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Associations of dietary flavonoids and subclasses with total and cardiovascular mortality among 369,827 older people: The NIH-AARP Diet and Health Study

  • Yimin Zhao
    Correspondence
    Corresponding author. Department of Epidemiology and Biostatistics, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China
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  • Duo Li
    Affiliations
    Institute of Nutrition & Health, Qingdao University, Qingdao, Shandong, 266071, China

    School of Public Health, Qingdao University, Qingdao, Shandong, 266071, China
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  • Tao Huang
    Correspondence
    Corresponding author. Department of Epidemiology and Biostatistics, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China

    Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, Beijing, 100191, China

    Center for Intelligent Public Health, Academy for Artificial Intelligence, Peking University, Beijing, 100191, China
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      Highlights

      • Total flavonoid intake was associated with lower total and CVD mortality among 369,827 older people.
      • The associations between dietary flavonoids and mortality might slightly differ between flavonoid subclasses.
      • The cardiovascular benefits of dietary flavonoids were more evident in the former/current smokers than in the never-smokers.

      Abstract

      Background and aims

      This study aimed to investigate the associations between flavonoid intake and total and cardiovascular mortality in the older participants from the prospective National Institute of Health-American Association of Retired Persons Diet and Health Study.

      Methods

      We included 369,827 eligible participants (mean age 61.2 ± 5.4 years) who were free of cardiovascular diseases (CVDs), cancers, diabetes, and end-stage renal disease at baseline. Dietary flavonoids and major subclasses (flavan-3-ols, flavones, anthocyanidins, flavonones, and flavonols) were assessed using a validated food frequency questionnaire.

      Results

      During a median follow-up of 23.5 years, we identified 143,403 deaths, of which 40,660 from CVDs. After adjustment for major confounders, total dietary flavonoids and most flavonoid subclasses were related to significantly lower total mortality (hazard ratios: 0.87–0.94), comparing the highest and lowest quintiles. Besides, higher intakes of total flavonoids, flavonols, anthocyanidins, and flavones were consistently associated with lower risks of death from all CVDs (hazard ratios: 0.90–0.93), ischemic heart disease (hazard ratios: 0.89–0.94), cerebrovascular disease (hazard ratios: 0.84–0.89), and peripheral artery disease (hazard ratios: 0.79–0.81). Subgroup analysis revealed that the inverse relationships between dietary flavonoids and total and CVD mortality were more evident in former/current smokers than in never-smokers.

      Conclusions

      In conclusion, high intakes of flavonoids were linked to lower total and CVD mortality among older people. Our results extended the current evidence that frequent consumption of flavonoids could be a practical approach to improving cardiovascular health during aging.

      Graphical abstract

      Keywords

      1. Introduction

      Cardiovascular diseases (CVDs) remain the predominant cause of disease burden accounting for nearly one-third of global deaths, and affecting more than 70% of people above 60 years [
      Global, regional, and National age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      ,
      • O'Neill D.E.
      • Forman D.E.
      Cardiovascular care of older adults.
      ]. A poor-quality diet is among the leading risk factors for CVDs, particularly in older people [
      • Roth G.A.
      • Mensah G.A.
      • Johnson C.O.
      • et al.
      Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.
      ]. Notably, the diet-related global disease burden of CVDs has increased substantially in the recent 30 years [
      • Roth G.A.
      • Mensah G.A.
      • Johnson C.O.
      • et al.
      Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.
      ]. Therefore, maintaining a healthy diet in midlife acts as an important strategy for promoting cardiovascular health during aging [
      • Lichtenstein A.H.
      • Appel L.J.
      • Vadiveloo M.
      • et al.
      Dietary guidance to improve cardiovascular health: a scientific statement from the American heart association.
      ]. More specifically, consistent evidence shows the beneficial effects of fruits and vegetables in the prevention of CVDs [
      • Lichtenstein A.H.
      • Appel L.J.
      • Vadiveloo M.
      • et al.
      Dietary guidance to improve cardiovascular health: a scientific statement from the American heart association.
      ,
      • Arnett D.K.
      • Blumenthal R.S.
      • Albert M.A.
      • et al.
      ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
      ,
      • Du H.
      • Li L.
      • Bennett D.
      • et al.
      Fresh fruit consumption and major cardiovascular disease in China.
      ,
      • Wang D.D.
      • Li Y.
      • Bhupathiraju S.N.
      • et al.
      Fruit and vegetable intake and mortality: results from 2 prospective cohort studies of US men and women and a meta-analysis of 26 cohort studies.
      ]. However, only less than 10% of adults meet the dietary guidelines for fruits and vegetables in the United States, according to the National Health and Nutrition Examination Survey 2015–2016 [
      • Virani S.S.
      • Alonso A.
      • Aparicio H.J.
      • et al.
      Heart disease and stroke statistics-2021 update: a report from the American heart association.
      ].
      Flavonoids are among the most plentiful bioactive phytochemicals in the diet, which are abundant in fruits, vegetables, and teas [
      • Chen L.
      • Cao H.
      • Huang Q.
      • et al.
      Absorption, metabolism and bioavailability of flavonoids: a review.
      ]. The average total flavonoid intake in the United States was estimated to be around 200 mg/day [
      • Kim K.
      • Vance T.M.
      • Chun O.K.
      Estimated intake and major food sources of flavonoids among US adults: changes between 1999-2002 and 2007-2010 in NHANES.
      ,
      • Chun O.K.
      • Chung S.J.
      • Song W.O.
      Estimated dietary flavonoid intake and major food sources of U.S. adults.
      ]. Major flavonoid subclasses include flavan-3-ols, flavonones, flavonols, anthocyanidins, flavones, and isoflavones. Previous studies have suggested that dietary flavonoids are the main contributors to the cardiovascular benefits of fruits and vegetables [
      • Mulvihill E.E.
      • Burke A.C.
      • Huff M.W.
      Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis.
      ,
      • Ross J.A.
      • Kasum C.M.
      Dietary flavonoids: bioavailability, metabolic effects, and safety.
      ]. Indeed, short-term small-scale clinical trials have collectively demonstrated the beneficial effects of flavonoids and flavonoid-rich foods on the surrogate biomarkers of cardiovascular health, including endothelial function, blood lipids, inflammation, and oxidative stress [
      • Raman G.
      • Avendano E.E.
      • Chen S.
      • et al.
      Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies.
      ,
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ]. Despite meta-analyses of prospective cohort studies showing an inverse association of flavonoid intake and CVD risks, considerable between-study heterogeneity exists [
      • Grosso G.
      • Micek A.
      • Godos J.
      • et al.
      Dietary flavonoid and lignan intake and mortality in prospective cohort studies: systematic review and dose-response meta-analysis.
      ,
      • Liu X.M.
      • Liu Y.J.
      • Huang Y.
      • et al.
      Dietary Total Flavonoids Intake and Risk of Mortality from All Causes and Cardiovascular Disease in the General Population: A Systematic Review and Meta-Analysis of Cohort Studies.
      ]. Most included studies were of relatively small sample sizes and short follow-up periods [
      • Grosso G.
      • Micek A.
      • Godos J.
      • et al.
      Dietary flavonoid and lignan intake and mortality in prospective cohort studies: systematic review and dose-response meta-analysis.
      ,
      • Liu X.M.
      • Liu Y.J.
      • Huang Y.
      • et al.
      Dietary Total Flavonoids Intake and Risk of Mortality from All Causes and Cardiovascular Disease in the General Population: A Systematic Review and Meta-Analysis of Cohort Studies.
      ]. More importantly, evidence is still lacking concerning the long-term associations between flavonoid intake and CVD mortality among older people who are more vulnerable to the disease burden of CVDs [
      • O'Neill D.E.
      • Forman D.E.
      Cardiovascular care of older adults.
      ].
      In the present study, we aimed to investigate the associations between flavonoid intake and total and CVD mortality, including deaths due to all CVDs, ischemic heart disease (IHD), cerebrovascular disease, and cardiac arrest, among the older participants from the National Institute of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study.

