Identifying patterns to uncover the importance of biological pathways on known drug repurposing scenarios.

BACKGROUND: Drug repurposing plays a significant role in providing effective treatments for certain diseases faster and more cost-effectively. Successful repurposing cases are mostly supported by a classical paradigm that stems from de novo drug development. This paradigm is based on the "one-drug-one-target-one-disease" idea. It consists of designing drugs specifically for a single disease and its drug's gene target. In this article, we investigated the use of biological pathways as potential elements to achieve effective drug repurposing. METHODS: Considering a total of 4214 successful cases of drug repurposing, we identified cases in which biological pathways serve as the underlying basis for successful repurposing, referred to as DREBIOP. Once the repurposing cases based on pathways were identified, we studied their inherent patterns by considering the different biological elements associated with this dataset, as well as the pathways involved in these cases. Furthermore, we obtained gene-disease association values to demonstrate the diminished significance of the drug's gene target in these repurposing cases. To achieve this, we compared the values obtained for the DREBIOP set with the overall association values found in DISNET, as well as with the drug's target gene (DREGE) based repurposing cases using the Mann-Whitney U Test. RESULTS: A collection of drug repurposing cases, known as DREBIOP, was identified as a result. DREBIOP cases exhibit distinct characteristics compared with DREGE cases. Notably, DREBIOP cases are associated with a higher number of biological pathways, with Vitamin D Metabolism and ACE inhibitors being the most prominent pathways. Additionally, it was observed that the association values of GDAs in DREBIOP cases were significantly lower than those in DREGE cases (p-value < 0.05). CONCLUSIONS: Biological pathways assume a pivotal role in drug repurposing cases. This investigation successfully revealed patterns that distinguish drug repurposing instances associated with biological pathways. These identified patterns can be applied to any known repurposing case, enabling the detection of pathway-based repurposing scenarios or the classical paradigm.

Protein sequence analysis in the context of drug repurposing.

MOTIVATION: Drug repurposing speeds up the development of new treatments, being less costly, risky, and time consuming than de novo drug discovery. There are numerous biological elements that contribute to the development of diseases and, as a result, to the repurposing of drugs. METHODS: In this article, we analysed the potential role of protein sequences in drug repurposing scenarios. For this purpose, we embedded the protein sequences by performing four state of the art methods and validated their capacity to encapsulate essential biological information through visualization. Then, we compared the differences in sequence distance between protein-drug target pairs of drug repurposing and non - drug repurposing data. Thus, we were able to uncover patterns that define protein sequences in repurposing cases. RESULTS: We found statistically significant sequence distance differences between protein pairs in the repurposing data and the rest of protein pairs in non-repurposing data. In this manner, we verified the potential of using numerical representations of sequences to generate repurposing hypotheses in the future.

Role of potassium transporter KUP8 in plant responses to heavy metals.

Heavy metal concentrations, which have been increasing over the last 200 years, affect soil quality and crop yields. These elements are difficult to eliminate from soils and may constitute a human health hazard by entering the food chain. Recently, we obtained a selection of mutants with different degrees of tolerance to a mixture of heavy metals (HMmix) in order to gain a deeper insight into the underlying mechanism regulating plant responses to these elements. In this study, we characterized the mutant obtained Atkup8 (in this work, Atkup8-2), which showed one of the most resistant phenotypes, as determined by seedling root length. Atkup8-2 is affected in the potassium transporter KUP8, a member of the high-affinity K+ uptake family KUP/HAK/KT. Atkup8-2 mutants, which are less affected as measured by seedling root length under HMmix conditions, showed a resistant phenotype with respect to WT seedlings which, despite their delayed growth, are able to develop true leaves at levels similar to those under control conditions. Adult Atkup8-2 plants had a higher fresh weight than WT plants, a resistant phenotype under HMmix stress conditions and lower levels of oxidative damage. KUP8 did not appear to be involved in heavy metal or macro- and micro-nutrient uptake and translocation from roots to leaves, as total concentrations of these elements were similar in both Atkup8-2 and WT plants. However, alterations in cellular K+ homeostasis in this mutant cannot be ruled out.

Disease networks and their contribution to disease understanding: A review of their evolution, techniques and data sources.

