PubMed-Scale Chemical Concept Embeddings Reconstruct Physical Protein Interaction Networks.
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ABSTRACT:
SUBMITTER: Skrlj B
PROVIDER: S-EPMC8076635 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The recently proposed concept of molecular connectivity maps enables researchers to integrate experimental measurements of genes, proteins, metabolites, and drug compounds under similar biological conditions. The study of these maps provides opportunities for future toxicogenomics and drug discovery applications. We developed a computational framework to build disease-specific drug-protein connectivity maps. We integrated gene/protein and drug connectivity information based on protein interaction networks and literature mining, without requiring gene expression profile information derived from drug perturbation experiments on disease samples. We described the development and application of this computational framework using Alzheimer's Disease (AD) as a primary example in three steps. First, molecular interaction networks were incorporated to reduce bias and improve relevance of AD seed proteins. Second, PubMed abstracts were used to retrieve enriched drug terms that are indirectly associated with AD through molecular mechanistic studies. Third and lastly, a comprehensive AD connectivity map was created by relating enriched drugs and related proteins in literature. We showed that this molecular connectivity map development approach outperformed both curated drug target databases and conventional information retrieval systems. Our initial explorations of the AD connectivity map yielded a new hypothesis that diltiazem and quinidine may be investigated as candidate drugs for AD treatment. Molecular connectivity maps derived computationally can help study molecular signature differences between different classes of drugs in specific disease contexts. To achieve overall good data coverage and quality, a series of statistical methods have been developed to overcome high levels of data noise in biological networks and literature mining results. Further development of computational molecular connectivity maps to cover major disease areas will likely set up a new model for drug development, in which therapeutic/toxicological profiles of candidate drugs can be checked computationally before costly clinical trials begin.
| S-EPMC2709445 | biostudies-literature
Project description:A massive number of biological entities, such as genes and mutations, are mentioned in the biomedical literature. The capturing of the semantic relatedness of biological entities is vital to many biological applications, such as protein-protein interaction prediction and literature-based discovery. Concept embeddings-which involve the learning of vector representations of concepts using machine learning models-have been employed to capture the semantics of concepts. To develop concept embeddings, named-entity recognition (NER) tools are first used to identify and normalize concepts from the literature, and then different machine learning models are used to train the embeddings. Despite multiple attempts, existing biomedical concept embeddings generally suffer from suboptimal NER tools, small-scale evaluation, and limited availability. In response, we employed high-performance machine learning-based NER tools for concept recognition and trained our concept embeddings, BioConceptVec, via four different machine learning models on ~30 million PubMed abstracts. BioConceptVec covers over 400,000 biomedical concepts mentioned in the literature and is of the largest among the publicly available biomedical concept embeddings to date. To evaluate the validity and utility of BioConceptVec, we respectively performed two intrinsic evaluations (identifying related concepts based on drug-gene and gene-gene interactions) and two extrinsic evaluations (protein-protein interaction prediction and drug-drug interaction extraction), collectively using over 25 million instances from nine independent datasets (17 million instances from six intrinsic evaluation tasks and 8 million instances from three extrinsic evaluation tasks), which is, by far, the most comprehensive to our best knowledge. The intrinsic evaluation results demonstrate that BioConceptVec consistently has, by a large margin, better performance than existing concept embeddings in identifying similar and related concepts. More importantly, the extrinsic evaluation results demonstrate that using BioConceptVec with advanced deep learning models can significantly improve performance in downstream bioinformatics studies and biomedical text-mining applications. Our BioConceptVec embeddings and benchmarking datasets are publicly available at https://github.com/ncbi-nlp/BioConceptVec.
| S-EPMC7237030 | biostudies-literature
Project description:Inhibiting protein kinases (PKs) that cause cancers has been an important topic in cancer therapy for years. So far, almost 8% of >530 PKs have been targeted by FDA-approved medications, and around 150 protein kinase inhibitors (PKIs) have been tested in clinical trials. We present an approach based on natural language processing and machine learning to investigate the relations between PKs and cancers, predicting PKs whose inhibition would be efficacious to treat a certain cancer. Our approach represents PKs and cancers as semantically meaningful 100-dimensional vectors based on word and concept neighborhoods in PubMed abstracts. We use information about phase I-IV trials in ClinicalTrials.gov to construct a training set for random forest classification. Our results with historical data show that associations between PKs and specific cancers can be predicted years in advance with good accuracy. Our tool can be used to predict the relevance of inhibiting PKs for specific cancers and to support the design of well-focused clinical trials to discover novel PKIs for cancer therapy.
| S-EPMC8652379 | biostudies-literature
Project description:It has recently been demonstrated that many biological networks exhibit a "scale-free" topology, for which the probability of observing a node with a certain number of edges (k) follows a power law: i.e., p(k) approximately k(-gamma). This observation has been reproduced by evolutionary models. Here we consider the network of protein-protein interactions (PPIs) and demonstrate that two published independent measurements of these interactions produce graphs that are only weakly correlated with one another despite their strikingly similar topology. We then propose a physical model based on the fundamental principle that (de)solvation is a major physical factor in PPIs. This model reproduces not only the scale-free nature of such graphs but also a number of higher-order correlations in these networks. A key support of the model is provided by the discovery of a significant correlation between the number of interactions made by a protein and the fraction of hydrophobic residues on its surface. The model presented in this paper represents a physical model for experimentally determined PPIs that comprehensively reproduces the topological features of interaction networks. These results have profound implications for understanding not only PPIs but also other types of scale-free networks.
| S-EPMC1326177 | biostudies-literature
Project description:Interpreting data from large-scale protein interaction experiments has been a challenging task because of the widespread presence of random false positives. Here, we present a network-based statistical algorithm that overcomes this difficulty and allows us to derive functions of unannotated proteins from large-scale interaction data. Our algorithm uses the insight that if two proteins share significantly larger number of common interaction partners than random, they have close functional associations. Analysis of publicly available data from Saccharomyces cerevisiae reveals >2,800 reliable functional associations, 29% of which involve at least one unannotated protein. By further analyzing these associations, we derive tentative functions for 81 unannotated proteins with high certainty. Our method is not overly sensitive to the false positives present in the data. Even after adding 50% randomly generated interactions to the measured data set, we are able to recover almost all (approximately 89%) of the original associations.
| S-EPMC240660 | biostudies-literature
Project description:OBJECTIVE:Neural network-based representations ("embeddings") have dramatically advanced natural language processing (NLP) tasks, including clinical NLP tasks such as concept extraction. Recently, however, more advanced embedding methods and representations (eg, ELMo, BERT) have further pushed the state of the art in NLP, yet there are no common best practices for how to integrate these representations into clinical tasks. The purpose of this study, then, is to explore the space of possible options in utilizing these new models for clinical concept extraction, including comparing these to traditional word embedding methods (word2vec, GloVe, fastText). MATERIALS AND METHODS:Both off-the-shelf, open-domain embeddings and pretrained clinical embeddings from MIMIC-III (Medical Information Mart for Intensive Care III) are evaluated. We explore a battery of embedding methods consisting of traditional word embeddings and contextual embeddings and compare these on 4 concept extraction corpora: i2b2 2010, i2b2 2012, SemEval 2014, and SemEval 2015. We also analyze the impact of the pretraining time of a large language model like ELMo or BERT on the extraction performance. Last, we present an intuitive way to understand the semantic information encoded by contextual embeddings. RESULTS:Contextual embeddings pretrained on a large clinical corpus achieves new state-of-the-art performances across all concept extraction tasks. The best-performing model outperforms all state-of-the-art methods with respective F1-measures of 90.25, 93.18 (partial), 80.74, and 81.65. CONCLUSIONS:We demonstrate the potential of contextual embeddings through the state-of-the-art performance these methods achieve on clinical concept extraction. Additionally, we demonstrate that contextual embeddings encode valuable semantic information not accounted for in traditional word representations.
