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The creation of biological pathway knowledge bases is largely driven by manual effort to curate based on evidences from the scientific literature. It is highly challenging for the curators to keep up with the literature. Text mining applications have been developed in the last decade to assist human curators to speed up the curation pace where majority of them aim to identify the most relevant papers for curation with little attempt to directly extract the pathway information from text. In this paper, we describe a rule-based literature mining system to extract pathway information from text. We evaluated the system using curated pharmacokinetic (PK) and pharmacodynamic (PD) pathways in PharmGKB. The system achieved an F-measure of 63.11% and 34.99% for entity extraction and event extraction respectively against all PubMed abstracts cited in PharmGKB. It may be possible to improve the system performance by incorporating using statistical machine learning approaches. This study also helped us gain insights into the barriers towards automated event extraction from text for pathway curation.
PMCID: PMC3902837  PMID: 24297561
2.  Normalization and standardization of electronic health records for high-throughput phenotyping: the SHARPn consortium 
Research objective
To develop scalable informatics infrastructure for normalization of both structured and unstructured electronic health record (EHR) data into a unified, concept-based model for high-throughput phenotype extraction.
Materials and methods
Software tools and applications were developed to extract information from EHRs. Representative and convenience samples of both structured and unstructured data from two EHR systems—Mayo Clinic and Intermountain Healthcare—were used for development and validation. Extracted information was standardized and normalized to meaningful use (MU) conformant terminology and value set standards using Clinical Element Models (CEMs). These resources were used to demonstrate semi-automatic execution of MU clinical-quality measures modeled using the Quality Data Model (QDM) and an open-source rules engine.
Using CEMs and open-source natural language processing and terminology services engines—namely, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) and Common Terminology Services (CTS2)—we developed a data-normalization platform that ensures data security, end-to-end connectivity, and reliable data flow within and across institutions. We demonstrated the applicability of this platform by executing a QDM-based MU quality measure that determines the percentage of patients between 18 and 75 years with diabetes whose most recent low-density lipoprotein cholesterol test result during the measurement year was <100 mg/dL on a randomly selected cohort of 273 Mayo Clinic patients. The platform identified 21 and 18 patients for the denominator and numerator of the quality measure, respectively. Validation results indicate that all identified patients meet the QDM-based criteria.
End-to-end automated systems for extracting clinical information from diverse EHR systems require extensive use of standardized vocabularies and terminologies, as well as robust information models for storing, discovering, and processing that information. This study demonstrates the application of modular and open-source resources for enabling secondary use of EHR data through normalization into standards-based, comparable, and consistent format for high-throughput phenotyping to identify patient cohorts.
PMCID: PMC3861933  PMID: 24190931
Electronic health record; Meaningful Use; Normalization; Natural Language Processing; Phenotype Extraction
3.  Automated chart review for asthma cohort identification using natural language processing: an exploratory study 
A significant proportion of children with asthma have delayed diagnosis of asthma by health care providers. Manual chart review according to established criteria is more accurate than directly using diagnosis codes, which tend to under-identify asthmatics, but chart reviews are more costly and less timely.
To evaluate the accuracy of a computational approach to asthma ascertainment, characterizing its utility and feasibility toward large-scale deployment in electronic medical records.
A natural language processing (NLP) system was developed for extracting predetermined criteria for asthma from unstructured text in electronic medical records and then inferring asthma status based on these criteria. Using manual chart reviews as a gold standard, asthma status (yes vs no) and identification date (first date of a “yes” asthma status) were determined by the NLP system.
Patients were a group of children (n =112, 84% Caucasian, 49% girls) younger than 4 years (mean 2.0 years, standard deviation 1.03 years) who participated in previous studies. The NLP approach to asthma ascertainment showed sensitivity, specificity, positive predictive value, negative predictive value, and median delay in diagnosis of 84.6%, 96.5%, 88.0%, 95.4%, and 0 months, respectively; this compared favorably with diagnosis codes, at 30.8%, 93.2%, 57.1%, 82.2%, and 2.3 months, respectively.
Automated asthma ascertainment from electronic medical records using NLP is feasible and more accurate than traditional approaches such as diagnosis codes. Considering the difficulty of labor-intensive manual record review, NLP approaches for asthma ascertainment should be considered for improving clinical care and research, especially in large-scale efforts.
