Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective.

Background: The World Health Organization (WHO)'s Essential Medicines List (EML) plays an important role in advocating for access to key treatments for conditions affecting people in all geographic settings. We applied our established drug repurposing methods to one EML agent, N-acetylcysteine (NAC), to identify additional uses of relevance to the global health community beyond its existing EML indication (acetaminophen toxicity).

Methods: We undertook a phenome-wide association study (PheWAS) of a variant in the glutathione synthetase () gene in approximately 35,000 patients to explore novel indications for use of NAC, which targets glutathione.

Walk before you run: Feasibility challenges and lessons learned from the PROCLAIM study, a multicenter randomized controlled trial of misoprostol for prevention of recurrent Clostridioides difficile during COVID-19.

We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years.

Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases.

Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions.

PheWAS-ME: a web-app for interactive exploration of multimorbidity patterns in PheWAS.

Summary: Electronic health records (EHRs) linked with a DNA biobank provide unprecedented opportunities for biomedical research in precision medicine. The Phenome-wide association study (PheWAS) is a widely used technique for the evaluation of relationships between genetic variants and a large collection of clinical phenotypes recorded in EHRs. PheWAS analyses are typically presented as static tables and charts of summary statistics obtained from statistical tests of association between a genetic variant and individual phenotypes.

The Astounding Breadth of Health Disparity: Phenome-Wide Effects of Race on Disease Risk.

Objective: We conducted a phenotype-wide association study (PheWAS) to compare diagnoses among Blacks with those of Whites in one health center in Tennessee using data from 1,883,369 patients.

Methods: We used our deidentified EHR, the Synthetic Derivative, to assess risk of diagnoses associated with Black as compared with White race using Firth logistic regression with covariates including age, sex, and density of clinical encounters.

Results: There were anchoring associations in both directions, including the highest increased risk for Blacks of having sickle cell anemia, and strongest decreased risk of basal cell carcinoma.

Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use.

Introduction: When a new drug or biologic product enters the market, its full spectrum of side effects is not yet fully understood, as use in the real world often uncovers nuances not suggested within the relatively narrow confines of preapproval preclinical and trial work.

Objective: We describe a new, phenome-wide association study (PheWAS)- and evidence-based approach for detection of potential adverse drug effects.

Methods: We leveraged our established platform, which integrates human genetic data with associated phenotypes in electronic health records from 29,722 patients of European ancestry, to identify gene-phenotype associations that may represent known safety issues.

Systematically Prioritizing Candidates in Genome-Based Drug Repurposing.

Drug repurposing is the application of approved drugs to treat diseases separate and distinct from their original indications. Herein, we define the scope of all practical precision drug repurposing using DrugBank, a publicly available database of pharmacological agents, and BioVU, a large, de-identified DNA repository linked to longitudinal electronic health records at Vanderbilt University Medical Center. We present a method of repurposing candidate prioritization through integration of pharmacodynamic and marketing variables from DrugBank with quality control thresholds for genomic data derived from the DNA samples within BioVU.

Acute kidney injury risk-based screening in pediatric inpatients: a pragmatic randomized trial.

Background: Pediatric acute kidney injury (AKI) is common and associated with increased morbidity, mortality, and length of stay. We performed a pragmatic randomized trial testing the hypothesis that AKI risk alerts increase AKI screening.

Methods: All intensive care and ward admissions of children aged 28 days through 21 years without chronic kidney disease from 12/6/2016 to 11/1/2017 were included.

Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data.

The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity.

A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Infection.

Coagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection.

Motivation for Launching a Cancer Metastasis Inhibition (CMI) Program.

Metastatic cancers impose significant burdens on patients, affecting quality of life, morbidity, and mortality. Even during remission, microscopic metastases can lurk, but few therapies directly target tumor cell metastasis. Agents that interfere with this process would represent a new paradigm in cancer management, changing the 'waiting game' into a time of active prevention.

When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data.

Many animal models of disease are suboptimal in their representation of human diseases and lack of predictive power in the success of pivotal human trials. In the context of repurposing drugs with known human safety, it is sometimes appropriate to conduct the "last experiment first," that is, progressing directly to human investigations. However, there are not accepted criteria for when to proceed straight to humans to test a new indication.

Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.

Introduction: When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities.

Mining 100 million notes to find homelessness and adverse childhood experiences: 2 case studies of rare and severe social determinants of health in electronic health records.

Objective: Understanding how to identify the social determinants of health from electronic health records (EHRs) could provide important insights to understand health or disease outcomes. We developed a methodology to capture 2 rare and severe social determinants of health, homelessness and adverse childhood experiences (ACEs), from a large EHR repository.

Materials And Methods: We first constructed lexicons to capture homelessness and ACE phenotypic profiles.

Electronic health record-based predictive models for acute kidney injury screening in pediatric inpatients.

BackgroundAcute kidney injury (AKI) is common in pediatric inpatients and is associated with increased morbidity, mortality, and length of stay. Its early identification can reduce severity.MethodsTo create and validate an electronic health record (EHR)-based AKI screening tool, we generated temporally distinct development and validation cohorts using retrospective data from our tertiary care children's hospital, including children aged 28 days through 21 years with sufficient serum creatinine measurements to determine AKI status.

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples.

Acute Kidney Injury Incidence in Noncritically Ill Hospitalized Children, Adolescents, and Young Adults: A Retrospective Observational Study.

Background: Acute kidney injury (AKI) has been characterized in high-risk pediatric hospital inpatients, in whom AKI is frequent and associated with increased mortality, morbidity, and length of stay. The incidence of AKI among patients not requiring intensive care is unknown.

Study Design: Retrospective cohort study.

Secondary use of clinical data: the Vanderbilt approach.

The last decade has seen an exponential growth in the quantity of clinical data collected nationwide, triggering an increase in opportunities to reuse the data for biomedical research. The Vanderbilt research data warehouse framework consists of identified and de-identified clinical data repositories, fee-for-service custom services, and tools built atop the data layer to assist researchers across the enterprise. Providing resources dedicated to research initiatives benefits not only the research community, but also clinicians, patients and institutional leadership.

The CTSA Consortium's Catalog of Assets for Translational and Clinical Health Research (CATCHR).

The 61 CTSA Consortium sites are home to valuable programs and infrastructure supporting translational science and all are charged with ensuring that such investments translate quickly to improved clinical care. Catalog of Assets for Translational and Clinical Health Research (CATCHR) is the Consortium's effort to collect and make available information on programs and resources to maximize efficiency and facilitate collaborations. By capturing information on a broad range of assets supporting the entire clinical and translational research spectrum, CATCHR aims to provide the necessary infrastructure and processes to establish and maintain an open-access, searchable database of consortium resources to support multisite clinical and translational research studies.

Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients.