Publications by authors named "Carlos Iribarren"

167 Publications

QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System.

J Am Heart Assoc 2021 10 28;10(19):e018513. Epub 2021 Sep 28.

Division of Research Kaiser Permanente Oakland CA.

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.
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http://dx.doi.org/10.1161/JAHA.120.018513DOI Listing
October 2021

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

Ann Noninvasive Electrocardiol 2021 Sep 21:e12888. Epub 2021 Sep 21.

Division of Research, Kaiser Permanente, Oakland, CA, USA.

Background: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia.

Objective: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting.

Methods: Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018.

Results: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively.

Conclusions: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.
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http://dx.doi.org/10.1111/anec.12888DOI Listing
September 2021

A polygenic risk score for asthma in a large racially diverse population.

Clin Exp Allergy 2021 Nov 5;51(11):1410-1420. Epub 2021 Sep 5.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, Massachusetts, USA.

Background: Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes.

Objective: We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations.

Methods: We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire.

Results: For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)).

Conclusion: Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.
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http://dx.doi.org/10.1111/cea.14007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551047PMC
November 2021

Effect of SLCO1B1 T521C on Statin-Related Myotoxicity With Use of Lovastatin and Atorvastatin.

Clin Pharmacol Ther 2021 09 23;110(3):733-740. Epub 2021 Jul 23.

Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA.

The association between the c.521T>C variant allele in SLCO1B1 (reference single nucleotide polymorphism (rs)4149056) and simvastatin-induced myotoxicity was discovered over a decade ago; however, whether this relationship represents a class effect is still not fully known. The aim of this study was to investigate the relationship between rs4149056 genotype and statin-induced myotoxicity in patients taking atorvastatin and lovastatin. Study participants were from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. A total of 233 statin-induced myopathy + rhabdomyolysis cases met the criteria for inclusion and were matched to 2,342 controls. To validate the drug response phenotype, we replicated the previously established association between rs4149056 genotype and simvastatin-induced myotoxicity. In particular, compared with homozygous T allele carriers, there was a significantly increased risk of simvastatin-induced myopathy + rhabdomyolysis in homozygous carriers of the C allele (CC vs. TT, odds ratio [OR] 4.62, 95% confidence interval [CI] 1.58-11.90, P = 0.003). For lovastatin users, homozygous carriers of the C allele were also at increased risk of statin-induced myopathy + rhabdomyolysis (CC vs. TT, OR 4.49, 95% CI 1.68-10.80, P = 0.001). In atorvastatin users, homozygous carriers of the C allele were twice as likely to experience statin-induced myopathy, though this association did not achieve statistical significance (CC vs. TT, OR 2.00, 95% CI 0.44-6.59, P = 0.30). In summary, our findings suggest that the association of rs4149056 with simvastatin-related myotoxicity may also extend to lovastatin. More data is needed to determine the extent of the association in atorvastatin users. Altogether, these data expand the evidence base for informing guidelines of pharmacogenetic-based statin prescribing practices.
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http://dx.doi.org/10.1002/cpt.2337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376784PMC
September 2021

Usage of long-acting muscarinic antagonists and biologics as add-on therapy for patients in the United States with moderate-to-severe asthma.

J Asthma 2021 May 22:1-11. Epub 2021 May 22.

Genentech, Inc, South San Francisco, CA, USA.

Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD.

This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 ( = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates.

Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI: 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD.

Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.
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http://dx.doi.org/10.1080/02770903.2021.1922915DOI Listing
May 2021

Magnesium intake was inversely associated with hostility among American young adults.

Nutr Res 2021 05 21;89:35-44. Epub 2021 Apr 21.

