Search

TIN-X (Target Importance and Novelty eXplorer) is an interactive visualization tool for illuminating associations between diseases and potential drug targets and is publicly available at newdrugtargets.org. TIN-X uses natural language processing to identify disease and protein mentions within PubMed content using previously published tools for named entity recognition (NER) of gene/protein and disease names. Target data is obtained from the Target Central Resource Database (TCRD). Two important metrics, novelty and importance, are computed from this data and when plotted as log(importance) vs. log(novelty), aid the user in visually exploring the novelty of drug targets and their associated importance to diseases. TIN-X Version 3.0 has been significantly improved with an expanded dataset, modernized architecture including a REST API, and an improved user interface (UI). The dataset has been expanded to include not only PubMed publication titles and abstracts, but also full-text articles when available. This results in approximately 9-fold more target/disease associations compared to previous versions of TIN-X. Additionally, the TIN-X database containing this expanded dataset is now hosted in the cloud via Amazon RDS. Recent enhancements to the UI focuses on making it more intuitive for users to find diseases or drug targets of interest while providing a new, sortable table-view mode to accompany the existing plot-view mode. UI improvements also help the user browse the associated PubMed publications to explore and understand the basis of TIN-X’s predicted association between a specific disease and a target of interest. While implementing these upgrades, computational resources are balanced between the webserver and the user’s web browser to achieve adequate performance while accommodating the expanded dataset. Together, these advances aim to extend the duration that users can benefit from TIN-X while providing both an expanded dataset and new features that researchers can use to better illuminate understudied proteins.

Abstract Background Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. Methods To further characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with a focus on associations between birth defects, drugs, and genes. Specifically, we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression changes in cell lines, known drug targets, genetic burden scores for human genes, and placental crossing scores for small molecules. Results Using ReproTox-KG and semi-supervised learning (SSL), we scored >30,000 preclinical small molecules for their potential to cross the placenta and induce birth defects, and identified >500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG can be accessed via a web-based user interface available at https://maayanlab.cloud/reprotox-kg . This site enables users to explore the associations between birth defects, approved and preclinical drugs, and all human genes. Conclusions ReproTox-KG provides a resource for exploring knowledge about the molecular mechanisms of birth defects with the potential of predicting the likelihood of genes and preclinical small molecules to induce birth defects.

Abstract Identifying novel autophagy (ATG) associated genes in humans remains an important task for understanding this fundamental physiological process. Machine learning (ML) can highlight potentially “missing pieces” linking core ATG genes with understudied, “dark” genes by mining functional genomic data. Here, a set of 103 (out of 288 genes from the Autophagy Database) was used as training set, based on ATG‐associated terms annotated from 3 secondary sources: GO (gene ontology), Kyoto Encyclopedia of Genes and Genomes pathway, and UniProt keywords, as additional confirmation of their importance in ATG. As negative labels, an OMIM list of genes associated with monogenic diseases was used (after excluding the 288 ATG‐associated genes). Data related to these genes from 17 different sources were compiled and used to derive a trained MetaPath/XGBoost (MPxgb) ML model for distinguishing ATG and non‐ATG genes (10‐fold cross‐validated, 100‐times randomized models, median area under the curve = 0.994 ± 0.008). Sixteen ATG‐relevant variables explained 64% of the total model gain. Overall, 23% of the top 251 predicted genes are annotated in the Autophagy Database, whereas 193 genes (77%) are not. In 2019, we suggested that some of these 193 genes may represent “ATG dark genes.” A literature search in 2022 for those top 20 predicted ATG dark genes found that 9 were subsequently reported as ATG genes during the intervening 3.5 years. A post‐factum evaluation of data leakage (the presence of ATG‐associated terms in the top 40 ML features) confirms that 7 out of these 9 genes and 2 out of 3 other recently validated predictions from the bottom 20 are novel. Those genes with the largest number of ATG features would be most likely to yield valuable experimental insights. Modern high‐throughput testing would be capable of spanning the full 193 ATG genes list reported here. Our analysis demonstrates that ML can guide genomics research to gain a more complete functional and pathway annotation of complex processes. Key points –A knowledge‐graph based machine learning model was designed for predicting unknown autophagy genes via mining functional genomic data. –Literature search validated predicted genes. –Our machine learning models could be generalized and applied to other genomic libraries to uncover dark genes for various functions.

