Publications by authors named "Amit Khera"

258 Publications

OPTIMIZING THE POTENTIAL FOR TELEHEALTH IN CARDIOVASCULAR CARE (IN THE ERA OF COVID-19): TIME WILL TELL.

Am J Med 2021 Apr 9. Epub 2021 Apr 9.

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Before the COVID-19 pandemic, use of telehealth services had been limited in cardiovascular care. Potential benefits of telehealth include improved access to care, more efficient care management, reduced costs, the ability to assess patients within their homes while involving key caretakers in medical decisions, maintaining social distancing, and increased patient satisfaction. Challenges include changes in payment models, issues with data security and privacy, potential depersonalization of the patient-clinician relationship, limitations in the use of digital health technologies, and the potential impact on disparities - socioeconomic, gender, age-related, and access to technology and broadband. Implementation and expansion of telehealth from a policy and reimbursement practice standpoint are filled with difficult decisions, yet addressing these are critical to the future of healthcare.
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http://dx.doi.org/10.1016/j.amjmed.2021.03.007DOI Listing
April 2021

Concordance of a High Polygenic Score Among Relatives: Implications for Genetic Counseling and Cascade Screening.

Circ Genom Precis Med 2021 Apr 2:CIRCGEN120003262. Epub 2021 Apr 2.

Department of Medicine, Harvard Medical School, Center for Genomic Medicine and Division of Cardiology, Massachusetts General Hospital, Boston (D.G.B., C.E.L., R.P., A.V.K.).

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http://dx.doi.org/10.1161/CIRCGEN.120.003262DOI Listing
April 2021

Improving reporting standards for polygenic scores in risk prediction studies.

Nature 2021 Mar 10;591(7849):211-219. Epub 2021 Mar 10.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
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http://dx.doi.org/10.1038/s41586-021-03243-6DOI Listing
March 2021

U.S. population at increased risk of severe illness from COVID-19.

Am J Prev Cardiol 2021 Jun 13;6:100156. Epub 2021 Feb 13.

Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States.

Background: The U.S. Centers for Disease Control and Prevention (CDC) recognizes that older adults and individuals with certain medical conditions are at increased risk of severe COVID-19 infection. Understanding the proportion of the population at risk of severe infection, including among those with heart disease, could assist current vaccine strategy efforts.

Methods: Using data from the 2015-2018 National Health and Nutrition Examination Survey (NHANES), we estimated the weighted prevalence of any of eight of eleven increased-risk conditions (including age ≥65) in U.S. adults aged ≥18 ( = 10,581) and extrapolated these results to a population of 233.8 million U.S. adults ≥18, and subgroups from the overall population defined by race/ethnicity, education, income and history of heart disease.

Results: An estimated 176.1 million individuals representing 75.4% of U.S. adults had at least one increased-risk condition, 40.3% ≥2 and, 18.5% ≥3 conditions. Approximately 129 million adults aged <65 (69.2%) were also estimated to be at increased-risk. Compared to Whites, similar proportions of Blacks in the overall population (78.0 vs. 75.6%, >0.05) and Hispanics in the younger population (70.8 vs 68.4%) were estimated to be at increased-risk. Conversely, a greater proportion of individuals with lower education and income levels were estimated to be at increased-risk both in the overall and younger population. In addition, an estimated 6.2 million individuals (14.5%) had heart disease. Among these, virtually all had at least one additional CDC risk factor (97.9%) and most had ≥2 or ≥3 risk factors (83.8% and 58.5%, respectively).

Conclusions: As vaccination strategies are being explored, these results demonstrate that >75% of adults in the U.S. would be considered at increased-risk for severe COVID-19 infection by CDC criteria. Risk factor prevalence alone may not adequately capture the totality of risk, particularly among Black and Hispanic racial/ethnic groups and those with heart disease.
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http://dx.doi.org/10.1016/j.ajpc.2021.100156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880833PMC
June 2021

Effect of micro-osteoperforations on rate of space closure by mini-implant supported maxillary anterior en-masse retraction: A randomized clinical trial.

J Oral Biol Craniofac Res 2021 Apr-Jun;11(2):185-191. Epub 2021 Jan 22.

Department of Orthodontics, Subharti Dental College, Meerut, UP, India.