PMCID: PMC3839107  PMID: 24125142
4.  Automated Recommendation for Cervical Cancer Screening and Surveillance 
Cancer Informatics  2014;13(Suppl 3):1-6.
Because of the complexity of cervical cancer prevention guidelines, clinicians often fail to follow best-practice recommendations. Moreover, existing clinical decision support (CDS) systems generally recommend a cervical cytology every three years for all female patients, which is inappropriate for patients with abnormal findings that require surveillance at shorter intervals. To address this problem, we developed a decision tree-based CDS system that integrates national guidelines to provide comprehensive guidance to clinicians. Validation was performed in several iterations by comparing recommendations generated by the system with those of clinicians for 333 patients. The CDS system extracted relevant patient information from the electronic health record and applied the guideline model with an overall accuracy of 87%. Providers without CDS assistance needed an average of 1 minute 39 seconds to decide on recommendations for management of abnormal findings. Overall, our work demonstrates the feasibility and potential utility of automated recommendation system for cervical cancer screening and surveillance.
PMCID: PMC4214690  PMID: 25368505
cervical cancer; clinical decision support; natural language processing; Papanicolaou test; colposcopy
5.  Automatically extracting sentences from Medline citations to support clinicians’ information needs 
Online health knowledge resources contain answers to most of the information needs raised by clinicians in the course of care. However, significant barriers limit the use of these resources for decision-making, especially clinicians’ lack of time. In this study we assessed the feasibility of automatically generating knowledge summaries for a particular clinical topic composed of relevant sentences extracted from Medline citations.
The proposed approach combines information retrieval and semantic information extraction techniques to identify relevant sentences from Medline abstracts. We assessed this approach in two case studies on the treatment alternatives for depression and Alzheimer's disease.
A total of 515 of 564 (91.3%) sentences retrieved in the two case studies were relevant to the topic of interest. About one-third of the relevant sentences described factual knowledge or a study conclusion that can be used for supporting information needs at the point of care.
The high rate of relevant sentences is desirable, given that clinicians’ lack of time is one of the main barriers to using knowledge resources at the point of care. Sentence rank was not significantly associated with relevancy, possibly due to most sentences being highly relevant. Sentences located closer to the end of the abstract and sentences with treatment and comparative predications were likely to be conclusive sentences. Our proposed technical approach to helping clinicians meet their information needs is promising. The approach can be extended for other knowledge resources and information need types.
PMCID: PMC3756259  PMID: 23100128
clinical decision support; information needs; knowledge summary; natural language processing
6.  Comprehensive temporal information detection from clinical text: medical events, time, and TLINK identification 
Temporal information detection systems have been developed by the Mayo Clinic for the 2012 i2b2 Natural Language Processing Challenge.
To construct automated systems for EVENT/TIMEX3 extraction and temporal link (TLINK) identification from clinical text.
Materials and methods
The i2b2 organizers provided 190 annotated discharge summaries as the training set and 120 discharge summaries as the test set. Our Event system used a conditional random field classifier with a variety of features including lexical information, natural language elements, and medical ontology. The TIMEX3 system employed a rule-based method using regular expression pattern match and systematic reasoning to determine normalized values. The TLINK system employed both rule-based reasoning and machine learning. All three systems were built in an Apache Unstructured Information Management Architecture framework.
Our TIMEX3 system performed the best (F-measure of 0.900, value accuracy 0.731) among the challenge teams. The Event system produced an F-measure of 0.870, and the TLINK system an F-measure of 0.537.
Our TIMEX3 system demonstrated good capability of regular expression rules to extract and normalize time information. Event and TLINK machine learning systems required well-defined feature sets to perform well. We could also leverage expert knowledge as part of the machine learning features to further improve TLINK identification performance.
