, and computer program and web development, is accessible at our Comparative RNA Web (CRW) Site http://www.rna.icmb.utexas.edu. In the future, more data and information will be added to these existing categories, new categories will be developed, and additional RNAs will be studied and presented at the CRW Site.
doi:10.1186/1471-2105-3-2
PMCID: PMC65690  PMID: 11869452
7.  Aptamer Database 
Nucleic Acids Research  2004;32(Database issue):D95-D100.
The aptamer database is designed to contain comprehensive sequence information on aptamers and unnatural ribozymes that have been generated by in vitro selection methods. Such data are not normally collected in ‘natural’ sequence databases, such as GenBank. Besides serving as a storehouse of sequences that may have diagnostic or therapeutic utility, the database serves as a valuable resource for theoretical biologists who describe and explore fitness landscapes. The database is updated monthly and is publicly available at http://aptamer.icmb.utexas.edu/.
doi:10.1093/nar/gkh094
PMCID: PMC308828  PMID: 14681367
8.  Fast and Efficient XML Data Access for Next-Generation Mass Spectrometry 
PLoS ONE  2015;10(4):e0125108.
Motivation
In mass spectrometry-based proteomics, XML formats such as mzML and mzXML provide an open and standardized way to store and exchange the raw data (spectra and chromatograms) of mass spectrometric experiments. These file formats are being used by a multitude of open-source and cross-platform tools which allow the proteomics community to access algorithms in a vendor-independent fashion and perform transparent and reproducible data analysis. Recent improvements in mass spectrometry instrumentation have increased the data size produced in a single LC-MS/MS measurement and put substantial strain on open-source tools, particularly those that are not equipped to deal with XML data files that reach dozens of gigabytes in size.
Results
Here we present a fast and versatile parsing library for mass spectrometric XML formats available in C++ and Python, based on the mature OpenMS software framework. Our library implements an API for obtaining spectra and chromatograms under memory constraints using random access or sequential access functions, allowing users to process datasets that are much larger than system memory. For fast access to the raw data structures, small XML files can also be completely loaded into memory. In addition, we have improved the parsing speed of the core mzML module by over 4-fold (compared to OpenMS 1.11), making our library suitable for a wide variety of algorithms that need fast access to dozens of gigabytes of raw mass spectrometric data.
Availability
Our C++ and Python implementations are available for the Linux, Mac, and Windows operating systems. All proposed modifications to the OpenMS code have been merged into the OpenMS mainline codebase and are available to the community at https://github.com/OpenMS/OpenMS.
doi:10.1371/journal.pone.0125108
PMCID: PMC4416046  PMID: 25927999
9.  PRIDE Inspector Toolsuite: Moving Toward a Universal Visualization Tool for Proteomics Data Standard Formats and Quality Assessment of ProteomeXchange Datasets*  
The original PRIDE Inspector tool was developed as an open source standalone tool to enable the visualization and validation of mass-spectrometry (MS)-based proteomics data before data submission or already publicly available in the Proteomics Identifications (PRIDE) database. The initial implementation of the tool focused on visualizing PRIDE data by supporting the PRIDE XML format and a direct access to private (password protected) and public experiments in PRIDE.
The ProteomeXchange (PX) Consortium has been set up to enable a better integration of existing public proteomics repositories, maximizing its benefit to the scientific community through the implementation of standard submission and dissemination pipelines. Within the Consortium, PRIDE is focused on supporting submissions of tandem MS data. The increasing use and popularity of the new Proteomics Standards Initiative (PSI) data standards such as mzIdentML and mzTab, and the diversity of workflows supported by the PX resources, prompted us to design and implement a new suite of algorithms and libraries that would build upon the success of the original PRIDE Inspector and would enable users to visualize and validate PX “complete” submissions. The PRIDE Inspector Toolsuite supports the handling and visualization of different experimental output files, ranging from spectra (mzML, mzXML, and the most popular peak lists formats) and peptide and protein identification results (mzIdentML, PRIDE XML, mzTab) to quantification data (mzTab, PRIDE XML), using a modular and extensible set of open-source, cross-platform libraries. We believe that the PRIDE Inspector Toolsuite represents a milestone in the visualization and quality assessment of proteomics data. It is freely available at http://github.com/PRIDE-Toolsuite/.
doi:10.1074/mcp.O115.050229
PMCID: PMC4762524  PMID: 26545397
10.  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
11.  An XML standard for the dissemination of annotated 2D gel electrophoresis data complemented with mass spectrometry results 
BMC Bioinformatics  2004;5:9.
Background
Many proteomics initiatives require a seamless bioinformatics integration of a range of analytical steps between sample collection and systems modeling immediately assessable to the participants involved in the process. Proteomics profiling by 2D gel electrophoresis to the putative identification of differentially expressed proteins by comparison of mass spectrometry results with reference databases, includes many components of sample processing, not just analysis and interpretation, are regularly revisited and updated. In order for such updates and dissemination of data, a suitable data structure is needed. However, there are no such data structures currently available for the storing of data for multiple gels generated through a single proteomic experiments in a single XML file. This paper proposes a data structure based on XML standards to fill the void that exists between data generated by proteomics experiments and storing of data.
Results
In order to address the resulting procedural fluidity we have adopted and implemented a data model centered on the concept of annotated gel (AG) as the format for delivery and management of 2D Gel electrophoresis results. An eXtensible Markup Language (XML) schema is proposed to manage, analyze and disseminate annotated 2D Gel electrophoresis results. The structure of AG objects is formally represented using XML, resulting in the definition of the AGML syntax presented here.
Conclusion
The proposed schema accommodates data on the electrophoresis results as well as the mass-spectrometry analysis of selected gel spots. A web-based software library is being developed to handle data storage, analysis and graphic representation. Computational tools described will be made available at . Our development of AGML provides a simple data structure for storing 2D gel electrophoresis data.
doi:10.1186/1471-2105-5-9
PMCID: PMC341449  PMID: 15005801
12.  The Ruby UCSC API: accessing the UCSC genome database using Ruby 
BMC Bioinformatics  2012;13:240.
Background
The University of California, Santa Cruz (UCSC) genome database is among the most used sources of genomic annotation in human and other organisms. The database offers an excellent web-based graphical user interface (the UCSC genome browser) and several means for programmatic queries. A simple application programming interface (API) in a scripting language aimed at the biologist was however not yet available. Here, we present the Ruby UCSC API, a library to access the UCSC genome database using Ruby.
Results
The API is designed as a BioRuby plug-in and built on the ActiveRecord 3 framework for the object-relational mapping, making writing SQL statements unnecessary. The current version of the API supports databases of all organisms in the UCSC genome database including human, mammals, vertebrates, deuterostomes, insects, nematodes, and yeast.
The API uses the bin index—if available—when querying for genomic intervals. The API also supports genomic sequence queries using locally downloaded *.2bit files that are not stored in the official MySQL database. The API is implemented in pure Ruby and is therefore available in different environments and with different Ruby interpreters (including JRuby).
Conclusions
Assisted by the straightforward object-oriented design of Ruby and ActiveRecord, the Ruby UCSC API will facilitate biologists to query the UCSC genome database programmatically. The API is available through the RubyGem system. Source code and documentation are available at https://github.com/misshie/bioruby-ucsc-api/ under the Ruby license. Feedback and help is provided via the website at http://rubyucscapi.userecho.com/.
doi:10.1186/1471-2105-13-240
PMCID: PMC3542311  PMID: 22994508
13.  AANT: the Amino Acid–Nucleotide Interaction Database 
Nucleic Acids Research  2004;32(Database issue):D174-D181.