| S-EPMC6798561 | biostudies-literature
Project description:BackgroundProtein-protein interaction (PPI) prediction is an important task towards the understanding of many bioinformatics functions and applications, such as predicting protein functions, gene-disease associations and disease-drug associations. However, many previous PPI prediction researches do not consider missing and spurious interactions inherent in PPI networks. To address these two issues, we define two corresponding tasks, namely missing PPI prediction and spurious PPI prediction, and propose a method that employs graph embeddings that learn vector representations from constructed Gene Ontology Annotation (GOA) graphs and then use embedded vectors to achieve the two tasks. Our method leverages on information from both term-term relations among GO terms and term-protein annotations between GO terms and proteins, and preserves properties of both local and global structural information of the GO annotation graph.ResultsWe compare our method with those methods that are based on information content (IC) and one method that is based on word embeddings, with experiments on three PPI datasets from STRING database. Experimental results demonstrate that our method is more effective than those compared methods.ConclusionOur experimental results demonstrate the effectiveness of using graph embeddings to learn vector representations from undirected GOA graphs for our defined missing and spurious PPI tasks.
| S-EPMC7739483 | biostudies-literature
Project description:MotivationFinding protein-protein interaction (PPI) information from literature is challenging but an important issue. However, keyword search in PubMed(®) is often time consuming because it requires a series of actions that refine keywords and browse search results until it reaches a goal. Due to the rapid growth of biomedical literature, it has become more difficult for biologists and curators to locate PPI information quickly. Therefore, a tool for prioritizing PPI informative articles can be a useful assistant for finding this PPI-relevant information.ResultsPIE (Protein Interaction information Extraction) the search is a web service implementing a competition-winning approach utilizing word and syntactic analyses by machine learning techniques. For easy user access, PIE the search provides a PubMed-like search environment, but the output is the list of articles prioritized by PPI confidence scores. By obtaining PPI-related articles at high rank, researchers can more easily find the up-to-date PPI information, which cannot be found in manually curated PPI databases.Availabilityhttp://www.ncbi.nlm.nih.gov/IRET/PIE/.
| S-EPMC3278758 | biostudies-literature
Project description:The PubMed database offers an extensive set of publication data that can be useful, yet inherently complex to use without automated computational techniques. Data repositories such as the Genomic Data Commons (GDC) and the Gene Expression Omnibus (GEO) offer experimental data storage and retrieval as well as curated gene expression profiles. Genetic interaction databases, including Reactome and Ingenuity Pathway Analysis, offer pathway and experiment data analysis using data curated from these publications and data repositories. We have created a method to generate and analyze consensus networks, inferring potential gene interactions, using large numbers of Bayesian networks generated by data mining publications in the PubMed database. Through the concept of network resolution, these consensus networks can be tailored to represent possible genetic interactions. We designed a set of experiments to confirm that our method is stable across variation in both sample and topological input sizes. Using gene product interactions from the KEGG pathway database and data mining PubMed publication abstracts, we verify that regardless of the network resolution or the inferred consensus network, our method is capable of inferring meaningful gene interactions through consensus Bayesian network generation with multiple, randomized topological orderings. Our method can not only confirm the existence of currently accepted interactions, but has the potential to hypothesize new ones as well. We show our method confirms the existence of known gene interactions such as JAK-STAT-PI3K-AKT-mTOR, infers novel gene interactions such as RAS- Bcl-2 and RAS-AKT, and found significant pathway-pathway interactions between the JAK-STAT signaling and Cardiac Muscle Contraction KEGG pathways.
| S-EPMC5648141 | biostudies-literature
Project description:BackgroundPhylogenetic networks are employed to visualize evolutionary relationships among a group of nucleotide sequences, genes or species when reticulate events like hybridization, recombination, reassortant and horizontal gene transfer are believed to be involved. In comparison to traditional distance-based methods, quartet-based methods consider more information in the reconstruction process and thus have the potential to be more accurate.ResultsWe introduce QuartetSuite, which includes a set of new quartet-based methods, namely QuartetS, QuartetA, and QuartetM, to reconstruct phylogenetic networks from nucleotide sequences. We tested their performances and compared them with other popular methods on two simulated nucleotide sequence data sets: one generated from a tree topology and the other from a complicated evolutionary history containing three reticulate events. We further validated these methods to two real data sets: a bacterial data set consisting of seven concatenated genes of 36 bacterial species and an influenza data set related to recently emerging H7N9 low pathogenic avian influenza viruses in China.ConclusionQuartetS, QuartetA, and QuartetM have the potential to accurately reconstruct evolutionary scenarios from simple branching trees to complicated networks containing many reticulate events. These methods could provide insights into the understanding of complicated biological evolutionary processes such as bacterial taxonomy and reassortant of influenza viruses.
| S-EPMC3941989 | biostudies-literature