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

Hostility is a complex personality trait associated with many cardiovascular risk factor phenotypes. Although magnesium intake has been related to mood and cardio-metabolic disease, its relation with hostility remains unclear. We hypothesize that high total magnesium intake is associated with lower levels of hostility because of its putative antidepressant mechanisms. To test the hypothesis, we prospectively analyzed data in 4,716 young adults aged 18-30 years at baseline (1985-1986) from four U.S. cities over five years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Magnesium intake was estimated from a dietary history questionnaire plus supplements at baseline. Levels of hostility were assessed using the Cook-Medley scale at baseline and year 5 (1990-1991). Generalized estimating equations were applied to estimate the association of magnesium intake with hostility as repeated measures at the two time-points (baseline and year 5). General linear model was used to determine the association between magnesium intake and change in hostility over 5 years. After adjustment for socio-demographic and major lifestyle factors, a significant inverse association was observed between magnesium intake and hostility level over 5 years of follow-up. Beta coefficients (95% CI) across higher quintiles of magnesium intake were 0 (reference), -1.28 (-1.92, -0.65), -1.45 (-2.09, -0.81), -1.41 (-2.08, -0.75) and -2.16 (-2.85, -1.47), respectively (P<.01). The inverse association was independent of socio-demographic and major lifestyle factors, supplement use, and depression status at year 5. This prospective study provides evidence that in young adults, high magnesium intake was inversely associated with hostility level independent of socio-demographic and major lifestyle factors.
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http://dx.doi.org/10.1016/j.nutres.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098670PMC
May 2021

Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma.

Clin Exp Allergy 2021 Jan 11. Epub 2021 Jan 11.

Department of Bioanalysis, Ghent University, Ghent, Belgium.

Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses.

Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment.

Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome.

Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort.

Conclusion: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.
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http://dx.doi.org/10.1111/cea.13829DOI Listing
January 2021

Breast Arterial Calcification Is Not Associated with Mild Cognitive Impairment or Incident All-Cause Dementia Among Postmenopausal Women: The MINERVA Study.

J Womens Health (Larchmt) 2021 06 7;30(6):848-856. Epub 2020 Dec 7.

Departments of Psychiatry and Neurology and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.

Since vascular risk factors are implicated in cognitive decline, and breast arterial calcification (BAC) is related to vascular risk, we postulated that BAC may be associated with cognitive impairment and dementia. We used a multiethnic cohort of 3,913 asymptomatic women 60-79 years of age recruited after mammography screening at a large health plan in 2012-2015. A BAC mass score (mg) was derived from digital mammograms. Cognitive function was measured at baseline using the Montreal Cognitive Assessment (MoCA) and incident all-cause dementia ( = 49 events; median follow-up = 5.6 years) were ascertained with validated ICD-9 and ICD-10 codes. We used cross-sectional linear regression of MoCA scores on BAC, then multinomial logistic regression predicting mild cognitive impairment not progressing to dementia and incident all-cause dementia and, finally, Cox regression of incident all-cause dementia. No association by linear regression was found between MoCA scores and BAC presence in unadjusted or adjusted analysis. Women with severe (upper tertile) BAC had a MoCA score lower by 0.58 points (standard error [SE] = 0.18) relative to women with no BAC. However, this difference disappeared after multivariate adjustment. No significant associations were found in multinomial logistic regression for either BAC presence or gradation in unadjusted or adjusted analysis. No significant associations were found between BAC presence with incident all-cause dementia (fully adjusted hazard ratio = 0.74; 95% confidence interval: 0.39-1.39). Likewise, no significant association with incident all-cause dementia was noted for BAC gradation. Our results do not support the hypothesis that BAC presence or gradation may contribute to cognitive impairment or development of all-cause dementia.
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http://dx.doi.org/10.1089/jwh.2020.8372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217600PMC
June 2021

Occupation environmental factors in hypersensitivity pneumonitis: population attributable fraction.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Division of Pulmonary and Critical Care, Dept of Medicine, University of California, San Francisco, CA, USA.

Background: Despite well-documented case series of hypersensitivity pneumonitis (HP), epidemiological data delineating relative contributions of risk factors are sparse. To address this, we estimated HP risk in a case-referent study of occupational and nonoccupational exposures.

Methods: We recruited cases of HP by ICD-9 codes from an integrated healthcare delivery system (IHCDS) and a tertiary medical care centre. We drew referents, matched for age and sex, from the IHCDS. Participants underwent comprehensive, structured telephone interviews eliciting details of occupational and home environmental exposures. We employed a hierarchical analytic approach for data reduction based on the false discovery rate method within clusters of exposures. We measured lung function and selected biomarkers in a subset of participants. We used multivariate logistic regression to estimate exposure-associated odds ratios (ORs) and population attributable fractions (PAFs) for HP.

Results: We analysed data for 192 HP cases (148 IHCDS; 44 tertiary care) and 229 referents. Occupational exposures combined more than doubled the odds of developing HP (OR 2.67; 95% CI 1.73-4.14) with a PAF of 34% (95% CI 21-46%); nonoccupational bird exposure also doubled the HP odds (OR 2.02; 95% CI 1.13-3.60), with a PAF of 12% (3-21%). Lung function and selected biomarkers did not substantively modify the risk estimates on the basis of questionnaire data alone.