Over a decade ago, a new discipline called network medicine emerged as an approach to understand human diseases from a network theory point-of-view. Disease networks proved to be an intuitive and powerful way to reveal hidden connections among apparently unconnected biomedical entities such as diseases, physiological processes, signaling pathways, and genes. One of the fields that has benefited most from this improvement is the identification of new opportunities for the use of old drugs, known as drug repurposing. The importance of drug repurposing lies in the high costs and the prolonged time from target selection to regulatory approval of traditional drug development. In this document we analyze the evolution of disease network concept during the last decade and apply a data science pipeline approach to evaluate their functional units. As a result of this analysis, we obtain a list of the most commonly used functional units and the challenges that remain to be solved. This information can be very valuable for the generation of new prediction models based on disease networks.

Profiling Lung Cancer Patients Using Electronic Health Records.

If Electronic Health Records contain a large amount of information about the patient's condition and response to treatment, which can potentially revolutionize the clinical practice, such information is seldom considered due to the complexity of its extraction and analysis. We here report on a first integration of an NLP framework for the analysis of clinical records of lung cancer patients making use of a telephone assistance service of a major Spanish hospital. We specifically show how some relevant data, about patient demographics and health condition, can be extracted; and how some relevant analyses can be performed, aimed at improving the usefulness of the service. We thus demonstrate that the use of EHR texts, and their integration inside a data analysis framework, is technically feasible and worth of further study.

Assessing Time Series Reversibility through Permutation Patterns.

Time irreversibility, i.e., the lack of invariance of the statistical properties of a system under time reversal, is a fundamental property of all systems operating out of equilibrium. Time reversal symmetry is associated with important statistical and physical properties and is related to the predictability of the system generating the time series. Over the past fifteen years, various methods to quantify time irreversibility in time series have been proposed, but these can be computationally expensive. Here, we propose a new method, based on permutation entropy, which is essentially parameter-free, temporally local, yields straightforward statistical tests, and has fast convergence properties. We apply this method to the study of financial time series, showing that stocks and indices present a rich irreversibility dynamics. We illustrate the comparative methodological advantages of our method with respect to a recently proposed method based on visibility graphs, and discuss the implications of our results for financial data analysis and interpretation.

Using data crawlers and semantic Web to build financial XBRL data generators: the SONAR extension approach.

Precise, reliable and real-time financial information is critical for added-value financial services after the economic turmoil from which markets are still struggling to recover. Since the Web has become the most significant data source, intelligent crawlers based on Semantic Technologies have become trailblazers in the search of knowledge combining natural language processing and ontology engineering techniques. In this paper, we present the SONAR extension approach, which will leverage the potential of knowledge representation by extracting, managing, and turning scarce and disperse financial information into well-classified, structured, and widely used XBRL format-oriented knowledge, strongly supported by a proof-of-concept implementation and a thorough evaluation of the benefits of the approach.

Unlocking the power of AI models: exploring protein folding prediction through comparative analysis.

Protein structure determination has made progress with the aid of deep learning models, enabling the prediction of protein folding from protein sequences. However, obtaining accurate predictions becomes essential in certain cases where the protein structure remains undescribed. This is particularly challenging when dealing with rare, diverse structures and complex sample preparation. Different metrics assess prediction reliability and offer insights into result strength, providing a comprehensive understanding of protein structure by combining different models. In a previous study, two proteins named ARM58 and ARM56 were investigated. These proteins contain four domains of unknown function and are present in Leishmania spp. ARM refers to an antimony resistance marker. The study's main objective is to assess the accuracy of the model's predictions, thereby providing insights into the complexities and supporting metrics underlying these findings. The analysis also extends to the comparison of predictions obtained from other species and organisms. Notably, one of these proteins shares an ortholog with Trypanosoma cruzi and Trypanosoma brucei, leading further significance to our analysis. This attempt underscored the importance of evaluating the diverse outputs from deep learning models, facilitating comparisons across different organisms and proteins. This becomes particularly pertinent in cases where no previous structural information is available.

From Web to RheumaLpack: Creating a Linguistic Corpus for Exploitation and Knowledge Discovery in Rheumatology.

