Risk of Major Adverse Cardiovascular Events Following Nicotinamide Exposure.

Importance: Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking.

Objective: To determine whether nicotinamide use results in an increase of MACE.

Frequency and timing of multiple skin cancer development in five cohorts.

Background: Many patients will develop more than one skin cancer; however, most research to date has examined only case status.

Objective: Describe the frequency and timing of the treatment of multiple skin cancers in individual patients over time.

Methods: We conducted a longitudinal claims and electronic health record-based cohort study to examine the frequency of skin cancer multiplicity.

Large language models improve the identification of emergency department visits for symptomatic kidney stones.

Recent advancements of large language models (LLMs) like generative pre-trained transformer 4 (GPT-4) have generated significant interest among the scientific community. Yet, the potential of these models to be utilized in clinical settings remains largely unexplored. In this study, we investigated the abilities of multiple LLMs and traditional machine learning models to analyze emergency department (ED) reports and determine if the corresponding visits were due to symptomatic kidney stones.

The impact of imprecise case definitions in electronic health record research: a melanoma case-study from the Million Veteran Program.

Cases for a disease can be defined broadly using diagnostic codes, or narrowly using gold-standard confirmation that often is not available in large administrative datasets. These different definitions can have significant impacts on the results and conclusions of studies. We conducted this study to assess how using melanoma phecodes versus histologic confirmation for invasive or in situ melanoma impacts the results of a genome-wide association study (GWAS) using the Million Veteran Program.

Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis.

Not available.

No Increased Risk of Major Adverse Cardiovascular Events following Nicotinamide Exposure.

Importance: Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking.

Objective: To determine whether nicotinamide use results in an increase of MACE.

Large Language Models Improve the Identification of Emergency Department Visits for Symptomatic Kidney Stones.

Background: Recent advancements of large language models (LLMs) like Generative Pre-trained Transformer 4 (GPT-4) have generated significant interest among the scientific community. Yet, the potential of these models to be utilized in clinical settings remains largely unexplored. This study investigated the abilities of multiple LLMs and traditional machine learning models to analyze emergency department (ED) reports and determine if the corresponding visits were caused by symptomatic kidney stones.

Toward personalized skin cancer care: multiple skin cancer development in five cohorts.

Importance: Many patients will develop more than one skin cancer, however most research to date has examined only case status.

Objective: Describe the frequency and timing of the treatment of multiple skin cancers in individual patients over time.

Design: Longitudinal claims and electronic health record-based cohort study.

Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable.

Background: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations.

The association of infant urinary adrenal steroids with the risk of childhood asthma development.

Background: Adrenal steroids play important roles in early-life development. However, our understanding of the effects of perinatal adrenal steroids on the development of childhood asthma is incomplete.

Objective: To evaluate the associations between early-life adrenal steroid levels and childhood asthma.

Clonal hematopoiesis and inflammation in the vasculature: CHIVE, a prospective, longitudinal clonal hematopoiesis cohort and biorepository.

Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research.

Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph.

Solid Organ Transplant Recipients Exhibit More TET2-Mutant Clonal Hematopoiesis of Indeterminate Potential Not Driven by Increased Transplantation Risk.

Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants.

Experimental Design: We use two national biobank cohorts comprised of >650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS) and UC (PRS) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients.

Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes.

Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear.

Methods: We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping.

Evaluation of genetic associations with clinical phenotypes of kidney stone disease.

Introduction And Objective: We sought to replicate and discover genetic associations of kidney stone disease within a large-scale electronic health record (EHR) system.

Methods: We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5,571 cases and 83,692 controls. Among the significant risk variants, we performed association analyses of stone composition and first-time 24-hour urine parameters.

Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance.

Background: Despite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) therapy in various cancer types. The genetic and epigenetic pathways modulating tsMHC-II expression remain incompletely characterized.

Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk.

Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p).

Evidence of recent and ongoing admixture in the U.S. and influences on health and disparities.

Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes.

Cost-effective and scalable clonal hematopoiesis assay provides insight into clonal dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable.