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1.  Enhancing interacting residue prediction with integrated contact matrix prediction in protein-protein interaction 
Identifying the residues in a protein that are involved in protein-protein interaction and identifying the contact matrix for a pair of interacting proteins are two computational tasks at different levels of an in-depth analysis of protein-protein interaction. Various methods for solving these two problems have been reported in the literature. However, the interacting residue prediction and contact matrix prediction were handled by and large independently in those existing methods, though intuitively good prediction of interacting residues will help with predicting the contact matrix. In this work, we developed a novel protein interacting residue prediction system, contact matrix-interaction profile hidden Markov model (CM-ipHMM), with the integration of contact matrix prediction and the ipHMM interaction residue prediction. We propose to leverage what is learned from the contact matrix prediction and utilize the predicted contact matrix as “feedback” to enhance the interaction residue prediction. The CM-ipHMM model showed significant improvement over the previous method that uses the ipHMM for predicting interaction residues only. It indicates that the downstream contact matrix prediction could help the interaction site prediction.
doi:10.1186/s13637-016-0051-z
PMCID: PMC5075339  PMID: 27818677
Protein-protein interaction; Contact matrix prediction; Interaction site prediction; Machine learning
2.  BioCreative V BioC track overview: collaborative biocurator assistant task for BioGRID 
BioC is a simple XML format for text, annotations and relations, and was developed to achieve interoperability for biomedical text processing. Following the success of BioC in BioCreative IV, the BioCreative V BioC track addressed a collaborative task to build an assistant system for BioGRID curation. In this paper, we describe the framework of the collaborative BioC task and discuss our findings based on the user survey. This track consisted of eight subtasks including gene/protein/organism named entity recognition, protein–protein/genetic interaction passage identification and annotation visualization. Using BioC as their data-sharing and communication medium, nine teams, world-wide, participated and contributed either new methods or improvements of existing tools to address different subtasks of the BioC track. Results from different teams were shared in BioC and made available to other teams as they addressed different subtasks of the track. In the end, all submitted runs were merged using a machine learning classifier to produce an optimized output. The biocurator assistant system was evaluated by four BioGRID curators in terms of practical usability. The curators’ feedback was overall positive and highlighted the user-friendly design and the convenient gene/protein curation tool based on text mining.
Database URL: http://www.biocreative.org/tasks/biocreative-v/track-1-bioc/
doi:10.1093/database/baw121
PMCID: PMC5009341  PMID: 27589962
3.  Overview of the interactive task in BioCreative V 
Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user participation were offered to broaden curator involvement and obtain more feedback on usability aspects. The full level participation involved training on the system, curation of a set of documents with and without TM assistance, tracking of time-on-task, and completion of a user survey. The partial level participation was designed to focus on usability aspects of the interface and not the performance per se. In this case, biocurators navigated the system by performing pre-designed tasks and then were asked whether they were able to achieve the task and the level of difficulty in completing the task. In this manuscript, we describe the development of the interactive task, from planning to execution and discuss major findings for the systems tested.
Database URL: http://www.biocreative.org
doi:10.1093/database/baw119
PMCID: PMC5009325  PMID: 27589961
4.  Protein-protein interaction prediction based on multiple kernels and partial network with linear programming 
BMC Systems Biology  2016;10(Suppl 2):45.
Background
Prediction of de novo protein-protein interaction is a critical step toward reconstructing PPI networks, which is a central task in systems biology. Recent computational approaches have shifted from making PPI prediction based on individual pairs and single data source to leveraging complementary information from multiple heterogeneous data sources and partial network structure. However, how to quickly learn weights for heterogeneous data sources remains a challenge. In this work, we developed a method to infer de novo PPIs by combining multiple data sources represented in kernel format and obtaining optimal weights based on random walk over the existing partial networks.
Results
Our proposed method utilizes Barker algorithm and the training data to construct a transition matrix which constrains how a random walk would traverse the partial network. Multiple heterogeneous features for the proteins in the network are then combined into the form of weighted kernel fusion, which provides a new "adjacency matrix" for the whole network that may consist of disconnected components but is required to comply with the transition matrix on the training subnetwork. This requirement is met by adjusting the weights to minimize the element-wise difference between the transition matrix and the weighted kernels. The minimization problem is solved by linear programming. The weighted kernel fusion is then transformed to regularized Laplacian (RL) kernel to infer missing or new edges in the PPI network, which can potentially connect the previously disconnected components.