      2. Patients and methods

      2.1 Study population

      Details of the NIH-AARP Diet and Health Study have been described elsewhere [
      • Schatzkin A.
      • Subar A.F.
      • Thompson F.E.
      • et al.
      Design and serendipity in establishing a large cohort with wide dietary intake distributions : the national institutes of health-American association of retired persons diet and health study.
      ]. Between 1995 and 1996, the study team mailed questionnaires to AARP members aged 50–71 years who resided in one of six states (California, Florida, Pennsylvania, New Jersey, North Carolina, and Louisiana) or two metropolitan areas (Atlanta, Georgia and Detroit, Michigan). The baseline questionnaires collected information concerning demographic characteristics, lifestyles, anthropometric measurements, diet, and medical history. A total of 566,398 participants satisfactorily completed the questionnaires. This study has been approved by the Special Studies institutional review board of the National Cancer Institute. Completion of the baseline questionnaire was considered to imply informed consent.

      2.2 Ascertainment of mortality

      The primary outcomes of this study were total and CVD mortality. The vital status of participants was ascertained via linkage to the Social Security Administration Death Master File. The specific cause of death was provided by follow-up searches of the National Death Index Plus. The accuracy of the ascertainment method was estimated to be above 95% [
      • Hermansen S.W.
      • Leitzmann M.F.
      • Schatzkin A.
      The impact on national death index ascertainment of limiting submissions to social security administration death master file matches in epidemiologic studies of mortality.
      ]. We identified deaths due to CVDs using the International Classification of Diseases, Tenth Revision (ICD-10) codes: all CVDs, I00-I99; IHD, I20-I25; cerebrovascular disease, I60-I69; cardiac arrest, I30-I51; peripheral artery disease, I70-I74 [
      • Lim C.C.
      • Hayes R.B.
      • Ahn J.
      • et al.
      Mediterranean diet and the association between air pollution and cardiovascular disease mortality risk.
      ,
      • Bondonno N.P.
      • Murray K.
      • Cassidy A.
      • et al.
      Higher habitual flavonoid intakes are associated with a lower risk of peripheral artery disease hospitalizations.
      ].