Discussion: In a case-referent approach evaluating HP risk, identifiable exposures accounted, on an epidemiological basis, for approximately two in three cases of disease; conversely, for one in three, the risk factors for disease remained elusive.
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http://dx.doi.org/10.1183/23120541.00374-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533383PMC
October 2020

Impact of Idiopathic Pulmonary Fibrosis on Longitudinal Health-care Utilization in a Community-Based Cohort of Patients.

Chest 2021 01 24;159(1):219-227. Epub 2020 Jul 24.

Department of Medicine, University of California San Francisco, San Francisco.

Background: Idiopathic pulmonary fibrosis (IPF) is a rare, chronic lung disease associated with substantial symptom burden, morbidity, and cost. Delivery of high-quality effective care in IPF requires understanding health-care resource utilization (HRU) patterns; however, longitudinal data from real-world populations are limited.

Research Question: This study aimed to define HRU attributable to IPF by evaluating a longitudinal cohort of community patients with IPF compared with matched control subjects.

Study Design And Methods: Incident IPF cases were identified in the Kaiser Permanente Northern California electronic health records (2000-2015) using case-validated code-based algorithms. IPF cases were compared with matched control subjects by age, sex, and length of enrollment. Annual rates of HRU measures were assessed during the 5 years pre- and postdiagnosis. Poisson generalized estimating equations were used to estimate adjusted case-control differences in HRU. IPF treatment trends were assessed before and after the availability of IPF-specific medications.

Results: A total of 691 IPF cases were identified and matched with 3,452 control subjects. Adjusted rates of all diagnostic procedures were significantly increased (P < .001) for IPF cases compared with control subjects in both the pre- and postindex periods, including chest CT scans (pre-relative risk [RR], 80.35; post-RR, 32.79), 6-min walk tests (pre-RR, 20.81; post-RR, 34.49), and pulmonary function tests (pre-RR, 9.50; post-RR, 13.24). All-cause hospitalizations (pre-RR, 1.42; post-RR, 2.33) and outpatient visits (pre-RR, 1.22; post-RR, 1.80) were significantly higher among cases compared with control subjects during both the preindex (P < .05) and postindex (P < .001) periods. We observed use of immunosuppressive and IPF-specific therapies prior to diagnosis, and high rates of corticosteroid use before and after diagnosis.

Interpretation: This study defines a marked increase in HRU in patients with IPF compared with control subjects, with accelerated use beginning at least 1 year prediagnosis and elevated use sustained over the following 5 years. To our knowledge, this is the first study to evaluate longitudinal medication trends in IPF. Collectively, this information is foundational to advancing IPF care delivery models and supporting clinical decision-making.
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http://dx.doi.org/10.1016/j.chest.2020.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803939PMC
January 2021

Analysis of putative cis-regulatory elements regulating blood pressure variation.

Hum Mol Genet 2020 07;29(11):1922-1932

Department of Genetic Medicine, McKusick-Nathans Institute, Baltimore, MD 21205, USA.

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
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http://dx.doi.org/10.1093/hmg/ddaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372556PMC
July 2020

Real-Life Patterns of Exacerbations While on Inhaled Corticosteroids and Long-Acting Beta Agonists for Asthma over 15 Years.

J Clin Med 2020 Mar 18;9(3). Epub 2020 Mar 18.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA 02115, USA.

Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS-LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS-LABAs to their own rates of exacerbation when off controller medications. We found ICS-LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93), = 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53), = 0.037). In conclusion, ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.
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http://dx.doi.org/10.3390/jcm9030819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141292PMC
March 2020

No Association Between Bone Mineral Density and Breast Arterial Calcification Among Postmenopausal Women.

J Endocr Soc 2020 Feb 27;4(2):bvz026. Epub 2019 Nov 27.

Kaiser Permanente Division of Research, Oakland, California.

Context: The association between bone mineral density (BMD) and breast arterial calcification (BAC) remains poorly understood and controversial.

Objective: The objective of this article is to examine the association between BMD and BAC in a large cohort of postmenopausal women undergoing routine mammography.

Design: A cross-sectional analysis of baseline data from a multiethnic cohort was performed.

Setting: The setting for this analysis is an integrated health care delivery system in Northern California in the United States.