We have created an Amino Acid–Nucleotide Interaction Database (AANT; http://aant.icmb.utexas.edu/) that categorizes all amino acid–nucleotide interactions from experimentally determined protein–nucleic acid structures, and provides users with a graphic interface for visualizing these interactions in aggregate. AANT accomplishes this by extracting individual amino acid–nucleotide interactions from structures in the Protein Data Bank, combining and superimposing these interactions into multiple structure files (e.g. 20 amino acids × 5 nucleotides) and grouping structurally similar interactions into more readily identifiable clusters. Using the Chime web browser plug-in, users can view 3D representations of the superimpositions and clusters. The unique collection and representation of data on amino acid–nucleotide interactions facilitates understanding the specificity of protein–nucleic acid interactions at a more fundamental level, and allows comparison of otherwise extremely disparate sets of structures. Moreover, by modularly representing the fundamental interactions that govern binding specificity it may prove possible to better engineer nucleic acid binding proteins.
doi:10.1093/nar/gkh128
PMCID: PMC308862  PMID: 14681388
14.  The Galaxy Framework as a Unifying Bioinformatics Solution for ‘omics’ Core Facilities 
Integration of different omics data (genomic, transcriptomic, proteomic) reveals novel discoveries into biological systems. Integration of these datasets is challenging however, involving use of multiple disparate software in a sequential manner. However, the use of multiple, disparate software in a sequential manner makes the integration of multi-omic data a serious challenge. We describe the extension of Galaxy for mass spectrometric-based proteomics software, enabling advanced multi-omic applications in proteogenomics and metaproteomics. We will demonstrate the benefits of Galaxy for these analyses, as well as its value for software developers seeking to publish new software. We will also share insights on the benefits of the Galaxy framework as a bioinformatics solution for proteomic/metabolomic core facilities. Multiple datasets for proteogenomics research (3D-fractionated salivary dataset and oral pre-malignant lesion (OPML) dataset) and metaproteomics research (OPML dataset and Severe Early Childhood Caries (SECC) dataset). Software required for analytical steps such as peaklist generation, database generation (RNA-Seq derived and others), database search (ProteinPilot and X! tandem) and for quantitative proteomics were deployed, tested and optimized for use in workflows. The software are shared in Galaxy toolshed (http://toolshed.g2.bx.psu.edu/). Usage of analytical workflows resulted in reliable identification of novel proteoforms (proteogenomics) or microorganisms (metaproteomics). Proteogenomics analysis identified novel proteoforms in the salivary dataset (51) and OPML dataset (38). Metaproteomics analysis led to microbial identification in OPML and SECC datasets using MEGAN software. As examples, workflows for proteogenomics analysis (http://z.umn.edu/pg140) and metaproteomic analysis (http://z.umn.edu/mp65) are available at the usegalaxyp.org website. Tutorials for workflow usage within Galaxy-P framework are also available (http://z.umn.edu/ppingp). We demonstrate the use of Galaxy for integrated analysis of multi-omic data, in an accessible, transparent and reproducible manner. Our results and experiences using this framework demonstrate the potential for Galaxy to be a unifying bioinformatics solution for ‘omics core facilities.