      2.3 Assessment of flavonoid intake

      Details of flavonoid intake assessment have been described elsewhere [
      • Sun L.
      • Subar A.F.
      • Bosire C.
      • et al.
      Dietary flavonoid intake reduces the risk of head and neck but not esophageal or gastric cancer in US men and women.
      ,
      • Arem H.
      • Bobe G.
      • Sampson J.
      • et al.
      Flavonoid intake and risk of pancreatic cancer in the national institutes of health-AARP diet and health study cohort.
      ]. In brief, the diet was assessed at baseline via a self-administrated 124-item food frequency questionnaire (FFQ), an early version of the National Cancer Institute Diet History Questionnaire. The participants were asked about the frequency and portion size of each food item over the past year. Flavonoid intake from each food item was calculated according to the United States Department of Agriculture (USDA) Expanded Flavonoid Database for the Assessment of Dietary Intakes, Release 1.1,[
      • Bhagwat S.
      • Haytowitz D.B.
      • Wasswa-Kintu S.
      USDA's expanded flavonoid Database for the assessment of dietary intakes.
      ] developed by the USDA Nutrient Data Laboratory, which contained flavonoid data on 29 individual flavonoid compounds for 2926 foods. For processed foods that only had flavonoid values for the raw foods, we assumed a 50% loss of flavonoids during processing based on comparing food items with flavonoid values for both raw and processed foods. The validity and reliability of this FFQ have been validated using two non-consecutive 24-h diet recalls completed within one year of the baseline questionnaire in a random sub-cohort (n = 2053) of the NIH-AARP Diet and Health Study [
      • Thompson F.E.
      • Kipnis V.
      • Midthune D.
      • et al.
      Performance of a food-frequency questionnaire in the US NIH-AARP (national institutes of health-American association of retired persons) diet and health study.
      ]. The correlation coefficients for deattenuated flavonoid intakes derived from the FFQ and the 24-h diet recalls were 0.57 in men and 0.65 in women [
      • Arem H.
      • Bobe G.
      • Sampson J.
      • et al.
      Flavonoid intake and risk of pancreatic cancer in the national institutes of health-AARP diet and health study cohort.
      ,
      • Thompson F.E.
      • Kipnis V.
      • Midthune D.
      • et al.
      Performance of a food-frequency questionnaire in the US NIH-AARP (national institutes of health-American association of retired persons) diet and health study.
      ].
      We derived five major flavonoid subclasses as follows: flavan-3-ols (catechin, epicatechin, epigallocatechin, epicatechin-3-gallate, epigallocatechin-3-gallate, theaflavin, theaflavin-3-gallate, theaflavin-3′-gallate, theaflavin-3, 3′-digallate, and thearubigins), flavones (apigenin and luteolin), anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin), flavonones (eriodictyol, hesperetin, and naringenin), and flavonols (kaempferol, isorhamnetin, myricetin, and quercetin). In the NIH-AARP Diet and Health Study, the leading food sources of each flavonoid subclass were: tea for flavan-3-ols, pepper, tomato, and grapes for flavones, berries, grapes, and red wine for anthocyanidins, oranges, and grapefruits for flavonones, and tea and apples for flavonols [
      • Sun L.
      • Subar A.F.
      • Bosire C.
      • et al.
      Dietary flavonoid intake reduces the risk of head and neck but not esophageal or gastric cancer in US men and women.
      ]. We did not include isoflavones because the median intake was less than 0.5 mg/day in the NIH-AARP Diet and Health Study, which is far below the level to reach clinical relevance [
      • Bertoia M.L.
      • Rimm E.B.
      • Mukamal K.J.
      • et al.
      Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years.
      ]. We calculated the total flavonoid intake by summing the five major subclasses.

      2.4 Statistical analysis

      Baseline characteristics of participants were expressed as means with standard deviations or medians with interquartile ranges for continuous variables and number with proportions for categorical variable. Between-group difference in baseline characteristics were compared using one-way analysis of variance, Kruskal-Wallis test, or chi-square test when appropriate. Flavonoid intake was adjusted for total energy to 2000 kcal/day using the residual method as described previously [
      • Willett W.C.
      • Howe G.R.
      • Kushi L.H.
      Adjustment for total energy intake in epidemiologic studies.
      ]. To minimize the influences of extreme intake, we categorized flavonoid intake into quintiles. We used Cox proportional hazards model to analyze the relationships between flavonoid intake and mortality, with the lowest quintile as the reference. Follow-up time was used as the time scale. Follow-up of the analytic cohort started upon the completion of the baseline questionnaire. Deaths due to causes other than CVDs and loss of follow-up were right-censored in the analysis of CVD mortality. We assessed the proportional hazards assumption via the Schoenfeld residuals. The Cox regression model adjusted for age (continuous), sex, body mass index (BMI, <25 kg/m2, 25 - < 30 kg/m2, and ≥30 kg/m2), ethnicity (non-Hispanic white, non-Hispanic black, and other), education attainment (<8 years, 8–11 years, 12 years or completed high school, post-high school or some college, and college and postgraduate), vigorous physical activity (physical activity ≥20 min that caused increases in breathing or heart rate, or worked up a sweat, never or rarely, <3 times per month, 1–4 times per week, and ≥5 times per week), smoking status (never, former, and current), excess alcohol intake (28 g/day for men and 14 g/day for women), marital status (married and not married), total energy intake (kcal/day), and Healthy Eating Index-2015 (HEI-2015, continuous). HEI-2015 is a measure of overall diet quality, which is calculated based on the intake of thirteen major food groups (https://epi.grants.cancer.gov/hei) [
      • Krebs-Smith S.M.
      • Pannucci T.E.
      • Subar A.F.
      • et al.
      Update of the healthy eating index: HEI-2015.
      ]. Because missing values in all covariates were less than 5%, we set an indicator for each missing value in the models. Trend analysis was conducted by treating the median intake of each quintile as a continuous variable. Multiplicative interactions by sex and lifestyle factors, including BMI, alcohol intake, physical activity, and smoking status, were tested by a likelihood ratio test comparing the models with and without the cross-product term. In the sensitivity analysis, we excluded deaths that occurred in the first five years of follow-up to reduce the possibility of reserve causality. Statistical analysis was performed in Stata/MP version 17.0. Statistical significance was set at p < 0.0017 (0.05/30 = 0.0017, six exposures and five cardiovascular outcomes) after Bonferroni correction accounting for multiple comparisons. In addition, a p value between 0.05 and 0.0017 was regarded as suggestive significance.