Conclusions
The results on synthetic data demonstrated the soundness and robustness of the proposed algorithms under various conditions. And the results on real data show that the accuracies of PPI prediction for yeast data and human data measured as AUC are increased by up to 19 % and 11 % respectively, as compared to a control method without using optimal weights. Moreover, the weights learned by our method Weight Optimization by Linear Programming (WOLP) are very consistent with that learned by sampling, and can provide insights into the relations between PPIs and various feature kernel, thereby improving PPI prediction even for disconnected PPI networks.
doi:10.1186/s12918-016-0296-x
PMCID: PMC4977483
Protein interaction network; Network inference; Interaction prediction; Random walk; Linear programming
5.  BioC interoperability track overview 
BioC is a new simple XML format for sharing biomedical text and annotations and libraries to read and write that format. This promotes the development of interoperable tools for natural language processing (NLP) of biomedical text. The interoperability track at the BioCreative IV workshop featured contributions using or highlighting the BioC format. These contributions included additional implementations of BioC, many new corpora in the format, biomedical NLP tools consuming and producing the format and online services using the format. The ease of use, broad support and rapidly growing number of tools demonstrate the need for and value of the BioC format.
Database URL: http://bioc.sourceforge.net/
doi:10.1093/database/bau053
PMCID: PMC4074764  PMID: 24980129
6.  BioC-compatible full-text passage detection for protein–protein interactions using extended dependency graph 
There has been a large growth in the number of biomedical publications that report experimental results. Many of these results concern detection of protein–protein interactions (PPI). In BioCreative V, we participated in the BioC task and developed a PPI system to detect text passages with PPIs in the full-text articles. By adopting the BioC format, the output of the system can be seamlessly added to the biocuration pipeline with little effort required for the system integration. A distinctive feature of our PPI system is that it utilizes extended dependency graph, an intermediate level of representation that attempts to abstract away syntactic variations in text. As a result, we are able to use only a limited set of rules to extract PPI pairs in the sentences, and additional rules to detect additional passages for PPI pairs. For evaluation, we used the 95 articles that were provided for the BioC annotation task. We retrieved the unique PPIs from the BioGRID database for these articles and show that our system achieves a recall of 83.5%. In order to evaluate the detection of passages with PPIs, we further annotated Abstract and Results sections of 20 documents from the dataset and show that an f-value of 80.5% was obtained. To evaluate the generalizability of the system, we also conducted experiments on AIMed, a well-known PPI corpus. We achieved an f-value of 76.1% for sentence detection and an f-value of 64.7% for unique PPI detection.
Database URL: http://proteininformationresource.org/iprolink/corpora
doi:10.1093/database/baw072
PMCID: PMC4915133  PMID: 27170286
7.  Evolutionary model selection and parameter estimation for protein-protein interaction network based on differential evolution algorithm 
Revealing the underlying evolutionary mechanism plays an important role in understanding protein interaction networks in the cell. While many evolutionary models have been proposed, the problem about applying these models to real network data, especially for differentiating which model can better describe evolutionary process for the observed network urgently remains as a challenge. The traditional way is to use a model with presumed parameters to generate a network, and then evaluate the fitness by summary statistics, which however cannot capture the complete network structures information and estimate parameter distribution.
In this work we developed a novel method based on Approximate Bayesian Computation and modified Differential Evolution (ABC-DEP) that is capable of conducting model selection and parameter estimation simultaneously and detecting the underlying evolutionary mechanisms more accurately. We tested our method for its power in differentiating models and estimating parameters on the simulated data and found significant improvement in performance benchmark, as compared with a previous method. We further applied our method to real data of protein interaction networks in human and yeast. Our results show Duplication Attachment model as the predominant evolutionary mechanism for human PPI networks and Scale-Free model as the predominant mechanism for yeast PPI networks.
doi:10.1109/TCBB.2014.2366748
PMCID: PMC4719153  PMID: 26357273
Minimax approximation and algorithms; Eigenvalues and eigenvectors; Probabilistic algorithms; Convergence
8.  miRiaD: A Text Mining Tool for Detecting Associations of microRNAs with Diseases 
Background
MicroRNAs are increasingly being appreciated as critical players in human diseases, and questions concerning the role of microRNAs arise in many areas of biomedical research. There are several manually curated databases of microRNA-disease associations gathered from the biomedical literature; however, it is difficult for curators of these databases to keep up with the explosion of publications in the microRNA-disease field. Moreover, automated literature mining tools that assist manual curation of microRNA-disease associations currently capture only one microRNA property (expression) in the context of one disease (cancer). Thus, there is a clear need to develop more sophisticated automated literature mining tools that capture a variety of microRNA properties and relations in the context of multiple diseases to provide researchers with fast access to the most recent published information and to streamline and accelerate manual curation.
Methods
We have developed miRiaD (microRNAs in association with Disease), a text-mining tool that automatically extracts associations between microRNAs and diseases from the literature. These associations are often not directly linked, and the intermediate relations are often highly informative for the biomedical researcher. Thus, miRiaD extracts the miR-disease pairs together with an explanation for their association. We also developed a procedure that assigns scores to sentences, marking their informativeness, based on the microRNA-disease relation observed within the sentence.
Results
miRiaD was applied to the entire Medline corpus, identifying 8301 PMIDs with miR-disease associations. These abstracts and the miR-disease associations are available for browsing at http://biotm.cis.udel.edu/miRiaD. We evaluated the recall and precision of miRiaD with respect to information of high interest to public microRNA-disease database curators (expression and target gene associations), obtaining a recall of 88.46–90.78. When we expanded the evaluation to include sentences with a wide range of microRNA-disease information that may be of interest to biomedical researchers, miRiaD also performed very well with a F-score of 89.4. The informativeness ranking of sentences was evaluated in terms of nDCG (0.977) and correlation metrics (0.678-0.727) when compared to an annotator’s ranked list.
Conclusions
miRiaD, a high performance system that can capture a wide variety of microRNA-disease related information, extends beyond the scope of existing microRNA-disease resources. It can be incorporated into manual curation pipelines and serve as a resource for biomedical researchers interested in the role of microRNAs in disease. In our ongoing work we are developing an improved miRiaD web interface that will facilitate complex queries about microRNA-disease relationships, such as “In what diseases does microRNA regulation of apoptosis play a role?” or “Is there overlap in the sets of genes targeted by microRNAs in different types of dementia?”.”
Electronic supplementary material
The online version of this article (doi:10.1186/s13326-015-0044-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13326-015-0044-y
PMCID: PMC4877743  PMID: 27216254
MicroRNA; Disease; Associations; Text-mining; Relation extraction; Natural language processing
9.  Inference of protein-protein interaction networks from multiple heterogeneous data 
Protein-protein interaction (PPI) prediction is a central task in achieving a better understanding of cellular and intracellular processes. Because high-throughput experimental methods are both expensive and time-consuming, and are also known of suffering from the problems of incompleteness and noise, many computational methods have been developed, with varied degrees of success. However, the inference of PPI network from multiple heterogeneous data sources remains a great challenge. In this work, we developed a novel method based on approximate Bayesian computation and modified differential evolution sampling (ABC-DEP) and regularized laplacian (RL) kernel. The method enables inference of PPI networks from topological properties and multiple heterogeneous features including gene expression and Pfam domain profiles, in forms of weighted kernels. The optimal weights are obtained by ABC-DEP, and the kernel fusion built based on optimal weights serves as input to RL to infer missing or new edges in the PPI network. Detailed comparisons with control methods have been made, and the results show that the accuracy of PPI prediction measured by AUC is increased by up to 23 %, as compared to a baseline without using optimal weights. The method can provide insights into the relations between PPIs and various feature kernels and demonstrates strong capability of predicting faraway interactions that cannot be well detected by traditional RL method.
doi:10.1186/s13637-016-0040-2
PMCID: PMC4761017  PMID: 26941784
Protein interaction network; Network inference; Interaction prediction; Differential evolution
10.  The Protein Ontology: a structured representation of protein forms and complexes 
Nucleic Acids Research  2010;39(Database issue):D539-D545.
The Protein Ontology (PRO) provides a formal, logically-based classification of specific protein classes including structured representations of protein isoforms, variants and modified forms. Initially focused on proteins found in human, mouse and Escherichia coli, PRO now includes representations of protein complexes. The PRO Consortium works in concert with the developers of other biomedical ontologies and protein knowledge bases to provide the ability to formally organize and integrate representations of precise protein forms so as to enhance accessibility to results of protein research. PRO (http://pir.georgetown.edu/pro) is part of the Open Biomedical Ontology Foundry.
doi:10.1093/nar/gkq907
PMCID: PMC3013777  PMID: 20935045
11.  Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer 
PLoS ONE  2015;10(10):e0141773.
Given the wealth of bioinformatics resources and the growing complexity of biological information, it is valuable to integrate data from disparate sources to gain insight into the role of genes/proteins in health and disease. We have developed a bioinformatics framework that combines literature mining with information from biomedical ontologies and curated databases to create knowledge “maps” of genes/proteins of interest. We applied this approach to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated in cancer. The knowledge map includes post-translational modifications (PTMs), protein-protein interactions, disease-associated mutations, and transcription factors co-activated by beta-catenin and their targets and captures the major processes in which beta-catenin is known to participate. Using the map, we generated testable hypotheses about beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple relation types, we identified proteins that may participate in feedback loops regulating beta-catenin transcriptional activity. By combining multiple network relations with PTM proteoform-specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity. Finally, by overlaying cancer-associated mutation data with sequence features, we observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin mutations can contribute to cancer. The approach described, which captures rich information for molecular species from genes and proteins to PTM proteoforms, is extensible to other proteins and their involvement in disease.
doi:10.1371/journal.pone.0141773
PMCID: PMC4624812  PMID: 26509276
12.  RNA-Seq Analysis of Abdominal Fat in Genetically Fat and Lean Chickens Highlights a Divergence in Expression of Genes Controlling Adiposity, Hemostasis, and Lipid Metabolism 
PLoS ONE  2015;10(10):e0139549.
Genetic selection for enhanced growth rate in meat-type chickens (Gallus domesticus) is usually accompanied by excessive adiposity, which has negative impacts on both feed efficiency and carcass quality. Enhanced visceral fatness and several unique features of avian metabolism (i.e., fasting hyperglycemia and insulin insensitivity) mimic overt symptoms of obesity and related metabolic disorders in humans. Elucidation of the genetic and endocrine factors that contribute to excessive visceral fatness in chickens could also advance our understanding of human metabolic diseases. Here, RNA sequencing was used to examine differential gene expression in abdominal fat of genetically fat and lean chickens, which exhibit a 2.8-fold divergence in visceral fatness at 7 wk. Ingenuity Pathway Analysis revealed that many of 1687 differentially expressed genes are associated with hemostasis, endocrine function and metabolic syndrome in mammals. Among the highest expressed genes in abdominal fat, across both genotypes, were 25 differentially expressed genes associated with de novo synthesis and metabolism of lipids. Over-expression of numerous adipogenic and lipogenic genes in the FL chickens suggests that in situ lipogenesis in chickens could make a more substantial contribution to expansion of visceral fat mass than previously recognized. Distinguishing features of the abdominal fat transcriptome in lean chickens were high abundance of multiple hemostatic and vasoactive factors, transporters, and ectopic expression of several hormones/receptors, which could control local vasomotor tone and proteolytic processing of adipokines, hemostatic factors and novel endocrine factors. Over-expression of several thrombogenic genes in abdominal fat of lean chickens is quite opposite to the pro-thrombotic state found in obese humans. Clearly, divergent genetic selection for an extreme (2.5–2.8-fold) difference in visceral fatness provokes a number of novel regulatory responses that govern growth and metabolism of visceral fat in this unique avian model of juvenile-onset obesity and glucose-insulin imbalance.
doi:10.1371/journal.pone.0139549
PMCID: PMC4596860  PMID: 26445145
13.  miRTex: A Text Mining System for miRNA-Gene Relation Extraction 
PLoS Computational Biology  2015;11(9):e1004391.
MicroRNAs (miRNAs) regulate a wide range of cellular and developmental processes through gene expression suppression or mRNA degradation. Experimentally validated miRNA gene targets are often reported in the literature. In this paper, we describe miRTex, a text mining system that extracts miRNA-target relations, as well as miRNA-gene and gene-miRNA regulation relations. The system achieves good precision and recall when evaluated on a literature corpus of 150 abstracts with F-scores close to 0.90 on the three different types of relations. We conducted full-scale text mining using miRTex to process all the Medline abstracts and all the full-length articles in the PubMed Central Open Access Subset. The results for all the Medline abstracts are stored in a database for interactive query and file download via the website at http://proteininformationresource.org/mirtex. Using miRTex, we identified genes potentially regulated by miRNAs in Triple Negative Breast Cancer, as well as miRNA-gene relations that, in conjunction with kinase-substrate relations, regulate the response to abiotic stress in Arabidopsis thaliana. These two use cases demonstrate the usefulness of miRTex text mining in the analysis of miRNA-regulated biological processes.