Patients: A total of 1273 women age 60 to 79 years (mean age, 67 years) were recruited within 12 months of screening mammography.

Main Outcome Measure: A BAC score (mg) was obtained from digital mammograms using a novel densitometry method. BAC presence was defined as a BAC score greater than 0 mg, and severe BAC as a BAC score greater than 20 mg.

Results: Overall, 53% of women had osteopenia and 21% had osteoporosis. The prevalence of BAC greater than 0 mg was 29%, 30%, and 29% among women with normal BMD, osteopenia, and osteoporosis, respectively ( = 0.98). The prevalence of BAC greater than 20 mg was 5%, 3%, and 5% among women with normal BMD, osteopenia and osteoporosis, respectively ( = .65). The odds ratios (ORs) of BAC greater than 0 mg vs BAC = 0 mg after multivariable adjustment were 1.09 (95% CI, 0.81-1.48;  = .54) for osteopenia and 0.99 (95% CI, 0.69-1.48;  = .98) for osteoporosis. The adjusted ORs for BAC greater than 20 mg vs BAC 20 mg or less were 1.03 (95% CI, 0.52-2.01;  = .93) for osteopenia and 1.89 (95 CI, 0.81-4.47;  = .14) for osteoporosis.

Conclusion: Our findings do not support an association of either osteopenia or osteoporosis with BAC presence or severity among postmenopausal women.
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http://dx.doi.org/10.1210/jendso/bvz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009123PMC
February 2020

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change.

NPJ Genom Med 2020 16;5. Epub 2020 Jan 16.

2Institute for Human Genetics, University of California, San Francisco, CA 94143 USA.

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (, and /). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (, , and ). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (/) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.
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http://dx.doi.org/10.1038/s41525-019-0109-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965183PMC
January 2020

Adult Life-Course Trajectories of Lung Function and the Development of Emphysema: The CARDIA Lung Study.

Am J Med 2020 02 29;133(2):222-230.e11. Epub 2019 Jul 29.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill.

Background: Peak lung function and rate of decline predict future airflow obstruction and nonrespiratory comorbid conditions. Associations between lung function trajectories and emphysema have not been explored.

Methods: Using data from the population-based CARDIA Study, we sought to describe the prevalence of visually ascertained emphysema at multiple time points and contextualize its development based upon participant's adult life course measures of lung function. There were 3171 men and women enrolled at a mean age of 25 years, who underwent serial spirometric examinations through a mean age of 55 years. Trajectories for the change in percent-predicted forced expiratory volume in one second (FEV) were determined by fitting a mixture model via maximum likelihood. Emphysema was visually identified on computed tomographic scans and its prevalence reported at mean ages of 40, 45, and 50 years.

Results: We identified 5 trajectories describing peak and change in FEV: "Preserved Ideal," "Preserved Good," "Preserved Impaired," "Worsening," and "Persistently Poor." Ever smokers comprised part of all 5 trajectories. The prevalence of emphysema was 1.7% (n = 46; mean age of 40 years), 2.5% (n = 67; mean age of 45 years), and 7.1% (n = 189; mean age of 50 years). Of those with emphysema at a mean age of 50 years, 18.0% were never smokers. Worsening and poor lung health trajectories were associated with increased odds of future emphysema independent of chronic tobacco smoke exposure (odds ratio 5.06; confidence interval, 1.84-13.96; odds ratio 4.85; confidence interval, 1.43-16.44).

Conclusions: Lower peak and accelerated decline in FEV are risk factors for future emphysema independent of smoking status.
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http://dx.doi.org/10.1016/j.amjmed.2019.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980254PMC
February 2020

Evaluation of commonly used ectoderm markers in iPSC trilineage differentiation.

Stem Cell Res 2019 05 10;37:101434. Epub 2019 Apr 10.

Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA. Electronic address:

Patient-derived induced pluripotent stem cells (iPSCs) have become a promising resource for exploring genetics of complex diseases, discovering new drugs, and advancing regenerative medicine. Increasingly, laboratories are creating their own banks of iPSCs derived from diverse donors. However, there are not yet standardized guidelines for qualifying these cell lines, i.e., distinguishing between bona fide human iPSCs, somatic cells, and imperfectly reprogrammed cells. Here, we report the establishment of a panel of 30 iPSCs from CD34 peripheral blood mononuclear cells, of which 10 were further differentiated in vitro into all three germ layers. We characterized these different cell types with commonly used pluripotent and lineage specific markers, and showed that NES, TUBB3, and OTX2 cannot be reliably used as ectoderm differentiation markers. Our work highlights the importance of marker selection in iPSC authentication, and the need for the field to establish definitive standard assays.
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http://dx.doi.org/10.1016/j.scr.2019.101434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570500PMC
May 2019

Association of Breast Arterial Calcification Presence and Gradation with the Ankle-Brachial Index among Postmenopausal Women.