      3. Results

      3.1 Baseline characteristics

      In this study, we excluded participants with existing CVDs (n = 58,298), cancers (n = 51,260), diabetes (n = 42,178), or end-stage renal disease (n = 769). We also excluded participants whose questionnaires were complete by proxies (n = 15,760), had self-reported poor health status (n = 8365), or had an extreme total energy intake (above two-fold of the interquartile range of sex-specific log-transformed intake, n = 3440). Thereby, the analytic cohort was comprised of 369,827 people (Fig. 1).
      The median flavonoid intakes were 192 mg/day for total flavonoids, 101.2 mg/day for flavan-3-ols, 36.8 mg/day for flavonones, 18.2 mg/day for flavonols, 12.1 mg/day for anthocyanidins, and 1.1 mg/day for flavones in this study. Table 1 shows the baseline characteristics of the study population by the quintiles of total flavonoid intake. Participants in the lowest quintile of total flavonoid intake were more likely to be men, younger, more obese, have less vigorous physical activity, have lower educational attainment, be former/current smokers, and have poorer overall diet quality.
      Table 1Baseline characteristics of the study population by quintiles of unadjusted total flavonoid intake.
      VariableQuintiles of total flavonoid intake
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Total flavonoids, median (IQR), mg/day76 (46)134 (25)192 (37)319 (103)651 (604)
      Women, %29.244.547.947.649.6
      Age, mean (SD), years60.9 (5.5)61.3 (5.4)61.3 (5.4)61.1 (5.4)61.3 (5.4)
      BMI, mean (SD), kg/m227.0 (4.9)26.5 (4.7)26.5 (4.7)26.8 (4.9)26.7 (5.0)
      non-Hispanic white, %92.692.091.691.891.7
      Never-smoking, %29.736.339.439.940.3
      Vigorous physical activity ≥1 time/week, %42.947.249.247.445.9
      College and postcollege education, %37.442.043.039.839.4
      Married, %73.367.566.466.965.3
      Total energy intake, median (IQR), kcal/day2023 (964)1524 (788)1511 (751)1686 (874)1743 (903)
      Alcohol intake, median (IQR), g/day2.5 (17.1)2.6 (14.0)2.4 (11.8)1.8 (9.6)1.8 (8.9)
      Fruits, median (IQR), servings/day1.1 (1.2)1.6 (1.3)2.0 (1.7)2.0 (2.0)1.9 (1.8)
      Vegetables, median (IQR), servings/day1.7 (1.3)1.6 (1.2)1.6 (1.2)1.8 (1.3)1.8 (1.4)
      Red meat, median (IQR), servings/day2.3 (2.2)1.4 (1.5)1.3 (1.4)1.5 (1.7)1.5 (1.7)
      HEI-2015, mean (SD)62.9 (9.8)68.8 (8.8)70.3 (8.7)68.8 (9.4)67.6 (9.5)
      BMI, body mass index; HEI, healthy eating index; IQR, interquartile range; SD, standard deviation.

      3.2 Flavonoid intake and total mortality

      During a median follow-up of 23.5 years (7,506,082 total person-years), we identified 143,403 deaths from all causes. Table 2 shows the hazard ratios of total mortality by the quintiles of total flavonoid intake and their subclasses. After adjustment for major confounders, total flavonoids and the subclasses were consistently associated with a statistically significant reduction in total mortality. The hazard ratios (HRs) of total mortality for participants in the highest quintiles of intake of total flavonoids, flavan-3-ols, flavonones, flavonols, anthocyanidins, and flavones were 0.92 (95% confidence interval (CI): 0.91, 0.94; p for trend <0.001), 0.94 (95% CI: 0.92, 0.95; p for trend <0.001), 0.92 (95% CI: 0.91, 0.94; p for trend <0.001), 0.89 (95% CI: 0.88, 0.91; p for trend <0.001), and 0.87 (95% CI:0.85, 0.88; p for trend <0.001), respectively.
      Table 2Hazard ratios of all-cause mortality by quintiles of flavonoid intake.
      Quintiles of flavonoid intakep for trend
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Total flavonoids
      Median intake, mg/day76.2133.9192.0319.1651.5
      Cases per 100,000 person-years21741891181118451838
      Hazard ratio, 95% CI1.000.94 (0.93, 0.96)0.92 (0.90, 0.94)0.95 (0.93, 0.96)0.92 (0.91, 0.94)<0.001
      Flavan-3-ols
      Median intake, mg/day21.857.2101.2224.6550.5
      Cases per 100,000 person-years21471888182818411853
      Hazard ratio, 95% CI1.000.95 (0.93, 0.97)0.94 (0.93, 0.96)0.95 (0.94, 0.97)0.94 (0.92, 0.95)<0.001
      Flavonones
      Median intake, mg/day7.821.936.855.996.3
      Cases per 100,000 person-years21421867183418411873
      Hazard ratio, 95% CI1.000.95 (0.93, 0.96)0.92 (0.90, 0.93)0.90 (0.89, 0.92)0.92 (0.91, 0.94)<0.001
      Flavonols
      Median intake, mg/day9.914.318.223.837.5
      Cases per 100,000 person-years22311907180818251791
      Hazard ratio, 95% CI1.000.92 (0.91, 0.94)0.90 (0.89, 0.92)0.92 (0.91, 0.94)0.91 (0.89, 0.92)<0.001
      Anthocyanidins
      Median intake, mg/day4.78.712.116.526.2
      Cases per 100,000 person-years22571955183617441775
      Hazard ratio, 95% CI1.000.94 (0.92, 0.95)0.90 (0.88, 0.91)0.88 (0.86, 0.89)0.89 (0.88, 0.91)<0.001
      Flavones
      Median intake, mg/day0.40.81.11.62.7
      Cases per 100,000 person-years22811938181517611774
      Hazard ratio, 95% CI1.000.92 (0.90, 0.93)0.89 (0.87, 0.90)0.86 (0.85, 0.88)0.87 (0.85, 0.88)<0.001
      The hazard ratios were calculated using Cox regression model. Model 1 adjusted for sex, body mass index, total energy intake, alcohol intake, education attainment, physical activity, ethnicity, smoking status, and marital status. The p for trend was analyzed by treating the median intake in each quintile as a continuous variable. Flavonoid intakes were adjusted using the residual method. CI, confidence interval.