PMCID: PMC4162280
15.  Verification of a Parkinson's Disease Protein Signature by Multiple Reaction Monitoring 
OBJECTIVE: Integration of different ‘omics data (genomic, transcriptomic, proteomic) reveals novel discoveries into biological systems. Integration of these datasets is challenging however, involving use of multiple disparate software in a sequential manner. However, the use of multiple, disparate software in a sequential manner makes the integration of multi-omic data a serious challenge. We describe the extension of Galaxy for mass spectrometric-based proteomics software, enabling advanced multi-omic applications in proteogenomics and metaproteomics. We will demonstrate the benefits of Galaxy for these analyses, as well as its value for software developers seeking to publish new software. We will also share insights on the benefits of the Galaxy framework as a bioinformatics solution for proteomic/metabolomic core facilities. METHODS: Multiple datasets for proteogenomics research (3D-fractionated salivary dataset and oral pre-malignant lesion (OPML) dataset) and metaproteomics research (OPML dataset and Severe Early Childhood Caries (SECC) dataset). Software required for analytical steps such as peaklist generation, database generation (RNA-Seq derived and others), database search (ProteinPilot and X! tandem) and for quantitative proteomics were deployed, tested and optimized for use in workflows. The software are shared in Galaxy toolshed (http://toolshed.g2.bx.psu.edu/). Results: Usage of analytical workflows resulted in reliable identification of novel proteoforms (proteogenomics) or microorganisms (metaproteomics). Proteogenomics analysis identified novel proteoforms in the salivary dataset (51) and OPML dataset (38). Metaproteomics analysis led to microbial identification in OPML and SECC datasets using MEGAN software. As examples, workflows for proteogenomics analysis (http://z.umn.edu/pg140) and metaproteomic analysis (http://z.umn.edu/mp65) are available at the usegalaxyp.org website. Tutorials for workflow usage within Galaxy-P framework are also available (http://z.umn.edu/ppingp). CONCLUSIONS: We demonstrate the use of Galaxy for integrated analysis of multi-omic data, in an accessible, transparent and reproducible manner. Our results and experiences using this framework demonstrate the potential for Galaxy to be a unifying bioinformatics solution for ‘omics core facilities.
PMCID: PMC4162281
16.  BioRuby: bioinformatics software for the Ruby programming language 
Bioinformatics  2010;26(20):2617-2619.
Summary: The BioRuby software toolkit contains a comprehensive set of free development tools and libraries for bioinformatics and molecular biology, written in the Ruby programming language. BioRuby has components for sequence analysis, pathway analysis, protein modelling and phylogenetic analysis; it supports many widely used data formats and provides easy access to databases, external programs and public web services, including BLAST, KEGG, GenBank, MEDLINE and GO. BioRuby comes with a tutorial, documentation and an interactive environment, which can be used in the shell, and in the web browser.
Availability: BioRuby is free and open source software, made available under the Ruby license. BioRuby runs on all platforms that support Ruby, including Linux, Mac OS X and Windows. And, with JRuby, BioRuby runs on the Java Virtual Machine. The source code is available from http://www.bioruby.org/.
Contact: katayama@bioruby.org
doi:10.1093/bioinformatics/btq475
PMCID: PMC2951089  PMID: 20739307
17.  jmzIdentML API: A Java interface to the mzIdentML standard for peptide and protein identification data 
Proteomics  2012;12(6):790-794.
We present a Java application programming interface (API), jmzIdentML, for the Human Proteome Organisation (HUPO) Proteomics Standards Initiative (PSI) mzIdentML standard for peptide and protein identification data. The API combines the power of Java Architecture of XML Binding (JAXB) and an XPath-based random-access indexer to allow a fast and efficient mapping of extensible markup language (XML) elements to Java objects. The internal references in the mzIdentML files are resolved in an on-demand manner, where the whole file is accessed as a random-access swap file, and only the relevant piece of XMLis selected for mapping to its corresponding Java object. The APIis highly efficient in its memory usage and can handle files of arbitrary sizes. The APIfollows the official release of the mzIdentML (version 1.1) specifications and is available in the public domain under a permissive licence at http://www.code.google.com/p/jmzidentml/.
doi:10.1002/pmic.201100577
PMCID: PMC3933944  PMID: 22539429
Bioinformatics; Java API; mzIdentML; Proteomics standards initiative (PSI); XML
18.  PEPPI: a peptidomic database of human protein isoforms for proteomics experiments 
BMC Bioinformatics  2010;11(Suppl 6):S7.