Background: Micro-osteoperforations is one of the non-invasive surgical techniques used in attempt to accelerate OTM. Conflicting reports on its effectiveness has been reported in the literature.

Objectives: The objectives of this trial were to investigate the effect of micro-osteoperforations on the rate of space closure and on molar anchorage loss during mini-implant supported maxillary anterior en-masse retraction.

Trial Design: A single center, parallel arm, randomized controlled trial was conducted.

Method: Sixty, male and female subjects (age range 16-25 years) having Class I bimaxillary protrusion or Class II div 1 malocclusion, who required fixed mechanotherapy with either upper 1st premolar or all four 1st premolar extractions were allocated into two groups using 1:1 allocation ratio. The allocation was done by block randomization method with a block size of 6. In the experimental group, 5 MOPs per side were performed only once just before the en-masse anterior retraction. Mini-screws were placed in order to obtain maximum anchorage. Impressions were taken every month till 4 months and rate of space closure was measured on 3D study models.

Results: Data of 27 subjects in control (attrition ​= ​3) and 28 subjects in experimental group (attrition ​= ​2) were analyzed at the end of this trial. There was a statistically significant increase in the rate of en-masse retraction for the 1st month(p ​= ​0.001,95%CI, 0.17, 0.37 ​mm) but there was no statistically significant difference for the subsequent 2nd (p ​= ​0.450,95%CI,0.13,0.43 ​mm), 3rd(p ​= ​0.204,95%CI,0.23,0.47 ​mm) and 4th month (p ​= ​0.680,95%CI,0.21,0.41 ​mm) between experimental and control groups. There was also no difference (p ​> ​0.05) in molar anchorage loss between both groups at all time intervals.

Conclusion: Micro-osteoperforations (MOPs) did not accelerate the rate of anterior en-masse retraction over a period of 4 months; however, it temporarily increases the rate of retraction only for first month and no affect on molar anchorage.

Trial Registration: The trial was registered at www.ctri.nic.in with CTRI No- CTRI/2019/03/018140).
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http://dx.doi.org/10.1016/j.jobcr.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868723PMC
January 2021

Genetic Predictor to Identify Individuals With High Lipoprotein(a) Concentrations.

Circ Genom Precis Med 2021 Feb 1;14(1):e003182. Epub 2021 Feb 1.

Center for Genomic Medicine (J.S.D., A.P.P., A.V.K.), Massachusetts General Hospital, Boston.

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http://dx.doi.org/10.1161/CIRCGEN.120.003182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887018PMC
February 2021

Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.

Gastroenterology 2021 Apr 11;160(5):1620-1633.e13. Epub 2020 Dec 11.

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.

Methods: We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.

Results: Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P < .001).

Conclusions: Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.
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http://dx.doi.org/10.1053/j.gastro.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035329PMC
April 2021

Performance of Atrial Fibrillation Risk Prediction Models in Over 4 Million Individuals.

Circ Arrhythm Electrophysiol 2021 Jan 9;14(1):e008997. Epub 2020 Dec 9.

Cardiovascular Disease Initiative, Broad Institute of the Massachusetts Institute of Technology & Harvard University, Cambridge (S.K., J.M.A., A.P., A.V.K., P.T.E., S.A.L.).

Background: Atrial fibrillation (AF) is associated with increased risks of stroke and heart failure. Electronic health record (EHR)-based AF risk prediction may facilitate efficient deployment of interventions to diagnose or prevent AF altogether.

Methods: We externally validated an electronic health record AF (EHR-AF) score in IBM Explorys Life Sciences, a multi-institutional dataset containing statistically deidentified EHR data for over 21 million individuals (Explorys Dataset). We included individuals with complete AF risk data, ≥2 office visits within 2 years, and no prevalent AF. We compared EHR-AF to existing scores including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), CHEST (coronary artery disease or chronic obstructive pulmonary disease, hypertension, elderly, systolic heart failure, thyroid disease), and CHADS-VASc. We assessed association between AF risk scores and 5-year incident AF, stroke, and heart failure using Cox proportional hazards modeling, 5-year AF discrimination using C indices, and calibration of predicted AF risk to observed AF incidence.

Results: Of 21 825 853 individuals in the Explorys Dataset, 4 508 180 comprised the analysis (age 62.5, 56.3% female). AF risk scores were strongly associated with 5-year incident AF (hazard ratio per SD increase 1.85 using CHADS-VASc to 2.88 using EHR-AF), stroke (1.61 using CHEST to 1.92 using CHARGE-AF), and heart failure (1.91 using CHADS-VASc to 2.58 using EHR-AF). EHR-AF (C index, 0.808 [95% CI, 0.807-0.809]) demonstrated favorable AF discrimination compared to CHARGE-AF (0.806 [95% CI, 0.805-0.807]), CHEST (0.683 [95% CI, 0.682-0.684]), and CHADS-VASc (0.720 [95% CI, 0.719-0.722]). Of the scores, EHR-AF demonstrated the best calibration to incident AF (calibration slope, 1.002 [95% CI, 0.997-1.007]). In subgroup analyses, AF discrimination using EHR-AF was lower in individuals with stroke (C index, 0.696 [95% CI, 0.692-0.700]) and heart failure (0.621 [95% CI, 0.617-0.625]).

Conclusions: EHR-AF demonstrates predictive accuracy for incident AF using readily ascertained EHR data. AF risk is associated with incident stroke and heart failure. Use of such risk scores may facilitate decision support and population health management efforts focused on minimizing AF-related morbidity.
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http://dx.doi.org/10.1161/CIRCEP.120.008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856013PMC
January 2021

Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank.

Arterioscler Thromb Vasc Biol 2021 01 29;41(1):465-474. Epub 2020 Oct 29.

Center for Genomic Medicine (A.P.P., J.P.P., P.T.E., A.V.K.), Massachusetts General Hospital, Boston.

Objective: Lp(a) (lipoprotein[a]) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and Results: Relationship of lipoprotein(a) to incident ASCVD was studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6-74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race-median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar-hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44-1.56) and 1.16 (95% CI, 1.05-1.27), respectively.

Conclusions: Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.
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http://dx.doi.org/10.1161/ATVBAHA.120.315291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769893PMC
January 2021

Value of Coronary Artery Calcium Scanning in Association With the Net Benefit of Aspirin in Primary Prevention of Atherosclerotic Cardiovascular Disease.

JAMA Cardiol 2021 Feb;6(2):179-187

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.

Importance: Higher coronary artery calcium (CAC) identifies individuals at increased atherosclerotic cardiovascular disease (ASCVD) risk. Whether it can also identify individuals likely to derive net benefit from aspirin therapy is unclear.

Objective: To examine the association between CAC, bleeding, and ASCVD and explore the net estimated effect of aspirin at different CAC thresholds.

Design, Setting, And Participants: Prospective population-based cohort study of Dallas Heart Study participants, free from ASCVD and not taking aspirin at baseline. Data were analyzed between February 1, 2020, and July 15, 2020.

Exposures: Coronary artery calcium score in the following categories: 0, 1-99, and 100 or higher.

Main Outcomes And Measures: Major bleeding and ASCVD events were identified from International Statistical Classification of Diseases and Related Health Problems, Ninth Revision codes. Meta-analysis-derived aspirin effect estimates were applied to observed ASCVD and bleeding rates to model the net effect of aspirin at different CAC thresholds.

Results: A total of 2191 participants (mean [SD], age 44 [9.1] years, 1247 women [57%], and 1039 black individuals [47%]) had 116 major bleeding and 123 ASCVD events over a median follow-up of 12.2 years. Higher CAC categories (CAC 1-99 and ≥100 vs CAC 0) were associated with both ASCVD and bleeding events (hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; HR, 2.6; 95% CI, 1.5-4.3; HR, 4.8; 95% CI, 2.8-8.2; P < .001; HR, 5.3; 95% CI, 3.6-7.9; P < .001), but the association between CAC and bleeding was attenuated after multivariable adjustment. Applying meta-analysis estimates, irrespective of CAC, aspirin use was estimated to result in net harm in individuals at low (<5%) and intermediate (5%-20%) 10-year ASCVD risk and net benefit in those at high (≥20%) ASCVD risk. Among individuals at lower bleeding risk, a CAC score of at least 100 identified individuals who would experience net benefit, but only in those at borderline or higher (≥5%) 10-year ASCVD risk. In individuals at higher bleeding risk, there would be net harm from aspirin irrespective of CAC and ASCVD risk.