Author Summary
MicroRNAs (miRNAs) are an important class of RNAs that regulate a wide range of biological processes by post-transcriptional regulation of gene expression. The amount of literature describing experimentally validated miRNA targets is increasing rapidly, which poses a challenge to researchers and biocurators to stay up-to-date with the available information. Text mining methods have been used to extract miRNA-gene associated pairs and assist in curation. In this paper, we describe miRTex, a text mining system that extracts miRNA-target, miRNA-gene regulation and gene-miRNA regulation relations. We evaluate miRTex performance on two corpora, and show that the elaborate use of lexico-syntactic information and linguistic generalizations enables it to achieve the state-of-the-art performance. We have processed the all the Medline abstracts and all the full-length articles in the PubMed Central Open Access Subset with miRTex, and provide a website to access the extraction results from all the Medline abstracts. The full-scale text mining results will be a useful resource for miRNA researchers, while the miRTex tool itself can be integrated into literature-based curation pipelines. We present two use cases (for animal and plant miRNAs, respectively) that show how the full-scale text mining can be used in combination with other bioinformatics resources to gain insight into biological processes.
doi:10.1371/journal.pcbi.1004391
PMCID: PMC4583433  PMID: 26407127
14.  RLIMS-P 2.0: A Generalizable Rule-Based Information Extraction System for Literature Mining of Protein Phosphorylation Information 
We introduce RLIMS-P version 2.0, an enhanced rule-based information extraction (IE) system for mining kinase, substrate, and phosphorylation site information from scientific literature. Consisting of natural language processing and IE modules, the system has integrated several new features, including the capability of processing full-text articles and generalizability towards different post-translational modifications (PTMs). To evaluate the system, sets of abstracts and full-text articles, containing a variety of textual expressions, were annotated. On the abstract corpus, the system achieved F-scores of 0.91, 0.92, and 0.95 for kinases, substrates, and sites, respectively. The corresponding scores on the full-text corpus were 0.88, 0.91, and 0.92. It was additionally evaluated on the corpus of the 2013 BioNLP-ST GE task, and achieved an F-score of 0.87 for the phosphorylation core task, improving upon the results previously reported on the corpus. Full-scale processing of all abstracts in MEDLINE and all articles in PubMed Central Open Access Subset has demonstrated scalability for mining rich information in literature, enabling its adoption for biocuration and for knowledge discovery. The new system is generalizable and it will be adapted to tackle other major PTM types. RLIMS-P 2.0 online system is available online (http://proteininformationresource.org/rlimsp/) and the developed corpora are available from iProLINK (http://proteininformationresource.org/iprolink/).
doi:10.1109/TCBB.2014.2372765
PMCID: PMC4568560  PMID: 26357075
Biology and genetics; context analysis and indexing; natural language processing; text mining
15.  eFIP: A Tool for Mining Functional Impact of Phosphorylation from Literature 
Technologies and experimental strategies have improved dramatically in the field of genomics and proteomics facilitating analysis of cellular and biochemical processes, as well as of proteins networks. Based on numerous such analyses, there has been a significant increase of publications in life sciences and biomedicine. In this respect, knowledge bases are struggling to cope with the literature volume and they may not be able to capture in detail certain aspects of proteins and genes. One important aspect of proteins is their phosphorylated states and their implication in protein function and protein interacting networks. For this reason, we developed eFIP, a web-based tool, which aids scientists to find quickly abstracts mentioning phosphorylation of a given protein (including site and kinase), coupled with mentions of interactions and functional aspects of the protein. eFIP combines information provided by applications such as eGRAB, RLIMS-P, eGIFT and AIIAGMT, to rank abstracts mentioning phosphorylation, and to display the results in a highlighted and tabular format for a quick inspection. In this chapter, we present a case study of results returned by eFIP for the protein BAD, which is a key regulator of apoptosis that is posttranslationally modified by phosphorylation.
doi:10.1007/978-1-60761-977-2_5
PMCID: PMC4563866  PMID: 21082428
Text mining; BioNLP; Information extraction; Phosphorylation; Protein–protein interaction; PPI; Knowledge discovery
16.  PIRSF Family Classification System for Protein Functional and Evolutionary Analysis 
The PIRSF protein classification system (http://pir.georgetown.edu/pirsf/) reflects evolutionary relationships of full-length proteins and domains. The primary PIRSF classification unit is the homeomorphic family, whose members are both homologous (evolved from a common ancestor) and homeomorphic (sharing full-length sequence similarity and a common domain architecture). PIRSF families are curated systematically based on literature review and integrative sequence and functional analysis, including sequence and structure similarity, domain architecture, functional association, genome context, and phyletic pattern. The results of classification and expert annotation are summarized in PIRSF family reports with graphical viewers for taxonomic distribution, domain architecture, family hierarchy, and multiple alignment and phylogenetic tree. The PIRSF system provides a comprehensive resource for bioinformatics analysis and comparative studies of protein function and evolution. Domain or fold-based searches allow identification of evolutionarily related protein families sharing domains or structural folds. Functional convergence and functional divergence are revealed by the relationships between protein classification and curated family functions. The taxonomic distribution allows the identification of lineage-specific or broadly conserved protein families and can reveal horizontal gene transfer. Here we demonstrate, with illustrative examples, how to use the web-based PIRSF system as a tool for functional and evolutionary studies of protein families.