PMCID: PMC3756269  PMID: 23558168
7.  Integrating information retrieval with distant supervision for Gene Ontology annotation 
This article describes our participation of the Gene Ontology Curation task (GO task) in BioCreative IV where we participated in both subtasks: A) identification of GO evidence sentences (GOESs) for relevant genes in full-text articles and B) prediction of GO terms for relevant genes in full-text articles. For subtask A, we trained a logistic regression model to detect GOES based on annotations in the training data supplemented with more noisy negatives from an external resource. Then, a greedy approach was applied to associate genes with sentences. For subtask B, we designed two types of systems: (i) search-based systems, which predict GO terms based on existing annotations for GOESs that are of different textual granularities (i.e., full-text articles, abstracts, and sentences) using state-of-the-art information retrieval techniques (i.e., a novel application of the idea of distant supervision) and (ii) a similarity-based system, which assigns GO terms based on the distance between words in sentences and GO terms/synonyms. Our best performing system for subtask A achieves an F1 score of 0.27 based on exact match and 0.387 allowing relaxed overlap match. Our best performing system for subtask B, a search-based system, achieves an F1 score of 0.075 based on exact match and 0.301 considering hierarchical matches. Our search-based systems for subtask B significantly outperformed the similarity-based system.
Database URL:
PMCID: PMC4150992  PMID: 25183856
8.  Overview of the gene ontology task at BioCreative IV 
Gene Ontology (GO) annotation is a common task among model organism databases (MODs) for capturing gene function data from journal articles. It is a time-consuming and labor-intensive task, and is thus often considered as one of the bottlenecks in literature curation. There is a growing need for semiautomated or fully automated GO curation techniques that will help database curators to rapidly and accurately identify gene function information in full-length articles. Despite multiple attempts in the past, few studies have proven to be useful with regard to assisting real-world GO curation. The shortage of sentence-level training data and opportunities for interaction between text-mining developers and GO curators has limited the advances in algorithm development and corresponding use in practical circumstances. To this end, we organized a text-mining challenge task for literature-based GO annotation in BioCreative IV. More specifically, we developed two subtasks: (i) to automatically locate text passages that contain GO-relevant information (a text retrieval task) and (ii) to automatically identify relevant GO terms for the genes in a given article (a concept-recognition task). With the support from five MODs, we provided teams with >4000 unique text passages that served as the basis for each GO annotation in our task data. Such evidence text information has long been recognized as critical for text-mining algorithm development but was never made available because of the high cost of curation. In total, seven teams participated in the challenge task. From the team results, we conclude that the state of the art in automatically mining GO terms from literature has improved over the past decade while much progress is still needed for computer-assisted GO curation. Future work should focus on addressing remaining technical challenges for improved performance of automatic GO concept recognition and incorporating practical benefits of text-mining tools into real-world GO annotation.
Database URL:
PMCID: PMC4142793  PMID: 25157073
9.  Standardizing adverse drug event reporting data 
The Adverse Event Reporting System (AERS) is an FDA database providing rich information on voluntary reports of adverse drug events (ADEs). Normalizing data in the AERS would improve the mining capacity of the AERS for drug safety signal detection and promote semantic interoperability between the AERS and other data sources. In this study, we normalize the AERS and build a publicly available normalized ADE data source. The drug information in the AERS is normalized to RxNorm, a standard terminology source for medication, using a natural language processing medication extraction tool, MedEx. Drug class information is then obtained from the National Drug File-Reference Terminology (NDF-RT) using a greedy algorithm. Adverse events are aggregated through mapping with the Preferred Term (PT) and System Organ Class (SOC) codes of Medical Dictionary for Regulatory Activities (MedDRA). The performance of MedEx-based annotation was evaluated and case studies were performed to demonstrate the usefulness of our approaches.
Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). In total, the AERS-DM contains 37,029,228 Drug-ADE records. Seventy-one percent (10,221/14,490) of normalized drug concepts in the AERS were classified to 9 classes in NDF-RT. The number of unique pairs is 4,639,613 between RxNorm concepts and MedDRA Preferred Term (PT) codes and 205,725 between RxNorm concepts and SOC codes after ADE aggregation.
We have built an open-source Drug-ADE knowledge resource with data being normalized and aggregated using standard biomedical ontologies. The data resource has the potential to assist the mining of ADE from AERS for the data mining research community.
