AESurv: autoencoder survival analysis for accurate early prediction of coronary heart disease.

Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in the United States. Accurate time-to-event CHD prediction models with high-dimensional DNA methylation and clinical features may assist with early prediction and intervention strategies. We developed a state-of-the-art deep learning autoencoder survival analysis model (AESurv) to effectively analyze high-dimensional blood DNA methylation features and traditional clinical risk factors by learning low-dimensional representation of participants for time-to-event CHD prediction. We demonstrated the utility of our model in two cohort studies: the Strong Heart Study cohort (SHS), a prospective cohort studying cardiovascular disease and its risk factors among American Indians adults; the Women's Health Initiative (WHI), a prospective cohort study including randomized clinical trials and observational study to improve postmenopausal women's health with one of the main focuses on cardiovascular disease. Our AESurv model effectively learned participant representations in low-dimensional latent space and achieved better model performance (concordance index-C index of 0.864 ± 0.009 and time-to-event mean area under the receiver operating characteristic curve-AUROC of 0.905 ± 0.009) than other survival analysis models (Cox proportional hazard, Cox proportional hazard deep neural network survival analysis, random survival forest, and gradient boosting survival analysis models) in the SHS. We further validated the AESurv model in WHI and also achieved the best model performance. The AESurv model can be used for accurate CHD prediction and assist health care professionals and patients to perform early intervention strategies. We suggest using AESurv model for future time-to-event CHD prediction based on DNA methylation features.

Cardiovascular Disease Risk Factors in Women: The Impact of Race and Ethnicity: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading cause of death in women, yet differences exist among certain racial and ethnic groups. Aside from traditional risk factors, behavioral and environmental factors and social determinants of health affect cardiovascular health and risk in women. Language barriers, discrimination, acculturation, and health care access disproportionately affect women of underrepresented races and ethnicities. These factors result in a higher prevalence of cardiovascular disease and significant challenges in the diagnosis and treatment of cardiovascular conditions. Culturally sensitive, peer-led community and health care professional education is a necessary step in the prevention of cardiovascular disease. Equitable access to evidence-based cardiovascular preventive health care should be available for all women regardless of race and ethnicity; however, these guidelines are not equally incorporated into clinical practice. This scientific statement reviews the current evidence on racial and ethnic differences in cardiovascular risk factors and current cardiovascular preventive therapies for women in the United States.

Plasma lipidomic profile of depressive symptoms: a longitudinal study in a large sample of community-dwelling American Indians in the strong heart study.

Dyslipidemia has been associated with depression, but individual lipid species associated with depression remain largely unknown. The temporal relationship between lipid metabolism and the development of depression also remains to be determined. We studied 3721 fasting plasma samples from 1978 American Indians attending two exams (2001-2003, 2006-2009, mean ~5.5 years apart) in the Strong Heart Family Study. Plasma lipids were repeatedly measured by untargeted liquid chromatography-mass spectrometry (LC-MS). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies for Depression (CES-D). Participants at risk for depression were defined as total CES-D score ≥16. Generalized estimating equation (GEE) was used to examine the associations of lipid species with incident or prevalent depression, adjusting for covariates. The associations between changes in lipids and changes in depressive symptoms were additionally adjusted for baseline lipids. We found that lower levels of sphingomyelins and glycerophospholipids and higher level of lysophospholipids were significantly associated with incident and/or prevalent depression. Changes in sphingomyelins, glycerophospholipids, acylcarnitines, fatty acids and triacylglycerols were associated with changes in depressive symptoms and other psychosomatic traits. We also identified differential lipid networks associated with risk of depression. The observed alterations in lipid metabolism may affect depression through increasing the activities of acid sphingomyelinase and phospholipase A2, disturbing neurotransmitters and membrane signaling, enhancing inflammation, oxidative stress, and lipid peroxidation, and/or affecting energy storage in lipid droplets or membrane formation. These findings illuminate the mechanisms through which dyslipidemia may contribute to depression and provide initial evidence for targeting lipid metabolism in developing preventive and therapeutic interventions for depression.

Associations of plasma sphingolipids with measures of insulin sensitivity, ß-cell function, and incident diabetes in Japanese Americans.

