Publications by authors named "Elisa Lee"

185 Publications

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer Epidemiol 2021 Jul 19;74:101978. Epub 2021 Jul 19.

MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD, 20782, USA; Georgetown, Howard Universities Center for Clinical and Translational Research, Washington, DC, 2000, USA. Electronic address:

Background: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

Methods: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

Results: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

Conclusions: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.
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http://dx.doi.org/10.1016/j.canep.2021.101978DOI Listing
July 2021

Analysis of aflatoxin signature mutation in hepatocellular carcinomas from Guatemala: A cross-sectional study (2016-2017).

Health Sci Rep 2020 Jun 6;3(2):e155. Epub 2020 May 6.

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland.

Background And Aims: Guatemala has the highest incidence of hepatocellular carcinoma (HCC) in the Western hemisphere. The major risk factors in Guatemala are not well characterized, but the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) appears to be low, while the prevalence of aflatoxin (AFB) exposure appears to be high. To examine whether AFB may contribute to the elevated incidence of HCC in Guatemala, this study examined the frequency of the AFB-signature mutation in the gene (R249S) as well as other somatic mutations. In addition, we assessed whether the frequency of the mutation differed by sex.

Methods: Formalin-fixed, paraffin-embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City between 2016 and 2017. In addition, tumor tissues preserved in RNAlater were also obtained. Sociodemographic and clinical information including HBV and HCV status were collected. Targeted sequencing of was performed in the FFPE samples, and a panel of 253 cancer-related genes was sequenced in the RNAlater samples.

Results: Ninety-one FFPE tissues were examined, from 52 men and 39 women. Median (IQR) age at diagnosis was 62 (51-70). Among those with known HBV and HCV status, two were HBV+ and three were HCV+. Overall, 47% of the HCCs had a mutation. The AFB-signature R249S mutation was present in 24%. No overlap between the R249S mutation and HBV+ was observed in this cohort. Among 18 RNAlater samples examined, 44% had any mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes.

Conclusions: The presence of the R249S mutation in the samples studied suggests that AFB may contribute to the high incidence of HCC in Guatemala. The proportion of HBV+ tumors was low, suggesting that AFB may be associated with HCC in the absence of concomitant HBV infection. Further investigation of AFB and other risk factors for HCC in Guatemala is warranted.
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http://dx.doi.org/10.1002/hsr2.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202218PMC
June 2020

Trends in Cardiovascular Disease Morbidity and Mortality in American Indians Over 25 Years: The Strong Heart Study.

J Am Heart Assoc 2019 11 25;8(21):e012289. Epub 2019 Oct 25.

MedStar Health Research Institute Georgetown/Howard University Center for Clinical and Translational Sciences Hyattsville MD.

Background American Indians experience high rates of cardiovascular disease. We evaluated whether cardiovascular disease incidence, mortality, and prevalence changed over 25 years among American Indians aged 30 to 85. Methods and Results The SHS (Strong Heart Study) and SHFS (Strong Heart Family Study) are prospective studies of cardiovascular disease in American Indians. Participants enrolled in 1989 to 1990 or 2000 to 2003 with birth years from 1915 to 1984 were followed for cardiovascular disease events through 2013. We used Poisson regression to analyze data for 5627 individuals aged 30 to 85 years during follow-up. Outcomes reflect change in age-specific cardiovascular disease incidence, mortality, and prevalence, stratified by sex. To illustrate generational change, 5-year relative risk compared most recent birth years for ages 45, 55, 65, and 75 to same-aged counterparts born 1 generation (23-25 years) earlier. At all ages, cardiovascular disease incidence was lower for people with more recent birth years. Cardiovascular disease mortality declined consistently among men, while prevalence declined among women. Generational comparisons were similar for women aged 45 to 75 (relative risk, 0.39-0.46), but among men magnitudes strengthened from age 45 to 75 (relative risk, 0.91-0.39). For cardiovascular disease mortality, risk was lower in the most recent versus the earliest birth years for women (relative risk, 0.56-0.83) and men (relative risk, 0.40-0.54), but results for women were inconclusive. Conclusions Cardiovascular disease incidence declined over a generation in an American Indian cohort. Mortality declined more for men, while prevalence declined more for women. These trends might reflect more improvement in case survival among men compared with women.
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http://dx.doi.org/10.1161/JAHA.119.012289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898852PMC
November 2019

Genetic analysis of hsCRP in American Indians: The Strong Heart Family Study.

PLoS One 2019 17;14(10):e0223574. Epub 2019 Oct 17.

Department of Nutrition and Nutrition Research Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.

Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.

Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.

Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4.

Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223574PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797125PMC
March 2020

Depressed Myocardial Energetic Efficiency Increases Risk of Incident Heart Failure: The Strong Heart Study.

J Clin Med 2019 Jul 17;8(7). Epub 2019 Jul 17.

Hypertension Research Center, University Federico II of Naples, I-80131 Naples, Italy.

An estimation of myocardial mechano-energetic efficiency (MEE) per unit of left ventricular (LV) mass (MEEi) can significantly predict composite cardiovascular (CV) events in treated hypertensive patients with normal ejection fraction (EF), after adjustment for LV hypertrophy (LVH). We have tested whether MEEi predicts incident heart failure (HF), after adjustment for LVH, in the population-based cohort of a "Strong Heart Study" (SHS) with normal EF. We included 1,912 SHS participants (age 59 ± 8 years; 64% women) with preserved EF (≥50%) and without prevalent CV disease. MEE was estimated as the ratio of stroke work to the "double product" of heart rate times systolic blood pressure. MEEi was calculated as MEE/LV mass, and analyzed in quartiles. During a follow-up study of 9.2 ± 2.3 years, 126 participants developed HF (7%). HF was preceded by acute myocardial infarction (AMI) in 94 participants. A Kaplan-Meier plot, in quartiles of MEEi, demonstrated significant differences, substantially due to the deviation of the lowest quartile ( < 0.0001). Using AMI as a competing risk event, sequential models of Cox regression for incident HF (including significant confounders), demonstrated that low MEEi predicted incident HF not due to AMI ( = 0.026), after adjustment for significant effect of age, LVH, prolonged LV relaxation, diabetes, and smoking habits with negligible effects for sex, hypertension, antihypertensive therapy, obesity, and hyperlipemia. Low LV mechano-energetic efficiency per unit of LVM, is a predictor of incident, non-AMI related, HF in subjects with initially normal EF.
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http://dx.doi.org/10.3390/jcm8071044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678469PMC
July 2019

Associations of diet soda and non-caloric artificial sweetener use with markers of glucose and insulin homeostasis and incident diabetes: the Strong Heart Family Study.

Eur J Clin Nutr 2020 02 28;74(2):322-327. Epub 2019 Jun 28.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Background/objectives: Non-caloric artificial sweeteners (NAS) are marketed as healthier alternatives to sugar, but the relationship between consumption of NAS and development of diabetes is unclear. This study assessed the associations of diet soda and NAS consumption with (1) early markers of insulin and glucose homeostasis (cross-sectionally) and (2) incident diabetes (over an average of 8 years of follow-up) among American Indians, a population with high rates of obesity.

Subjects/methods: The study population included Strong Heart Family Study participants without cardiovascular disease or diabetes who participated in the 2007-2009 study exam (n = 1359). Diet soda and NAS consumption were assessed using a Block food frequency questionnaire and supplemental NAS questionnaire at the study exam. Fasting plasma glucose and insulin were measured during the study exam after a 12-h overnight fast. Participants were followed for incident diabetes through December 2017 using a single phone interview and medical record review; diabetes was identified by self-report and confirmed by documentation in medical records. Associations of diet soda and NAS consumption with fasting insulin, glucose, and incident diabetes were assessed using generalized estimating equations (fasting insulin and glucose analyses) and parametric survival models with Weibull distributions (incident diabetes analyses).

Results: Just under half of participants reported regularly consuming diet soda (40%) or using NAS to sweeten their beverages (41%). During an average 8 years of follow-up, we identified 98 cases of incident diabetes. After correction for multiple comparisons, there were no statistically significant associations of reported diet soda and NAS consumption with fasting insulin, fasting glucose, or incident diabetes.

Conclusions: Although reported consumption of diet soda and NAS were high, neither were associated with diabetes risk.
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http://dx.doi.org/10.1038/s41430-019-0461-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934923PMC
February 2020

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

Geroscience 2019 06 22;41(3):351-361. Epub 2019 Jun 22.

Department of Epidemiology, College of Public Health and Health Professions, College of Medicine, University of Florida, 2004 Mowry Road, Gainesville, FL, 32610, USA.

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.
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http://dx.doi.org/10.1007/s11357-019-00080-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702505PMC
June 2019

Myocardial mechano-energetic efficiency and insulin resistance in non-diabetic members of the Strong Heart Study cohort.

Cardiovasc Diabetol 2019 04 30;18(1):56. Epub 2019 Apr 30.

Weill Cornell Med, New York, NY, USA.

Background: Myocardial energetic efficiency (MEE), is a strong predictor of CV events in hypertensive patient and is reduced in patients with diabetes and metabolic syndrome. We hypothesized that severity of insulin resistance (by HOMA-IR) negatively influences MEE in participants from the Strong Heart Study (SHS).

Methods: We selected non-diabetic participants (n = 3128, 47 ± 17 years, 1807 women, 1447 obese, 870 hypertensive) free of cardiovascular (CV) disease, by merging two cohorts (Strong Heart Study and Strong Heart Family Study, age range 18-93). MEE was estimated as stroke work (SW = systolic blood pressure [SBP] × stroke volume [SV])/"double product" of SBP × heart rate (HR), as an estimate of O consumption, which can be simplified as SV/HR ratio and expressed in ml/sec. Due to the strong correlation, MEE was normalized by left ventricular (LV) mass (MEEi).

Results: Linear trend analyses showed that with increasing quartiles of HOMA-IR patients were older, more likely to be women, obese and hypertensive, with a trend toward a worse lipid profile (all p for trend < 0.001), progressive increase in LV mass index, stroke index and cardiac index and decline of wall mechanics (all p < 0.0001). In multivariable regression, after adjusting for confounders, and including a kinship coefficient to correct for relatedness, MEEi was negatively associated with HOMA-IR, independently of significant associations with age, sex, blood pressure, lipid profile and central obesity (all p < 0.0001).

Conclusions: Severity of insulin resistance has significant and independent negative impact on myocardial mechano-energetic efficiency in nondiabetic individual from a population study of American Indians. Trial registration number NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134 , Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988.
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http://dx.doi.org/10.1186/s12933-019-0862-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492323PMC
April 2019

Large Cohort Data Based Cost-Effective Disease Prevention Design Strategy: Strong Heart Study.

World J Cardiovasc Dis 2018 Dec 29;8(12):588-601. Epub 2018 Dec 29.

Center for American Indian Health Research, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background And Objective: A multitude of large cohort studies have collected data on incidence and covariates/risk factors of various chronic diseases. However, approaches for utilization of these large data and translation of the valuable results to inform and guide clinical disease prevention practice are not well developed. In this paper, we proposed, based on large cohort study data, a novel conceptual cost-effective disease prevention design strategy for a target group when it is not affordable to include everyone in the target group for intervention.