      3.3 Flavonoid intake and total CVD mortality

      During the follow-up, we identified 40,660 CVD deaths. Table 3 shows the hazard ratios of total CVD mortality by the quintiles of total flavonoid intake and their subclasses. Comparing the highest with lowest quintile of intake, dietary total flavonoids, flavan-3-ols, flavonols, anthocyanidins, and flavones were associated with 7% (HR: 0.93; 95% CI: 0.90, 0.96; p for trend = 0.001), 5% (HR: 0.95; 95% CI: 0.92, 0.98; p for trend = 0.003), 8% (HR: 0.93; 95% CI: 0.89, 0.94; p for trend <0.001), 8% (HR: 0.93; 95% CI: 0.89, 0.95; p for trend <0.001), and 10% (HR: 0.93; 95% CI: 0.87, 0.93; p for trend <0.001) lower risks of death from any CVDs.
      Table 3Hazard ratios of all cardiovascular disease mortality by quintiles of flavonoid intake.
      Quintiles of flavonoid intakep for trend
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Total flavonoids
      Median intake, mg/day76.2133.9192.0319.1651.5
      Cases per 100,000 person-years599536526526524
      Hazard ratio, 95% CI1.000.95 (0.92, 0.98)0.95 (0.92, 0.98)0.96 (0.93, 0.99)0.93 (0.90, 0.96)0.001
      Flavan-3-ols
      Median intake, mg/day21.857.2101.2224.6550.5
      Cases per 100,000 person-years598545522521525
      Hazard ratio, 95% CI1.000.99 (0.95, 1.02)0.97 (0.94, 1.00)0.97 (0.94, 1.00)0.95 (0.92, 0.98)0.003
      Flavonones
      Median intake, mg/day7.821.936.855.996.3
      Cases per 100,000 person-years576509526532567
      Hazard ratio, 95% CI1.000.94 (0.91, 0.97)0.94 (0.91, 0.97)0.92 (0.89, 0.95)0.98 (0.95, 1.01)0.75
      Flavonols
      Median intake, mg/day9.914.318.223.837.5
      Cases per 100,000 person-years621543516526506
      Hazard ratio, 95% CI1.000.94 (0.91, 0.97)0.92 (0.89, 0.95)0.95 (0.92, 0.98)0.92 (0.89, 0.94)<0.001
      Anthocyanidins
      Median intake, mg/day4.78.712.116.526.2
      Cases per 100,000 person-years610548531506517
      Hazard ratio, 95% CI1.000.94 (0.91, 0.97)0.92 (0.90, 0.95)0.90 (0.87, 0.93)0.92 (0.89, 0.95)<0.001
      Flavones
      Median intake, mg/day0.40.81.11.62.7
      Cases per 100,000 person-years619546521513513
      Hazard ratio, 95% CI1.000.93 (0.91, 0.96)0.91 (0.88, 0.94)0.90 (0.87, 0.93)0.90 (0.87, 0.93)<0.001
      The hazard ratios were calculated using Cox regression model. Model 1 adjusted for sex, body mass index, total energy intake, alcohol intake, education attainment, physical activity, ethnicity, smoking status, and marital status. The p for trend was analyzed by treating the median intake in each quintile as a continuous variable. Flavonoid intakes were adjusted using the residual method. CI, confidence interval.