PMCID: PMC2674652  PMID: 19455212
Domain architecture; Functional convergence; Functional divergence; Genome context; Protein family classification; Taxonomic distribution
17.  pGenN, a Gene Normalization Tool for Plant Genes and Proteins in Scientific Literature 
PLoS ONE  2015;10(8):e0135305.
Background
Automatically detecting gene/protein names in the literature and connecting them to databases records, also known as gene normalization, provides a means to structure the information buried in free-text literature. Gene normalization is critical for improving the coverage of annotation in the databases, and is an essential component of many text mining systems and database curation pipelines.
Methods
In this manuscript, we describe a gene normalization system specifically tailored for plant species, called pGenN (pivot-based Gene Normalization). The system consists of three steps: dictionary-based gene mention detection, species assignment, and intra species normalization. We have developed new heuristics to improve each of these phases.
Results
We evaluated the performance of pGenN on an in-house expertly annotated corpus consisting of 104 plant relevant abstracts. Our system achieved an F-value of 88.9% (Precision 90.9% and Recall 87.2%) on this corpus, outperforming state-of-art systems presented in BioCreative III. We have processed over 440,000 plant-related Medline abstracts using pGenN. The gene normalization results are stored in a local database for direct query from the pGenN web interface (proteininformationresource.org/pgenn/). The annotated literature corpus is also publicly available through the PIR text mining portal (proteininformationresource.org/iprolink/).
doi:10.1371/journal.pone.0135305
PMCID: PMC4530884  PMID: 26258475
18.  An Integrated Approach for Analyzing Clinical Genomic Variant Data from Next-Generation Sequencing 
Next-generation sequencing (NGS) technologies provide the potential for developing high-throughput and low-cost platforms for clinical diagnostics. A limiting factor to clinical applications of genomic NGS is downstream bioinformatics analysis for data interpretation. We have developed an integrated approach for end-to-end clinical NGS data analysis from variant detection to functional profiling. Robust bioinformatics pipelines were implemented for genome alignment, single nucleotide polymorphism (SNP), small insertion/deletion (InDel), and copy number variation (CNV) detection of whole exome sequencing (WES) data from the Illumina platform. Quality-control metrics were analyzed at each step of the pipeline by use of a validated training dataset to ensure data integrity for clinical applications. We annotate the variants with data regarding the disease population and variant impact. Custom algorithms were developed to filter variants based on criteria, such as quality of variant, inheritance pattern, and impact of variant on protein function. The developed clinical variant pipeline links the identified rare variants to Integrated Genome Viewer for visualization in a genomic context and to the Protein Information Resource’s iProXpress for rich protein and disease information. With the application of our system of annotations, prioritizations, inheritance filters, and functional profiling and analysis, we have created a unique methodology for downstream variant filtering that empowers clinicians and researchers to interpret more effectively the relevance of genomic alterations within a rare genetic disease.
doi:10.7171/jbt.15-2601-002
PMCID: PMC4310222  PMID: 25649353
bioinformatics; genetic alterations; Mendelian Genetics; protein information resources
19.  Construction of phosphorylation interaction networks by text mining of full-length articles using the eFIP system 
Protein phosphorylation is a reversible post-translational modification where a protein kinase adds a phosphate group to a protein, potentially regulating its function, localization and/or activity. Phosphorylation can affect protein–protein interactions (PPIs), abolishing interaction with previous binding partners or enabling new interactions. Extracting phosphorylation information coupled with PPI information from the scientific literature will facilitate the creation of phosphorylation interaction networks of kinases, substrates and interacting partners, toward knowledge discovery of functional outcomes of protein phosphorylation. Increasingly, PPI databases are interested in capturing the phosphorylation state of interacting partners. We have previously developed the eFIP (Extracting Functional Impact of Phosphorylation) text mining system, which identifies phosphorylated proteins and phosphorylation-dependent PPIs. In this work, we present several enhancements for the eFIP system: (i) text mining for full-length articles from the PubMed Central open-access collection; (ii) the integration of the RLIMS-P 2.0 system for the extraction of phosphorylation events with kinase, substrate and site information; (iii) the extension of the PPI module with new trigger words/phrases describing interactions and (iv) the addition of the iSimp tool for sentence simplification to aid in the matching of syntactic patterns. We enhance the website functionality to: (i) support searches based on protein roles (kinases, substrates, interacting partners) or using keywords; (ii) link protein entities to their corresponding UniProt identifiers if mapped and (iii) support visual exploration of phosphorylation interaction networks using Cytoscape. The evaluation of eFIP on full-length articles achieved 92.4% precision, 76.5% recall and 83.7% F-measure on 100 article sections. To demonstrate eFIP for knowledge extraction and discovery, we constructed phosphorylation-dependent interaction networks involving 14-3-3 proteins identified from cancer-related versus diabetes-related articles. Comparison of the phosphorylation interaction network of kinases, phosphoproteins and interactants obtained from eFIP searches, along with enrichment analysis of the protein set, revealed several shared interactions, highlighting common pathways discussed in the context of both diseases.
