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BackgroundMaternal psychiatric morbidities include a range of psychopathologies; one condition is post-traumatic stress disorder (PTSD) that develops following a traumatic childbirth experience and may undermine maternal and infant health. Although assessment for maternal mental health problems is integrated in routine perinatal care, screening for maternal childbirth-related PTSD (CB-PTSD) remains lacking. Acute emotional distress in response to a traumatic event strongly associates with PTSD. The brief 13-item Peritraumatic Distress Inventory (PDI) is a common tool to assess acute distress in non-postpartum individuals. How well the PDI specified to childbirth can classify women likely to endorse CB-PTSD is unknown.ObjectivesWe sought to determine the utility of the PDI to detect CB-PTSD in the early postpartum period. This involved examining the psychometric properties of the PDI specified to childbirth, pertaining to its factorial structure, and establishing an optimal cutoff point for the classification of women with high vs. low likelihood of endorsing CB-PTSD.Study DesignA sample of 3,039 eligible women who had recently given birth provided information about their mental health and childbirth experience. They completed the PDI regarding their recent childbirth event, and a PTSD symptom screen to determine CB-PTSD. We employed Exploratory Graph Analysis (EGA) and bootstrapping analysis to reveal the factorial structure of the PDI and the optimal PDI cutoff value for CB-PTSD classification.ResultsFactor analysis of the PDI shows two strongly correlated stable factors based on a modified 12-item version of the PDI consisting of (1) negative emotions and (2) bodily arousal and threat appraisal in regard to recent childbirth. This structure largely accords with prior studies of individuals who experienced acute distress resulting from other forms of trauma. We report that a score of 15 or higher on the modified PDI produces strong sensitivity and specificity. 88% of women with a positive CB-PTSD screen in the first postpartum months and 93% with a negative screen are identified as such using the established cutoff.ConclusionsOur work reveals that a brief self-report screening concerning a woman’s immediate emotional reactions to childbirth that uses our modified PDI tool can detect women likely to endorse CB-PTSD in the early postpartum period. This form of maternal mental health assessment may serve as the initial step of managing symptoms to ultimately prevent chronic symptom manifestation. Future research is needed to examine the utility of employing the PDI as an assessment performed during maternity hospitalization stay in women following complicated deliveries to further guide recommendations to implement maternal mental health screening for women at high risk for developing CB-PTSD.

BackgroundMaternal mental disorders are considered a leading complication of childbirth and a common contributor to maternal death. In addition to undermining maternal welfare, untreated postpartum psychopathology can result in child emotional and physical neglect, and associated significant pediatric health costs. Some women may experience a traumatic childbirth and develop posttraumatic stress disorder (PTSD) symptoms following delivery (CB-PTSD). Although women are routinely screened for postpartum depression in the U.S., there is no recommended protocol to inform the identification of women who are likely to experience CB-PTSD. Advancements in computational methods of free text has shown promise in informing diagnosis of psychiatric conditions. Although the language in narratives of stressful events has been associated with post-trauma outcomes, whether the narratives of childbirth processed via machine learning can be useful for CB-PTSD screening is unknown.ObjectiveThis study examined the utility of written narrative accounts of personal childbirth experience for the identification of women with provisional CB-PTSD. To this end, we developed a model based on natural language processing (NLP) and machine learning (ML) algorithms to identify CB-PTSD via classification of birth narratives.Study DesignA total of 1,127 eligible postpartum women who enrolled in a study survey during the COVID-19 era provided short written childbirth narrative accounts in which they were instructed to focus on the most distressing aspects of their childbirth experience. They also completed a PTSD symptom screen to determine provisional CB-PTSD. After exclusion criteria were applied, data from 995 participants was analyzed. An ML-based Sentence-Transformer NLP model was used to represent narratives as vectors that served as inputs for a neural network ML model developed in this study to identify participants with provisional CB-PTSD.ResultsThe ML model derived from NLP of childbirth narratives achieved good performance: AUC 0.75, F1-score 0.76, sensitivity 0.8, and specificity 0.70. Moreover, women with provisional CB-PTSD generated longer narratives (t-test results: t=2.30, p=0.02) and used more negative emotional expressions (Wilcoxon test: ‘sadness’: p=8.90e-04, W=31,017; ‘anger’: p=1.32e-02, W=35,005.50) and death-related words (Wilcoxon test: p=3.48e-05, W=34,538) in describing their childbirth experience than those with no CB-PTSD.ConclusionsThis study provides proof of concept that personal childbirth narrative accounts generated in the early postpartum period and analyzed via advanced computational methods can detect with relatively high accuracy women who are likely to endorse CB-PTSD and those at low risk. This suggests that birth narratives could be promising for informing low-cost, non-invasive tools for maternal mental health screening, and more research that utilizes ML to predict early signs of maternal psychiatric morbidity is warranted.

The Library of Integrated Network-based Cellular Signatures (LINCS) was an NIH Common Fund program that aimed to expand our knowledge about human cellular responses to chemical, genetic, and microenvironment perturbations. Responses to perturbations were measured by transcriptomics, proteomics, cellular imaging, and other high content assays. The second phase of the LINCS program, which lasted 7 years, involved the engagement of six data and signature generation centers (DSGCs) and one data coordination and integration center (DCIC). The DSGCs and the DCIC developed several digital resources, including tools, databases, and workflows that aim to facilitate the use of the LINCS data and integrate this data with other publicly available data. The digital resources developed by the DSGCs and the DCIC can be used to gain new biological and pharmacological insights that can lead to the development of novel therapeutics. This protocol provides step-by-step instructions for processing the LINCS data into signatures, and utilizing the digital resources developed by the LINCS consortia for hypothesis generation and knowledge discovery. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Navigating L1000 tools and data in CLUE.io Basic Protocol 2: Computing signatures from the L1000 data with the CD method Basic Protocol 3: Analyzing lists of differentially expressed genes and querying them against the L1000 data with BioJupies and the Bulk RNA-seq Appyter Basic Protocol 4: Utilizing the L1000FWD resource for drug discovery Basic Protocol 5: KINOMEscan and the KINOMEscan Appyter Basic Protocol 6: LINCS P100 and GCP Proteomics Assays Basic Protocol 7: The LINCS Joint Project (LJP) Basic Protocol 8: The LINCS Data Portals and SigCom LINCS Basic Protocol 9: Creating and analyzing signatures with iLINCS.

While hundreds of genes have been associated with pain, much of the molecular mechanisms of pain remain unknown. As a result, current analgesics are limited to few clinically validated targets. Here, we trained a machine learning (ML) ensemble model to predict new targets for 17 categories of pain. The model utilizes features from transcriptomics, proteomics, and gene ontology to prioritize targets for modulating pain. We focused on identifying novel G-protein-coupled receptors (GPCRs), ion channels, and protein kinases because these proteins represent the most successful drug target families. The performance of the model to predict novel pain targets is 0.839 on average based on AUROC, while the predictions for arthritis had the highest accuracy (AUROC = 0.929). The model predicts hundreds of novel targets for pain; for example, GPR132 and GPR109B are highly ranked GPCRs for rheumatoid arthritis. Overall, gene-pain association predictions cluster into three groups that are enriched for cytokine, calcium, and GABA-related cell signaling pathways. These predictions can serve as a foundation for future experimental exploration to advance the development of safer and more effective analgesics.

Connectivity mapping resources consist of signatures representing changes in cellular state following systematic small-molecule, disease, gene, or other form of perturbations. Such resources enable the characterization of signatures from novel perturbations based on similarity; provide a global view of the space of many themed perturbations; and allow the ability to predict cellular, tissue, and organismal phenotypes for perturbagens. A signature search engine enables hypothesis generation by finding connections between query signatures and the database of signatures. This framework has been used to identify connections between small molecules and their targets, to discover cell-specific responses to perturbations and ways to reverse disease expression states with small molecules, and to predict small-molecule mimickers for existing drugs. This review provides a historical perspective and the current state of connectivity mapping resources with a focus on both methodology and community implementations.