BACKGROUND AND AIMS: To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, ß-cell function, and incident diabetes in the Japanese American Community Diabetes Study. METHODS AND RESULTS: Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), ß-cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10-1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%-212.5 %). CONCLUSION: Plasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes.

Assessing the use of GEE methods for analyzing binary outcomes in family studies: the Strong Heart Family Study.

The generalized estimating equations method (GEE) is commonly applied to analyze data obtained from family studies. GEE is well known for its robustness on misspecification of correlation structure. However, the unbalanced distribution of family sizes and complicated genetic relatedness structure within each family may challenge GEE performance. We focused our research on binary outcomes. To evaluate the performance of GEE, we conducted a series of simulations, on data generated adopting the kinship matrix (correlation structure within each family) from the Strong Heart Family Study (SHFS). We performed a fivefold cross-validation to further evaluate the GEE predictive power on data from the SHFS. A Bayesian modeling approach, with direct integration of the kinship matrix, was also included to contrast with GEE. Our simulation studies revealed that GEE performs well on a binary outcome from families having a relatively simple kinship structure. However, data with a binary outcome generated from families with complex kinship structures, especially with a large genetic variance, can challenge the performance of GEE.

Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis.

AIMS: Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort. METHODS AND RESULTS: The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (HR: 1.09, 95% CI: 1.00-1.09), and death due to kidney failure (HR: 1.44, 95% CI: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (HR: 1.10, 95% CI: 1.05-1.14) and death due to kidney failure (HR: 1.54, 95% CI: 1.26-1.89) but not other deaths. CONCLUSION: Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.

High-Density Lipoprotein Lipidomics in Chronic Kidney Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles as compared with the general population. Understanding the lipid composition of HDL may provide mechanistic insight. We tested associations of estimated glomerular filtration rate (eGFR) and albuminuria with relative HDL abundance of ceramides, sphingomyelins, and phosphatidylcholines in participants with CKD. METHODS: We studied 490 participants with CKD from the Seattle Kidney Study. HDL was isolated from plasma; targeted lipidomics was used to quantify the relative abundance of ceramides, sphingomyelins, and phosphatidylcholines per 10 µg of total HDL protein. We evaluated the associations of eGFR and albuminuria with levels of individual lipids and lipid classes (including 7 ceramides, 6 sphingomyelins, and 24 phosphatidylcholines) using multivariable linear regression, controlling for multiple comparisons via the false discovery rate. RESULTS: The mean (SD) eGFR was 45 (24) mL/min/1.73 m2; the median (IQR[interquartile range]) albuminuria was 108 (16, 686) mg/g (12.2 [1.8, 77.6] mg/mmol) urine creatinine. After adjusting for demographics, past medical history, laboratory values, and medication use, eGFR was not associated with higher relative abundance of any class of lipids or individual lipids. Greater albuminuria was significantly associated with a higher relative abundance of total ceramides and moderate-long R-chain sphingomyelins, ceramides 22:0 and 24:1, hexosylceramide 16:0, sphingomyelin 16:0, and phosphatidylcholines 29:0, 30:1, and 38:2; the strongest association was for hexosylceramide 16:0 (increase per doubling of urine albumin to creatinine ratio 0.022 (95% CI, 0.012-0.032). CONCLUSIONS: Greater albuminuria was significantly associated with specific alterations in the lipid composition of HDL in participants with CKD.

Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.

BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways. METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways. RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association. CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.

Associations of pedometer-measured ambulatory activity with incidence of atherosclerotic cardiovascular diseases: Strong heart family study.

OBJECTIVE: Coronary heart disease has several risk factors that require a multifactorial community intervention approach in prevention efforts. Prevalence of coronary heart disease and its risk factors have been disproportionately high among American Indians. The objective of this study is to evaluate the impact of ambulatory activity levels on the development of coronary heart disease in this population. METHODS: Using pedometer data and other lifestyle and clinical factors from 2492 participants in the Strong Heart Family Study, we examined the associations of average daily step counts with incident coronary heart disease during an 18 to 20 year follow-up. RESULTS: After adjusting for potential confounders, participants with daily step counts in the 4th quartile (>7282 steps per day) had significantly lower odds of developing coronary heart disease compared to those in the 1st quartile (<3010 steps per day) (p = 0.035). CONCLUSIONS: Higher daily step count (over 7282 steps per day) is significantly associated with lower incidence of coronary heart disease among American Indian participants of the Strong Heart Family Study in a 20-year follow-up period.

Adapting a cooking, food budgeting and nutrition intervention for a rural community of American Indians with type 2 diabetes in the North-Central United States.

American Indian (AI) communities experience persistent diabetes-related disparities, yet few nutrition interventions are designed for AI with type 2 diabetes or address socio-contextual barriers to healthy eating. We describe our process of adapting the evidence-based Cooking Matters® program for use by AI adults with type 2 diabetes in a rural and resource-limited setting in the North-Central United States. We conducted three focus groups with AI adults with diabetes to (i) identify Cooking Matters® adaptations and (ii) gather feedback on appropriateness of the adapted intervention using Barrera and Castro's cultural adaptation framework. Transcripts were coded using an inductive, constant comparison approach. Queries of codes were reviewed to identify themes. Contextual considerations included limited access to grocery stores and transportation barriers, reliance on government food assistance and the intergenerational burden of diabetes. Adaptations to content and delivery included incorporating traditional and locally available foods; appealing to children or others in multigenerational households and prioritizing visual over written content. Our use of Barrera and Castro's framework adds rigor and structure to the cultural adaptation process and increases the likelihood of future intervention success. Other researchers may benefit from using this framework to guide the adaptation of evidence-based interventions in AI communities.

Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults.

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic ß-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic ß-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic ß-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Circulating ceramides and sphingomyelins and the risk of incident cardiovascular disease among people with diabetes: the strong heart study.

BACKGROUND: Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes. METHODS: This analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case-control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis. RESULTS: There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05-3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26-0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006. CONCLUSIONS: While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes.

Mid-Life Physical Activity and Late-Life Cognitive Performance among American Indians.

INTRODUCTION: Research on factors associated with late-life cognitive performance in diverse racial/ethnic groups is increasingly important due to the growing size and racial diversity of the elder population. METHODS: Using data on American Indians (AIs) from the Strong Heart Study, we measured associations between mid-life physical activity (PA), assessed by a questionnaire or pedometer, and performance on tests of general cognitive function, phonemic fluency, verbal learning and memory, and processing speed. Cognitive tests were administered 7-21 years after PA measurements. To estimate associations, we used regression models with and without inverse-probability weights to account for potential attrition bias in the cohort. RESULTS: Questionnaire and pedometer measures of PA were positively associated with cognitive function. Participants in the top quartile of questionnaire-based PA had Modified Mini-Mental State examination scores 3.2 (95% CI: 1.5-4.9) points higher than participants in the lowest quartile. Phonemic fluency scores also trended higher for participants in the top compared to the bottom categories for both PA measures: top questionnaire quartile = 2.7 (95% CI: 0.6-4.8) points higher and top pedometry tertile = 6.7 (95% CI: 2.7-10.7) points higher. We observed no associations between PA and tests assessing verbal learning and memory, or processing speed. Weighted model results were similar, but less precise. CONCLUSIONS: In this cohort of AIs with relatively low levels of PA, positive associations between mid-life PA and late-life cognitive performance were dose-dependent and of modest clinical significance.

Subclinical atherosclerosis in adolescents and young adults and the risk of cardiovascular disease: The Strong Heart Family Study (SHFS).

BACKGROUND AND AIMS: Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Although we have observed an association between atherosclerosis and CVD in older adults, the potential association among young AI is unclear. Therefore, we aim to describe the prevalence of atherosclerosis among young AI and determine its association with CVD and all-cause mortality. METHODS AND RESULTS: We evaluated AI participants from the Strong Heart Family Study (SHFS), who were <40 years old and CVD free at the baseline examination, 2001-2003 (n = 1376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified CVD events and all-cause mortality through 2019, with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between atherosclerosis and time to CVD event or all-cause mortality, while controlling for covariates. Among 1376 participants, 71 (5.2%) had atherosclerosis at baseline. During follow-up, 120 (8.7%) had CVD events and 104 (7.6%) died from any cause. CVD incidence was higher in participants who had baseline atherosclerosis (13.51/1000 person-years) than in those who did not (4.95/1000 person-years, p = 0.0003). CVD risk and all-cause mortality were higher in participants with atherosclerosis, while controlling for covariates (CVD HR = 1.85, 95%CI = 1.02-3.37, p = 0.0420; all-cause mortality HR = 2.04, 95%CI = 1.07-3.89, p = 0.0291). CONCLUSIONS: Among young AI, atherosclerosis was independently associated with incident CVD and all-cause mortality later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.

Plasma ceramides containing saturated fatty acids are associated with risk of type 2 diabetes.

Recent studies suggest that the type of saturated fatty acid bound to sphingolipids influences the biological activity of those sphingolipids. However, it is unknown whether associations of sphingolipids with diabetes may differ by the identity of bound lipid species. Here, we investigated associations of 15 ceramide (Cer) and SM species (i.e., all sphingolipids, measured with coefficient of variation less than 20%) with incident type 2 diabetes in the Cardiovascular Health Study (n = 3,645), a large cohort study of cardiovascular disease among elderly adults who were followed from 1989 to 2015. Diabetes incidence was defined as fasting glucose ≥126 mg/dl or nonfasting glucose ≥200 mg/dl; reported use of insulin or oral hypoglycemic medication; or documentation of diabetes diagnosis through the Centers for Medicare and Medicaid Services records. Associations of each sphingolipid with incident diabetes were assessed using a Cox proportional hazards regression model. We found that higher circulating levels of Cer with acylated palmitic acid (Cer-16), stearic acid containing Cer (Cer-18), arachidic acid containing Cer (Cer-20), and behenic acid containing Cer (Cer-22) were each associated with a higher risk of diabetes. The hazard ratios for incident diabetes per 1 SD higher log levels of each Cer species were as follows: 1.21 (95% CI: 1.09-1.34) for Cer-16, 1.23 (95% CI: 1.10-1.37) for Cer-18, 1.14 (95% CI: 1.02-1.26) for Cer-20, and 1.18 (95% CI: 1.06-1.32) for Cer-22. In conclusion, higher levels of Cer-16, Cer-18, Cer-20, and Cer-22 were associated with a higher risk of diabetes.

Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study.

BACKGROUND: Recent studies suggest that associations of ceramides (Cer) and sphingomyelins (SM) with health outcomes differ according to the fatty acid acylated to the sphingoid backbone. The purpose of this study was to assess associations of Cer and SM species with mortality. METHODS: The study population included participants from the Cardiovascular Health Study (CHS), a community-based cohort of adults aged ≥65 years who were followed from 1992-2015 (n = 4612). Associations of plasma Cer and SM species carrying long-chain (i.e., 16:0) and very-long-chain (i.e., 20:0, 22:0, 24:0) saturated fatty acids with mortality were assessed using Cox proportional hazards models. RESULTS: During a median follow-up of 10.2 years, 4099 deaths occurred. High concentrations of Cer and SM carrying fatty acid 16:0 were each associated with an increased risk of mortality. Conversely, high concentrations of several ceramide and sphingomyelin species carrying longer fatty acids were each associated with a decreased risk of mortality. The hazard ratios for total mortality per 2-fold difference in each Cer and SM species were: 1.89 (95% CI), 1.65-2.17 for Cer-16, 0.79 (95% CI, 0.70-0.88) for Cer-22, 0.74 (95% CI, 0.65-0.84) for Cer-24, 2.51 (95% CI, 2.01-3.14) for SM-16, 0.68 (95% CI, 0.58-0.79) for SM-20, 0.57 (95% CI, 0.49-0.67) for SM-22, and 0.66 (0.57-0.75) for SM-24. We found no association of Cer-20 with risk of death. CONCLUSIONS: Associations of Cer and SM with the risk of death differ according to the length of their acylated saturated fatty acid. Future studies are needed to explore mechanisms underlying these relationships.

