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Objective To analyze the impact, performance, degree of specialization, and collaboration patterns of the worldwide scientific production on tissue engineering in otorhinolaryngology at the level of countries and institutions. Methods Two different techniques were used, performance and science mapping analyses, using as samples all the available documents regarding tissue engineering focused on otorhinolaryngology applications. The dataset was retrieved from the Core Collection of the Web of Science database from 1900 to 2020. Social structure was analyzed using science mapping analysis with VOSviewer software. Results The United States was the main producer, followed by Germany, and Japan. Malaysia and Germany had the highest Relative Specialization Index, indicating their greater relative interest in this area compared to other countries. The social structure analysis showed that the United States and Germany had significant co‐authorship relationships with other countries. The University of California System, Kyoto University, and Harvard University were the leading institutions producing literature in this field. These latter two institutions showed the largest number of collaborations, although most of them were with institutions within their own country. There was a lack of connections between different communities of research. Conclusion The United States is the main country driving progress in this research area, housing the most notable institutions. However, significant collaborations between these research centers are currently lacking. Encouraging greater cooperation among these institutions and their researchers would promote the exchange of knowledge, ultimately facilitating and accelerating advancements in this field. Bibliometric analysis of tissue engineering production in otorhinolaryngology to identify global trends, impact, and social structure among the different research centers.

Background Support vector machines (SVM) are a powerful tool to analyze data with a number of predictors approximately equal or larger than the number of observations. However, originally, application of SVM to analyze biomedical data was limited because SVM was not designed to evaluate importance of predictor variables. Creating predictor models based on only the most relevant variables is essential in biomedical research. Currently, substantial work has been done to allow assessment of variable importance in SVM models but this work has focused on SVM implemented with linear kernels. The power of SVM as a prediction model is associated with the flexibility generated by use of non-linear kernels. Moreover, SVM has been extended to model survival outcomes. This paper extends the Recursive Feature Elimination (RFE) algorithm by proposing three approaches to rank variables based on non-linear SVM and SVM for survival analysis. Results The proposed algorithms allows visualization of each one the RFE iterations, and hence, identification of the most relevant predictors of the response variable. Using simulation studies based on time-to-event outcomes and three real datasets, we evaluate the three methods, based on pseudo-samples and kernel principal component analysis, and compare them with the original SVM-RFE algorithm for non-linear kernels. The three algorithms we proposed performed generally better than the gold standard RFE for non-linear kernels, when comparing the truly most relevant variables with the variable ranks produced by each algorithm in simulation studies. Generally, the RFE-pseudo-samples outperformed the other three methods, even when variables were assumed to be correlated in all tested scenarios. Conclusions The proposed approaches can be implemented with accuracy to select variables and assess direction and strength of associations in analysis of biomedical data using SVM for categorical or time-to-event responses. Conducting variable selection and interpreting direction and strength of associations between predictors and outcomes with the proposed approaches, particularly with the RFE-pseudo-samples approach can be implemented with accuracy when analyzing biomedical data. These approaches, perform better than the classical RFE of Guyon for realistic scenarios about the structure of biomedical data.

Background System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes/proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries. While many enrichment analysis tools and gene-set libraries databases have been developed, there is still room for improvement. Results Here, we present Enrichr, an integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. We applied Enrichr to analyze nine cancer cell lines by comparing their enrichment signatures to the enrichment signatures of matched normal tissues. We observed a common pattern of up regulation of the polycomb group PRC2 and enrichment for the histone mark H3K27me3 in many cancer cell lines, as well as alterations in Toll-like receptor and interlukin signaling in K562 cells when compared with normal myeloid CD33+ cells. Such analyses provide global visualization of critical differences between normal tissues and cancer cell lines but can be applied to many other scenarios. Conclusions Enrichr is an easy to use intuitive enrichment analysis web-based tool providing various types of visualization summaries of collective functions of gene lists. Enrichr is open source and freely available online at: http://amp.pharm.mssm.edu/Enrichr .

Background This article provides an overview of the first BioASQ challenge, a competition on large-scale biomedical semantic indexing and question answering ( QA ), which took place between March and September 2013. BioASQ assesses the ability of systems to semantically index very large numbers of biomedical scientific articles, and to return concise and user-understandable answers to given natural language questions by combining information from biomedical articles and ontologies. Results The 2013 BioASQ competition comprised two tasks, Task 1a and Task 1b. In Task 1a participants were asked to automatically annotate new PubMed documents with MeSH headings. Twelve teams participated in Task 1a, with a total of 46 system runs submitted, and one of the teams performing consistently better than the MTI indexer used by NLM to suggest MeSH headings to curators. Task 1b used benchmark datasets containing 29 development and 282 test English questions, along with gold standard (reference) answers, prepared by a team of biomedical experts from around Europe and participants had to automatically produce answers. Three teams participated in Task 1b, with 11 system runs. The BioASQ infrastructure, including benchmark datasets, evaluation mechanisms, and the results of the participants and baseline methods, is publicly available. Conclusions A publicly available evaluation infrastructure for biomedical semantic indexing and QA has been developed, which includes benchmark datasets, and can be used to evaluate systems that: assign MeSH headings to published articles or to English questions; retrieve relevant RDF triples from ontologies, relevant articles and snippets from PubMed Central; produce “exact” and paragraph-sized “ideal” answers (summaries). The results of the systems that participated in the 2013 BioASQ competition are promising. In Task 1a one of the systems performed consistently better from the NLM ’s MTI indexer. In Task 1b the systems received high scores in the manual evaluation of the “ideal” answers; hence, they produced high quality summaries as answers. Overall, BioASQ helped obtain a unified view of how techniques from text classification, semantic indexing, document and passage retrieval, question answering, and text summarization can be combined to allow biomedical experts to obtain concise, user-understandable answers to questions reflecting their real information needs.