Jessica Binder et al. developed a machine learning model to discover potential drug targets for Alzheimer’s disease. They validated their 20 top candidates in several in vitro models, and highlight FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2, and TMEFF2 as potential AD risk genes.

Abstract Background LINCS, "Library of Integrated Network-based Cellular Signatures", and IDG, "Illuminating the Druggable Genome", are both NIH projects and consortia that have generated rich datasets for the study of the molecular basis of human health and disease. LINCS L1000 expression signatures provide unbiased systems/omics experimental evidence. IDG provides compiled and curated knowledge for illumination and prioritization of novel drug target hypotheses. Together, these resources can support a powerful new approach to identifying novel drug targets for complex diseases, such as Parkinson's disease (PD), which continues to inflict severe harm on human health, and resist traditional research approaches. Results Integrating LINCS and IDG, we built the Knowledge Graph Analytics Platform (KGAP) to support an important use case: identification and prioritization of drug target hypotheses for associated diseases. The KGAP approach includes strong semantics interpretable by domain scientists and a robust, high performance implementation of a graph database and related analytical methods. Illustrating the value of our approach, we investigated results from queries relevant to PD. Approved PD drug indications from IDG’s resource DrugCentral were used as starting points for evidence paths exploring chemogenomic space via LINCS expression signatures for associated genes, evaluated as target hypotheses by integration with IDG. The KG-analytic scoring function was validated against a gold standard dataset of genes associated with PD as elucidated, published mechanism-of-action drug targets, also from DrugCentral. IDG's resource TIN-X was used to rank and filter KGAP results for novel PD targets, and one, SYNGR3 (Synaptogyrin-3), was manually investigated further as a case study and plausible new drug target for PD. Conclusions The synergy of LINCS and IDG, via KG methods, empowers graph analytics methods for the investigation of the molecular basis of complex diseases, and specifically for identification and prioritization of novel drug targets. The KGAP approach enables downstream applications via integration with resources similarly aligned with modern KG methodology. The generality of the approach indicates that KGAP is applicable to many disease areas, in addition to PD, the focus of this paper.

Objectives: This investigation aimed to examine the effects of the COVID-19 pandemic on treatment delays and the severity of initial disease presentation in cholesteatoma patients treated in the prepandemic and pandemic periods., Methods:  This retrospective cohort study was of patients who underwent primary surgical management of cholesteatoma between October 2018 and December 2021, split between the prepandemic (October 2018 to February 2020) and pandemic (April 2020 to December 2021) time periods. Data collected included time from referral to otology clinic visit, time of diagnosis, and time of surgical interventions. The extent of cholesteatoma disease and surgery, hearing loss levels, and the need for additional surgical intervention were also considered. The datasets were compared using the Wilcoxon rank-sum test., Results:  Eighty-six patients met inclusion criteria, 36 of whom were treated prepandemic and 50 after March 2020. Of the examined variables, only time from diagnosis to surgery and case duration were significantly different between the two cohorts, with the pandemic cohort experiencing less time between initial diagnosis and surgery (51.4 days prepandemic vs. 38.4 days pandemic, p = 0.02) and shorter case duration (221.0 minutes prepandemic vs. 171.8 minutes pandemic, p = 0.0008). There was no difference between the severity of presentation in the prepandemic and pandemic populations., Conclusions:  There was no significant difference in disease severity or delays in treatment when comparing the prepandemic to the pandemic population. There was a quicker time from referral to surgery and decreased surgical times during the pandemic., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Louisiana State University Institutional Review Board issued approval 2055. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shires et al.)