PMCID: PMC4142531  PMID: 25157320
10.  Network-based analysis reveals distinct association patterns in a semantic MEDLINE-based drug-disease-gene network 
A huge amount of associations among different biological entities (e.g., disease, drug, and gene) are scattered in millions of biomedical articles. Systematic analysis of such heterogeneous data can infer novel associations among different biological entities in the context of personalized medicine and translational research. Recently, network-based computational approaches have gained popularity in investigating such heterogeneous data, proposing novel therapeutic targets and deciphering disease mechanisms. However, little effort has been devoted to investigating associations among drugs, diseases, and genes in an integrative manner.
We propose a novel network-based computational framework to identify statistically over-expressed subnetwork patterns, called network motifs, in an integrated disease-drug-gene network extracted from Semantic MEDLINE. The framework consists of two steps. The first step is to construct an association network by extracting pair-wise associations between diseases, drugs and genes in Semantic MEDLINE using a domain pattern driven strategy. A Resource Description Framework (RDF)-linked data approach is used to re-organize the data to increase the flexibility of data integration, the interoperability within domain ontologies, and the efficiency of data storage. Unique associations among drugs, diseases, and genes are extracted for downstream network-based analysis. The second step is to apply a network-based approach to mine the local network structure of this heterogeneous network. Significant network motifs are then identified as the backbone of the network. A simplified network based on those significant motifs is then constructed to facilitate discovery. We implemented our computational framework and identified five network motifs, each of which corresponds to specific biological meanings. Three case studies demonstrate that novel associations are derived from the network topology analysis of reconstructed networks of significant network motifs, further validated by expert knowledge and functional enrichment analyses.
We have developed a novel network-based computational approach to investigate the heterogeneous drug-gene-disease network extracted from Semantic MEDLINE. We demonstrate the power of this approach by prioritizing candidate disease genes, inferring potential disease relationships, and proposing novel drug targets, within the context of the entire knowledge. The results indicate that such approach will facilitate the formulization of novel research hypotheses, which is critical for translational medicine research and personalized medicine.
PMCID: PMC4137727  PMID: 25170419
11.  Transcription poisoning by topoisomerase I is controlled by gene length, splice sites and miR-142-3p 
Cancer research  2013;73(15):10.1158/0008-5472.CAN-12-3504.
Topoisomerase I (Top1) relaxes DNA supercoiling by forming transient cleavage complexes (Top1cc) up- and down-stream of transcription complexes. Top1cc can be trapped by carcinogenic and endogenous DNA lesions and by camptothecins resulting in transcription blocks. Here, we undertook genome-wide analysis of camptothecin-treated cells at exon resolution. RNA samples from HCT116 and MCF7 cells were analyzed with the Affy Exon array platform, allowing high resolution mapping along 18,537 genes. Long genes that are highly expressed were the most susceptible to down-regulation, whereas short genes were preferentially up-regulated. Along the body of genes, down-regulation was most important toward the 3’-end, and increased with the number of exon-intron junctions. Ubiquitin and RNA degradation-related pathway genes were selectively down-regulated. Parallel analysis of microRNA with the Agilent miRNA microarray platform revealed that miR-142-3p was highly induced by camptothecin. More than 10% of the down-regulated genes were targets of this p53-dependent microRNA. Our study demonstrates the profound impact of Top1cc on transcription elongation, especially at exon-intron junctions and on transcript stability by microRNA miR-142-3p up-regulation.
PMCID: PMC3874869  PMID: 23786772
Camptothecin; miRNA; RNA degradation; Topoisomerase I; ubiquitin
12.  Genome-Wide Analysis of Loss of Heterozygosity in Breast Infiltrating Ductal Carcinoma Distant Normal Tissue Highlights Arm Specific Enrichment and Expansion across Tumor Stages 
PLoS ONE  2014;9(4):e95783.