      3.4 Flavonoid intake and cause-specific CVD mortality

      In the present study, we documented 18,137 deaths due to IHD, 7841 deaths due to cerebrovascular disease, 8678 deaths due to cardiac arrest, and 1566 deaths due to peripheral artery disease. Table 4 shows the fully adjusted hazard ratios of each cause-specific CVD mortality by the quintiles of total flavonoid intake and the subclasses. Compared with participants in the lowest quintiles, those in the highest quintiles of total flavonoids, flavonols, anthocyanidins, and flavones were associated with 6% (HR: 0.94; 95% CI: 0.90, 0.98; p for trend = 0.07), 9% (HR: 0.91; 95% CI: 0.87, 0.95; p for trend = 0.005), 11% (HR: 0.89; 95% CI: 0.85, 0.94; p for trend <0.001), and 11% (HR: 0.89; 95% CI: 0.85, 0.94; p for trend <0.001) lower risks of IHD death. Participants in the highest quintile of total flavonoid, flavan-3-ol, flavonol, anthocyanidin, and flavone intake were associated with 11% (HR: 0.89; 95% CI: 0.83, 0.96; p for trend = 0.03), 8% (HR: 0.92; 95% CI: 0.85, 0.98; p for trend = 0.03), 11% (HR: 0.89; 95% CI: 0.83, 0.96; p for trend = 0.004), 12% (HR: 0.88; 95% CI: 0.82, 0.95; p for trend = 0.002), and 16% (HR: 0.84; 95% CI: 0.78, 0.90; p for trend <0.001) lower cerebrovascular disease mortality, respectively. The hazard ratios (HRs) of peripheral artery disease mortality for participants in the highest quintiles of intake of total flavonoids, flavan-3-ols, flavonols, anthocyanidins, and flavones were 0.81 (95% CI: 0.69, 0.94; p for trend = 0.007), 0.83 (95% CI: 0.71, 0.98; p for trend = 0.03), 0.80 (95% CI: 0.68, 0.93; p for trend = 0.009), 0.79 (95% CI: 0.67, 0.93; p for trend = 0.008), and 0.80 (95% CI:0.69, 0.94; p for trend = 0.02), respectively. However, total flavonoids and the subclasses were not related to any significant changes in mortality from cardiac arrest in the present study.
      Table 4Hazard ratios of cause-specific cardiovascular disease mortality by quintiles of flavonoid intake.
      Quintiles of total flavonoid intakep for trend
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Ischemic heart disease
      Total flavonoids1.000.94 (0.90, 0.99)0.95 (0.91, 1.00)0.96 (0.91, 1.00)0.94 (0.90, 0.98)0.07
      Flavan-3-ols1.000.98 (0.93, 1.03)0.97 (0.93, 1.02)0.98 (0.94, 1.03)0.95 (0.91, 1.00)0.09
      Flavonones1.000.92 (0.88, 0.96)0.92 (0.88, 0.97)0.90 (0.85, 0.94)0.97 (0.93, 1.02)0.70
      Flavonols1.000.91 (0.87, 0.95)0.90 (0.86, 0.94)0.93 (0.89, 0.98)0.91 (0.87, 0.95)0.005
      Anthocyanidins1.000.91 (0.87, 0.95)0.88 (0.84, 0.92)0.85 (0.81, 0.89)0.89 (0.85, 0.94)<0.001
      Flavones1.000.92 (0.88, 0.96)0.91 (0.87, 0.95)0.88 (0.84, 0.92)0.89 (0.85, 0.94)<0.001
      Cerebrovascular disease
      Total flavonoids1.000.92 (0.86, 0.99)0.90 (0.84, 0.97)0.92 (0.86, 0.99)0.89 (0.83, 0.96)0.03
      Flavan-3-ols1.000.97 (0.90, 1.04)0.93 (0.87, 1.00)0.92 (0.86, 0.99)0.92 (0.85, 0.98)0.03
      Flavonones1.000.94 (0.87, 1.02)0.93 (0.86, 1.00)0.93 (0.86, 1.00)0.96 (0.89, 1.03)0.55
      Flavonols1.000.96 (0.89, 1.03)0.92 (0.86, 0.99)0.96 (0.89, 1.03)0.89 (0.83, 0.96)0.004
      Anthocyanidins1.000.96 (0.89, 1.03)0.96 (0.89, 1.04)0.97 (0.90, 1.05)0.88 (0.82, 0.95)0.002
      Flavones1.000.96 (0.89, 1.03)0.92 (0.85, 0.99)0.93 (0.86, 1.00)0.84 (0.78, 0.90)<0.001
      Cardiac arrest
      Total flavonoids1.000.99 (0.93, 1.06)0.98 (0.91, 1.05)1.06 (0.99, 1.14)0.97 (0.91, 1.04)0.64
      Flavan-3-ols1.001.03 (0.96, 1.11)1.01 (0.94, 1.08)1.03 (0.96, 1.10)1.00 (0.93, 1.07)0.58
      Flavonones1.000.99 (0.92, 1.06)1.00 (0.93, 1.07)0.98 (0.91, 1.05)1.03 (0.96, 1.10)0.34
      Flavonols1.000.99 (0.92, 1.05)0.97 (0.91, 1.04)1.00 (0.94, 1.07)0.98 (0.91, 1.05)0.70
      Anthocyanidins1.000.96 (0.90, 1.03)1.00 (0.93, 1.07)0.96 (0.90, 1.03)1.03 (0.97, 1.11)0.19
      Flavones1.000.98 (0.91, 1.05)0.94 (0.88, 1.01)0.98 (0.91, 1.05)1.01 (0.94, 1.08)0.45
      Peripheral artery disease
      Total flavonoids1.000.92 (0.79, 1.07)0.91 (0.78, 1.06)0.82 (0.70, 0.96)0.81 (0.69, 0.94)0.007
      Flavan-3-ols1.000.95 (0.81, 1.12)0.91 (0.78, 1.07)0.90 (0.77, 1.05)0.83 (0.71, 0.98)0.03
      Flavonones1.000.91 (0.77, 1.06)0.92 (0.78, 1.08)0.85 (0.72, 1.00)0.98 (0.84, 1.14)0.92
      Flavonols1.000.92 (0.79, 1.06)0.83 (0.71, 0.97)0.89 (0.76, 1.03)0.80 (0.68, 0.93)0.009
      Anthocyanidins1.000.99 (0.85, 1.15)0.91 (0.78, 1.07)0.81 (0.69, 0.96)0.79 (0.67, 0.93)0.008
      Flavones1.000.86 (0.74, 1.01)0.84 (0.72, 0.98)0.80 (0.68, 0.94)0.80 (0.69, 0.94)0.02
      The hazard ratios were calculated using Cox regression model. Model 1 adjusted for sex, body mass index, total energy intake, alcohol intake, education attainment, physical activity, ethnicity, smoking status, and marital status. The p for trend was analyzed by treating the median intake in each quintile as a continuous variable. Flavonoid intakes were adjusted using the residual method.