Methods And Results: Data from American Indian participants (n = 3516; 2056 women) aged 45 - 74 years in the Strong Heart Study, the diabetes risk prediction model from the study, a utility function, and regression models were used. A conceptual cost-effective disease prevention design strategy based on large cohort data was initiated. The application of the proposed strategy for diabetes prevention was illustrated.

Discussion: The strategy may provide reasonable solutions to address cost-effective prevention design issues. These issues include complex associations of a disease with its significant risk factors, cost-effectively selecting individuals at high risk of developing disease to undergo intervention, individual differences in health conditions, choosing intervention risk factors and setting their appropriate, attainable, gradual and adaptive goal levels for different subgroups, and assessing effectiveness of the prevention program.

Conclusions: The strategy and methods shown in the illustrative example can also be analogously adopted and applied to other diseases preventions. The proposed strategy provides a way to translate and apply epidemiological study results to clinical disease prevention practice.
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http://dx.doi.org/10.4236/wjcd.2018.812058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343848PMC
December 2018

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study.

Front Genet 2018 12;9:466. Epub 2018 Oct 12.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing ( < 4.13 × 10). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near (rs2961831, = 6.39 × 10). In the replication study, we found a signal at rs4607517 near ( = 0.01). Variants near candidate diabetes genes (especially and ) were also nominally associated with HOMA-IR and cHOMA-B. We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at , , and with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.
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http://dx.doi.org/10.3389/fgene.2018.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194194PMC
October 2018

Large Cohort Data Based Group or Community Disease Prevention Design Strategy: Strong Heart Study.

World J Cardiovasc Dis 2018 Mar 27;8(3):196-207. Epub 2018 Mar 27.

College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background And Objective: A multitude of large cohort studies have data on incidence rates and predictors of various chronic diseases. However, approaches for utilization of these costly collected data and translation of these valuable results to inform and guide clinical disease prevention practice are not well developed. In this paper we proposed a novel conceptual group/community disease prevention design strategy based on large cohort study data.

Methods And Results: The data from participants (n = 3516; 2056 women) aged 45 to 74 years and the diabetes risk prediction model from Strong Heart Study were used. The Strong Heart Study is a population-based cohort study of cardiovascular disease and its risk factors in American Indians. A conceptual group/community disease prevention design strategy based on large cohort data was initiated. The application of the proposed strategy for group diabetes prevention was illustrated.

Discussion: The strategy may provide reasonable solutions to the prevention design issues. These issues include complex associations of a disease with its combined and correlated risk factors, individual differences, choosing intervention risk factors and setting their appropriate, attainable, gradual and adaptive goal levels for different subgroups, and assessing effectiveness of the prevention program.

Conclusions: The strategy and methods shown in the illustration example can be analogously adopted and applied for other diseases preventions. The proposed strategy for a target group/community in a population provides a way to translate and apply epidemiological study results to clinical disease prevention practice.
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http://dx.doi.org/10.4236/wjcd.2018.83019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167019PMC
March 2018

Association of Low-Moderate Arsenic Exposure and Arsenic Metabolism with Incident Diabetes and Insulin Resistance in the Strong Heart Family Study.

Environ Health Perspect 2017 12 20;125(12):127004. Epub 2017 Dec 20.

Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Background: High arsenic exposure has been related to diabetes, but at low-moderate levels the evidence is mixed. Arsenic metabolism, which is partly genetically controlled and may rely on certain B vitamins, plays a role in arsenic toxicity.

Objective: We evaluated the prospective association of arsenic exposure and metabolism with type 2 diabetes and insulin resistance.

Methods: We included 1,838 American Indian men and women free of diabetes (median age, 36 y). Arsenic exposure was assessed as the sum of inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) urine concentrations (ΣAs). Arsenic metabolism was evaluated by the proportions of iAs, MMA, and DMA over their sum (iAs%, MMA%, and DMA%). Homeostasis model assessment for insulin resistance (HOMA2-IR) was measured at baseline and follow-up visits. Incident diabetes was evaluated at follow-up.

Results: Median ΣAs, iAs%, MMA%, and DMA% was 4.4 μg/g creatinine, 9.5%, 14.4%, and 75.6%, respectively. Over 10,327 person-years of follow-up, 252 participants developed diabetes. Median HOMA2-IR at baseline was 1.5. The fully adjusted hazard ratio [95% confidence interval (CI)] for incident diabetes per an interquartile range increase in ΣAs was 1.57 (95% CI: 1.18, 2.08) in participants without prediabetes at baseline. Arsenic metabolism was not associated with incident diabetes. ΣAs was positively associated with HOMA2-IR at baseline but negatively with HOMA2-IR at follow-up. Increased MMA% was associated with lower HOMA2-IR when either iAs% or DMA% decreased. The association of arsenic metabolism with HOMA2-IR differed by B-vitamin intake and genetics variants.

Conclusions: Among participants without baseline prediabetes, arsenic exposure was associated with incident diabetes. Low MMA% was cross-sectional and prospectively associated with higher HOMA2-IR. Research is needed to confirm possible interactions of arsenic metabolism with B vitamins and variants on diabetes risk. https://doi.org/10.1289/EHP2566.
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http://dx.doi.org/10.1289/EHP2566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963590PMC
December 2017

Risk Factors and Prediction of Stroke in a Population with High Prevalence of Diabetes: The Strong Heart Study.

World J Cardiovasc Dis 2017 May 27;7(5):145-162. Epub 2017 May 27.

College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background And Objective: American Indians have a high prevalence of diabetes and higher incidence of stroke than that of whites and blacks in the U.S. Stroke risk prediction models based on data from American Indians would be of clinical and public health value.

Methods And Results: A total of 3483 (2043 women) Strong Heart Study participants free of stroke at baseline were followed from 1989 to 2010 for incident stroke. Overall, 297 stroke cases (179 women) were identified. Cox models with stroke-free time and risk factors recorded at baseline were used to develop stroke risk prediction models. Assessment of the developed stroke risk prediction models regarding discrimination and calibration was performed by an analogous C-statistic (C) and a version of the Hosmer-Lemeshow statistic (HL), respectively, and validated internally through use of Bootstrapping methods.

Results: Age, smoking status, alcohol consumption, waist circumference, hypertension status, an-tihypertensive therapy, fasting plasma glucose, diabetes medications, high/low density lipoproteins, urinary albumin/creatinine ratio, history of coronary heart disease/heart failure, atrial fibrillation, or Left ventricular hypertrophy, and parental history of stroke were identified as the significant optimal risk factors for incident stroke.

Discussion: The models produced a C = 0.761 and HL = 4.668 (p = 0.792) for women, and a C = 0.765 and HL = 9.171 (p = 0.328) for men, showing good discrimination and calibration.

Conclusions: Our stroke risk prediction models provide a mechanism for stroke risk assessment designed for American Indians. The models may be also useful to other populations with high prevalence of obesity and/or diabetes for screening individuals for risk of incident stroke and designing prevention programs.
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http://dx.doi.org/10.4236/wjcd.2017.75014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538319PMC
May 2017

Target organ damage and incident type 2 diabetes mellitus: the Strong Heart Study.

Cardiovasc Diabetol 2017 05 12;16(1):64. Epub 2017 May 12.

Weill Cornell Medicine, New York, NY, USA.

Background: Recent analyses in a registry of hypertensive patients suggested that preceding left ventricular (LV) hypertrophy (LVH) and/or carotid atherosclerosis are associated with incident type 2 diabetes, independent of confounders. We assess the relation between prevalent cardio-renal target organ damage (TOD) and subsequent incident type 2 diabetes in a population-based study with high prevalence of obesity.

Methods: We selected 2887 non-diabetic participants from two cohorts of the Strong Heart Study (SHS). Clinical exam, laboratory tests and echocardiograms were performed. Adjudicated TODs were LVH, left atrium (LA) dilatation, and high urine albumin/creatinine ratio (UACR). Multivariable logistic regression models were used to identify variables responsible for the association between initial TODs and incident diabetes at 4-year follow-up (FU).

Results: After 4 years, 297 new cases of diabetes (10%) were identified, 216 of whom exhibited baseline impaired fasting glucose (IFG, 73%, p < 0.0001). Participants developing type 2 diabetes exhibited higher inflammatory markers, fat-free mass and adipose mass and higher prevalence of initial LVH and LA dilatation than those without (both p < 0.04). In multivariable logistic regression, controlling for age, sex, family relatedness, presence of arterial hypertension and IFG, all three indicators of TOD predicted incident diabetes (all p < 0.01). However, the effects of TOD was offset when body fat and inflammatory markers were introduced into the model.

Conclusions: In this population-based study with high prevalence of obesity, TOD precedes clinical appearance of type 2 diabetes and is related to the preceding metabolic status, body composition and inflammatory status. Trial registration Trial registration number: NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134, Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988.
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http://dx.doi.org/10.1186/s12933-017-0542-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427627PMC
May 2017

Apolipoproteins A-I, B, and C-III and Obesity in Young Adult Cherokee.

J Lipids 2017 3;2017:8236325. Epub 2017 Apr 3.

Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.

Since young adult Cherokee are at increased risk for both diabetes and cardiovascular disease, we assessed association of apolipoproteins (A-I, B, and C-III in non-HDL and HDL) with obesity and related risk factors. Obese participants (BMI ≥ 30) aged 20-40 years ( = 476) were studied. Metabolically healthy obese (MHO) individuals were defined as not having any of four components of the ATP-III metabolic syndrome after exclusion of waist circumference, and obese participants not being MHO were defined as metabolically abnormal obese (MAO). Associations were evaluated by correlation and regression modeling. Obesity measures, blood pressure, insulin resistance, lipids, and apolipoproteins were significantly different between groups except for total cholesterol, LDL-C, and HDL-apoC-III. Apolipoproteins were not correlated with obesity measures with the exception of apoA-I with waist and the waist : height ratio. In a logistic regression model apoA-I and the apoB : apoA-I ratio were significantly selected for identifying those being MHO, and the result (-statistic = 0.902) indicated that apoA-I and the apoB : apoA-I ratio can be used to identify a subgroup of obese individuals with a significantly less atherogenic lipid and apolipoprotein profile, particularly in obese Cherokee men in whom MHO is more likely.
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http://dx.doi.org/10.1155/2017/8236325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394387PMC
April 2017

Red meat consumption and cardiovascular target organ damage (from the Strong Heart Study).

J Hypertens 2017 09;35(9):1794-1800

aDepartment of Internal Medicine I, Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Bavaria, Germany bCenter for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma cCardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, Washington dDepartment of Medicine, Columbia University Medical Center, New York, New York eMedStar Health Research Institute, Hyattsville, Maryland fDivision of Cardiology, New York-Presbyterian Hospital/Weill Cornell Medical College, New York, New York, USA.

Objective: The aim of this study was to investigate whether red meat consumption is related to changes in left ventricular mass (LVM), left atrial diameter and carotid atherosclerosis in American Indians.

Methods: We prospectively analyzed echocardiographic and carotid ultrasound data of 1090 adults aged 40 years and older enrolled in the Strong Heart Family Study who were free of cardiovascular disease at baseline - 535 (49%) were hypertensive and 555 (51%) participants were nonhypertensive. Processed and unprocessed red meat intake was ascertained by using a Block food-frequency questionnaire at baseline. Cardiac and vascular biomarkers were assessed at baseline and 4 years later. Marginal models with multivariate adjustment were used to assess the associations of red meat intake with LVM, left atrial diameter, intima-media thickness and presence and extent of carotid atherosclerosis.

Results: Participants with hypertension were older, had a higher BMI, were more likely to be diabetic and less physically active. Processed and unprocessed red meat consumption was related to an increase in the presence of atherosclerotic plaques in male and female hypertensive individuals. In male hypertensive participants, processed meat intake was further observed to be associated with an increase in intima-media thickness, atrial diameter but not LVM. In nonhypertensive participants, neither unprocessed nor processed red meat intake was associated with changes in cardiac parameters or carotid atherosclerosis.

Conclusion: Over a 4-year period, red meat consumption was related to cardiovascular target organ damage in hypertensive American Indians. These findings emphasize the importance of dietary measures for cardiovascular disease prevention.
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http://dx.doi.org/10.1097/HJH.0000000000001385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728368PMC
September 2017

Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study.

J Hypertens 2017 09;35(9):1787-1793

aDepartment of Epidemiology, College of Public Health and Health Professions, College of Medicine, University of Florida, Gainesville, Florida bCenter for American Indian Health Research, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA cDepartment of Clinical and Experimental Medicine, Federico II University, Naples, Italy dEagle Butte Industries Research Inc, Timber Lake, South Dakota eMedStar Health Research Institute, Hyattsville, Maryland, USA.

Objectives: Deficient plasminogen activator inhibitor-1 (PAI-1) prevented hypertension in mice. Plasma PAI-1 was associated with hypertension in cross-sectional analyses, but the prospective association of PAI-1 with incident hypertension in large epidemiological studies is scarce.

Methods: Leveraging two longitudinal cohorts of American Indians in the Strong Heart Study (SHS, N = 1019) and the Strong Heart Family Study (SHFS, N = 1502), we examined the prospective association of plasma PAI-1 with incident hypertension by multivariate logistic regression, adjusting for age, sex, study site, smoking, drinking, dietary sodium, obesity, lipids, fasting glucose, kidney function, inflammation, and follow-up years. Family relatedness in the SHFS was accounted for using the GLIMMIX procedure. Plasma PAI-1 level at baseline was measured by immunoassay. All participants were free of hypertension, cardiovascular diseases, and chronic kidney disease at baseline.

Results: A total of 305 and 258 participants, respectively, from the SHS (57 ± 7 years) and the SHFS (33 ± 13 years) developed incident hypertension during follow-up. In the SHS, higher level of log-transformed PAI-1 was associated with 1.35-fold increased risk of hypertension [odds ratio (OR) (95% confidence interval): 1.35 (1.06-1.72)]. Analysis using categorical PAI-1 (in tertiles) showed that participants in the highest tertile (≥58 ng/ml) had 63% increased risk for hypertension [OR = 1.63 (1.12-2.37)] compared with those in the lowest tertile (<33 ng/ml). This association was confirmed in the SHFS with similar effect sizes [OR = 1.41 (1.11-1.81) for log-transformed PAI-1; OR = 1.64 (1.08-2.50) for categorical PAI-1: ≥58 vs. <33 ng/ml].

Conclusion: A higher level of plasma PAI-1 is significantly associated with hypertension in American Indians, independent of established risk factors. The potential causality warrants further investigation.
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http://dx.doi.org/10.1097/HJH.0000000000001375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615403PMC
September 2017

Influence of Left Ventricular Stroke Volume on Incident Heart Failure in a Population With Preserved Ejection Fraction (from the Strong Heart Study).

Am J Cardiol 2017 04 5;119(7):1047-1052. Epub 2017 Jan 5.

Hypertension Research Center, Federico II University, Naples, Italy; Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Translational Medical Sciences, Federico II University, Naples, Italy. Electronic address:

At a given level of left ventricular (LV) systolic function, LV pump performance (assessed by stroke index [SVi]) may differ, depending on LV size. We evaluated whether low SVi may be considered a marker of risk for incident congestive heart failure (HF), independent of LV geometry and systolic function, assessed by ejection fraction (EF) or midwall fractional shortening (MFS), in a large population-based sample with normal EF. Clinical and echocardiographic data from the second Strong Heart Study (SHS) examination, including 2,885 American Indians (59 ± 8 years; 63% women) with normal EF (EF ≥51% in men and EF ≥55% in women) and without prevalent HF or significant valve disease, were analyzed. Low SVi was defined as SVi ≤22 ml/m. Low SVi was more common among men and associated with lower body mass index, systolic blood pressure, LV mass index, left atrial dimension, EF, and MFS and with higher relative wall thickness. During a mean 12-year follow-up, 209 participants developed HF and 246 had acute myocardial infarction. In Cox regression analysis, low SVi was associated with higher risk of incident HF (hazard ratio 1.38; 95% confidence interval 1.06 to 1.80), independently of age, gender, body mass index, heart rate, hypertension, prevalent cardiovascular disease, left atrial dimension index, LV mass index, LV concentric geometry, EF or MFS, and abnormal wall motion, also accounting for myocardial infarction as a competing risk event. In conclusion, in the SHS, low SVi was associated with higher incident rate of HF, independently of LV geometry and systolic function and other major confounders.
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http://dx.doi.org/10.1016/j.amjcard.2016.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348268PMC
April 2017

Dietary determinants of cadmium exposure in the Strong Heart Family Study.

Food Chem Toxicol 2017 Feb 22;100:239-246. Epub 2016 Dec 22.

Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Urinary cadmium (Cd) concentrations in the Strong Heart Family Study (SHFS) participants are higher than in the general US population. This difference is unlikely to be related to tobacco smoking. We evaluated the association of consumption of processed meats and other dietary products with urinary Cd concentrations in the SHFS, a family-based study conducted in American Indian communities. We included 1725 participants with urine Cd concentrations (standardized to urine creatinine) and food frequency questionnaire data grouped in 24 categories, including processed meat. Median (IQR) urinary Cd concentrations were 0.42 (0.20-0.85) μg/g creatinine. The age, sex, smoking, education, center, body mass index, and total kcal adjusted geometric mean ratio (GMR) (95%CI) of urinary cadmium concentrations per IQR increase in each dietary category was 1.16 (1.04-1.29) for processed meat, 1.10 (1.00-1.21) for fries and chips, 0.87 (0.80-0.95) for dairy products, and 0.89 (0.82-0.97) for fruit juices. The results remained similar after further adjustment for the dietary categories associated with urinary Cd in the previous model except for fries and chips, which was no longer statistically significant. These findings revealed the potential importance of processed meat products as a dietary source of cadmium.
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http://dx.doi.org/10.1016/j.fct.2016.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373690PMC
February 2017

Depressive symptoms are associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study.

Aging (Albany NY) 2016 11;8(11):2961-2970

Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32611, USA.

Patients with depression have an increased risk for many aging-related disorders, but the biological mechanisms underlying this link remain to be determined. Here we examined the association between depressive symptoms and leukocyte telomere length (LTL), a marker of biological aging, among 2,175 American Indians participating in the Strong Heart Family Study. Depressive symptoms were assessed by the Center for Epidemiologic Studies of Depression Scale (CES-D), which was categorized into four levels: none (< 10), mild (10-15), moderate (16 -24), and severe (> 24). LTL (T/S ratio) was quantified by qPCR. The association between depressive symptoms and LTL was examined by multivariate generalized estimating equation models, adjusting for sociodemographic factors, lifestyle factors, and chronic conditions. Results showed that individuals with a higher level of depressive symptoms had shorter LTL. Specifically, LTL in participants reporting none, mild, moderate, and severe depressive symptoms were 1.000, 0.999, 0.988, and 0.966, respectively ( for trend = 0.0278). Moreover, gender appears to modulate the effect of reported depressive symptoms that fall in the severe range (CES-D > 24) on LTL ( for interaction = 0.0346). Our results suggest that depressive symptoms may accelerate biological aging through pathways beyond traditional risk factors in American Indians.
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http://dx.doi.org/10.18632/aging.101104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191880PMC
November 2016

Leukocyte telomere length and ideal cardiovascular health in American Indians: the Strong Heart Family Study.

Eur J Epidemiol 2017 01 22;32(1):67-75. Epub 2016 Sep 22.

Department of Epidemiology, College of Public Health and Health Professions, College of Medicine, University of Florida, 2004 Mowry Road, PO Box 100231, Gainesville, FL, 32610, USA.

Telomere length, a marker of biological aging, has been associated with cardiovascular disease (CVD) and its risk factors. Ideal cardiovascular health (CVH), defined by the American Heart Association (AHA), has also been associated with a reduced risk of CVD, but the relationship between telomere length and ideal CVH is unclear. We measured leukocyte telomere length (LTL) by qPCR in 2568 American Indians in the Strong Heart Family Study (SHFS). All participants were free of overt CVD at enrollment (2001-2003). CVH indices included four behavioral factors (smoking, physical activity, diet, BMI) and three health factors (blood pressure, cholesterol, fasting glucose). Each index was categorized as poor, intermediate, or ideal according to the AHA's guideline. CVH was further categorized into below average (0-1), average (2-3) and above average (≥4) based on the total number of ideal indices. Results showed that, 29, 50 and 21 % of study participants had below average, average, and above average CVH, respectively. Participants with above average CVH had significantly longer LTL than those with below average CVH (β = 0.034, P = 0.042) after adjusting for age, sex, education level, marital status, processed meat consumption, alcohol consumption, and study site. Compared to the U.S. general population, American Indians achieved lower rates for five out of the seven ideal CVH metrics, including smoking, BMI, physical activity, diet, and blood pressure. Achieving four or more ideal CVH metrics was significantly associated with longer LTL. This finding suggests that achieving an ideal CVH may prevent or delay CVD, probably through promoting healthy aging.
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http://dx.doi.org/10.1007/s10654-016-0199-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618104PMC
January 2017

Cranial Magnetic Resonance Imaging in Elderly American Indians: Design, Methods, and Implementation of the Cerebrovascular Disease and Its Consequences in American Indians Study.

Neuroepidemiology 2016 8;47(2):67-75. Epub 2016 Sep 8.

Partnerships for Native Health, Elson S. Floyd College of Medicine, Washington State University, Seattle, Wash., USA.

The Cerebrovascular Disease and its Consequences in American Indians (CDCAI) Study recruited surviving members of a 20-year, longitudinal, population-based cohort of American Indians focused on cardiovascular disease, its risk factors, and its consequences. The goal of the CDCAI Study is to characterize the burden, risk factors, and manifestations of vascular brain injury identified on cranial MRI. The CDCAI Study investigators enrolled 1,033 participants aged 60 and older from 11 American Indian communities and tribes in the Northern Plains, Southern Plains, and Southwestern United States. In addition to cranial MRI performed according to standardized protocols, participants underwent extensive medical interview, clinical examination, neurocognitive testing, physical function evaluation, electrocardiogram, and provided blood and urine specimens. Participants also self-administered questionnaires covering demographics, quality of life, and medical history. This report describes the design, implementation, and some of the unique challenges of this study and data collection.
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http://dx.doi.org/10.1159/000443277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121036PMC
December 2017

Impact of biological aging on arterial aging in American Indians: findings from the Strong Heart Family Study.

