Biomedical subjects

Joshua C Denny

Publications and source records attributed to Joshua C Denny.

11 recordsLinked to original sources

PubMed2026

Robust replication of associations across patient-mediated and provider-sourced EHR data in the All of Us research program.

The All of Us Research Program is assembling a nationwide cohort with electronic health record (EHR) resources through two complementary pathways: healthcare provider organization (HPO)-sourced EHRs and patient-mediated EHR (PME) contributed through patient portal linkages. The comparative research utility of these two data sources has not been systematically evaluated. Here, we compared PME and HPO EHRs with respect to disease prevalence, phenotype-phenotype associations, and replication of established genotype-phenotype associations using data from 19,703 PME and 373,887 HPO participants. We benchmarked disease prevalence against national estimates, conducted phenome-wide association studies for 10 commonly studied diseases, and tested replication of more than 5000 established genotype-phenotype associations across multiple ancestral groups. Disease prevalence was consistently lower in PME than in HPO, although prevalence of most diseases in both cohorts exceeded national estimates. Both data sources reproduced known phenotype-phenotype associations and showed moderate-to-strong concordance in effect sizes across the phenome. The overall genotype-phenotype replication rate was 49.1% (5399/10,999) in HPO and 5.9% (381/6482) in PME across ancestral groups, with effect sizes strongly correlated among well-powered associations (R = 0.84, P < 0.001). To disentangle the impact of sample size from data quality, we performed 1:1 propensity score matching. After matching, the replication gap in genotype-phenotype associations narrowed from 8.3-fold to 1.3-fold, with equivalent replication rates among adequately powered associations and strongly concordant effect sizes; comorbidity patterns were also consistent across all 10 diseases tested. These findings demonstrate that both data sources are valuable for clinical and genomic research and can inform other cohorts integrating provider-derived and patient-mediated EHRs.

Computational biology and bioinformatics↗

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed2023

The phenotype-genotype reference map: Improving biobank data science through replication.

Population-scale biobanks linked to electronic health record data provide vast opportunities to extend our knowledge of human genetics and discover new phenotype-genotype associations. Given their dense phenotype data, biobanks can also facilitate replication studies on a phenome-wide scale. Here, we introduce the phenotype-genotype reference map (PGRM), a set of 5,879 genetic associations from 523 GWAS publications that can be used for high-throughput replication experiments. PGRM phenotypes are standardized as phecodes, ensuring interoperability between biobanks. We applied the PGRM to five ancestry-specific cohorts from four independent biobanks and found evidence of robust replications across a wide array of phenotypes. We show how the PGRM can be used to detect data corruption and to empirically assess parameters for phenome-wide studies. Finally, we use the PGRM to explore factors associated with replicability of GWAS results.

Humans↗

PubMed2005

"Where do we teach what?" Finding broad concepts in the medical school curriculum.

BACKGROUND: Often, medical educators and students do not know where important concepts are taught and learned in medical school. Manual efforts to identify and track concepts covered across the curriculum are inaccurate and resource intensive. OBJECTIVE: To test the ability of a web-based application called KnowledgeMap (KM) to automatically locate where broad biomedical concepts are covered in lecture documents in the Vanderbilt School of Medicine. METHODS: In 2003, the authors derived a gold standard set of curriculum documents by ranking 383 lecture documents as high, medium, or low relevance in their coverage of 4 broad biomedical concepts: genetics, women's health, dermatology, and radiology. We compared the gold standard rankings to KM, an automated tool that generates a variable number of subconcepts for each broad concept to calculate a relevance score for each document. Receiver operating characteristic (ROC) curves and area-under-the-curve were derived for each ranking using varying relevance score cutoffs. RESULTS: Receiver operating characteristic curve areas were acceptably high for each broad concept (range 0.74 to 0.98). At relevance scores that optimized sensitivity and specificity, 78% to 100% of highly relevant documents were identified. The best results were obtained with the application of 63 to 1437 subconcepts for a given broad concept. The search time was fast. CONCLUSIONS: The KM tool capably and automatically locates the detailed coverage of broad concepts across medical school documents in real time. Use of KM or similar tools may prove useful for other medical schools to identify broad concepts in their curricula.