This study introduces RheumaLinguisticpack (RheumaLpack), the first specialised linguistic web corpus designed for the field of musculoskeletal disorders. By combining web mining (i.e., web scraping) and natural language processing (NLP) techniques, as well as clinical expertise, RheumaLpack systematically captures and curates structured and unstructured data across a spectrum of web sources including clinical trials registers (i.e., ClinicalTrials.gov), bibliographic databases (i.e., PubMed), medical agencies (i.e. European Medicines Agency), social media (i.e., Reddit), and accredited health websites (i.e., MedlinePlus, Harvard Health Publishing, and Cleveland Clinic). Given the complexity of rheumatic and musculoskeletal diseases (RMDs) and their significant impact on quality of life, this resource can be proposed as a useful tool to train algorithms that could mitigate the diseases' effects. Therefore, the corpus aims to improve the training of artificial intelligence (AI) algorithms and facilitate knowledge discovery in RMDs. The development of RheumaLpack involved a systematic six-step methodology covering data identification, characterisation, selection, collection, processing, and corpus description. The result is a non-annotated, monolingual, and dynamic corpus, featuring almost 3 million records spanning from 2000 to 2023. RheumaLpack represents a pioneering contribution to rheumatology research, providing a useful resource for the development of advanced AI and NLP applications. This corpus highlights the value of web data to address the challenges posed by musculoskeletal diseases, illustrating the corpus's potential to improve research and treatment paradigms in rheumatology. Finally, the methodology shown can be replicated to obtain data from other medical specialities. The code and details on how to build RheumaLpack are also provided to facilitate the dissemination of such resource.

Analyzing Dropout in Alcohol Recovery Programs: A Machine Learning Approach.

Background: Retention in treatment is crucial for the success of interventions targeting alcohol use disorder (AUD), which affects over 100 million people globally. Most previous studies have used classical statistical techniques to predict treatment dropout, and their results remain inconclusive. This study aimed to use novel machine learning tools to identify models that predict dropout with greater precision, enabling the development of better retention strategies for those at higher risk. Methods: A retrospective observational study of 39,030 (17.3% female) participants enrolled in outpatient-based treatment for alcohol use disorder in a state-wide public treatment network has been used. Participants were recruited between 1 January 2015 and 31 December 2019. We applied different machine learning algorithms to create models that allow one to predict the premature cessation of treatment (dropout). With the objective of increasing the explainability of those models with the best precision, considered as black-box models, explainability technique analyses were also applied. Results: Considering as the best models those obtained with one of the so-called black-box models (support vector classifier (SVC)), the results from the best model, from the explainability perspective, showed that the variables that showed greater explanatory capacity for treatment dropout are previous drug use as well as psychiatric comorbidity. Among these variables, those of having undergone previous opioid substitution treatment and receiving coordinated psychiatric care in mental health services showed the greatest capacity for predicting dropout. Conclusions: By using novel machine learning techniques on a large representative sample of patients enrolled in alcohol use disorder treatment, we have identified several machine learning models that help in predicting a higher risk of treatment dropout. Previous treatment for other substance use disorders (SUDs) and concurrent psychiatric comorbidity were the best predictors of dropout, and patients showing these characteristics may need more intensive or complementary interventions to benefit from treatment.

Uncovering hidden therapeutic indications through drug repurposing with graph neural networks and heterogeneous data.

Drug repurposing has gained the attention of many in the recent years. The practice of repurposing existing drugs for new therapeutic uses helps to simplify the drug discovery process, which in turn reduces the costs and risks that are associated with de novo development. Representing biomedical data in the form of a graph is a simple and effective method to depict the underlying structure of the information. Using deep neural networks in combination with this data represents a promising approach to address drug repurposing. This paper presents BEHOR a more comprehensive version of the REDIRECTION model, which was previously presented. Both versions utilize the DISNET biomedical graph as the primary source of information, providing the model with extensive and intricate data to tackle the drug repurposing challenge. This new version's results for the reported metrics in the RepoDB test are 0.9604 for AUROC and 0.9518 for AUPRC. Additionally, a discussion is provided regarding some of the novel predictions to demonstrate the reliability of the model. The authors believe that BEHOR holds promise for generating drug repurposing hypotheses and could greatly benefit the field.

Understanding the role and adoption of artificial intelligence techniques in rheumatology research: An in-depth review of the literature.

The major and upward trend in the number of published research related to rheumatic and musculoskeletal diseases, in which artificial intelligence plays a key role, has exhibited the interest of rheumatology researchers in using these techniques to answer their research questions. In this review, we analyse the original research articles that combine both worlds in a five- year period (2017-2021). In contrast to other published papers on the same topic, we first studied the review and recommendation articles that were published during that period, including up to October 2022, as well as the publication trends. Secondly, we review the published research articles and classify them into one of the following categories: disease identification and prediction, disease classification, patient stratification and disease subtype identification, disease progression and activity, treatment response, and predictors of outcomes. Thirdly, we provide a table with illustrative studies in which artificial intelligence techniques have played a central role in more than twenty rheumatic and musculoskeletal diseases. Finally, the findings of the research articles, in terms of disease and/or data science techniques employed, are highlighted in a discussion. Therefore, the present review aims to characterise how researchers are applying data science techniques in the rheumatology medical field. The most immediate conclusions that can be drawn from this work are: multiple and novel data science techniques have been used in a wide range of rheumatic and musculoskeletal diseases including rare diseases; the sample size and the data type used are heterogeneous, and new technical approaches are expected to arrive in the short-middle term.

How medical doctors and students should use Social Media: a review of the main guidelines for proposing practical recommendations.

Social Media has grown exponentially and in the last few years there has been an increasing use amongst medical doctors and students. There is intense debate about the complexities of ensuring medical professionalism in the digital age and especially on using open and massive online services. The objectives of this paper are: first, to gather the main recommendations on using Social Media platforms and websites by medical doctors and students, which are proposed by several international organizations, institutions and universities of reference and second, to propose a set of practical recommendations, based on the comparison of the statements and items of the guidelines, in order to find agreements and differences among them and select the most common and practical items stated. A Decalogue of good practices has been drawn up, pointing out the most important aspects that should be considered, highlighting the relevance of maintaining professional behavior in these environments, taking into account the advantages and drawbacks when using them.

Repositioning Drugs for Rare Diseases Based on Biological Features and Computational Approaches.

Rare diseases are a group of uncommon diseases in the world population. To date, about 7000 rare diseases have been documented. However, most of them do not have a known treatment. As a result of the relatively low demand for their treatments caused by their scarce prevalence, the pharmaceutical industry has not sufficiently encouraged the research to develop drugs to treat them. This work aims to analyse potential drug-repositioning strategies for this kind of disease. Drug repositioning seeks to find new uses for existing drugs. In this context, it seeks to discover if rare diseases could be treated with medicines previously indicated to heal other diseases. Our approaches tackle the problem by employing computational methods that calculate similarities between rare and non-rare diseases, considering biological features such as genes, proteins, and symptoms. Drug candidates for repositioning will be checked against clinical trials found in the scientific literature. In this study, 13 different rare diseases have been selected for which potential drugs could be repositioned. By verifying these drugs in the scientific literature, successful cases were found for 75% of the rare diseases studied. The genetic associations and phenotypical features of the rare diseases were examined. In addition, the verified drugs were classified according to the anatomical therapeutic chemical (ATC) code to highlight the types with a higher predisposition to be repositioned. These promising results open the door for further research in this field of study.

Integrating heterogeneous data to facilitate COVID-19 drug repurposing.

In the COVID-19 pandemic, drug repositioning has presented itself as an alternative to the time-consuming process of generating new drugs. This review describes a drug repurposing process that is based on a new data-driven approach: we put forward five information paths that associate COVID-19-related genes and COVID-19 symptoms with drugs that directly target these gene products, that target the symptoms or that treat diseases that are symptomatically or genetically similar to COVID-19. The intersection of the five information paths results in a list of 13 drugs that we suggest as potential candidates against COVID-19. In addition, we have found information in published studies and in clinical trials that support the therapeutic potential of the drugs in our final list.

Negation and uncertainty detection in clinical texts written in Spanish: a deep learning-based approach.

Detecting negation and uncertainty is crucial for medical text mining applications; otherwise, extracted information can be incorrectly identified as real or factual events. Although several approaches have been proposed to detect negation and uncertainty in clinical texts, most efforts have focused on the English language. Most proposals developed for Spanish have focused mainly on negation detection and do not deal with uncertainty. In this paper, we propose a deep learning-based approach for both negation and uncertainty detection in clinical texts written in Spanish. The proposed approach explores two deep learning methods to achieve this goal: (i) Bidirectional Long-Short Term Memory with a Conditional Random Field layer (BiLSTM-CRF) and (ii) Bidirectional Encoder Representation for Transformers (BERT). The approach was evaluated using NUBES and IULA, two public corpora for the Spanish language. The results obtained showed an F-score of 92% and 80% in the scope recognition task for negation and uncertainty, respectively. We also present the results of a validation process conducted using a real-life annotated dataset from clinical notes belonging to cancer patients. The proposed approach shows the feasibility of deep learning-based methods to detect negation and uncertainty in Spanish clinical texts. Experiments also highlighted that this approach improves performance in the scope recognition task compared to other proposals in the biomedical domain.