Studies have shown concurrent loss of heterozygosity (LOH) in breast infiltrating ductal carcinoma (IDC) and adjacent or distant normal tissue. However, the overall extent of LOH in normal tissue and their significance to tumorigenesis remain unknown, as existing studies are largely based on selected microsatellite markers. Here we present the first autosome-wide study of LOH in IDC and distant normal tissue using informative loci deduced from SNP array-based and sequencing-based techniques. We show a consistently high LOH concurrence rate in IDC (mean = 24%) and distant normal tissue (m = 54%), suggesting for most patients (31/33) histologically normal tissue contains genomic instability that can be a potential marker of increased IDC risk. Concurrent LOH is more frequent in fragile site related genes like WWOX (9/31), NTRK2 (10/31), and FHIT (7/31) than traditional genetic markers like BRCA1 (0/23), BRCA2 (2/29) and TP53 (1/13). Analysis at arm level shows distant normal tissue has low level but non-random enrichment of LOH (topped by 8p and 16q) significantly correlated with matched IDC (Pearson r = 0.66, p = 3.5E-6) (topped by 8p, 11q, 13q, 16q, 17p, and 17q). The arm-specific LOH enrichment was independently observed in tumor samples from 548 IDC patients when stratified by tumor size based T stages. Fine LOH structure from sequencing data indicates LOH in low order tissues non-randomly overlap (∼67%) with LOH that usually has longer tract length (the length of genomic region affected by LOH) in high order tissues. The consistent observations from multiple datasets suggest progressive LOH in the development of IDC potentially through arm-specific pile up effect with discernible signature in normal tissue. Our finding also suggests that LOH detected in IDC by comparing to paired adjacent or distant normal tissue are more likely underestimated.
PMCID: PMC3991715  PMID: 24748104
13.  Automatic identification of comparative effectiveness research from Medline citations to support clinicians’ treatment information needs 
Online knowledge resources such as Medline can address most clinicians’ patient care information needs. Yet, significant barriers, notably lack of time, limit the use of these sources at the point of care. The most common information needs raised by clinicians are treatment-related. Comparative effectiveness studies allow clinicians to consider multiple treatment alternatives for a particular problem. Still, solutions are needed to enable efficient and effective consumption of comparative effectiveness research at the point of care.
Design and assess an algorithm for automatically identifying comparative effectiveness studies and extracting the interventions investigated in these studies.
The algorithm combines semantic natural language processing, Medline citation metadata, and machine learning techniques. We assessed the algorithm in a case study of treatment alternatives for depression.
Both precision and recall for identifying comparative studies was 0.83. A total of 86% of the interventions extracted perfectly or partially matched the gold standard.
Overall, the algorithm achieved reasonable performance. The method provides building blocks for the automatic summarization of comparative effectiveness research to inform point of care decision-making.
PMCID: PMC3940695  PMID: 23920677
comparative effectiveness research; information needs
14.  An exploratory study of a text classification framework for Internet-based surveillance of emerging epidemics 
Early detection of infectious disease outbreaks is crucial to protecting the public health of a society. Online news articles provide timely information on disease outbreaks worldwide. In this study, we investigated automated detection of articles relevant to disease outbreaks using machine learning classifiers. In a real-life setting, it is expensive to prepare a training data set for classifiers, which usually consists of manually labeled relevant and irrelevant articles. To mitigate this challenge, we examined the use of randomly sampled unlabeled articles as well as labeled relevant articles.
Naïve Bayes and Support Vector Machine (SVM) classifiers were trained on 149 relevant and 149 or more randomly sampled unlabeled articles. Diverse classifiers were trained by varying the number of sampled unlabeled articles and also the number of word features. The trained classifiers were applied to 15 thousand articles published over 15 days. Top-ranked articles from each classifier were pooled and the resulting set of 1337 articles was reviewed by an expert analyst to evaluate the classifiers.
Daily averages of areas under ROC curves (AUCs) over the 15-day evaluation period were 0.841 and 0.836, respectively, for the naïve Bayes and SVM classifier. We referenced a database of disease outbreak reports to confirm that this evaluation data set resulted from the pooling method indeed covered incidents recorded in the database during the evaluation period.
The proposed text classification framework utilizing randomly sampled unlabeled articles can facilitate a cost-effective approach to training machine learning classifiers in a real-life Internet-based biosurveillance project. We plan to examine this framework further using larger data sets and using articles in non-English languages.
PMCID: PMC3904285  PMID: 21134784
Natural language processing; Information storage and retrieval; Medical informatics applications; Disease notification; Disease outbreaks; Biosurveillance; Internet
15.  Microarray probes and probe sets 
DNA microarrays have gained wide use in biomedical research by simultaneously monitoring the expression levels of a large number of genes. The successful implementation of DNA microarray technologies requires the development of methods and techniques for the fabrication of microarrays, the selection of probes to represent genes, the quantification of hybridization, and data analysis. In this paper, we concentrate on probes that are either spotted or synthesized on the glass slides through several aspects: sources of probes, the criteria for selecting probes, tools available for probe selections, and probes used in commercial microarray chips. We then provide a detailed review of one type of DNA microarray: Affymetrix GeneChips, discuss the need to re-annotate probes, review different methods for regrouping probes into probe sets, and compare various redefinitions through public available datasets.
PMCID: PMC3902802  PMID: 20036881
Microarray; GeneChips; Probes; Probe sets; Review
16.  Detecting concept mentions in biomedical text using hidden Markov model: multiple concept types at once or one at a time? 
Identifying phrases that refer to particular concept types is a critical step in extracting information from documents. Provided with annotated documents as training data, supervised machine learning can automate this process. When building a machine learning model for this task, the model may be built to detect all types simultaneously (all-types-at-once) or it may be built for one or a few selected types at a time (one-type- or a-few-types-at-a-time). It is of interest to investigate which strategy yields better detection performance.
Hidden Markov models using the different strategies were evaluated on a clinical corpus annotated with three concept types (i2b2/VA corpus) and a biology literature corpus annotated with five concept types (JNLPBA corpus). Ten-fold cross-validation tests were conducted and the experimental results showed that models trained for multiple concept types consistently yielded better performance than those trained for a single concept type. F-scores observed for the former strategies were higher than those observed for the latter by 0.9 to 2.6% on the i2b2/VA corpus and 1.4 to 10.1% on the JNLPBA corpus, depending on the target concept types. Improved boundary detection and reduced type confusion were observed for the all-types-at-once strategy.
The current results suggest that detection of concept phrases could be improved by simultaneously tackling multiple concept types. This also suggests that we should annotate multiple concept types in developing a new corpus for machine learning models. Further investigation is expected to gain insights in the underlying mechanism to achieve good performance when multiple concept types are considered.
PMCID: PMC3908466  PMID: 24438362
Natural language processing; Information storage and retrieval; Data mining; Electronic health records
17.  Protein Complex Identification by Integrating Protein-Protein Interaction Evidence from Multiple Sources 
PLoS ONE  2013;8(12):e83841.
Understanding protein complexes is important for understanding the science of cellular organization and function. Many computational methods have been developed to identify protein complexes from experimentally obtained protein-protein interaction (PPI) networks. However, interaction information obtained experimentally can be unreliable and incomplete. Reconstructing these PPI networks with PPI evidences from other sources can improve protein complex identification.
We combined PPI information from 6 different sources and obtained a reconstructed PPI network for yeast through machine learning. Some popular protein complex identification methods were then applied to detect yeast protein complexes using the new PPI networks. Our evaluation indicates that protein complex identification algorithms using the reconstructed PPI network significantly outperform ones on experimentally verified PPI networks.
We conclude that incorporating PPI information from other sources can improve the effectiveness of protein complex identification.
PMCID: PMC3873956  PMID: 24386289
18.  One-Pot Microbial Method to Synthesize Dual-Doped Graphene and Its Use as High-Performance Electrocatalyst 
Scientific Reports  2013;3:3499.
A novel strategy to synthesize nitrogen (N) and sulfur (S)-doped graphene (G) is developed through sulfate-reducing bacteria treating graphene oxide (GO). The N, S-doped G demonstrates significantly improved electrocatalytic properties and electrochemical sensing performances in comparison with single-doped graphene due to the synergistic effects of dual dopants on the properties of graphene.
PMCID: PMC3863812  PMID: 24336153
19.  Network-based analysis of vaccine-related associations reveals consistent knowledge with the vaccine ontology 
Ontologies are useful in many branches of biomedical research. For instance, in the vaccine domain, the community-based Vaccine Ontology (VO) has been widely used to promote vaccine data standardization, integration, and computer-assisted reasoning. However, a major challenge in the VO has been to construct ontologies of vaccine functions, given incomplete vaccine knowledge and inconsistencies in how this knowledge is manually curated.