Understanding the underlying molecular and structural similarities between seemingly heterogeneous sets of drugs can aid in identifying drug repurposing opportunities and assist in the discovery of novel properties of preclinical small molecules. A wealth of information about drug and small molecule structure, targets, indications and side effects; induced gene expression signatures; and other attributes are publicly available through web-based tools, databases and repositories. By processing, abstracting and aggregating information from these resources into drug set libraries, knowledge about novel properties of drugs and small molecules can be systematically imputed with machine learning. In addition, drug set libraries can be used as the underlying database for drug set enrichment analysis. Here, we present Drugmonizome, a database with a search engine for querying annotated sets of drugs and small molecules for performing drug set enrichment analysis. Utilizing the data within Drugmonizome, we also developed Drugmonizome-ML. Drugmonizome-ML enables users to construct customized machine learning pipelines using the drug set libraries from Drugmonizome. To demonstrate the utility of Drugmonizome, drug sets from 12 independent SARS-CoV-2 in vitro screens were subjected to consensus enrichment analysis. Despite the low overlap among these 12 independent in vitro screens, we identified common biological processes critical for blocking viral replication. To demonstrate Drugmonizome-ML, we constructed a machine learning pipeline to predict whether approved and preclinical drugs may induce peripheral neuropathy as a potential side effect. Overall, the Drugmonizome and Drugmonizome-ML resources provide rich and diverse knowledge about drugs and small molecules for direct systems pharmacology applications.Database URL: https://maayanlab.cloud/drugmonizome/.

The coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 (COVID-19) pandemic has received rapid response by the research community to offer suggestions for repurposing of approved drugs as well as to improve our understanding of the COVID-19 viral life cycle molecular mechanisms. In a short period, tens of thousands of research preprints and other publications have emerged including those that report lists of experimentally validated drugs and compounds as potential COVID-19 therapies. In addition, gene sets from interacting COVID-19 virus-host proteins and differentially expressed genes when comparing infected to uninfected cells are being published at a fast rate. To organize this rapidly accumulating knowledge, we developed the COVID-19 Gene and Drug Set Library (https://amp.pharm.mssm.edu/covid19/), a collection of gene and drug sets related to COVID-19 research from multiple sources. The COVID-19 Gene and Drug Set Library is delivered as a web-based interface that enables users to view, download, analyze, visualize, and contribute gene and drug sets related to COVID-19 research. To evaluate the content of the library, we performed several analyses including comparing the results from 6 in-vitro drug screens for COVID-19 repurposing candidates. Surprisingly, we observe little overlap across these initial screens. The most common and unique hit across these screen is mefloquine, a malaria drug that should receive more attention as a potential therapeutic for COVID-19. Overall, the library of gene and drug sets can be used to identify community consensus, make researchers and clinicians aware of the development of new potential therapies, as well as allow the research community to work together towards a cure for COVID-19. Funding: This project is partially funded by U54HL127624 and U24CA224260.

Motivation Micro-blogging with Twitter to communicate new results, discuss ideas and share techniques is becoming central. While most Twitter users are real people, the Twitter API provides the opportunity to develop Twitter bots and to analyze global trends in tweets. Results EnrichrBot is a bot that tracks and tweets information about human genes implementing six principal functions: (i) tweeting information about under-studied genes including non-coding lncRNAs, (ii) replying to requests for information about genes, (iii) responding to GWASbot, another bot that tweets Manhattan plots from genome-wide association study analysis of the UK Biobank, (iv) tweeting randomly selected gene sets from the Enrichr database for analysis with Enrichr, (v) responding to mentions of human genes in tweets with additional information about these genes and (vi) tweeting a weekly report about the most trending genes on Twitter. Availability and implementation https://twitter.com/botenrichr; source code: https://github.com/MaayanLab/EnrichrBot. Supplementary information Supplementary data are available at Bioinformatics online.