Database URL: http://proteininformationresource.org/efip
doi:10.1093/database/bav020
PMCID: PMC4381107  PMID: 25833953
20.  Development of Bioinformatics Pipeline for Analyzing Clinical Pediatric NGS Data 
Using an Illumina exome sequencing dataset generated from pediatric Acute Myeloid Leukemia patients (AML; type FLT3/ITD+) a comprehensive bioinformatics pipeline was developed to aid in a better clinical understanding of the genetic data associated with the clinical phenotype. The pipeline starts with raw next generation sequencing reads and using both publicly available resources and custom scripts, analyzes the genomic data for variants associated with pediatric AML. By incorporating functional information such as Gene Ontology annotation and protein-protein interactions, the methodology prioritizes genomic variants and returns disease specific results and knowledge maps. Furthermore, it compares the somatic mutations at diagnosis with the somatic mutations at relapse and outputs variants and functional annotations that are specific for the relapse state.
PMCID: PMC4525226  PMID: 26306272
21.  An Integrated Approach for Analyzing Clinical Genomic Variant Data from Next-Generation Sequencing 
Next-generation sequencing (NGS) technologies provide the potential for developing high-throughput and low-cost platforms for clinical diagnostics. A limiting factor to clinical applications of genomic NGS is downstream bioinformatics analysis for data interpretation. We have developed an integrated approach for end-to-end clinical NGS data analysis from variant detection to functional profiling. Robust bioinformatics pipelines were implemented for genome alignment, single nucleotide polymorphism (SNP), small insertion/deletion (InDel), and copy number variation (CNV) detection of whole exome sequencing (WES) data from the Illumina platform. Quality-control metrics were analyzed at each step of the pipeline by use of a validated training dataset to ensure data integrity for clinical applications. We annotate the variants with data regarding the disease population and variant impact. Custom algorithms were developed to filter variants based on criteria, such as quality of variant, inheritance pattern, and impact of variant on protein function. The developed clinical variant pipeline links the identified rare variants to Integrated Genome Viewer for visualization in a genomic context and to the Protein Information Resource’s iProXpress for rich protein and disease information. With the application of our system of annotations, prioritizations, inheritance filters, and functional profiling and analysis, we have created a unique methodology for downstream variant filtering that empowers clinicians and researchers to interpret more effectively the relevance of genomic alterations within a rare genetic disease.
doi:10.7171/jbt.15-2601-002
PMCID: PMC4310222  PMID: 25649353
bioinformatics; genetic alterations; Mendelian Genetics; protein information resources
22.  The InterPro protein families database: the classification resource after 15 years 
Nucleic Acids Research  2014;43(Database issue):D213-D221.
The InterPro database (http://www.ebi.ac.uk/interpro/) is a freely available resource that can be used to classify sequences into protein families and to predict the presence of important domains and sites. Central to the InterPro database are predictive models, known as signatures, from a range of different protein family databases that have different biological focuses and use different methodological approaches to classify protein families and domains. InterPro integrates these signatures, capitalizing on the respective strengths of the individual databases, to produce a powerful protein classification resource. Here, we report on the status of InterPro as it enters its 15th year of operation, and give an overview of new developments with the database and its associated Web interfaces and software. In particular, the new domain architecture search tool is described and the process of mapping of Gene Ontology terms to InterPro is outlined. We also discuss the challenges faced by the resource given the explosive growth in sequence data in recent years. InterPro (version 48.0) contains 36 766 member database signatures integrated into 26 238 InterPro entries, an increase of over 3993 entries (5081 signatures), since 2012.
doi:10.1093/nar/gku1243
PMCID: PMC4383996  PMID: 25428371
23.  UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches 
Bioinformatics  2014;31(6):926-932.
