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Development and Validation of the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) Equations

Khan, Sadiya S; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Grams, Morgan E; Surapaneni, Aditya; Blaha, Michael J; Carson, April P; Chang, Alexander R; Ciemins, Elizabeth; Go, Alan S; Gutierrez, Orlando M; Hwang, Shih-Jen; Jassal, Simerjot K; Kovesdy, Csaba P; Lloyd-Jones, Donald M; Shlipak, Michael G; Palaniappan, Latha P; Sperling, Laurence; Virani, Salim S; Tuttle, Katherine; Neeland, Ian J; Chow, Sheryl L; Rangaswami, Janani; Pencina, Michael J; Ndumele, Chiadi E; Coresh, Josef; ,
PMID: 37947085
ISSN: 1524-4539
CID: 5607782

A probabilistic computation framework to estimate the dawn phenomenon in type 2 diabetes using continuous glucose monitoring

Barua, Souptik; Glantz, Namino; Larez, Arianna; Bevier, Wendy; Sabharwal, Ashutosh; Kerr, David
In type 2 diabetes (T2D), the dawn phenomenon is an overnight glucose rise recognized to contribute to overall glycemia and is a potential target for therapeutic intervention. Existing CGM-based approaches do not account for sensor error, which can mask the true extent of the dawn phenomenon. To address this challenge, we developed a probabilistic framework that incorporates sensor error to assign a probability to the occurrence of dawn phenomenon. In contrast, the current approaches label glucose fluctuations as dawn phenomena as a binary yes/no. We compared the proposed probabilistic model with a standard binary model on CGM data from 173 participants (71% female, 87% Hispanic/Latino, 54 ± 12 years, with either a diagnosis of T2D for six months or with an elevated risk of T2D) stratified by HbA1c levels into normal but at risk for T2D, with pre-T2D, or with non-insulin-treated T2D. The probabilistic model revealed a higher dawn phenomenon frequency in T2D [49% (95% CI 37-63%)] compared to pre-T2D [36% (95% CI 31-48%), p = 0.01] and at-risk participants [34% (95% CI 27-39%), p < 0.0001]. While these trends were also found using the binary approach, the probabilistic model identified significantly greater dawn phenomenon frequency than the traditional binary model across all three HbA1c sub-groups (p < 0.0001), indicating its potential to detect the dawn phenomenon earlier across diabetes risk categories.
PMID: 38316854
ISSN: 2045-2322
CID: 5632842

Trial Emulation Methods

Shin, Jung-Im; Grams, Morgan E
PMID: 37783304
ISSN: 1523-6838
CID: 5614162

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events

Myers, Rachel A; Ortel, Thomas L; Waldrop, Alexander; Cornwell, MacIntosh; Newman, Jonathan D; Levy, Natalie K; Barrett, Tessa J; Ruggles, Kelly; Sowa, Marcin A; Dave, Sandeep; Ginsburg, Geoffrey S; Berger, Jeffrey S; Voora, Deepak
BACKGROUND/UNASSIGNED:Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. METHODS/UNASSIGNED:Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. RESULTS/UNASSIGNED:Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. CONCLUSIONS/UNASSIGNED:Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.
PMID: 38059352
ISSN: 1524-4636
CID: 5591292

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C

Fu, Edouard L; Carrero, Juan-Jesus; Sang, Yingying; Evans, Marie; Ishigami, Junichi; Inker, Lesley A; Grams, Morgan E; Levey, Andrew S; Coresh, Josef; Ballew, Shoshana H
BACKGROUND/UNASSIGNED:), which may be less accurate in older adults. OBJECTIVE/UNASSIGNED:) and 8 outcomes. DESIGN/UNASSIGNED:Population-based cohort study. SETTING/UNASSIGNED:Stockholm, Sweden, 2010 to 2019. PARTICIPANTS/UNASSIGNED:82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS/UNASSIGNED:Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS/UNASSIGNED:, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION/UNASSIGNED:No GFR measurements. CONCLUSION/UNASSIGNED:was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE/UNASSIGNED:Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.
PMID: 38285982
ISSN: 1539-3704
CID: 5627392

Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells

Calderon, Alexander; Mestvirishvili, Tamara; Boccalatte, Francesco; Ruggles, Kelly V; David, Gregory
BACKGROUND:Blood homeostasis requires the daily production of millions of terminally differentiated effector cells that all originate from hematopoietic stem cells (HSCs). HSCs are rare and exhibit unique self-renewal and multipotent properties, which depend on their ability to maintain quiescence through ill-defined processes. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignancy. In particular, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Previous studies have identified chromatin coordination as a key regulator of differentiation in embryonic stem cells. RESULTS:phase of the cell cycle, which correlates with the engagement of specific signaling pathways, including aberrant expression of cell adhesion molecules and the interferon signaling program in LT-HSCs. In addition, we uncover the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, which points to cell cycle progression possibly dictating the priming of HSCs for differentiation. CONCLUSIONS:Our findings provide new insights into controlled cell cycle progression as a potential regulator of HSC lineage commitment through the modulation of chromatin features.
PMID: 38254205
ISSN: 1756-8935
CID: 5624732

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study

Xu, Yunwen; Boyle, Thomas A.; Lyu, Beini; Ballew, Shoshana H.; Selvin, Elizabeth; Chang, Alexander R.; Inker, Lesley A.; Grams, Morgan E.; Shin, Jung Im
Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. Objective: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. Design: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. Participants: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. Exposures: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. Main Measures: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. Key Results: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). Conclusions: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.
ISSN: 0884-8734
CID: 5630152

Eicosanoids and related metabolites associated with end stage kidney disease in a community-based cohort

Surapaneni, Aditya L; Schlosser, Pascal; Rhee, Eugene P; Cheng, Susan; Jain, Mohit; Alotaiabi, Mona; Coresh, Josef; Grams, Morgan E
BACKGROUND:Eicosanoids are derivatives of polyunsaturated fatty acids (PUFAs) and participate in the inflammatory response as well as the maintenance of endothelial function. Specific eicosanoids have been linked to various diseases, including hypertension and asthma, and may also reduce renal blood flow. A systematic investigation of eicosanoid-related metabolites and adverse kidney outcomes could identify key mediators of kidney disease and inform ongoing work in drug development. METHODS:Profiling of eicosanoid-related metabolites was performed in 9,650 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 2; mean age, 57 years). The associations between metabolite levels and the development of end-stage kidney disease (ESKD) was investigated using a series of progressively adjusted models and Cox proportional hazards regression (N= 256 events; median follow-up, 25.5 years). Metabolites with statistically significant associations with ESKD were evaluated for a potential causal role using bidirectional Mendelian randomization techniques, linking genetic instruments for eicosanoid levels to genome-wide association study summary statistics of estimated glomerular filtration rate (eGFR). RESULTS:The 223 eicosanoid-related metabolites that were profiled and passed QC were generally uncorrelated with eGFR in cross-sectional analyses (median Spearman correlation, -0.03; IQR -0.05 to 0.002). In models adjusted for multiple covariates, including baseline eGFR, three metabolites had statistically significant associations with ESKD (p-value <0.05/223). These included a hydroxyoctadecenoic acid, a dihydroxydocosapentaenoic acid, and arachidonic acid, with higher levels of the former two protective against ESKD and higher levels of arachidonic acid having a positive association with risk of ESKD. Mendelian randomization analyses suggested a causal role for the hydroxyoctadecenoic and arachidonic acid in determining eGFR. Spectral analysis identified the former metabolite as either 11-hydroxy-9-octadecenoic acid or 10-hydroxy-11-octadecenoic acid. CONCLUSIONS:High throughput eicosanoid profiling can identify metabolites that may play a protective role in the development of kidney disease.
PMID: 38047655
ISSN: 2641-7650
CID: 5583422

3D Enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages

Murphy, Dylan; Salataj, Eralda; Di Giammartino, Dafne Campigli; Rodriguez-Hernaez, Javier; Kloetgen, Andreas; Garg, Vidur; Char, Erin; Uyehara, Christopher M; Ee, Ly-Sha; Lee, UkJin; Stadtfeld, Matthias; Hadjantonakis, Anna-Katerina; Tsirigos, Aristotelis; Polyzos, Alexander; Apostolou, Effie
Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates. We observe extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, which strongly associate with transcriptional changes, although distinct groups of genes are irresponsive to topological changes. In each lineage, a high degree of connectivity, or 'hubness', positively correlates with levels of gene expression and enriches for cell-type specific and essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation across lineages compared to genes in linear proximity or within the same contact domains. By incorporating 3D chromatin features, we build a predictive model for transcriptional regulation (3D-HiChAT) that outperforms models using only 1D promoter or proximal variables to predict levels and cell-type specificity of gene expression. Using 3D-HiChAT, we identify, in silico, candidate functional enhancers and hubs in each cell lineage, and with CRISPRi experiments, we validate several enhancers that control gene expression in their respective lineages. Our study identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to comprehensively understand lineage-specific transcriptional behaviors.
PMID: 38053013
ISSN: 1545-9985
CID: 5595532

Baclofen and the risk of fall and fracture in older adults: A real-world cohort study

Hwang, Y Joseph; Chang, Alex R; Brotman, Daniel J; Inker, Lesley A; Grams, Morgan E; Shin, Jung-Im
BACKGROUND:The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs' adverse sedative effects. Baclofen is a gamma-aminobutyric acid agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other muscle relaxants (tizanidine or cyclobenzaprine) in older adults. METHODS:We designed a new-user, active-comparator study using tertiary health system data from Geisinger Health, Pennsylvania (January 2005 through December 2018). Older adults (aged ≥65 years) newly treated with baclofen, tizanidine, or cyclobenzaprine were included. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the treatment groups on 58 baseline characteristics. Fine-Gray competing risk regression was used to estimate the risk of fall and fracture. RESULTS:The study cohort comprised of 2205 new baclofen users, 1103 new tizanidine users, and 9708 new cyclobenzaprine users. During a median follow-up of 100 days, baclofen was associated with a higher risk of fall compared to tizanidine (IPTW incidence rate, 108.4 vs. 61.9 per 1000 person-years; subdistribution hazard ratio [SHR], 1.68 [95% CI, 1.20-2.36]). The risk of fall associated with baclofen was comparable to cyclobenzaprine (SHR, 1.17 [95% CI, 0.93-1.47]) with a median follow-up of 106 days. The risk of fracture was similar among patients treated with baclofen versus tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) or cyclobenzaprine (SHR, 0.85 [95% CI, 0.67-1.07]). CONCLUSIONS:The risk of fall associated with baclofen was greater than tizanidine, but not compared to cyclobenzaprine in older adults. The risk of fracture was comparable among the older users of baclofen, tizanidine, and cyclobenzaprine. Our findings may inform risk-benefit considerations in the increasingly common clinical encounters where oral muscle relaxants are prescribed.
PMID: 37933734
ISSN: 1532-5415
CID: 5624322