Curriculum↗

PubMed2005

Identifying UMLS concepts from ECG Impressions using KnowledgeMap.

Electrocardiogram (ECG) impressions represent a wealth of medical information for potential decision support and drug-effect discovery. Much of this information is inaccessible to automated methods in the free-text portion of the ECG report. We studied the application of the KnowledgeMap concept identifier (KMCI) to map Unified Medical Language System (UMLS) concepts from ECG impressions. ECGs were processed by KMCI and the results scored for accuracy by multiple raters. Reviewers also recorded unidentified concepts through the scoring interface. Overall, KMCI correctly identified 1059 out of 1171 concepts for a recall of 0.90. Precision, indicating the proportion of ECG concepts correctly identified, was 0.94. KMCI was particularly effective at identifying ECG rhythms (330/333), perfusion changes (65/66), and noncardiac medical concepts (11/11). In conclusion, KMCI is an effective method for mapping ECG impressions to UMLS concepts.

Abstracting and Indexing↗

PubMed2005

Can users estimate their usage of a web-based application? Validating a self-report usage questionnaire.

User surveys are often used to estimate usage of online systems. We asked medical student to estimate their weekly use of KnowledgeMap, an online medical education system, during the previous semester. The information was validated against server log files. The average number of log-on days was significantly different across four categories of self-reported use. Self-reported frequency scales may be used to correctly segregate users into discrete ordinal usage groups.

Curriculum↗

PubMed2004

Portal venous hyperinsulinemia does not stimulate gut glucose absorption in the conscious dog.

The purpose of the present study was to assess whether physiological portal vein hyperinsulinemia stimulates gut glucose absorption in vivo. Chronically catheterized (femoral artery, portal vein, inferior vena cava, and proximal and distal duodenum) and instrumented (Doppler flow probe on portal vein) insulin (INS, 2 mU.kg(-1).min(-1), n = 6) or saline (SAL, n = 5) infused dogs were studied during basal (30 minutes) and experimental (90 minutes) periods. Arterial and portal vein plasma insulin were 3.3- and 3.2-fold higher, respectively, throughout the study in INS compared to SAL. An intraduodenal glucose infusion of 8 mg.kg(-1).min(-1) was initiated at t = 0 minutes. At t = 20 and 80 minutes, a bolus of 3-O-[3H]methylglucose (MG) and L-[14C]glucose (L-GLC) was injected intraduodenally. Phloridzin, an inhibitor of the Na+ -dependent glucose transporter (SGLT1), was infused from t = 60 to 90 minutes in the presence of a peripheral isoglycemic clamp. Net gut glucose output (NGGO) was 5.2 +/- 0.6 and 4.6 +/- 0.8 mg.kg(-1).min(-1) in INS and SAL, respectively, from t = 20 to 60 minutes. Transporter-mediated absorption was 87% +/- 2% of NGGO in both INS and SAL. Passive gut glucose absorption was 13% +/- 2% of NGGO in both INS and SAL. Phloridzin-induced inhibition of transporter-mediated absorption completely abolished passive absorption of L-GLC in both groups. This study shows that under physiological conditions, a portal vein insulin infusion that results in circulating hyperinsulinemia does not increase either transporter-mediated or passive absorption of an intraduodenal glucose load.

Algorithms↗

PubMed2003

"Understanding" medical school curriculum content using KnowledgeMap.

OBJECTIVE: To describe the development and evaluation of computational tools to identify concepts within medical curricular documents, using information derived from the National Library of Medicine's Unified Medical Language System (UMLS). The long-term goal of the KnowledgeMap (KM) project is to provide faculty and students with an improved ability to develop, review, and integrate components of the medical school curriculum. DESIGN: The KM concept identifier uses lexical resources partially derived from the UMLS (SPECIALIST lexicon and Metathesaurus), heuristic language processing techniques, and an empirical scoring algorithm. KM differentiates among potentially matching Metathesaurus concepts within a source document. The authors manually identified important "gold standard" biomedical concepts within selected medical school full-content lecture documents and used these documents to compare KM concept recognition with that of a known state-of-the-art "standard"-the National Library of Medicine's MetaMap program. MEASUREMENTS: The number of "gold standard" concepts in each lecture document identified by either KM or MetaMap, and the cause of each failure or relative success in a random subset of documents. RESULTS: For 4,281 "gold standard" concepts, MetaMap matched 78% and KM 82%. Precision for "gold standard" concepts was 85% for MetaMap and 89% for KM. The heuristics of KM accurately matched acronyms, concepts underspecified in the document, and ambiguous matches. The most frequent cause of matching failures was absence of target concepts from the UMLS Metathesaurus. CONCLUSION: The prototypic KM system provided an encouraging rate of concept extraction for representative medical curricular texts. Future versions of KM should be evaluated for their ability to allow administrators, lecturers, and students to navigate through the medical curriculum to locate redundancies, find interrelated information, and identify omissions. In addition, the ability of KM to meet specific, personal information needs should be assessed.

Abstracting and Indexing↗

PubMed2003

The KnowledgeMap project: development of a concept-based medical school curriculum database.

We developed the KnowledgeMap (KM) system as an online, concept-based database of medical school curriculum documents. It uses the KM concept indexer to map full-text documents and match search queries to concepts in the Unified Medical Language System (UMLS). In this paper, we describe the design of KM and report the first seven months of its implementation into a medical school. Despite being emphasized in only two first year courses and one fourth year course, students from all four classes used KM to search and browse documents. All faculty members involved with courses piloting KM used the system to upload and manage lecture documents. Currently, we are working with eight course directors to transition their courses to KM for next year.

Abstracting and Indexing↗

PubMed2003

Formative evaluation to guide early deployment of an online content management tool for medical curriculum.

KM is a Web-accessible, comprehensive database that organizes course materials (at the level of full lectures, not just outlines or syllabi) from the Vanderbilt School of Medicine curriculum. KM uses natural language processing techniques to analyze educational documents for biomedical concepts. Lecture handouts and Microsoft PowerPoint presentations are indexed and available online for students, faculty and administrators to search for individual or interrelated concepts across the medical school curriculum.

Anatomy↗

PubMed2002

Prevention of overt hypoglycemia during exercise: stimulation of endogenous glucose production independent of hepatic catecholamine action and changes in pancreatic hormone concentration.

These studies were conducted to determine the magnitude and mechanism of compensation for impaired glucagon and insulin responses to exercise. For this purpose, dogs underwent surgery >16 days before experiments, at which time flow probes were implanted and silastic catheters were inserted. During experiments, glucagon and insulin were fixed at basal levels during rest and exercise using a pancreatic clamp with glucose clamped (PC/GC; n = 5), a pancreatic clamp with glucose unclamped (PC; n = 7), or a pancreatic clamp with glucose unclamped + intraportal propranolol and phentolamine hepatic alpha- and beta-adrenergic receptor blockade (PC/HAB; n = 6). Glucose production (R(a)) was measured isotopically. Plasma glucose was constant in PC/GC, but fell from basal to exercise in PC and PC/HAB. R(a) was unchanged with exercise in PC/GC, but was slightly increased during exercise in PC and PC/HAB. Despite minimal increases in epinephrine in PC/GC, epinephrine increased approximately sixfold in PC and PC/HAB during exercise. In summary, during moderate exercise, 1) the increase in R(a) is absent in PC/GC; 2) only a moderate fall in arterial glucose occurs in PC, due to a compensatory increase in R(a); and 3) the increase in R(a) is preserved in PC/HAB. In conclusion, stimulation of R(a) by a mechanism independent of pancreatic hormones and hepatic adrenergic stimulation is a primary defense against overt hypoglycemia.

Adrenergic alpha-Antagonists↗