Conclusions And Relevance: Higher CAC is associated with both ASCVD and bleeding events, with a stronger association with ASCVD. A high CAC score identifies individuals estimated to derive net benefit from primary prevention aspirin therapy from those who would not, but only in the setting of lower bleeding risk and estimated ASCVD risk that is not low.
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http://dx.doi.org/10.1001/jamacardio.2020.4939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593878PMC
February 2021

Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.

Arterioscler Thromb Vasc Biol 2020 11 22;40(11):2738-2746. Epub 2020 Sep 22.

Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha (G.H.). Program of Medical and Population Genetics, Broad Institute, Cambridge, MA (K.G.A., M.C., S.K., A.V.K.). Center for Genomic Medicine (K.G.A., A.V.K.) and Division of Cardiology, Department of Medicine (S.K., A.V.K.), Massachusetts General Hospital, Boston. Department of Medicine, Harvard Medical School, Boston, MA (K.G.A., S.K., A.V.K.). Center for Computational Health, IBM Research, Cambridge, MA (K.N.). Regeneron Genetics Center, Tarrytown, NY (L.A.L., A.B.). Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden (I.D., M.O.-M., O.M.).

Objective: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPS decile to 48% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

Conclusions: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.
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http://dx.doi.org/10.1161/ATVBAHA.120.314856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577949PMC
November 2020

Primary Prevention Trial Designs Using Coronary Imaging: A National Heart, Lung, and Blood Institute Workshop.

JACC Cardiovasc Imaging 2020 Sep 11. Epub 2020 Sep 11.

Department of Medicine (Division of Experimental Medicine), McGill University Health Center, Montreal, Quebec, Canada.

Coronary artery calcium (CAC) is considered a useful test for enhancing risk assessment in the primary prevention setting. Clinical trials are under consideration. The National Heart, Lung, and Blood Institute convened a multidisciplinary working group on August 26 to 27, 2019, in Bethesda, Maryland, to review available evidence and consider the appropriateness of conducting further research on coronary artery calcium (CAC) testing, or other coronary imaging studies, as a way of informing decisions for primary preventive treatments for cardiovascular disease. The working group concluded that additional evidence to support current guideline recommendations for use of CAC in middle-age adults is very likely to come from currently ongoing trials in that age group, and a new trial is not likely to be timely or cost effective. The current trials will not, however, address the role of CAC testing in younger adults or older adults, who are also not addressed in existing guidelines, nor will existing trials address the potential benefit of an opportunistic screening strategy made feasible by the application of artificial intelligence. Innovative trial designs for testing the value of CAC across the lifespan were strongly considered and represent important opportunities for additional research, particularly those that leverage existing trials or other real-world data streams including clinical computed tomography scans. Sex and racial/ethnic disparities in cardiovascular disease morbidity and mortality, and inclusion of diverse participants in future CAC trials, particularly those based in the United States, would enhance the potential impact of these studies.
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http://dx.doi.org/10.1016/j.jcmg.2020.06.042DOI Listing
September 2020

Racial and Geographic Disparities in Internet Use in the United States Among Patients with Atherosclerotic Cardiovascular Disease.

Am J Cardiol 2020 11 11;134:146-147. Epub 2020 Aug 11.

Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Health Policy, Quality & Informatics Program, Michael E. DeBakey VA Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas; Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.amjcard.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418766PMC
November 2020

Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.

Circ Genom Precis Med 2020 10 30;13(5):417-423. Epub 2020 Aug 30.

Center for Genomic Medicine (C.A.E., P.N., N.G., S.G., A.V.K., S.K.), Massachusetts General Hospital, Boston.

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
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http://dx.doi.org/10.1161/CIRCGEN.119.002871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983048PMC
October 2020

ASPC President's message: The work must go on.

Authors:
Amit Khera

Am J Prev Cardiol 2020 Jun 24;2:100039. Epub 2020 Jul 24.

Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.

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http://dx.doi.org/10.1016/j.ajpc.2020.100039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377977PMC
June 2020

Continuity of care and outpatient management for patients with and at high risk for cardiovascular disease during the COVID-19 pandemic: A scientific statement from the American Society for Preventive Cardiology.