In this study, we show that network-based analysis of vaccine-related networks can identify underlying structural information consistent with that captured by the VO, and commonalities in the vaccine adverse events for vaccines and for diseases to produce new hypotheses about pathomechanisms involving the vaccine and the disease status. First, a vaccine-vaccine network was inferred by applying a bipartite network projection strategy to the vaccine-disease network extracted from the Semantic MEDLINE database. In total, 76 vaccines and 573 relationships were identified to construct the vaccine network. The shortest paths between all pairs of vaccines were calculated within the vaccine network. The correlation between the shortest paths of vaccine pairs and their semantic similarities in the VO was then investigated. Second, a vaccine-gene network was also constructed. In this network, 4 genes were identified as hubs interacting with at least 3 vaccines, and 4 vaccines were identified as hubs associated with at least 3 genes. These findings correlate with existing knowledge and provide new hypotheses in the fundamental interaction mechanisms involving vaccines, diseases, and genes.
In this study, we demonstrated that a combinatorial analysis using a literature knowledgebase, semantic technology, and ontology is able to reveal important unidentified knowledge critical to biomedical research and public health and to generate testable hypotheses for future experimental verification. As the associations from Semantic MEDLINE remain incomplete, we expect to extend this work by (1) integrating additional association databases to complement Semantic MEDLINE knowledge, (2) extending the neighbor genes of vaccine-associated genes, and (3) assigning confidence weights to different types of associations or associations from different sources.
PMCID: PMC4177205  PMID: 24209834
20.  Identifying protein complexes with fuzzy machine learning model 
Proteome Science  2013;11(Suppl 1):S21.
Many computational approaches have been developed to detect protein complexes from protein-protein interaction (PPI) networks. However, these PPI networks are always built from high-throughput experiments. The presence of unreliable interactions in PPI network makes this task very challenging.
In this study, we proposed a Genetic-Algorithm Fuzzy Naïve Bayes (GAFNB) filter to classify the protein complexes from candidate subgraphs. It takes unreliability into consideration and tackles the presence of unreliable interactions in protein complex. We first got candidate protein complexes through existed popular methods. Each candidate protein complex is represented by 29 graph features and 266 biological property based features. GAFNB model is then applied to classify the candidate complexes into positive or negative.
Our evaluation indicates that the protein complex identification algorithms using the GAFNB model filtering outperform original ones. For evaluation of GAFNB model, we also compared the performance of GAFNB with Naïve Bayes (NB). Results show that GAFNB performed better than NB. It indicates that a fuzzy model is more suitable when unreliability is present.
We conclude that filtering candidate protein complexes with GAFNB model can improve the effectiveness of protein complex identification. It is necessary to consider the unreliability in this task.
PMCID: PMC3908516  PMID: 24565338
21.  Coreference analysis in clinical notes: a multi-pass sieve with alternate anaphora resolution modules 
This paper describes the coreference resolution system submitted by Mayo Clinic for the 2011 i2b2/VA/Cincinnati shared task Track 1C. The goal of the task was to construct a system that links the markables corresponding to the same entity.
Materials and methods
The task organizers provided progress notes and discharge summaries that were annotated with the markables of treatment, problem, test, person, and pronoun. We used a multi-pass sieve algorithm that applies deterministic rules in the order of preciseness and simultaneously gathers information about the entities in the documents. Our system, MedCoref, also uses a state-of-the-art machine learning framework as an alternative to the final, rule-based pronoun resolution sieve.
The best system that uses a multi-pass sieve has an overall score of 0.836 (average of B3, MUC, Blanc, and CEAF F score) for the training set and 0.843 for the test set.
A supervised machine learning system that typically uses a single function to find coreferents cannot accommodate irregularities encountered in data especially given the insufficient number of examples. On the other hand, a completely deterministic system could lead to a decrease in recall (sensitivity) when the rules are not exhaustive. The sieve-based framework allows one to combine reliable machine learning components with rules designed by experts.