Eur J Cardiovasc Med 2018 Nov 16;5(5):544-551. Epub 2018 Nov 16.

Department of Radiological Sciences, University of California Irvine School of Medicine, Irvine, CA 92697, USA.

Objective: To examine the association of breast arterial calcification (BAC) with the ankle brachial index (ABI), a sensitive metric of peripheral arterial disease (PAD), among postmenopausal women. Background: BAC is an emerging risk marker of cardiovascular disease (CVD).

Methods: MINERVA (MultIethNic study of brEast aRterial calcium gradation and cardioVAscular disease) is a cohort of women aged 60 to 79 at baseline (10/24/2012 - 2/13/2015) who were free of symptomatic CVD at baseline. The analytical sample comprised 3,800 women with available ABI, BAC assessment and covariates. We performed cross-sectional logistic regression analysis.

Results: 203 women (5.3%) had an ABI < 0.90 indicative of PAD, 26 (0.7%) had an ABI > 1.3 and 94% (n=3,571) had an ABI within normal limits. After adjustment for age, race/ethnicity, body mass index, smoking status, diabetes, hypertension, LDL-C, HDL-C, hs-CRP, estimated-GFR, urinary albumin/creatinine ratio, serum calcium, serum vitamin D and serum PTH, BAC presence remained significantly associated with ABI < 0.90 (OR=1.37; 95% CI, 1.01-1.87; p=0.04). After further adjustment for menopausal hormone therapy, parity and history of breast feeding, the association became marginally significant (OR=1.36; 95% CI, 0.99-1.85; p=0.05). No clear pattern of association was observed for increased gradation of BAC and ABI<0.9, and no significant associations were noted between BAC presence vs. absence or BAC gradation with ABI > 1.3.

Conclusions: Among asymptomatic postmenopausal women, presence of BAC was associated with PAD independently of traditional risk factors. Additional prospective studies are required to establish the value of BAC for prediction of incident PAD in the general population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385879PMC
November 2018

Kidney function, proteinuria and breast arterial calcification in women without clinical cardiovascular disease: The MINERVA study.

PLoS One 2019 17;14(1):e0210973. Epub 2019 Jan 17.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States of America.

Background: Breast arterial calcification (BAC) may be a predictor of cardiovascular events and is highly prevalent in persons with end-stage kidney disease. However, few studies to date have examined the association between mild-to-moderate kidney function and proteinuria with BAC.

Methods: We prospectively enrolled women with no prior cardiovascular disease aged 60 to 79 years undergoing mammography screening at Kaiser Permanente Northern California between 10/24/2012 and 2/13/2015. Urine albumin-to-creatinine ratio (uACR), along with specific laboratory, demographic, and medical data, were measured at the baseline visit. Baseline estimated glomerular filtration rate (eGFR), medication history, and other comorbidities were identified from self-report and/or electronic medical records. BAC presence and gradation (mass) was measured by digital quantification of full-field mammograms.

Results: Among 3,507 participants, 24.5% were aged ≥70 years, 63.5% were white, 7.5% had eGFR <60 ml/min/1.73m2, with 85.7% having uACR ≥30 mg/g and 3.3% having uACR ≥300 mg/g. The prevalence of any measured BAC (>0 mg) was 27.9%. Neither uACR ≥30 mg/g nor uACR ≥300 were significantly associated with BAC in crude or multivariable analyses. Reduced eGFR was associated with BAC in univariate analyses (odds ratio 1.53, 95% CI: 1.18-2.00), but the association was no longer significant after adjustment for potential confounders. Results were similar in various sensitivity analyses that used different BAC thresholds or analytic approaches.

Conclusions: Among women without cardiovascular disease undergoing mammography screening, reduced eGFR and albuminuria were not significantly associated with BAC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336275PMC
October 2019

Large-scale, multiethnic genome-wide association study identifies novel loci contributing to asthma susceptibility in adults.