Am J Prev Cardiol 2020 Mar 1;1:100009. Epub 2020 May 1.

Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA.

The coronavirus disease 2019 (COVID-19) pandemic has consumed our healthcare system, with immediate resource focus on the management of high numbers of critically ill patients. Those that fare poorly with COVID-19 infection more commonly have cardiovascular disease (CVD), hypertension and diabetes. There are also several other conditions that raise concern for the welfare of patients with and at high risk for CVD during this pandemic. Traditional ambulatory care is disrupted and many patients are delaying or deferring necessary care, including preventive care. New impediments to medication access and adherence have arisen. Social distancing measures can increase social isolation and alter physical activity and nutrition patterns. Virtually all facility based cardiac rehabilitation programs have temporarily closed. If not promptly addressed, these changes may result in delayed waves of vulnerable patients presenting for urgent and preventable CVD events. Here, we provide several recommendations to mitigate the adverse effects of these disruptions in outpatient care. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be continued in patients already taking these medications. Where possible, it is strongly preferred to continue visits via telehealth, and patients should be counselled about promptly reporting new symptoms. Barriers to medication access should be reviewed with patients at every contact, with implementation of strategies to ensure ongoing provision of medications. Team-based care should be leveraged to enhance the continuity of care and adherence to lifestyle recommendations. Patient encounters should include discussion of safe physical activity options and access to healthy food choices. Implementation of adaptive strategies for cardiac rehabilitation is recommended, including home based cardiac rehab, to ensure continuity of this essential service. While the practical implementation of these strategies will vary by local situation, there are a broad range of strategies available to ensure ongoing continuity of care and health preservation for those at higher risk of CVD during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.ajpc.2020.100009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194073PMC
March 2020

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.

Nat Commun 2020 08 20;11(1):3635. Epub 2020 Aug 20.

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.
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http://dx.doi.org/10.1038/s41467-020-17374-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441381PMC
August 2020

Predictive Value of Coronary Artery Calcium Score Categories for Coronary Events Versus Strokes: Impact of Sex and Race: MESA and DHS.

Circ Cardiovasc Imaging 2020 08 18;13(8):e010153. Epub 2020 Aug 18.

Division of Cardiology, Department of Internal Medicine (A.P., A.K., P.H.J.), University of Texas Southwestern Medical Center, Dallas.

Background: Coronary artery calcium (CAC) predicts atherosclerotic cardiovascular disease (ASCVD) events, inclusive of coronary heart disease (CHD) and stroke, and is a decision-making aid for primary prevention. The predictive value of CAC categories for CHD and stroke separately and across sex and race groups of an asymptomatic population is unclear.

Methods: White, Black, and Hispanic participants of MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) underwent CAC measurement at enrollment and were followed for incident ASCVD events. Ten-year CHD-to-stroke incidence ratios across CAC score categories 0, 1 to 99, and ≥100 were assessed. Associations of CAC with incident CHD and stroke events were evaluated using multivariable-adjusted Cox models and multiplicative interactions of CAC with sex/race were tested.

Results: Among 7042 participants (mean age, 57 years, 54% women, 36% Black, 23% Hispanic, 49% CAC=0, 19% CAC ≥100), 574 incident ASCVD events (333 CHD and 241 stroke) were observed over 12.3-year follow-up. Ten-year CHD-to-stroke incidence ratio increased significantly across CAC categories in men, women, Whites, Blacks, and Hispanics (all <0.001). High CAC burden (score ≥100) was independently associated with ASCVD and CHD risk in all groups and with stroke risk in the overall cohort and Blacks. No sex- or race-based CAC interactions for ASCVD, CHD, and stroke events were observed. Adding CAC to a traditional risk factor model improved risk discrimination and reclassification for CHD but not for stroke events.

Conclusions: In 2 population-based cohorts of asymptomatic individuals, 10-year CHD-to-stroke incidence ratio was higher with increasing CAC score categories across sex and race groups, and CAC was consistently a better predictor of CHD than stroke. High CAC burden comparably associated with ASCVD risk across sex and race groups.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.010153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440773PMC
August 2020

Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity: A Pooled Cohort Analysis.

Circulation 2020 Aug 18;142(7):657-669. Epub 2020 Jun 18.

University of Texas Southwestern Medical Center, Dallas (K.S., A.C., T.S., P.H.J., A.K., C.R.A., A.R.).

Background: High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C.

Methods: We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke.

Results: In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52-0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61-0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35-0.69]; for Blacks, 1.22 [95% CI, 0.76-1.98]; =0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36-0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08-2.83]; <0.0001).

Conclusions: Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425196PMC
August 2020

Lipoprotein(a) and Family History Predict Cardiovascular Disease Risk.

J Am Coll Cardiol 2020 08;76(7):781-793

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: Elevated lipoprotein(a) (Lp[a]) and family history (FHx) of coronary heart disease (CHD) are individually associated with cardiovascular risk, and Lp(a) is commonly measured in those with FHx.

Objectives: The aim of this study was to determine independent and joint associations of Lp(a) and FHx with atherosclerotic cardiovascular disease (ASCVD) and CHD among asymptomatic subjects.

Methods: Plasma Lp(a) was measured and FHx was ascertained in 2 cohorts. Elevated Lp(a) was defined as the highest race-specific quintile. Independent and joint associations of Lp(a) and FHx with cardiovascular risk were determined using Cox regression models adjusted for cardiovascular risk factors.

Results: Among 12,149 ARIC (Atherosclerosis Risk In Communities) participants (54 years, 56% women, 23% black, 44% with FHx), 3,114 ASCVD events were observed during 21 years of follow-up. FHx and elevated Lp(a) were independently associated with ASCVD (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.09 to 1.26, and HR: 1.25; 95% CI: 1.12 to 1.40, respectively), and no Lp(a)-by-FHx interaction was noted (p = 0.75). Compared with subjects without FHx and nonelevated Lp(a), those with either elevated Lp(a) or FHx were at a higher ASCVD risk, while those with both had the highest risk (HR: 1.43; 95% CI: 1.27 to 1.62). Similar findings were observed for CHD risk in ARIC, in analyses stratified by premature FHx, and in an independent cohort, the DHS (Dallas Heart Study). Presence of both elevated Lp(a) and FHx resulted in greater improvement in ASCVD and CHD risk reclassification and discrimination indexes than either marker alone.

Conclusions: Elevated plasma Lp(a) and FHx have independent and additive joint associations with cardiovascular risk and may be useful concurrently for guiding primary prevention therapy decisions.
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http://dx.doi.org/10.1016/j.jacc.2020.06.040DOI Listing
August 2020

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

J Am Coll Cardiol 2020 08;76(6):703-714

Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

Objectives: This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.

Methods: This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

Results: The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each).

Conclusions: The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.
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http://dx.doi.org/10.1016/j.jacc.2020.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592606PMC
August 2020

Combining Biomarkers and Imaging for Short-Term Assessment of Cardiovascular Disease Risk in Apparently Healthy Adults.

J Am Heart Assoc 2020 08 23;9(15):e015410. Epub 2020 Jul 23.

Department of Medicine University of Texas Southwestern Medical Center Dallas TX.

Background Current strategies for cardiovascular disease (CVD) risk assessment focus on 10-year or longer timeframes. Shorter-term CVD risk is also clinically relevant, particularly for high-risk occupations, but is under-investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi-Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N-terminal pro-B-type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high-sensitivity cardiac troponin T (abnormal >5 ng/L); high-sensitivity C-reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima-media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3-year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3-year multivariable-adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2-, 3-, 4.5- and 8-fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non-fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3-year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.
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http://dx.doi.org/10.1161/JAHA.119.015410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792258PMC
August 2020

Association of depressive symptom severity with coronary artery calcium: The Dallas heart study.

J Affect Disord 2020 11 18;276:267-271. Epub 2020 Jul 18.

Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas,Dallas, TX, USA. Electronic address:

Background: Previous studies have yielded mixed results regarding the relationship between depressive symptoms and coronary artery calcium (CAC). This analysis sought to evaluate this relationship using a multiethnic, population-based cohort.

Methods: Data were extracted from the second phase of the Dallas Heart Study (DHS-2). Depressive symptom severity was measured with the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS), a validated depressive symptom severity scale. A regression analysis was performed using QIDS score as the predictor variable and CAC as the outcome variable. Covariates included age, sex, ethnicity, diabetes, hypertension, smoking, systolic blood pressure, total cholesterol, HDL cholesterol, and body mass index.

Results: The cohort consisted of 2,293 individuals with a mean age of 50 years and included 47.1% female and 47.1% black participants. The mean QIDS score was 4.37(±3.69), and 43.3% had CAC > 0. Regression results indicated that QIDS does not statistically significantly predict whether one does or does not have CAC, when controlling for age, sex, and ethnicity (β = 0.088, p = .240, OR = 1.092, 95% CI 0.943-1.264).

Limitations: Cross sectional design is limited to one point in time, very depressed patients with higher CAC burden may not have participated, and depressive symptoms may be associated with subclinical atherosclerosis differently with a formal diagnosis of depression.

Conclusion: Depressive symptoms were not associated with presence or severity of CAC in a multiethnic population based sample. Future studies are needed to determine if other prognostic markers of coronary heart disease are associated with depressive symptoms.
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http://dx.doi.org/10.1016/j.jad.2020.07.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484243PMC
November 2020

New Recommendations and Revised Concepts in Recent Guidelines on the Management of Dyslipidemias to Prevent Cardiovascular Disease: the 2018 ACC/AHA and 2019 ESC/EAS Guidelines.

Curr Cardiol Rep 2020 07 9;22(9):87. Epub 2020 Jul 9.

Department of Internal Medicine and Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-8830, USA.

Purpose Of Review: The purpose of this review is to discuss the updated guideline recommendations on management of dyslipidemia for prevention and treatment of cardiovascular disease.

Recent Findings: The American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) published revised cholesterol management guidelines in 2018 and 2019, respectively, to reflect new evidence in the field. Broadly speaking, both emphasize refining cardiovascular disease risk estimation and aggressively lowering low-density lipoprotein-cholesterol (LDL-C) with statin and non-statin agents to curb cardiovascular risk. While they share the same guiding principles, there are important differences in the recommendations from both societies including how they define risk categories and goals for LDL-C lowering. This review summarizes current methods of managing dyslipidemia with a focus on the common themes and notable differences between the 2018 ACC/AHA and 2019 ESC/EAS cholesterol management guidelines.
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http://dx.doi.org/10.1007/s11886-020-01331-zDOI Listing
July 2020

Race, socioeconomic deprivation, and hospitalization for COVID-19 in English participants of a national biobank.

Int J Equity Health 2020 07 6;19(1):114. Epub 2020 Jul 6.

Center for Genomic Medicine and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Preliminary reports suggest that the Coronavirus Disease 2019 (COVID- 19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. We investigate the racial and socioeconomic associations of COVID- 19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both Black participants (odds ratio 3.7; 95%CI 2.5-5.3) and Asian participants (odds ratio 2.2; 95%CI 1.5-3.2) were at substantially increased risk as compared to White participants. We further observed a striking gradient in COVID- 19 hospitalization rates according to the Townsend Deprivation Index - a composite measure of socioeconomic deprivation - and household income. Adjusting for socioeconomic factors and cardiorespiratory comorbidities led to only modest attenuation of the increased risk in Black participants, adjusted odds ratio 2.4 (95%CI 1.5-3.7). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-White individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.
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http://dx.doi.org/10.1186/s12939-020-01227-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336098PMC
July 2020

Race, Socioeconomic Deprivation, and Hospitalization for COVID-19 in English participants of a National Biobank.

medRxiv 2020 May 2. Epub 2020 May 2.

Preliminary reports suggest that the Coronavirus Disease 2019 (COVID-19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. The extent to which these disparities are related to socioeconomic versus biologic factors is largely unknown. We investigate the racial and socioeconomic associations of COVID-19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both black participants (odds ratio 3.4; 95%CI 2.4-4.9) and Asian participants (odds ratio 2.1; 95%CI 1.5-3.2) were at substantially increased risk as compared to white participants. We further observed a striking gradient in COVID-19 hospitalization rates according to the Townsend Deprivation Index - a composite measure of socioeconomic deprivation - and household income. Adjusting for such factors led to only modest attenuation of the increased risk in black participants, adjusted odds ratio 3.1 (95%CI 2.0-4.8). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-white individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.
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http://dx.doi.org/10.1101/2020.04.27.20082107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276998PMC
May 2020