Using relatively simple rules, part-of-speech information, and semantic type properties, an effective coreference resolution system could be designed. The source code of the system described is available at
PMCID: PMC3422831  PMID: 22707745
Natural language processing; machine learning; information extraction; electronic medical record; coreference resolution; text mining; computational linguistics; named entity recognition; distributional semantics; relationship extraction; information storage and retrieval (text and images)
22.  CellMiner: a web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set 
Cancer Research  2012;72(14):3499-3511.
High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the US National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacological response platforms. In this report we introduce a CellMiner1 web application designed to improve use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,217 genes and 360 microRNAs along with activity reports for 18,549 chemical compounds including 91 drugs approved by the US Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross comparisons using a novel pattern-match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise.
PMCID: PMC3399763  PMID: 22802077
Systems Pharmacology; systems biology; omics; pharmacogenomics; biomarkers
23.  Using Empirically Constructed Lexical Resources for Named Entity Recognition 
Biomedical Informatics Insights  2013;6(Suppl 1):17-27.
Because of privacy concerns and the expense involved in creating an annotated corpus, the existing small-annotated corpora might not have sufficient examples for learning to statistically extract all the named-entities precisely. In this work, we evaluate what value may lie in automatically generated features based on distributional semantics when using machine-learning named entity recognition (NER). The features we generated and experimented with include n-nearest words, support vector machine (SVM)-regions, and term clustering, all of which are considered distributional semantic features. The addition of the n-nearest words feature resulted in a greater increase in F-score than by using a manually constructed lexicon to a baseline system. Although the need for relatively small-annotated corpora for retraining is not obviated, lexicons empirically derived from unannotated text can not only supplement manually created lexicons, but also replace them. This phenomenon is observed in extracting concepts from both biomedical literature and clinical notes.
PMCID: PMC3702195  PMID: 23847424
natural language processing; distributional semantics; concept extraction; named entity recognition; empirical lexical resources
24.  Analysis of Cross-Institutional Medication Description Patterns in Clinical Narratives 
Biomedical Informatics Insights  2013;6(Suppl 1):7-16.
A large amount of medication information resides in the unstructured text found in electronic medical records, which requires advanced techniques to be properly mined. In clinical notes, medication information follows certain semantic patterns (eg, medication, dosage, frequency, and mode). Some medication descriptions contain additional word(s) between medication attributes. Therefore, it is essential to understand the semantic patterns as well as the patterns of the context interspersed among them (ie, context patterns) to effectively extract comprehensive medication information. In this paper we examined both semantic and context patterns, and compared those found in Mayo Clinic and i2b2 challenge data. We found that some variations exist between the institutions but the dominant patterns are common.
PMCID: PMC3702197  PMID: 23847423
medication extraction; electronic medical record; natural language processing
25.  Formative evaluation of the accuracy of a clinical decision support system for cervical cancer screening 
We previously developed and reported on a prototype clinical decision support system (CDSS) for cervical cancer screening. However, the system is complex as it is based on multiple guidelines and free-text processing. Therefore, the system is susceptible to failures. This report describes a formative evaluation of the system, which is a necessary step to ensure deployment readiness of the system.
Materials and methods
Care providers who are potential end-users of the CDSS were invited to provide their recommendations for a random set of patients that represented diverse decision scenarios. The recommendations of the care providers and those generated by the CDSS were compared. Mismatched recommendations were reviewed by two independent experts.
A total of 25 users participated in this study and provided recommendations for 175 cases. The CDSS had an accuracy of 87% and 12 types of CDSS errors were identified, which were mainly due to deficiencies in the system's guideline rules. When the deficiencies were rectified, the CDSS generated optimal recommendations for all failure cases, except one with incomplete documentation.
Discussion and conclusions
The crowd-sourcing approach for construction of the reference set, coupled with the expert review of mismatched recommendations, facilitated an effective evaluation and enhancement of the system, by identifying decision scenarios that were missed by the system's developers. The described methodology will be useful for other researchers who seek rapidly to evaluate and enhance the deployment readiness of complex decision support systems.
PMCID: PMC3721177  PMID: 23564631
Uterine Cervical Neoplasms; Decision Support Systems, Clinical; Guideline Adherence; Validation Studies as Topic; Vaginal Smears; Crowdsourcing

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