      3.5 Subgroup analysis and sensitivity analysis

      Table 5 and Table 6 show the hazard ratios of total and CVD mortality for total flavonoids by baseline characteristics. Notably, total flavonoid intake was associated with greater reductions in total mortality and total CVD mortality in former/current smokers than in never-smokers. In the sensitivity analysis, excluding CVD deaths in the first five years of follow-up did not substantially alter the observed relationships between flavonoid intake and total and CVD mortality (data not shown).
      Table 5Hazard ratios of total mortality by quintiles of total flavonoid intake according to the baseline characteristics of participants.
      Quintiles of total flavonoid intakep for interaction
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Sex
      Women1.000.92 (0.89, 0.94)0.90 (0.87, 0.92)0.92 (0.89, 0.94)0.89 (0.86, 0.91)
      Men1.000.95 (0.93, 0.97)0.93 (0.91, 0.95)0.96 (0.94, 0.98)0.94 (0.92, 0.96)0.07
      BMI
      <25 kg/m21.000.93 (0.91, 0.96)0.89 (0.87, 0.92)0.93 (0.90, 0.96)0.91 (0.89, 0.94)
      ≥25 kg/m21.000.94 (0.92, 0.96)0.93 (0.91, 0.95)0.95 (0.94, 0.97)0.92 (0.91, 0.94)<0.001
      Alcohol intake
      Low to moderate intake1.000.94 (0.92, 0.95)0.92 (0.91, 0.94)0.95 (0.93, 0.96)0.92 (0.90, 0.94)
      Excess intake1.000.96 (0.93, 1.00)0.90 (0.87, 0.94)0.94 (0.90, 0.98)0.93 (0.89, 0.97)0.11
      Vigorous physical activity
      ≥1 time/week1.000.95 (0.93, 0.97)0.94 (0.92, 0.97)0.95 (0.93, 0.98)0.94 (0.92, 0.97)
      <1 time/week1.000.93 (0.91, 0.95)0.89 (0.87, 0.91)0.93 (0.91, 0.95)0.90 (0.88, 0.92)0.001
      Smoking status
      Never1.000.97 (0.94, 1.00)0.95 (0.92, 0.99)0.97 (0.94, 1.00)0.92 (0.89, 0.95)
      Former/Current1.000.89 (0.87, 0.91)0.86 (0.84, 0.87)0.89 (0.88, 0.91)0.89 (0.87, 0.91)<0.001
      The hazard ratios were calculated using Cox regression model. Model 1 adjusted for sex, body mass index, total energy intake, alcohol intake, education attainment, physical activity, ethnicity, smoking status, and marital status. Flavonoid intakes were adjusted using the residual method. BMI, body mass index.
      Table 6Hazard ratios of total cardiovascular disease mortality by quintiles of total flavonoid intake according to the baseline characteristics of participants.
      Quintiles of total flavonoid intakep for interaction
      Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5
      Sex
      Women1.000.90 (0.85, 0.95)0.87 (0.83, 0.92)0.90 (0.85, 0.95)0.86 (0.82, 0.91)
      Men1.000.97 (0.94, 1.01)0.98 (0.94, 1.02)0.98 (0.94, 1.02)0.97 (0.93, 1.00)0.03
      BMI
      <25 kg/m21.000.94 (0.89, 0.99)0.92 (0.87, 0.98)0.90 (0.85, 0.96)0.93 (0.88, 0.99)
      ≥25 kg/m21.000.95 (0.92, 0.99)0.95 (0.92, 0.99)0.98 (0.95, 1.02)0.93 (0.89, 0.96)0.02
      Alcohol intake
      Low to moderate intake1.000.94 (0.91, 0.98)0.95 (0.92, 0.98)0.95 (0.92, 0.99)0.93 (0.90, 0.96)
      Excess intake1.000.99 (0.92, 1.06)0.93 (0.86, 1.00)0.99 (0.92, 1.07)0.94 (0.87, 1.02)0.49
      Vigorous physical activity
      ≥1 time/week1.000.95 (0.91, 1.00)0.97 (0.92, 1.01)0.95 (0.91, 1.00)0.96 (0.92, 1.01)
      <1 time/week1.000.95 (0.91, 0.99)0.92 (0.88, 0.96)0.96 (0.92, 1.00)0.91 (0.87, 0.95)0.13
      Smoking status
      Never1.000.98 (0.92, 1.04)0.96 (0.91, 1.02)0.97 (0.92, 1.03)0.91 (0.86, 0.97)
      Former/Current1.000.91 (0.87, 0.94)0.90 (0.86, 0.93)0.92 (0.88, 0.95)0.91 (0.88, 0.95)0.005
      The hazard ratios were calculated using Cox regression model. Model 1 adjusted for sex, body mass index, total energy intake, alcohol intake, education attainment, physical activity, ethnicity, smoking status, and marital status. Flavonoid intakes were adjusted using the residual method. BMI, body mass index.