Motivation: UniRef databases provide full-scale clustering of UniProtKB sequences and are utilized for a broad range of applications, particularly similarity-based functional annotation. Non-redundancy and intra-cluster homogeneity in UniRef were recently improved by adding a sequence length overlap threshold. Our hypothesis is that these improvements would enhance the speed and sensitivity of similarity searches and improve the consistency of annotation within clusters.
Results: Intra-cluster molecular function consistency was examined by analysis of Gene Ontology terms. Results show that UniRef clusters bring together proteins of identical molecular function in more than 97% of the clusters, implying that clusters are useful for annotation and can also be used to detect annotation inconsistencies. To examine coverage in similarity results, BLASTP searches against UniRef50 followed by expansion of the hit lists with cluster members demonstrated advantages compared with searches against UniProtKB sequences; the searches are concise (∼7 times shorter hit list before expansion), faster (∼6 times) and more sensitive in detection of remote similarities (>96% recall at e-value <0.0001). Our results support the use of UniRef clusters as a comprehensive and scalable alternative to native sequence databases for similarity searches and reinforces its reliability for use in functional annotation.
Availability and implementation: Web access and file download from UniProt website at http://www.uniprot.org/uniref and ftp://ftp.uniprot.org/pub/databases/uniprot/uniref. BLAST searches against UniRef are available at http://www.uniprot.org/blast/
Contact: huang@dbi.udel.edu
doi:10.1093/bioinformatics/btu739
PMCID: PMC4375400  PMID: 25398609
24.  A fast Peptide Match service for UniProt Knowledgebase 
Bioinformatics  2013;29(21):2808-2809.
Summary: We have developed a new web application for peptide matching using Apache Lucene-based search engine. The Peptide Match service is designed to quickly retrieve all occurrences of a given query peptide from UniProt Knowledgebase (UniProtKB) with isoforms. The matched proteins are shown in summary tables with rich annotations, including matched sequence region(s) and links to corresponding proteins in a number of proteomic/peptide spectral databases. The results are grouped by taxonomy and can be browsed by organism, taxonomic group or taxonomy tree. The service supports queries where isobaric leucine and isoleucine are treated equivalent, and an option for searching UniRef100 representative sequences, as well as dynamic queries to major proteomic databases. In addition to the web interface, we also provide RESTful web services. The underlying data are updated every 4 weeks in accordance with the UniProt releases.
Availability: http://proteininformationresource.org/peptide.shtml
Contact: chenc@udel.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt484
PMCID: PMC3799477  PMID: 23958731
25.  A generalizable NLP framework for fast development of pattern-based biomedical relation extraction systems 
BMC Bioinformatics  2014;15(1):285.
Background
Text mining is increasingly used in the biomedical domain because of its ability to automatically gather information from large amount of scientific articles. One important task in biomedical text mining is relation extraction, which aims to identify designated relations among biological entities reported in literature. A relation extraction system achieving high performance is expensive to develop because of the substantial time and effort required for its design and implementation. Here, we report a novel framework to facilitate the development of a pattern-based biomedical relation extraction system. It has several unique design features: (1) leveraging syntactic variations possible in a language and automatically generating extraction patterns in a systematic manner, (2) applying sentence simplification to improve the coverage of extraction patterns, and (3) identifying referential relations between a syntactic argument of a predicate and the actual target expected in the relation extraction task.
Results
A relation extraction system derived using the proposed framework achieved overall F-scores of 72.66% for the Simple events and 55.57% for the Binding events on the BioNLP-ST 2011 GE test set, comparing favorably with the top performing systems that participated in the BioNLP-ST 2011 GE task. We obtained similar results on the BioNLP-ST 2013 GE test set (80.07% and 60.58%, respectively). We conducted additional experiments on the training and development sets to provide a more detailed analysis of the system and its individual modules. This analysis indicates that without increasing the number of patterns, simplification and referential relation linking play a key role in the effective extraction of biomedical relations.
Conclusions
In this paper, we present a novel framework for fast development of relation extraction systems. The framework requires only a list of triggers as input, and does not need information from an annotated corpus. Thus, we reduce the involvement of domain experts, who would otherwise have to provide manual annotations and help with the design of hand crafted patterns. We demonstrate how our framework is used to develop a system which achieves state-of-the-art performance on a public benchmark corpus.
doi:10.1186/1471-2105-15-285
PMCID: PMC4262219  PMID: 25149151

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