J Allergy Clin Immunol 2019 04 20;143(4):1633-1635. Epub 2018 Dec 20.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451881PMC
April 2019

Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort.

Circ Genom Precis Med 2018 09;11(9):e002043

Institute for Human Genetics (A.O., T.J.H., N.R.), University of California, San Francisco, CA.

Background: Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users.

Methods: We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined.

Results: Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P<10) which remained significant after adjusting for prespecified covariates (adjusted β, -5.59; SE, 0.12; P<10). Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least 1 first-degree relative who was also a statin user (n=1036), heritability of statin LDL-C response was estimated at 11.7% (SE, 8.6%; P=0.087).

Conclusions: Using electronic health record data, we observed a statin LDL-C dose-response consistent with the rule of 6% from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of electronic health records as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.
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http://dx.doi.org/10.1161/CIRCGEN.117.002043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214660PMC
September 2018

Weighted Multi-marker Genetic Risk Scores for Incident Coronary Heart Disease among Individuals of African, Latino and East-Asian Ancestry.

Sci Rep 2018 05 1;8(1):6853. Epub 2018 May 1.

Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain.

We examined the clinical utility of two multi-locus genetic risk scores (GRSs) previously validated in Europeans among persons of African (AFR; n = 2,089), Latino (LAT; n = 4,349) and East-Asian (EA; n = 4,804) ancestry. We used data from the GERA cohort (30-79 years old, 68 to 73% female). We utilized two GRSs with 12 and 51 SNPs, respectively, and the Framingham Risk Score (FRS) to estimate 10-year CHD risk. After a median 8.7 years of follow-up, 450 incident CHD events were documented (95 in AFR, 316 in LAT and 39 EA, respectively). In a model adjusting for principal components and risk factors, tertile 3 vs. tertile 1 of GRS_12 was associated with 1.86 (95% CI, 1.15-3.01), 1.52 (95% CI, 1.02-2.25) and 1.19 (95% CI, 0.77-1.83) increased hazard of CHD in AFR, LAT and EA, respectively. Inclusion of the GRSs in models containing the FRS did not increase the C-statistic but resulted in net overall reclassification of 10% of AFR, 7% LAT and EA and in reclassification of 13% of AFR and EA as well as 10% LAT in the intermediate FRS risk subset. Our results support the usefulness of incorporating genetic information into risk assessment for primary prevention among minority subjects in the U.S.
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http://dx.doi.org/10.1038/s41598-018-25128-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931622PMC
May 2018

A large electronic-health-record-based genome-wide study of serum lipids.

Nat Genet 2018 03 5;50(3):401-413. Epub 2018 Mar 5.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.
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http://dx.doi.org/10.1038/s41588-018-0064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942247PMC
March 2018

Respiratory Symptoms in Young Adults and Future Lung Disease. The CARDIA Lung Study.

Am J Respir Crit Care Med 2018 06;197(12):1616-1624

6 Applied Chest Imaging Laboratory, Department of Radiology, and.

Rationale: There are limited data on factors in young adulthood that predict future lung disease.

Objectives: To determine the relationship between respiratory symptoms, loss of lung health, and incident respiratory disease in a population-based study of young adults.

Methods: We examined prospective data from 2,749 participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed respiratory symptom questionnaires at baseline and 2 years later and repeated spirometry measurements over 30 years.

Measurements And Main Results: Cough or phlegm, episodes of bronchitis, wheeze, shortness of breath, and chest illnesses at both baseline and Year 2 were the main predictor variables in models assessing decline in FEV and FVC from Year 5 to Year 30, incident obstructive and restrictive lung physiology, and visual emphysema on thoracic computed tomography scan. After adjustment for covariates, including body mass index, asthma, and smoking, report of any symptom was associated with -2.71 ml/yr excess decline in FEV (P < 0.001) and -2.18 in FVC (P < 0.001) as well as greater odds of incident (prebronchodilator) obstructive (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.14) and restrictive (OR, 1.40; 95% CI, 1.09-1.80) physiology. Cough-related symptoms (OR, 1.56; 95% CI, 1.13-2.16) were associated with greater odds of future emphysema.

Conclusions: Persistent respiratory symptoms in young adults are associated with accelerated decline in lung function, incident obstructive and restrictive physiology, and greater odds of future radiographic emphysema.
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http://dx.doi.org/10.1164/rccm.201710-2108OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835093PMC
June 2018

A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis.