Aging (Albany NY) 2016 08;8(8):1583-92

Department of Epidemiology, Tulane University School of Public Health, New Orleans, LA 70112, USA.

Telomere length, a marker of biological aging, has been associated with cardiovascular disease (CVD). Increased arterial stiffness, an indicator of arterial aging, predicts adverse CVD outcomes. However, the relationship between telomere length and arterial stiffness is less well studied. Here we examined the cross-sectional association between leukocyte telomere length (LTL) and arterial stiffness in 2,165 American Indians in the Strong Heart Family Study (SHFS). LTL was measured by qPCR. Arterial stiffness was assessed by stiffness index β. The association between LTL and arterial stiffness was assessed by generalized estimating equation model, adjusting for sociodemographics (age, sex, education level), study site, metabolic factors (fasting glucose, lipids, systolic blood pressure, and kidney function), lifestyle (BMI, smoking, drinking, and physical activity), and prevalent CVD. Results showed that longer LTL was significantly associated with a decreased arterial stiffness (β=-0.070, P=0.007). This association did not attenuate after further adjustment for hsCRP (β=-0.071, P=0.005) or excluding participants with overt CVD (β=-0.068, P=0.012), diabetes (β=-0.070, P=0.005), or chronic kidney disease (β=-0.090, P=0.001). In summary, shorter LTL was significantly associated with an increased arterial stiffness, independent of known risk factors. This finding may shed light on the potential role of biological aging in arterial aging in American Indians.
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http://dx.doi.org/10.18632/aging.101013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032684PMC
August 2016

A Self-assessment Tool for Screening Young Adults at Risk of Type 2 Diabetes Using Strong Heart Family Study Data.

Diabetes Educ 2016 10 31;42(5):607-17. Epub 2016 Jul 31.

School of Medicine, Emory University, Atlanta, Georgia, USA (Dr Umpierrez)

Purpose: The purpose of this study is to characterize risk factors associated with type 2 diabetes in young adults aged 18 to 29 years to develop a noninvasive risk assessment tool for use with younger American populations.

Methods: The self-assessment tool was developed with the Strong Heart Family Study data. A total of 590 young American Indian adults (242 men) who had normoglycemia and were not receiving diabetes treatment were included. Risk factors recommended by the American Diabetes Association were used to assess diabetes risk in these young adults. A logistic regression model was developed to calculate the predicted probability. The area under the receiver operating characteristic curve was used to evaluate the model.

Results: The final model showed that parental history of diabetes, obesity level, alcohol consumption, and high fasting glucose, even within normal range, were significantly associated with onset of prediabetes/diabetes in 5 years. The area under the receiver operating characteristic curve value was 0.68 with original and validated data, indicating that the risk assessment tool had reasonably good discrimination ability.

Conclusions: This new noninvasive screening tool, based on data from American Indian young adults, has potential to screen young adults' early-onset diabetes risk. Future studies are warranted to test this risk assessment tool in other racial/ethnic young adults.
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http://dx.doi.org/10.1177/0145721716658709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026626PMC
October 2016

Metabolic Profiles of Obesity in American Indians: The Strong Heart Family Study.

PLoS One 2016 19;11(7):e0159548. Epub 2016 Jul 19.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States of America.

Obesity is a typical metabolic disorder resulting from the imbalance between energy intake and expenditure. American Indians suffer disproportionately high rates of obesity and diabetes. The goal of this study is to identify metabolic profiles of obesity in 431 normoglycemic American Indians participating in the Strong Heart Family Study. Using an untargeted liquid chromatography-mass spectrometry, we detected 1,364 distinct m/z features matched to known compounds in the current metabolomics databases. We conducted multivariate analysis to identify metabolic profiles for obesity, adjusting for standard obesity indicators. After adjusting for covariates and multiple testing, five metabolites were associated with body mass index and seven were associated with waist circumference. Of them, three were associated with both. Majority of the obesity-related metabolites belongs to lipids, e.g., fatty amides, sphingolipids, prenol lipids, and steroid derivatives. Other identified metabolites are amino acids or peptides. Of the nine identified metabolites, five metabolites (oleoylethanolamide, mannosyl-diinositol-phosphorylceramide, pristanic acid, glutamate, and kynurenine) have been previously implicated in obesity or its related pathways. Future studies are warranted to replicate these findings in larger populations or other ethnic groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951134PMC
July 2017

Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS).

Environ Health Perspect 2017 01 28;125(1):15-22. Epub 2016 Jun 28.

Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants.

Objectives: We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS).

Methods: We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing.

Results: Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10-5).

Conclusions: This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24. Citation: Balakrishnan P, Vaidya D, Franceschini N, Voruganti VS, Gribble MO, Haack K, Laston S, Umans JG, Francesconi KA, Goessler W, North KE, Lee E, Yracheta J, Best LG, MacCluer JW, Kent J Jr., Cole SA, Navas-Acien A. 2017. Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: the Strong Heart Family Study (SHFS). Environ Health Perspect 125:15-22; http://dx.doi.org/10.1289/EHP251.
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http://dx.doi.org/10.1289/EHP251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226702PMC
January 2017

Hemodynamic Correlates of Abnormal Aortic Root Dimension in an Adult Population: The Strong Heart Study.

J Am Heart Assoc 2015 Sep 28;4(10):e002309. Epub 2015 Sep 28.

Department of Medicine, Weill-Cornell Medical College, New York, NY (G.S., M.J.R., R.B.D.).

Background: We evaluated the relationship of aortic root dimension (ARD) with flow output and both peripheral and central blood pressure, using multivariable equations predicting ideal sex-specific ARD at a given age and body height.

Methods And Results: We measured echocardiographic diastolic ARD at the sinuses of Valsalva in 3160 adults (aged 42±16 years, 61% women) from the fourth examination of the Strong Heart Study who were free of prevalent coronary heart disease, and we compared measured data with the theoretical predicted value to calculate a z score. Central blood pressure was estimated by applanation tonometry of the radial artery in 2319 participants. ARD z scores were divided into tertiles representing small, normal, and large ARD. Participants with large ARD exhibited greater prevalence of central obesity and higher levels of inflammatory markers and lipids (0.05
Conclusions: Aortic root dilatation is associated with high diastolic blood pressure, high stroke volume, central fat distribution, and inflammatory status. In contrast, at a given diastolic blood pressure and stroke volume, aortic root dilatation is associated with lower pulse pressure and systolic blood pressure.
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http://dx.doi.org/10.1161/JAHA.115.002309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845134PMC
September 2015

Randomly and Non-Randomly Missing Renal Function Data in the Strong Heart Study: A Comparison of Imputation Methods.

PLoS One 2015 28;10(9):e0138923. Epub 2015 Sep 28.

MedStar Health Research Institute, Hyattsville, Maryland, United States of America; Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, District of Columbia, United States of America.

Kidney and cardiovascular disease are widespread among populations with high prevalence of diabetes, such as American Indians participating in the Strong Heart Study (SHS). Studying these conditions simultaneously in longitudinal studies is challenging, because the morbidity and mortality associated with these diseases result in missing data, and these data are likely not missing at random. When such data are merely excluded, study findings may be compromised. In this article, a subset of 2264 participants with complete renal function data from Strong Heart Exams 1 (1989-1991), 2 (1993-1995), and 3 (1998-1999) was used to examine the performance of five methods used to impute missing data: listwise deletion, mean of serial measures, adjacent value, multiple imputation, and pattern-mixture. Three missing at random models and one non-missing at random model were used to compare the performance of the imputation techniques on randomly and non-randomly missing data. The pattern-mixture method was found to perform best for imputing renal function data that were not missing at random. Determining whether data are missing at random or not can help in choosing the imputation method that will provide the most accurate results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138923PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587557PMC
June 2016

Association of diabetes and cancer mortality in American Indians: the Strong Heart Study.

Cancer Causes Control 2015 Nov 7;26(11):1551-60. Epub 2015 Aug 7.

Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Purpose: The metabolic abnormalities that accompany diabetes mellitus are associated with an increased risk of many cancers. These associations, however, have not been well studied in American Indian populations, which experience a high prevalence of diabetes. The Strong Heart Study is a population-based, prospective cohort study with extensive characterization of diabetes status.

Methods: Among a total cohort of 4,419 participants who were followed for up to 20 years, 430 cancer deaths were identified.

Results: After adjusting for sex, age, education, smoking status, drinking status, and body mass index, participants with diabetes at baseline showed an increased risk of gastric (HR 4.09; 95% CI 1.42-11.79), hepatocellular (HR 2.94; 95% CI 1.17-7.40), and prostate cancer mortality (HR 3.10; 95% CI 1.22-7.94). Further adjustment for arsenic exposure showed a significantly increased risk of all-cause cancer mortality with diabetes (HR 1.27; 95% CI 1.03-1.58). Insulin resistance among participants without diabetes at baseline was associated with hepatocellular cancer mortality (HR 4.70; 95% CI 1.55-14.26).

Conclusions: Diabetes mellitus, and/or insulin resistance among those without diabetes, is a risk factor for gastric, hepatocellular, and prostate cancer in these American Indian communities, although relatively small sample size suggests cautious interpretation. Additional research is needed to evaluate the role of diabetes and obesity on cancer incidence in American Indian communities as well as the importance of diabetes prevention and control in reducing the burden of cancer incidence and mortality in the study population.
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http://dx.doi.org/10.1007/s10552-015-0648-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596901PMC
November 2015

Smoking-attributable mortality in American Indians: findings from the Strong Heart Study.

Eur J Epidemiol 2015 Jul 13;30(7):553-61. Epub 2015 May 13.

Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St. Suite 2000 SL-18, New Orleans, LA, 70112, USA.

Cigarette smoking is the leading preventable cause of death worldwide. American Indians have the highest proportion of smoking in the United States. However, few studies have examined the impact of cigarette smoking on disease mortality in this ethnically important but traditionally understudied minority population. Here we estimated the association of cigarette smoking with cardiovascular disease (CVD), cancer and all-cause mortality in American Indians participating in the Strong Heart Study, a large community-based prospective cohort study comprising of 4549 American Indians (aged 45-74 years) followed for about 20 years (1989-2008). Hazard ratio and population attributable risk (PAR) associated with cigarette smoking were estimated by Cox proportional hazard model, adjusting for sex, study site, age, educational level, alcohol consumption, physical activity, BMI, lipids, renal function, hypertension or diabetes status at baseline, and interaction between current smoker and study site. We found that current smoking was significantly associated with cancer mortality (HR 5.0, [1.9-13.4]) in men, (HR 3.9 [1.6-9.7] in women) and all-cause mortality (HR 1.8, [1.2-2.6] in men, HR 1.6, [1.1-2.4] in women). PAR for cancer and all-cause mortality in men were 41.0 and 18.4 %, respectively, whereas the corresponding numbers in women were 24.9 and 10.9 %, respectively. Current smoking also significantly increases the risk of CVD deaths in women (HR 2.2 [1.1, 4.4]), but not men (HR 1.2 [0.6-2.4]). PAR for CVD mortality in women was 14.9 %. In summary, current smoking significantly increases the risk of CVD (in women), cancer and all-cause mortality in American Indians, independent of known risk factors. Culturally specific smoking cessation programs are urgently needed to reduce smoking-related premature deaths.
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http://dx.doi.org/10.1007/s10654-015-0031-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519414PMC
July 2015
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