Publications by authors named "Dan M Roden"

453 Publications

Heart failure clinical care analysis uncovers risk reduction opportunities for preserved ejection fraction subtype.

Sci Rep 2021 Sep 20;11(1):18618. Epub 2021 Sep 20.

Department of Medicine, Vanderbilt University Medical Center, 1285 Medical Research Building IV, Nashville, TN, 37232, USA.

Heart failure (HF) has no cure and, for HF with preserved ejection fraction (HFpEF), no life-extending treatments. Defining the clinical epidemiology of HF could facilitate earlier identification of high-risk individuals. We define the clinical epidemiology of HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]), identified among 2.7 million individuals receiving routine clinical care. Differences in patterns and rates of accumulation of comorbidities, frequency of hospitalization, use of specialty care, were defined for each HF subtype. Among 28,156 HF cases, 8322 (30%) were HFpEF and 11,677 (42%) were HFrEF. HFpEF was the more prevalent subtype among older women. 177 Phenotypes differentially associated with HFpEF versus HFrEF. HFrEF was more frequently associated with diagnoses related to ischemic cardiac injury while HFpEF was associated more with non-cardiac comorbidities and HF symptoms. These comorbidity patterns were frequently present 3 years prior to a HFpEF diagnosis. HF subtypes demonstrated distinct patterns of clinical co-morbidities and disease progression. For HFpEF, these comorbidities were often non-cardiac and manifested prior to the onset of a HF diagnosis. Recognizing these comorbidity patterns, along the care continuum, may present a window of opportunity to identify individuals at risk for developing incident HFpEF.
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http://dx.doi.org/10.1038/s41598-021-97831-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452678PMC
September 2021

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

JAMA Cardiol 2021 Sep 8. Epub 2021 Sep 8.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.

Objective: To examine the results of genetic testing for early-onset AF.

Design, Setting, And Participants: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.

Exposures: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main Outcomes And Measures: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

Results: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions And Relevance: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.
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http://dx.doi.org/10.1001/jamacardio.2021.3370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427496PMC
September 2021

Deep learning analysis of electrocardiogram for risk prediction of drug-induced arrhythmias and diagnosis of long QT syndrome.

Eur Heart J 2021 10;42(38):3948-3961

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Aims: Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, QTc has a low positive predictive value.

Methods And Results: We used convolutional neural network (CNN) models to quantify ECG alterations induced by sotalol, an IKr blocker associated with TdP, aiming to provide new tools (CNN models) to enhance the prediction of drug-induced TdP (diTdP) and diagnosis of cLQTS. Tested CNN models used single or multiple 10-s recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n = 14 135 ECGs); 487 cLQTS patients (n = 1083 ECGs: 560 type 1, 456 type 2, 67 type 3); and 48 patients with diTdP (n = 1105 ECGs, with 147 obtained within 48 h of a diTdP episode). CNN models outperformed models using QTc to identify exposure to sotalol [area under the receiver operating characteristic curve (ROC-AUC) = 0.98 vs. 0.72, P ≤ 0.001]. CNN models had higher ROC-AUC using multiple vs. single 10-s ECG (P ≤ 0.001). Performances were comparable for 8-lead vs. single-lead models. CNN models predicting sotalol exposure also accurately detected the presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC = 0.9) and were greatest shortly after a diTdP event and declining over time (P ≤ 0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake.

Conclusion: CNN models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT interval, congenital LQTS, and are greatest shortly after a diTdP episode.
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http://dx.doi.org/10.1093/eurheartj/ehab588DOI Listing
October 2021

Polygenic Risk Score to Identify Subclinical Coronary Heart Disease Risk in Young Adults.

Circ Genom Precis Med 2021 Oct 31;14(5):e003341. Epub 2021 Aug 31.

Department of Medicine (Q.S.W., M.B., A.W.A., D.K.G., C.M. Shaffer, W.-Q.W., N.S.V., C.M. Stein, D.M.R., J.D.M.), Vanderbilt University Medical Center.

Background: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known.

Methods: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both.

Results: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor-based model were 0.015 (0.004-0.028) and 0.020 (0.001-0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033-0.109) and 0.051 (0.017-0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (-0.006 to 0.054) in CARDIA and 0.039 (0.0005-0.072) in FOS.

Conclusions: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.
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http://dx.doi.org/10.1161/CIRCGEN.121.003341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530876PMC
October 2021

2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device.

Trials 2021 Aug 28;22(1):576. Epub 2021 Aug 28.

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules.

Methods: The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch.

Discussion: The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF.

Trial Registration: ClinicalTrials.gov NCT04433091 . Registered on June 3, 2020.
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http://dx.doi.org/10.1186/s13063-021-05553-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403349PMC
August 2021

Recurrent Pregnancy Loss and Concealed Long-QT Syndrome.

J Am Heart Assoc 2021 Sep 16;10(17):e021236. Epub 2021 Aug 16.

Institute of Biomedicine and Translational Medicine University of Tartu Estonia.

Background Recurrent pregnancy loss affects 1% to 2% of couples attempting childbirth. A large fraction of all cases remains idiopathic, which warrants research into monogenic causes of this distressing disorder. Methods and Results We investigated a nonconsanguineous Estonian family who had experienced 5 live births, intersected by 3 early pregnancy losses, and 6 fetal deaths, 3 of which occurred during the second trimester. No fetal malformations were described at the autopsies performed in 3 of 6 cases of fetal death. Parental and fetal chromosomal abnormalities (including submicroscopic) and maternal risk factors were excluded. Material for genetic testing was available from 4 miscarried cases (gestational weeks 11, 14, 17, and 18). Exome sequencing in 3 pregnancy losses and the mother identified no rare variants explicitly shared by the miscarried conceptuses. However, the mother and 2 pregnancy losses carried a heterozygous nonsynonymous variant, resulting in p.Val173Asp () in the ion channel gene . It is expressed not only in heart, where mutations cause type 1 long-QT syndrome, but also in other tissues, including uterus. The p.Val173Asp variant has been previously identified in a patient with type 1 long-QT syndrome, but not reported in the Genome Aggregation Database. With heterologous expression in CHO cells, our in vitro electrophysiologic studies indicated that the mutant slowly activating voltage-gated K+ channel () is dysfunctional. It showed reduced total activating and deactivating currents (<0.01), with dramatically positive shift of voltage dependence of activation by ≈10 mV (<0.05). Conclusions The current study uncovered concealed maternal type 1 long-QT syndrome as a potential novel cause behind recurrent fetal loss.
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http://dx.doi.org/10.1161/JAHA.121.021236DOI Listing
September 2021

Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study.

Eur Heart J 2021 10;42(38):3915-3928

INSERM, CIC-1901, Sorbonne Université, AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, CLIP² Galilée, Regional Pharmacovigilance Center, UNICO-GRECO Cardio-Oncology Program, Paris 75013, France.

Aims: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).

Methods And Results: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.

Conclusion: This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.

Clinical Trial Registration: NCT03530215.
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http://dx.doi.org/10.1093/eurheartj/ehab362DOI Listing
October 2021

Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare Variants.

Circ Genom Precis Med 2021 Aug 26;14(4):e003289. Epub 2021 Jul 26.

Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Departments of Medicine & Pharmacology (K.K., Y.W., C.E., M.J.O., A.M.G., J.D.M., D.M.R., B.C.K., B.M.K.), Vanderbilt University Medical Center, Nashville, TN.

Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene was diagnostically predictive for the autosomal dominant long QT syndrome.

Methods: We estimated the probability of a long QT diagnosis given the presence of each variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants.

Results: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations.

Conclusions: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.
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http://dx.doi.org/10.1161/CIRCGEN.120.003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373797PMC
August 2021

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

Circ Arrhythm Electrophysiol 2021 Jul 9;14(7):e009726. Epub 2021 Jul 9.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (W.Z.).

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
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http://dx.doi.org/10.1161/CIRCEP.120.009726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301722PMC
July 2021

Quinidine in the Management of Recurrent Ventricular Arrhythmias: A Reappraisal.

JACC Clin Electrophysiol 2021 10 30;7(10):1254-1263. Epub 2021 Jun 30.

Cardiovascular Division, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

Objectives: This study aimed to review the utility of quinidine in patients presenting with recurrent sustained ventricular arrhythmia (VA) and limited antiarrhythmic drug (AAD) options.

Background: Therapeutic options are often limited in patients with structural heart disease and recurrent VAs. Quinidine has an established role in rare arrhythmic syndromes, but its potential use in other difficult VAs has not been assessed in the present era.

Methods: We performed a retrospective analysis of 37 patients who had in-hospital quinidine initiation after multiple other therapies failed for VA suppression at our tertiary referral center. Clinical data and outcomes were obtained from the medical record.