Influenza and Measles-MMR: two case study of the trend and impact of vaccine-related Twitter posts in Spanish during 2015-2018.

Social media, and in particularly Twitter, can be a resource of enormous value to retrieve information about the opinion of general populaton to vaccines. The increasing popularity of this social media has allowed to use its content to have a clear picture of their users on this topic. In this paper, we perform a study about vaccine-related messages published in Spanish during 2015-2018. More specifically, the paper has focused on two specific diseases: influenza and measles (and MMR as its vaccine). By also including an analysis about the sentiment expressed on the published tweets, we have been able to identify the type of messages that are published on Twitter with respect these two pathologies and their vaccines. Results showed that in contrary on popular opinions, most of the messages published are non-negative. On the other hand, the analysis showed that some messages attracted a huge attention and provoked peaks in the number of published tweets, explaining some changes in the observed trends.

Classifying diseases by using biological features to identify potential nosological models.

Established nosological models have provided physicians an adequate enough classification of diseases so far. Such systems are important to correctly identify diseases and treat them successfully. However, these taxonomies tend to be based on phenotypical observations, lacking a molecular or biological foundation. Therefore, there is an urgent need to modernize them in order to include the heterogeneous information that is produced in the present, as could be genomic, proteomic, transcriptomic and metabolic data, leading this way to more comprehensive and robust structures. For that purpose, we have developed an extensive methodology to analyse the possibilities when it comes to generate new nosological models from biological features. Different datasets of diseases have been considered, and distinct features related to diseases, namely genes, proteins, metabolic pathways and genetical variants, have been represented as binary and numerical vectors. From those vectors, diseases distances have been computed on the basis of several metrics. Clustering algorithms have been implemented to group diseases, generating different models, each of them corresponding to the distinct combinations of the previous parameters. They have been evaluated by means of intrinsic metrics, proving that some of them are highly suitable to cover new nosologies. One of the clustering configurations has been deeply analysed, demonstrating its quality and validity in the research context, and further biological interpretations have been made. Such model was particularly generated by OPTICS clustering algorithm, by studying the distance between diseases based on gene sharedness and following cosine index metric. 729 clusters were formed in this model, which obtained a Silhouette coefficient of 0.43.

A data-driven methodology towards evaluating the potential of drug repurposing hypotheses.

Drug repurposing has become a widely used strategy to accelerate the process of finding treatments. While classical de novo drug development involves high costs, risks, and time-consuming paths, drug repurposing allows to reuse already-existing and approved drugs for new indications. Numerous research has been carried out in this field, both in vitro and in silico. Computational drug repurposing methods make use of modern heterogeneous biomedical data to identify and prioritize new indications for old drugs. In the current paper, we present a new complete methodology to evaluate new potentially repurposable drugs based on disease-gene and disease-phenotype associations, identifying significant differences between repurposing and non-repurposing data. We have collected a set of known successful drug repurposing case studies from the literature and we have analysed their dissimilarities with other biomedical data not necessarily participating in repurposing processes. The information used has been obtained from the DISNET platform. We have performed three analyses (at the genetical, phenotypical, and categorization levels), to conclude that there is a statistically significant difference between actual repurposing-related information and non-repurposing data. The insights obtained could be relevant when suggesting new potential drug repurposing hypotheses.

Leveraging network analysis to evaluate biomedical named entity recognition tools.

The ever-growing availability of biomedical text sources has resulted in a boost in clinical studies based on their exploitation. Biomedical named-entity recognition (bio-NER) techniques have evolved remarkably in recent years and their application in research is increasingly successful. Still, the disparity of tools and the limited available validation resources are barriers preventing a wider diffusion, especially within clinical practice. We here propose the use of omics data and network analysis as an alternative for the assessment of bio-NER tools. Specifically, our method introduces quality criteria based on edge overlap and community detection. The application of these criteria to four bio-NER solutions yielded comparable results to strategies based on annotated corpora, without suffering from their limitations. Our approach can constitute a guide both for the selection of the best bio-NER tool given a specific task, and for the creation and validation of novel approaches.