Abstract
Background
Protein isoform generation, which may derive from alternative splicing, genetic polymorphism, and posttranslational modification, is an essential source of achieving molecular diversity by eukaryotic cells. Previous studies have shown that protein isoforms play critical roles in disease diagnosis, risk assessment, sub-typing, prognosis, and treatment outcome predictions. Understanding the types, presence, and abundance of different protein isoforms in different cellular and physiological conditions is a major task in functional proteomics, and may pave ways to molecular biomarker discovery of human diseases. In tandem mass spectrometry (MS/MS) based proteomics analysis, peptide peaks with exact matches to protein sequence records in the proteomics database may be identified with mass spectrometry (MS) search software. However, due to limited annotation and poor coverage of protein isoforms in proteomics databases, high throughput protein isoform identifications, particularly those arising from alternative splicing and genetic polymorphism, have not been possible.
Results
Therefore, we present the PEPtidomics Protein Isoform Database (PEPPI, http://bio.informatics.iupui.edu/peppi), a comprehensive database of computationally-synthesized human peptides that can identify protein isoforms derived from either alternatively spliced mRNA transcripts or SNP variations. We collected genome, pre-mRNA alternative splicing and SNP information from Ensembl. We synthesized in silico isoform transcripts that cover all exons and theoretically possible junctions of exons and introns, as well as all their variations derived from known SNPs. With three case studies, we further demonstrated that the database can help researchers discover and characterize new protein isoform biomarkers from experimental proteomics data.
Conclusions
We developed a new tool for the proteomics community to characterize protein isoforms from MS-based proteomics experiments. By cataloguing each peptide configurations in the PEPPI database, users can study genetic variations and alternative splicing events at the proteome level. They can also batch-download peptide sequences in FASTA format to search for MS/MS spectra derived from human samples. The database can help generate novel hypotheses on molecular risk factors and molecular mechanisms of complex diseases, leading to identification of potentially highly specific protein isoform biomarkers.
doi:10.1186/1471-2105-11-S6-S7
PMCID: PMC3026381  PMID: 20946618
19.  Application of new multi-resolution methods for the comparison of biomolecular electrostatic properties in the absence of global structural similarity 
In this paper we present a method for the multi-resolution comparison of biomolecular electrostatic potentials without the need for global structural alignment of the biomolecules. The underlying computational geometry algorithm uses multi-resolution attributed contour trees (MACTs) to compare the topological features of volumetric scalar fields. We apply the MACTs to compute electrostatic similarity metrics for a large set of protein chains with varying degrees of sequence, structure, and function similarity. For calibration, we also compute similarity metrics for these chains by a more traditional approach based upon 3D structural alignment and analysis of Carbo similarity indices. Moreover, because the MACT approach does not rely upon pairwise structural alignment, its accuracy and efficiency promises to perform well on future large-scale classification efforts across groups of structurally-diverse proteins. The MACT method discriminates between protein chains at a level comparable to the Carbo similarity index method; i.e., it is able to accurately cluster proteins into functionally-relevant groups which demonstrate strong dependence on ligand binding sites. The results of the analyses are available from the linked web databases http://ccvweb.cres.utexas.edu/MolSignature/ and http://agave.wustl.edu/similarity/. The MACT analysis tools are available as part of the public domain library of the Topological Analysis and Quantitative Tools (TAQT) from the Center of Computational Visualization, at the University of Texas at Austin (http://ccvweb.csres.utexas.edu/software). The Carbo software is available for download with the open-source APBS software package at http://apbs.sf.net/.
doi:10.1137/050647670
PMCID: PMC2561295  PMID: 18841247
electrostatic; contour tree; similarity; clustering; Poisson-Boltzmann
20.  pep2pro: the high-throughput proteomics data processing, analysis, and visualization tool 
The pep2pro database was built to support effective high-throughput proteome data analysis. Its database schema allows the coherent integration of search results from different database-dependent search algorithms and filtering of the data including control for unambiguous assignment of peptides to proteins. The capacity of the pep2pro database has been exploited in data analysis of various Arabidopsis proteome datasets. The diversity of the datasets and the associated scientific questions required thorough querying of the data. This was supported by the relational format structure of the data that links all information on the sample, spectrum, search database, and algorithm to peptide and protein identifications and their post-translational modifications. After publication of datasets they are made available on the pep2pro website at www.pep2pro.ethz.ch. Further, the pep2pro data analysis pipeline also handles data export do the PRIDE database (http://www.ebi.ac.uk/pride) and data retrieval by the MASCP Gator (http://gator.masc-proteomics.org/). The utility of pep2pro will continue to be used for analysis of additional datasets and as a data warehouse. The capacity of the pep2pro database for proteome data analysis has now also been made publicly available through the release of pep2pro4all, which consists of a database schema and a script that will populate the database with mass spectrometry data provided in mzIdentML format.