Arsenic, blood pressure, and hypertension in the Strong Heart Family Study.

BACKGROUND: Arsenic has been associated with hypertension, though it is unclear whether associations persist at the exposure concentrations (e.g. <100 µg/L) in drinking water occurring in parts of the Western United States. METHODS: We assessed associations between arsenic biomarkers and systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension in the Strong Heart Family Study, a family-based cohort of American Indians from the Northern plains, Southern plains, and Southwest. We included 1910 participants from three study centers with complete baseline visit data (2001-2003) in the cross-sectional analysis of all three outcomes, and 1453 participants in the prospective analysis of incident hypertension (follow-up 2006-2009). We used generalized estimating equations with exchangeable correlation structure conditional on family membership to estimate the association of arsenic exposure biomarker levels with SBP or DBP (linear regressions) or hypertension prevalence and incidence (Poisson regressions), adjusting for urine creatinine, urine arsenobetaine, and measured confounders. RESULTS: We observed cross-sectional associations for a two-fold increase in inorganic and methylated urine arsenic species of 0.64 (95% CI: 0.07, 1.35) mm Hg for SBP, 0.49 (95% CI: 0.03, 1.02) mm Hg for DBP, and a prevalence ratio of 1.10 (95% CI: 1.01, 1.21) for hypertension in fully adjusted models. During follow-up, 14% of subjects developed hypertension. We observed non-monotonic relationships between quartiles of arsenic and incident hypertension. Effect estimates were null for incident hypertension with continuous exposure metrics. Stratification by study site revealed elevated associations in Arizona, the site with the highest arsenic levels, while results for Oklahoma and North and South Dakota were largely null. Blood pressure changes with increasing arsenic concentrations were larger for those with diabetes at baseline. CONCLUSIONS: Our results suggest a modest cross-sectional association of arsenic exposure biomarkers with blood pressure, and possible non-linear effects on incident hypertension.

Cooking for Health: a healthy food budgeting, purchasing, and cooking skills randomized controlled trial to improve diet among American Indians with type 2 diabetes.

BACKGROUND: The prevalence of poor diet quality and type 2 diabetes are exceedingly high in many rural American Indian (AI) communities. Because of limited resources and infrastructure in some communities, implementation of interventions to promote a healthy diet is challenging-which may exacerbate health disparities by region (urban/rural) and ethnicity (AIs/other populations). It is critical to adapt existing evidence-based healthy food budgeting, purchasing, and cooking programs to be relevant to underserved populations with a high burden of diabetes and related complications. The Cooking for Health Study will work in partnership with an AI community in South Dakota to develop a culturally-adapted 12-month distance-learning-based healthy food budgeting, purchasing, and cooking intervention to improve diet among AI adults with type 2 diabetes. METHODS: The study will enroll 165 AIs with physician-diagnosed type 2 diabetes who reside on the reservation. Participants will be randomized to an intervention or control arm. The intervention arm will receive a 12-month distance-learning curriculum adapted from Cooking Matters® that focuses on healthy food budgeting, purchasing, and cooking skills. In-person assessments at baseline, month 6 and month 12 will include completion of the Nutrition Assessment Shared Resources Food Frequency Questionnaire and a survey to assess frequency of healthy and unhealthy food purchases. Primary outcomes of interest are: (1) change in self-reported intake of sugar-sweetened beverages (SSBs); and (2) change in the frequency of healthy and unhealthy food purchases. Secondary outcomes include: (1) change in self-reported food budgeting skills; (2) change in self-reported cooking skills; and (3) a mixed-methods process evaluation to assess intervention reach, fidelity, satisfaction, and dose delivered/received. DISCUSSION: Targeted and sustainable interventions are needed to promote optimal health in rural AI communities. If effective, this intervention will reduce intake of SSBs and the purchase of unhealthy foods; increase the purchase of healthy foods; and improve healthy food budgeting and cooking skills among AIs with type 2 diabetes - a population at high risk of poor health outcomes. This work will help inform future health promotion efforts in resource-limited settings. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on October 9, 2018 with Identifier NCT03699709 .

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.