Background Named Entity Recognition (NER) is a key task in biomedical text mining. Accurate NER systems require task-specific, manually-annotated datasets, which are expensive to develop and thus limited in size. Since such datasets contain related but different information, an interesting question is whether it might be possible to use them together to improve NER performance. To investigate this, we develop supervised, multi-task, convolutional neural network models and apply them to a large number of varied existing biomedical named entity datasets. Additionally, we investigated the effect of dataset size on performance in both single- and multi-task settings. Results We present a single-task model for NER, a Multi-output multi-task model and a Dependent multi-task model. We apply the three models to 15 biomedical datasets containing multiple named entities including Anatomy, Chemical, Disease, Gene/Protein and Species. Each dataset represent a task. The results from the single-task model and the multi-task models are then compared for evidence of benefits from Multi-task Learning. With the Multi-output multi-task model we observed an average F-score improvement of 0.8% when compared to the single-task model from an average baseline of 78.4%. Although there was a significant drop in performance on one dataset, performance improves significantly for five datasets by up to 6.3%. For the Dependent multi-task model we observed an average improvement of 0.4% when compared to the single-task model. There were no significant drops in performance on any dataset, and performance improves significantly for six datasets by up to 1.1%. The dataset size experiments found that as dataset size decreased, the multi-output model’s performance increased compared to the single-task model’s. Using 50, 25 and 10% of the training data resulted in an average drop of approximately 3.4, 8 and 16.7% respectively for the single-task model but approximately 0.2, 3.0 and 9.8% for the multi-task model. Conclusions Our results show that, on average, the multi-task models produced better NER results than the single-task models trained on a single NER dataset. We also found that Multi-task Learning is beneficial for small datasets. Across the various settings the improvements are significant, demonstrating the benefit of Multi-task Learning for this task.

Background In the era of information overload, natural language processing (NLP) techniques are increasingly needed to support advanced biomedical information management and discovery applications. In this paper, we present an in-depth description of SemRep, an NLP system that extracts semantic relations from PubMed abstracts using linguistic principles and UMLS domain knowledge. We also evaluate SemRep on two datasets. In one evaluation, we use a manually annotated test collection and perform a comprehensive error analysis. In another evaluation, we assess SemRep’s performance on the CDR dataset, a standard benchmark corpus annotated with causal chemical-disease relationships. Results A strict evaluation of SemRep on our manually annotated dataset yields 0.55 precision, 0.34 recall, and 0.42 F 1 score. A relaxed evaluation, which more accurately characterizes SemRep performance, yields 0.69 precision, 0.42 recall, and 0.52 F 1 score. An error analysis reveals named entity recognition/normalization as the largest source of errors (26.9%), followed by argument identification (14%) and trigger detection errors (12.5%). The evaluation on the CDR corpus yields 0.90 precision, 0.24 recall, and 0.38 F 1 score. The recall and the F 1 score increase to 0.35 and 0.50, respectively, when the evaluation on this corpus is limited to sentence-bound relationships, which represents a fairer evaluation, as SemRep operates at the sentence level. Conclusions SemRep is a broad-coverage, interpretable, strong baseline system for extracting semantic relations from biomedical text. It also underpins SemMedDB, a literature-scale knowledge graph based on semantic relations. Through SemMedDB, SemRep has had significant impact in the scientific community, supporting a variety of clinical and translational applications, including clinical decision making, medical diagnosis, drug repurposing, literature-based discovery and hypothesis generation, and contributing to improved health outcomes. In ongoing development, we are redesigning SemRep to increase its modularity and flexibility, and addressing weaknesses identified in the error analysis.