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.

As more datasets, tools, workflows, APIs, and other digital resources are produced by the research community, it is becoming increasingly difficult to harmonize and organize these efforts for maximal synergistic integrated utilization. The Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge by making these digital resources follow common standards and best practices so that they can become more integrated and organized. Faced with the question of how to make digital resources more FAIR, it has become imperative to measure what it means to be FAIR. The diversity of resources, communities, and stakeholders have different goals and use cases and this makes assessment of FAIRness particularly challenging. To begin resolving this challenge, the FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual, semi- and fully-automated FAIR assessment capabilities. The FAIRshake toolkit contains a database that lists registered digital resources, with their associated metrics, rubrics, and assessments. The FAIRshake toolkit also has a browser extension and a bookmarklet that enables viewing and submitting assessments from any website. The FAIR assessment results are visualized as an insignia that can be viewed on the FAIRshake website, or embedded within hosting websites. Using FAIRshake, a variety of bioinformatics tools, datasets listed on dbGaP, APIs registered in SmartAPI, workflows in Dockstore, and other biomedical digital resources were manually and automatically assessed for FAIRness. In each case, the assessments revealed room for improvement, which prompted enhancements that significantly upgraded FAIRness scores of several digital resources.

As more digital resources are produced by the research community, it is becoming increasingly important to harmonize and organize them for synergistic utilization. The findable, accessible, interoperable, and reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge. The FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual and automated FAIR assessments. FAIR assessments are visualized as an insignia that can be embedded within digital-resources-hosting websites. Using FAIRshake, a variety of biomedical digital resources were manually and automatically evaluated for their level of FAIRness.

High-level spinal cord injury (SCI) in humans causes paralysis below the neck. Functional electrical stimulation (FES) technology applies electrical current to nerves and muscles to restore movement, and controllers for upper extremity FES neuroprostheses calculate stimulation patterns to produce desired arm movement. However, currently available FES controllers have yet to restore natural movements. Reinforcement learning (RL) is a reward-driven control technique; it can employ user-generated rewards, and human preferences can be used in training. To test this concept with FES, we conducted simulation experiments using computer-generated “pseudo-human” rewards. Rewards with varying properties were used with an actor-critic RL controller for a planar two-degree-of-freedom biomechanical human arm model performing reaching movements. Results demonstrate that sparse, delayed pseudo-human rewards permit stable and effective RL controller learning. The frequency of reward is proportional to learning success, and human-scale sparse rewards permit greater learning than exclusively automated rewards. Diversity of training task sets did not affect learning. Long-term stability of trained controllers was observed. Using human-generated rewards to train RL controllers for upper-extremity FES systems may be useful. Our findings represent progress toward achieving human–machine teaming in control of upper-extremity FES systems for more natural arm movements based on human user preferences and RL algorithm learning capabilities.

Summary Mechanistic molecular studies in biomedical research often discover important genes that are aberrantly over- or under-expressed in disease. However, manipulating these genes in an attempt to improve the disease state is challenging. Herein, we reveal Drug Gene Budger (DGB), a web-based and mobile application developed to assist investigators in order to prioritize small molecules that are predicted to maximally influence the expression of their target gene of interest. With DGB, users can enter a gene symbol along with the wish to up-regulate or down-regulate its expression. The output of the application is a ranked list of small molecules that have been experimentally determined to produce the desired expression effect. The table includes log-transformed fold change, P-value and q-value for each small molecule, reporting the significance of differential expression as determined by the limma method. Relevant links are provided to further explore knowledge about the target gene, the small molecule and the source of evidence from which the relationship between the small molecule and the target gene was derived. The experimental data contained within DGB is compiled from signatures extracted from the LINCS L1000 dataset, the original Connectivity Map (CMap) dataset and the Gene Expression Omnibus (GEO). DGB also presents a specificity measure for a drug–gene connection based on the number of genes a drug modulates. DGB provides a useful preliminary technique for identifying small molecules that can target the expression of a single gene in human cells and tissues. Availability and implementation The application is freely available on the web at http://DGB.cloud and as a mobile phone application on iTunes https://itunes.apple.com/us/app/drug-gene-budger/id1243580241? mt=8 and Google Play https://play.google.com/store/apps/details? id=com.drgenebudger. Supplementary information Supplementary data are available at Bioinformatics online.

When Functional Electrical Stimulation (FES) is used to restore movement in subjects with spinal cord injury (SCI), muscle stimulation patterns should be selected to generate accurate and efficient movements. Ideally, the controller for such a neuroprosthesis will have the simplest architecture possible, to facilitate translation into a clinical setting. In this study, we used the simulated annealing algorithm to optimize two proportional-derivative (PD) feedback controller gain sets for a 3-dimensional arm model that includes musculoskeletal dynamics and has 5 degrees of freedom and 22 muscles, performing goal-oriented reaching movements. Controller gains were optimized by minimizing a weighted sum of position errors, orientation errors, and muscle activations. After optimization, gain performance was evaluated on the basis of accuracy and efficiency of reaching movements, along with three other benchmark gain sets not optimized for our system, on a large set of dynamic reaching movements for which the controllers had not been optimized, to test ability to generalize. Robustness in the presence of weakened muscles was also tested. The two optimized gain sets were found to have very similar performance to each other on all metrics, and to exhibit significantly better accuracy, compared with the three standard gain sets. All gain sets investigated used physiologically acceptable amounts of muscular activation. It was concluded that optimization can yield significant improvements in controller performance while still maintaining muscular efficiency, and that optimization should be considered as a strategy for future neuroprosthesis controller design.

Biomedical data repositories such as the Gene Expression Omnibus (GEO) enable the search and discovery of relevant biomedical digital data objects. Similarly, resources such as OMICtools, index bioinformatics tools that can extract knowledge from these digital data objects. However, systematic access to pre-generated ‘canned’ analyses applied by bioinformatics tools to biomedical digital data objects is currently not available. Datasets2Tools is a repository indexing 31,473 canned bioinformatics analyses applied to 6,431 datasets. The Datasets2Tools repository also contains the indexing of 4,901 published bioinformatics software tools, and all the analyzed datasets. Datasets2Tools enables users to rapidly find datasets, tools, and canned analyses through an intuitive web interface, a Google Chrome extension, and an API. Furthermore, Datasets2Tools provides a platform for contributing canned analyses, datasets, and tools, as well as evaluating these digital objects according to their compliance with the findable, accessible, interoperable, and reusable (FAIR) principles. By incorporating community engagement, Datasets2Tools promotes sharing of digital resources to stimulate the extraction of knowledge from biomedical research data. Datasets2Tools is freely available from: http://amp.pharm.mssm.edu/datasets2tools.

RNA sequencing (RNA-seq) is the leading technology for genome-wide transcript quantification. However, publicly available RNA-seq data is currently provided mostly in raw form, a significant barrier for global and integrative retrospective analyses. ARCHS4 is a web resource that makes the majority of published RNA-seq data from human and mouse available at the gene and transcript levels. For developing ARCHS4, available FASTQ files from RNA-seq experiments from the Gene Expression Omnibus (GEO) were aligned using a cloud-based infrastructure. In total 187,946 samples are accessible through ARCHS4 with 103,083 mouse and 84,863 human. Additionally, the ARCHS4 web interface provides intuitive exploration of the processed data through querying tools, interactive visualization, and gene pages that provide average expression across cell lines and tissues, top co-expressed genes for each gene, and predicted biological functions and protein–protein interactions for each gene based on prior knowledge combined with co-expression., Publicly available RNA-seq data is provided mostly in raw form, resulting in a barrier for integrative analyses. Here, Lachmann et al. develop a high-throughput processing infrastructure and search database (ARCHS4) that provides processed RNA-seq data for 187,946 publicly available mouse and human samples to support exploration and reuse.