doi:10.3389/fpls.2012.00123
PMCID: PMC3371593  PMID: 22701464
database; mzIdentML; pep2pro; plant proteomics; standard format
21.  The MOLGENIS toolkit: rapid prototyping of biosoftware at the push of a button 
BMC Bioinformatics  2010;11(Suppl 12):S12.
Background
There is a huge demand on bioinformaticians to provide their biologists with user friendly and scalable software infrastructures to capture, exchange, and exploit the unprecedented amounts of new *omics data. We here present MOLGENIS, a generic, open source, software toolkit to quickly produce the bespoke MOLecular GENetics Information Systems needed.
Methods
The MOLGENIS toolkit provides bioinformaticians with a simple language to model biological data structures and user interfaces. At the push of a button, MOLGENIS’ generator suite automatically translates these models into a feature-rich, ready-to-use web application including database, user interfaces, exchange formats, and scriptable interfaces. Each generator is a template of SQL, JAVA, R, or HTML code that would require much effort to write by hand. This ‘model-driven’ method ensures reuse of best practices and improves quality because the modeling language and generators are shared between all MOLGENIS applications, so that errors are found quickly and improvements are shared easily by a re-generation. A plug-in mechanism ensures that both the generator suite and generated product can be customized just as much as hand-written software.
Results
In recent years we have successfully evaluated the MOLGENIS toolkit for the rapid prototyping of many types of biomedical applications, including next-generation sequencing, GWAS, QTL, proteomics and biobanking. Writing 500 lines of model XML typically replaces 15,000 lines of hand-written programming code, which allows for quick adaptation if the information system is not yet to the biologist’s satisfaction. Each application generated with MOLGENIS comes with an optimized database back-end, user interfaces for biologists to manage and exploit their data, programming interfaces for bioinformaticians to script analysis tools in R, Java, SOAP, REST/JSON and RDF, a tab-delimited file format to ease upload and exchange of data, and detailed technical documentation. Existing databases can be quickly enhanced with MOLGENIS generated interfaces using the ‘ExtractModel’ procedure.
Conclusions
The MOLGENIS toolkit provides bioinformaticians with a simple model to quickly generate flexible web platforms for all possible genomic, molecular and phenotypic experiments with a richness of interfaces not provided by other tools. All the software and manuals are available free as LGPLv3 open source at http://www.molgenis.org.
doi:10.1186/1471-2105-11-S12-S12
PMCID: PMC3040526  PMID: 21210979
22.  BioC implementations in Go, Perl, Python and Ruby 
As part of a communitywide effort for evaluating text mining and information extraction systems applied to the biomedical domain, BioC is focused on the goal of interoperability, currently a major barrier to wide-scale adoption of text mining tools. BioC is a simple XML format, specified by DTD, for exchanging data for biomedical natural language processing. With initial implementations in C++ and Java, BioC provides libraries of code for reading and writing BioC text documents and annotations. We extend BioC to Perl, Python, Go and Ruby. We used SWIG to extend the C++ implementation for Perl and one Python implementation. A second Python implementation and the Ruby implementation use native data structures and libraries. BioC is also implemented in the Google language Go. BioC modules are functional in all of these languages, which can facilitate text mining tasks. BioC implementations are freely available through the BioC site: http://bioc.sourceforge.net.
Database URL: http://bioc.sourceforge.net/
doi:10.1093/database/bau059
PMCID: PMC4067548  PMID: 24961236
23.  ms-data-core-api: an open-source, metadata-oriented library for computational proteomics 
Bioinformatics  2015;31(17):2903-2905.
Summary: The ms-data-core-api is a free, open-source library for developing computational proteomics tools and pipelines. The Application Programming Interface, written in Java, enables rapid tool creation by providing a robust, pluggable programming interface and common data model. The data model is based on controlled vocabularies/ontologies and captures the whole range of data types included in common proteomics experimental workflows, going from spectra to peptide/protein identifications to quantitative results. The library contains readers for three of the most used Proteomics Standards Initiative standard file formats: mzML, mzIdentML, and mzTab. In addition to mzML, it also supports other common mass spectra data formats: dta, ms2, mgf, pkl, apl (text-based), mzXML and mzData (XML-based). Also, it can be used to read PRIDE XML, the original format used by the PRIDE database, one of the world-leading proteomics resources. Finally, we present a set of algorithms and tools whose implementation illustrates the simplicity of developing applications using the library.
Availability and implementation: The software is freely available at https://github.com/PRIDE-Utilities/ms-data-core-api.
Supplementary information: Supplementary data are available at Bioinformatics online
Contact: juan@ebi.ac.uk
doi:10.1093/bioinformatics/btv250
PMCID: PMC4547611  PMID: 25910694
24.  TIPP: taxonomic identification and phylogenetic profiling 
Bioinformatics  2014;30(24):3548-3555.
Motivation: Abundance profiling (also called ‘phylogenetic profiling’) is a crucial step in understanding the diversity of a metagenomic sample, and one of the basic techniques used for this is taxonomic identification of the metagenomic reads.
Results: We present taxon identification and phylogenetic profiling (TIPP), a new marker-based taxon identification and abundance profiling method. TIPP combines SAT\'e-enabled phylogenetic placement a phylogenetic placement method, with statistical techniques to control the classification precision and recall, and results in improved abundance profiles. TIPP is highly accurate even in the presence of high indel errors and novel genomes, and matches or improves on previous approaches, including NBC, mOTU, PhymmBL, MetaPhyler and MetaPhlAn.
Availability and implementation: Software and supplementary materials are available at http://www.cs.utexas.edu/users/phylo/software/sepp/tipp-submission/.
Contact: warnow@illinois.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu721
PMCID: PMC4253836  PMID: 25359891
25.  ISPIDER Central: an integrated database web-server for proteomics 
Nucleic Acids Research  2008;36(Web Server issue):W485-W490.
Despite the growing volumes of proteomic data, integration of the underlying results remains problematic owing to differences in formats, data captured, protein accessions and services available from the individual repositories. To address this, we present the ISPIDER Central Proteomic Database search (http://www.ispider.manchester.ac.uk/cgi-bin/ProteomicSearch.pl), an integration service offering novel search capabilities over leading, mature, proteomic repositories including PRoteomics IDEntifications database (PRIDE), PepSeeker, PeptideAtlas and the Global Proteome Machine. It enables users to search for proteins and peptides that have been characterised in mass spectrometry-based proteomics experiments from different groups, stored in different databases, and view the collated results with specialist viewers/clients. In order to overcome limitations imposed by the great variability in protein accessions used by individual laboratories, the European Bioinformatics Institute's Protein Identifier Cross-Reference (PICR) service is used to resolve accessions from different sequence repositories. Custom-built clients allow users to view peptide/protein identifications in different contexts from multiple experiments and repositories, as well as integration with the Dasty2 client supporting any annotations available from Distributed Annotation System servers. Further information on the protein hits may also be added via external web services able to take a protein as input. This web server offers the first truly integrated access to proteomics repositories and provides a unique service to biologists interested in mass spectrometry-based proteomics.
doi:10.1093/nar/gkn196
PMCID: PMC2447780  PMID: 18440977

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