Background Current approaches to identifying drug-drug interactions (DDIs), include safety studies during drug development and post-marketing surveillance after approval, offer important opportunities to identify potential safety issues, but are unable to provide complete set of all possible DDIs. Thus, the drug discovery researchers and healthcare professionals might not be fully aware of potentially dangerous DDIs. Predicting potential drug-drug interaction helps reduce unanticipated drug interactions and drug development costs and optimizes the drug design process. Methods for prediction of DDIs have the tendency to report high accuracy but still have little impact on translational research due to systematic biases induced by networked/paired data. In this work, we aimed to present realistic evaluation settings to predict DDIs using knowledge graph embeddings. We propose a simple disjoint cross-validation scheme to evaluate drug-drug interaction predictions for the scenarios where the drugs have no known DDIs. Results We designed different evaluation settings to accurately assess the performance for predicting DDIs. The settings for disjoint cross-validation produced lower performance scores, as expected, but still were good at predicting the drug interactions. We have applied Logistic Regression, Naive Bayes and Random Forest on DrugBank knowledge graph with the 10-fold traditional cross validation using RDF2Vec, TransE and TransD. RDF2Vec with Skip-Gram generally surpasses other embedding methods. We also tested RDF2Vec on various drug knowledge graphs such as DrugBank, PharmGKB and KEGG to predict unknown drug-drug interactions. The performance was not enhanced significantly when an integrated knowledge graph including these three datasets was used. Conclusion We showed that the knowledge embeddings are powerful predictors and comparable to current state-of-the-art methods for inferring new DDIs. We addressed the evaluation biases by introducing drug-wise and pairwise disjoint test classes. Although the performance scores for drug-wise and pairwise disjoint seem to be low, the results can be considered to be realistic in predicting the interactions for drugs with limited interaction information.

Background Pathway enrichment techniques are useful for understanding experimental metabolomics data. Their purpose is to give context to the affected metabolites in terms of the prior knowledge contained in metabolic pathways. However, the interpretation of a prioritized pathway list is still challenging, as pathways show overlap and cross talk effects. Results We introduce FELLA, an R package to perform a network-based enrichment of a list of affected metabolites. FELLA builds a hierarchical representation of an organism biochemistry from the Kyoto Encyclopedia of Genes and Genomes (KEGG), containing pathways, modules, enzymes, reactions and metabolites. In addition to providing a list of pathways, FELLA reports intermediate entities (modules, enzymes, reactions) that link the input metabolites to them. This sheds light on pathway cross talk and potential enzymes or metabolites as targets for the condition under study. FELLA has been applied to six public datasets –three from Homo sapiens , two from Danio rerio and one from Mus musculus – and has reproduced findings from the original studies and from independent literature. Conclusions The R package FELLA offers an innovative enrichment concept starting from a list of metabolites, based on a knowledge graph representation of the KEGG database that focuses on interpretability. Besides reporting a list of pathways, FELLA suggests intermediate entities that are of interest per se. Its usefulness has been shown at several molecular levels on six public datasets, including human and animal models. The user can run the enrichment analysis through a simple interactive graphical interface or programmatically. FELLA is publicly available in Bioconductor under the GPL-3 license.

Background Predicting drug side effects is an important topic in the drug discovery. Although several machine learning methods have been proposed to predict side effects, there is still space for improvements. Firstly, the side effect prediction is a multi-label learning task, and we can adopt the multi-label learning techniques for it. Secondly, drug-related features are associated with side effects, and feature dimensions have specific biological meanings. Recognizing critical dimensions and reducing irrelevant dimensions may help to reveal the causes of side effects. Methods In this paper, we propose a novel method ‘feature selection-based multi-label k-nearest neighbor method’ (FS-MLKNN), which can simultaneously determine critical feature dimensions and construct high-accuracy multi-label prediction models. Results Computational experiments demonstrate that FS-MLKNN leads to good performances as well as explainable results. To achieve better performances, we further develop the ensemble learning model by integrating individual feature-based FS-MLKNN models. When compared with other state-of-the-art methods, the ensemble method produces better performances on benchmark datasets. Conclusions In conclusion, FS-MLKNN and the ensemble method are promising tools for the side effect prediction. The source code and datasets are available in the Additional file 1 .

Background Current biomedical research needs to leverage and exploit the large amount of information reported in scientific publications. Automated text mining approaches, in particular those aimed at finding relationships between entities, are key for identification of actionable knowledge from free text repositories. We present the BeFree system aimed at identifying relationships between biomedical entities with a special focus on genes and their associated diseases. Results By exploiting morpho-syntactic information of the text, BeFree is able to identify gene-disease, drug-disease and drug-target associations with state-of-the-art performance. The application of BeFree to real-case scenarios shows its effectiveness in extracting information relevant for translational research. We show the value of the gene-disease associations extracted by BeFree through a number of analyses and integration with other data sources. BeFree succeeds in identifying genes associated to a major cause of morbidity worldwide, depression, which are not present in other public resources. Moreover, large-scale extraction and analysis of gene-disease associations, and integration with current biomedical knowledge, provided interesting insights on the kind of information that can be found in the literature, and raised challenges regarding data prioritization and curation. We found that only a small proportion of the gene-disease associations discovered by using BeFree is collected in expert-curated databases. Thus, there is a pressing need to find alternative strategies to manual curation, in order to review, prioritize and curate text-mining data and incorporate it into domain-specific databases. We present our strategy for data prioritization and discuss its implications for supporting biomedical research and applications. Conclusions BeFree is a novel text mining system that performs competitively for the identification of gene-disease, drug-disease and drug-target associations. Our analyses show that mining only a small fraction of MEDLINE results in a large dataset of gene-disease associations, and only a small proportion of this dataset is actually recorded in curated resources (2%), raising several issues on data prioritization and curation. We propose that joint analysis of text mined data with data curated by experts appears as a suitable approach to both assess data quality and highlight novel and interesting information.