The NIH-funded LINCS Consortium is creating an extensive reference library of cell-based perturbation response signatures and sophisticated informatics tools incorporating a large number of perturbagens, model systems, and assays. To date, more than 350 datasets have been generated including transcriptomics, proteomics, epigenomics, cell phenotype and competitive binding profiling assays. The large volume and variety of data necessitate rigorous data standards and effective data management including modular data processing pipelines and end-user interfaces to facilitate accurate and reliable data exchange, curation, validation, standardization, aggregation, integration, and end user access. Deep metadata annotations and the use of qualified data standards enable integration with many external resources. Here we describe the end-to-end data processing and management at the DCIC to generate a high-quality and persistent product. Our data management and stewardship solutions enable a functioning Consortium and make LINCS a valuable scientific resource that aligns with big data initiatives such as the BD2K NIH Program and concords with emerging data science best practices including the findable, accessible, interoperable, and reusable (FAIR) principles.

Functional Electrical Stimulation (FES) employs neuroprostheses to apply electrical current to the nerves and muscles of individuals paralyzed by spinal cord injury (SCI) to restore voluntary movement. Neuroprosthesis controllers calculate stimulation patterns to produce desired actions. To date, no existing controller is able to efficiently adapt its control strategy to the wide range of possible physiological arm characteristics, reaching movements, and user preferences that vary over time. Reinforcement learning (RL) is a control strategy that can incorporate human reward signals as inputs to allow human users to shape controller behavior. In this study, ten neurologically intact human participants assigned subjective numerical rewards to train RL controllers, evaluating animations of goal-oriented reaching tasks performed using a planar musculoskeletal human arm simulation. The RL controller learning achieved using human trainers was compared with learning accomplished using human-like rewards generated by an algorithm; metrics included success at reaching the specified target; time required to reach the target; and target overshoot. Both sets of controllers learned efficiently and with minimal differences, significantly outperforming standard controllers. Reward positivity and consistency were found to be unrelated to learning success. These results suggest that human rewards can be used effectively to train RL-based FES controllers.

Genome-wide gene expression profiling of mammalian cells is becoming a staple of many published biomedical and biological research studies. Such data is deposited into data repositories such as the Gene Expression Omnibus (GEO) for potential reuse. However, these repositories currently do not provide simple interfaces to systematically analyze collections of related studies. Here we present GENE Expression and Enrichment Vector Analyzer (GEN3VA), a web-based system that enables the integrative analysis of aggregated collections of tagged gene expression signatures identified and extracted from GEO. Each tagged collection of signatures is presented in a report that consists of heatmaps of the differentially expressed genes; principal component analysis of all signatures; enrichment analysis with several gene set libraries across all signatures, which we term enrichment vector analysis; and global mapping of small molecules that are predicted to reverse or mimic each signature in the aggregate. We demonstrate how GEN3VA can be used to identify common molecular mechanisms of aging by analyzing tagged signatures from 244 studies that compared young vs. old tissues in mammalian systems. In a second case study, we collected 86 signatures from treatment of human cells with dexamethasone, a glucocorticoid receptor (GR) agonist. Our analysis confirms consensus GR target genes and predicts potential drug mimickers. GEN3VA can be used to identify, aggregate, and analyze themed collections of gene expression signatures from diverse but related studies. Such integrative analyses can be used to address concerns about data reproducibility, confirm results across labs, and discover new collective knowledge by data reuse. GEN3VA is an open-source web-based system that is freely available at: http://amp.pharm.mssm.edu/gen3va .