Results: Of 30 patients with in-hospital quantifiable VA episodes, quinidine reduced acute VA from a median of 3 episodes (interquartile range [IQR]: 2 to 7.5) to 0 (IQR: 0 to 0.5) during medians of 3 days before and 4 days after quinidine initiation (p < 0.001). VA events decreased from a median of 10.5 episodes per day (IQR: 5 to 15) to 0.5 episodes (IQR: 0 to 4) after quinidine initiation in the 12 patients presenting with electrical storm (p = 0.004). Among the 24 patients discharged on quinidine, 13 (54.2%) had VA recurrence during a median of 138 days. Adverse effects in 9 of the 37 patients (24.3%) led to drug discontinuation, most commonly gastrointestinal intolerance.

Conclusions: In patients with recurrent VAs and structural heart disease who have limited treatment options, quinidine can be useful, particularly as a short-term therapy.
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http://dx.doi.org/10.1016/j.jacep.2021.03.024DOI Listing
October 2021

Machine Learning Challenges in Pharmacogenomic Research.

Clin Pharmacol Ther 2021 09 3;110(3):552-554. Epub 2021 Jul 3.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.2329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376798PMC
September 2021

Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients.

JAMA Intern Med 2021 Aug;181(8):1100-1105

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count.

Objective: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count.

Design, Setting, And Participants: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children's Hospital of Philadelphia from January 1, 1998, to December 31, 2020.

Exposure: The rs2814778-CC genotype.

Main Outcomes And Measures: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result.

Results: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001).

Conclusions And Relevance: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.
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http://dx.doi.org/10.1001/jamainternmed.2021.3108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239990PMC
August 2021

Genome-Wide Approach to Measure Variant-Based Heritability of Drug Outcome Phenotypes.

Clin Pharmacol Ther 2021 09 12;110(3):714-722. Epub 2021 Jul 12.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Pharmacogenomic studies have successfully identified variants-typically with large effect sizes in drug target and metabolism enzymes-that predict drug outcome phenotypes. However, these variants may account for a limited proportion of phenotype variability attributable to the genome. Using genome-wide common variation, we measured the narrow-sense heritability ( ) of seven pharmacodynamic and five pharmacokinetic phenotypes across three cardiovascular drugs, two antibiotics, and three immunosuppressants. We used a Bayesian hierarchical mixed model, BayesR, to model the distribution of genome-wide variant effect sizes for each drug phenotype as a mixture of four normal distributions of fixed variance (0, 0.01%, 0.1%, and 1% of the total additive genetic variance). This model allowed us to parse into bins representing contributions of no-effect, small-effect, moderate-effect, and large-effect variants, respectively. For the 12 phenotypes, a median of 969 (range 235-6,304) unique individuals of European ancestry and a median of 1,201,626 (range 777,427-1,514,275) variants were included in our analyses. The number of variants contributing to ranged from 2,791 to 5,356 (median 3,347). Estimates for ranged from 0.05 (angiotensin-converting enzyme inhibitor-induced cough) to 0.59 (gentamicin concentration). Small-effect and moderate-effect variants contributed a majority to for every phenotype (range 61-95%). We conclude that drug outcome phenotypes are highly polygenic. Thus, larger genome-wide association studies of drug phenotypes are needed both to discover novel variants and to determine how genome-wide approaches may improve clinical prediction of drug outcomes.
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http://dx.doi.org/10.1002/cpt.2323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376753PMC
September 2021

High-throughput framework for genetic analyses of adverse drug reactions using electronic health records.

PLoS Genet 2021 06 1;17(6):e1009593. Epub 2021 Jun 1.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using "drug allergy" labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center's BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10-8, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine.
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http://dx.doi.org/10.1371/journal.pgen.1009593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195357PMC
June 2021

Pleiotropy of systemic lupus erythematosus risk alleles and cardiometabolic disorders: A phenome-wide association study and inverse-variance weighted meta-analysis.

Lupus 2021 Jul 12;30(8):1264-1272. Epub 2021 May 12.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, USA.

Objectives: To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders.

Methods: Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis.

Results: The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold.

Conclusion: A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.
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http://dx.doi.org/10.1177/09612033211014952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205989PMC
July 2021

Genetic Thyrotropin Regulation of Atrial Fibrillation Risk Is Mediated Through an Effect on Height.

J Clin Endocrinol Metab 2021 06;106(7):2124-2132

Department of Biomedical Informatics & Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Context: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms.

Objective: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk.

Methods: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH.

Results: Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association.

Conclusion: The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone-level elevations in later life.
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http://dx.doi.org/10.1210/clinem/dgab272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208678PMC
June 2021

Loperamide Induced Recurrent Torsades de Pointes: A Case Report.

J Pharm Pract 2021 Mar 29:8971900211004832. Epub 2021 Mar 29.

Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Purpose: A case of loperamide-induced recurrent torsades de pointes is reported to raise awareness of an increasingly common phenomenon that could be encountered by medical providers during the current opioid epidemic.

Summary: A 40 year-old-man with a prior history of opioid abuse who presented to the emergency department after taking up to 100 tablets of loperamide 2 mg daily for 5 years to blunt opioid withdrawal symptoms and was subsequently admitted to the intensive care unit for altered mental status and hyperthermia. The patient had prolonged QTc and 2 episodes of torsades de pointes (TdP) that resulted in cardiac arrest with return of spontaneous circulation. He was managed with isoproterenol, overdrive pacing, and methylnatrexone with no other events of TdP or cardiac arrest.

Conclusion: A 40-year-old male who developed torsades de pointes from loperamide overdose effectively treated with overdrive pacing, isoproterenol, and methylnatrexone.
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http://dx.doi.org/10.1177/08971900211004832DOI Listing
March 2021

Evidence for Pharmacogenomic Effects on Risperidone Outcomes in Pediatrics.

J Dev Behav Pediatr 2021 04;42(3):205-212

Departments of Pediatrics.

Objective: To determine the association between genetic variants reported to affect risperidone and adverse events (AEs) in children and adolescents.

Methods: Individuals aged 18 years or younger with ≥4 weeks of risperidone exposure in a deidentified DNA biobank were included. The primary outcome was AE frequency as a function of genotype. Individuals were classified according to metabolizer status for CYP2D6, CYP3A4, and CYP3A5; wild type, heterozygote, or homozygote for specific single nucleotide variants for DRD2, DRD3, HTR2A, and HTR2C; and wild type versus nonwild type for multiple uncommon variants in ABCG2, ABCB1, and HTR2C. Tests of association of each classification to AEs were performed using a Fisher exact test and logistic regression, and statistically significant classifications were included in a final logistic regression.

Results: The final cohort included 257 individuals. AEs were more common in CYP2D6 poor/intermediate metabolizers (PMs/IMs) than normal/rapid/ultrarapid metabolizers (NMs/RMs/UMs) in univariate and multivariate analysis. HTR2A-rs6311 heterozygotes and homozygotes had fewer AEs than wild types in logistic regression but not in univariate analysis. In the final multivariable model adjusting for age, race, sex, and risperidone dose, AEs were associated with CYP2D6 (adjusted odds ratio [AOR] 2.6, 95% CI 1.1-5.5, for PMs/IMs vs. NMs/RMs/UMs) and HTR2A-rs6311 (AOR 0.6, 95% CI 0.4-0.9, for each variant allele), both consistent with previous studies.

Conclusion: Children and adolescents who are CYP2D6 PMs/IMs may have an increased risk for risperidone AEs. Of the genes and variants studied, only CYP2D6 has consistent association and sufficient data for clinical use, whereas HTR2A-rs6311 has limited data and requires further study.
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http://dx.doi.org/10.1097/DBP.0000000000000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995603PMC
April 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 05;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

DDIWAS: High-throughput electronic health record-based screening of drug-drug interactions.

J Am Med Inform Assoc 2021 07;28(7):1421-1430

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list.

Materials And Methods: To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature.

Results: DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available.

Conclusions: In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.
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http://dx.doi.org/10.1093/jamia/ocab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279788PMC
July 2021

The Case for Expanding the FDA Box Warning on Clopidogrel to CYP2C19 Intermediate Metabolizers.

Clin Pharmacol Ther 2021 10 10;110(4):860-862. Epub 2021 Mar 10.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.2215DOI Listing
October 2021

Predictive Accuracy of a Polygenic Risk Score for Postoperative Atrial Fibrillation After Cardiac Surgery.

Circ Genom Precis Med 2021 04 1;14(2):e003269. Epub 2021 Mar 1.

Biomedical Informatics (J.H., L.B., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

Background: Postoperative atrial fibrillation (PoAF) remains a significant risk factor for increased morbidity and mortality after cardiac surgery. The ability to accurately identify patients at risk through clinical risk factors is limited. There is growing evidence that polygenic risk contributes significantly to PoAF and incorporating measures of genetic risk could enhance prediction.

Methods: A retrospective cohort study of 1047 patients of White European ancestry who underwent either coronary artery bypass grafting or valve surgery at a tertiary academic center and were free from a history or persistent preoperative atrial fibrillation. The primary outcome was defined as PoAF based on postoperative ECG reports, medical record documentation, and changes in medication. The exposure was a polygenic risk score (PRS) comprising 2746 single-nucleotide polymorphisms previously associated with atrial fibrillation risk. The prediction of PoAF risk was assessed using measures of model discrimination, calibration, and net reclassification improvement.

Results: A total of 259 patients (24.7%) developed PoAF. The PRS was significantly associated with a higher risk for PoAF (odds ratio, 1.63 per SD increase in PRS [95% CI, 1.41-1.90]). Addition of PRS to patient- and procedure-related predictors of PoAF significantly increased the C statistic from 0.742 to 0.782 (change in C statistic, 0.040 [95% CI, 0.021-0.060]) while maintaining good calibration. The addition of the PRS to patient- and procedure-related predictors of PoAF improved model fit (likelihood ratio test, =2.8×10) and significantly improved measures of reclassification (net reclassification improvement, 0.158 [95% CI, 0.066-0.274]).

Conclusions: The PRS for PoAF was associated with improved discrimination, calibration, and risk reclassification compared with conventional clinical predictors suggesting that a PoAF PRS may enhance risk prediction of PoAF in patients undergoing coronary artery bypass grafting or valve surgery.
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http://dx.doi.org/10.1161/CIRCGEN.120.003269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058298PMC
April 2021

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

J Biomed Inform 2021 01 10;113:103657. Epub 2020 Dec 10.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Objective: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data.

Materials And Methods: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis.

Results: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online.

Conclusion: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.
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http://dx.doi.org/10.1016/j.jbi.2020.103657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728428PMC
January 2021

Pharmacogenetics to Predict Adverse Events Associated With Antidepressants.

Pediatrics 2020 12;146(6)

Departments of Pediatrics.

Objectives: To determine the association between cytochrome P450 2C19 (CYP2C19) metabolizer status and risk for escitalopram and citalopram, collectively termed (es)citalopram, and sertraline adverse events (AEs) in children.

Methods: In this retrospective cohort study, we used deidentified electronic health records linked to DNA. The cohort included children ≤18 years with ≥2 days of (es)citalopram or ≥7 days of sertraline exposure. The primary outcome was AEs assessed by manual chart review. was genotyped for functional variants (*2, *3, *4, *6, *8, and *17), and individuals were assigned metabolizer status. Association between AEs and metabolizer status was determined by using Cox regression adjusting for age, race, ethnicity, dose, and concomitant CYP2C19-inhibiting medications.

Results: The cohort included 249 sertraline-exposed and 458 (es)citalopram-exposed children, with a median age of 14.2 years (interquartile range 11.2-16.2) and 13.4 years (interquartile range 10.1-15.9), respectively. Sertraline AEs were more common in normal metabolizers (NMs) compared to poor metabolizers (PMs) or intermediate metabolizers (IMs) (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.01-3.2; = .047) in unadjusted analysis and after adjustment (HR 1.9; CI 1.04-3.4; = .04). For (es)citalopram, more AEs were observed in NMs than PMs and IMs without statistically significant differences (unadjusted HR 1.6; CI 0.95-2.6;  = .08; adjusted HR 1.6; CI 0.95-2.6;  = .08).

Conclusions: In contrast to adults, in our pediatric cohort, CYP2C19 NMs experienced increased sertraline AEs than PMs and IMs. (Es)citalopram AEs were not associated with CYP2C19 status in the primary analysis. The mechanism underlying this pediatric-specific finding is unknown but may be related to physiologic differences of adolescence. Further research is required to inform genotype-guided prescribing for these drugs in children.
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http://dx.doi.org/10.1542/peds.2020-0957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786826PMC
December 2020

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).

Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

PheMap: a multi-resource knowledge base for high-throughput phenotyping within electronic health records.

J Am Med Inform Assoc 2020 11;27(11):1675-1687

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objective: Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach that leverages multiple independent, online resources to streamline the phenotyping process within EHRs.

Materials And Methods: PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype's quantified concepts and uses them to calculate an individual's probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2.

Results: In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online.

Conclusions: PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.
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http://dx.doi.org/10.1093/jamia/ocaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751140PMC
November 2020
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