J Allergy Clin Immunol 2018 11 9;142(5):1469-1478.e2. Epub 2018 Jan 9.

Program in Molecular and Integrative Physiological Sciences, Departments of Environmental Health and Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Mass. Electronic address:

Background: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive.

Objectives: We sought to identify and characterize functional variants in the 17q21 locus.

Methods: We used the Exome Aggregation Consortium browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants.

Results: Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10) and EVE (odds ratio, 0.85; joint P = 1.31 × 10). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein.

Conclusions: Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.
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http://dx.doi.org/10.1016/j.jaci.2017.11.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037620PMC
November 2018

MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease: cohort recruitment and baseline characteristics.

Ann Epidemiol 2018 01 5;28(1):41-47.e12. Epub 2017 Dec 5.

Department of Radiological Sciences, University of California Irvine School of Medicine, Irvine, CA.

Purpose: MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA) was designed to answer the question of whether a novel continuous breast arterial calcification (BAC) mass score improves cardiovascular risk stratification among asymptomatic postmenopausal women. This article describes recruitment and baseline characteristics.

Methods: MINERVA is a multiethnic longitudinal cohort study. The phenotype data include BAC mass by densitometry applied to digital mammograms, sociodemographic factors, self-reported medical history, medications, parental history, reproductive history, smoking, alcohol consumption, physical activity, anthropometry, ankle-brachial index, blood pressure, laboratory panel, breast volumes, cognitive function, bioelectrical impedance, habitual diet, dietary supplements, sleep, psychosocial factors, and sun exposure.

Results: A total of 5145 women aged 60 to 79 years with available digital, uncompressed mammograms were recruited from the membership of Kaiser Permanente of Northern California between October 24, 2012 and February 13, 2015 and completed a baseline clinic visit or an abbreviated phone questionnaire. Of those, 4153 underwent phlebotomy and have blood biomarkers. Overall prevalence of BAC was 26%, and it varied by age and race. The mean (SD) BAC mass was 12 (23) mg and the range 0-342 mg.

Conclusions: MINERVA is the first cohort with a continuous measure of BAC. The cohort is large, ethnically diverse, and deeply phenotyped in terms of socioeconomic, behavioral, and clinical factors, and blood biomarkers.
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http://dx.doi.org/10.1016/j.annepidem.2017.11.007DOI Listing
January 2018

Cohort Study of ECG Left Ventricular Hypertrophy Trajectories: Ethnic Disparities, Associations With Cardiovascular Outcomes, and Clinical Utility.

J Am Heart Assoc 2017 Oct 5;6(10). Epub 2017 Oct 5.

Cardiology Department, Kaiser Permanente San Francisco Medical Center, San Francisco, CA.

Background: ECG left ventricular hypertrophy (LVH) is a well-known predictor of cardiovascular disease. However, no prior study has characterized patterns of presence/absence of ECG LVH ("ECG LVH trajectories") across the adult lifespan in both sexes and across ethnicities. We examined: (1) correlates of ECG LVH trajectories; (2) the association of ECG LVH trajectories with incident coronary heart disease, transient ischemic attack, ischemic stroke, hemorrhagic stroke, and heart failure; and (3) reclassification of cardiovascular disease risk using ECG LVH trajectories.

Methods And Results: We performed a cohort study among 75 412 men and 107 954 women in the Northern California Kaiser Permanente Medical Care Program who had available longitudinal exposures of ECG LVH and covariates, followed for a median of 4.8 (range <1-9.3) years. ECG LVH was measured by Cornell voltage-duration product. Adverse trajectories of ECG LVH (persistent, new development, or variable pattern) were more common among blacks and Native American men and were independently related to incident cardiovascular disease with hazard ratios ranging from 1.2 for ECG LVH variable pattern and transient ischemic attack in women to 2.8 for persistent ECG LVH and heart failure in men. ECG LVH trajectories reclassified 4% and 7% of men and women with intermediate coronary heart disease risk, respectively.

Conclusions: ECG LVH trajectories were significant indicators of coronary heart disease, stroke, and heart failure risk, independently of level and change in cardiovascular disease risk factors, and may have clinical utility.
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http://dx.doi.org/10.1161/JAHA.116.004954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721817PMC
October 2017

Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States.

J Allergy Clin Immunol Pract 2018 Jan - Feb;6(1):295-297.e5. Epub 2017 Sep 19.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2017.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190591PMC
October 2019
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