      4. Discussion

      In this prospective analysis of the NIH-AARP Diet and Health Study, we found that total flavonoids and most flavonoid subclasses were associated with lower total and CVD mortality, including deaths due to IHD, cerebrovascular disease, and peripheral artery disease after adjustment for lifestyle and dietary factors. However, there was no statistically significant relationship between flavonoid intake and cardiac arrest mortality after adjustment for demographic, lifestyle, and dietary factors. In addition, the associations between total flavonoid intake and total and CVD mortality were more evident among former/current smokers than people that never smoked. The present study suggested that adequate intake of flavonoids and flavonoid-rich foods might attenuate CVD mortality in older people, while different flavonoid subclasses may have divergent effects.
      The cardiovascular benefits of flavonoids and flavonoid-rich foods have been well-documented in previous clinical trials and observational studies [
      • Raman G.
      • Avendano E.E.
      • Chen S.
      • et al.
      Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies.
      ,
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ]. A recent study also demonstrated that supplementation of anthocyanidins from bilberries could reduce circulating proatherogenic ceramides and improve cholesterol efflux capacity in people with dyslipidemia in a dose-dependent manner [
      • Zhao Y.
      • Xu H.
      • Tian Z.
      • et al.
      Dose-dependent reductions in plasma ceramides after anthocyanin supplementation are associated with improvements in plasma lipids and cholesterol efflux capacity in dyslipidemia: a randomized controlled trial.
      ]. In the present study, we found that the flavonoid-related reductions in CVD mortality might differ between flavonoid subclasses. Intake of flavan-3-ols, which are plentiful in tea and comprise the largest proportions of dietary flavonoids, was only related to marginally significant reductions in IHD mortality. Dietary flavonones, which are abundant in citrus fruits, were not related to any improvements in CVD mortality. In contrast, dietary flavonols, anthocyanidins, and flavones were associated with significantly lower risks of death due to all CVDs, IHD, cerebrovascular disease, and peripheral artery disease. It is possible that the structural variations of flavonoid subclasses could cause differential metabolic responses in the body [
      • Chen L.
      • Cao H.
      • Huang Q.
      • et al.
      Absorption, metabolism and bioavailability of flavonoids: a review.
      ,
      • Geleijnse J.M.
      • Hollman P.
      Flavonoids and cardiovascular health: which compounds, what mechanisms?.
      ]. Besides, the food matrix of the flavonoid sources and the processing procedures could also influence their physiological properties [
      • Bertoia M.L.
      • Rimm E.B.
      • Mukamal K.J.
      • et al.
      Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years.
      ,
      • Lu Q.
      • Peng Y.
      • Zhu C.
      • et al.
      Effect of thermal treatment on carotenoids, flavonoids and ascorbic acid in juice of orange cv. Cara Cara.
      ]. Despite inconsistent associations between flavonoid subclasses and CVD mortality, our results did not compromise the recommendations for adequate fruit and vegetable consumption to improve cardiovascular health. Instead, in line with previous studies, our results provided additional evidence that flavonoid intake was generally related to lower CVD mortality among older people, highlighting the necessity to increase the consumption of flavonoid-rich fruits and vegetables, including citrus, tomato, and berries, for promoting cardiovascular health during aging.
      In this study, the inverse relationships between flavonoids and total CVD mortality were more evident in current or former smokers than in never-smokers. Dark-colored berry fruits are the main dietary contributors of anthocyanidins [
      • Yang L.
      • Ling W.
      • Du Z.
      • et al.
      Effects of anthocyanins on cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials.
      ]. Supplementation of anthocyanidins from black current could effectively alleviate smoking-induced acute endothelial dysfunction in young smokers [
      • Tomisawa T.
      • Nanashima N.
      • Kitajima M.
      • et al.
      Effects of blackcurrant anthocyanin on endothelial function and peripheral temperature in young smokers.
      ]. Anthocyanidin-rich extracts from Aronia berry and Maqui Berry could improve the oxidative status and reduce blood lipids in healthy smokers [
      • Davinelli S.
      • Bertoglio J.C.
      • Zarrelli A.
      • et al.
      A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (Delphinol®) on oxidative stress biomarkers.
      ,
      • Xie L.
      • Vance T.
      • Kim B.
      • et al.
      Aronia berry polyphenol consumption reduces plasma total and low-density lipoprotein cholesterol in former smokers without lowering biomarkers of inflammation and oxidative stress: a randomized controlled trial.
      ]. Besides, short-term supplementation of green tea, a major contributor to dietary flavonoids, could rapidly enhance endothelial function in healthy smokers [
      • Kim W.
      • Jeong M.H.
      • Cho S.H.
      • et al.
      Effect of green tea consumption on endothelial function and circulating endothelial progenitor cells in chronic smokers.
      ]. In this context, habitual consumption of flavonoids and flavonoid-rich foods might confer better cardioprotective benefits among former/current smokers. In-depth studies are required to disentangle the roles of flavonoid-smoking interactions in relation to CVD mortality in the future.
      The chief strengths of the present study were the considerable sample size and the number of CVD deaths, which allowed us to identify even minor to moderate associations between flavonoid intake and CVD mortality with sufficient statistical power. In addition, the broad assessment of flavonoid intake from a wide range of dietary sources enabled us to investigate the associations between various flavonoid subclasses with cause-specific CVD mortality. Furthermore, the prospective cohort design, the long-term follow-up of over 20 years, and the comprehensive data collection of confounding factors also reduced the chance of residual confounding.
      The limitations of present study should also be put forward. First, the flavonoid intake was assessed via a food frequency questionnaire, which might not capture flavonoid intake from all food sources but record those from the main sources in habitual diet, leading to potentially biased risk estimates toward the null and underestimating the true associations [
      • Macdiarmid J.
      • Blundell J.
      Assessing dietary intake: who, what and why of under-reporting.
      ]. However, the median intakes of total flavonoids and subclasses in the present study were similar to those in other large-scale prospective cohort studies among American people and the nationally representative NHANES participants [
      • Virani S.S.
      • Alonso A.
      • Aparicio H.J.
      • et al.
      Heart disease and stroke statistics-2021 update: a report from the American heart association.
      ,
      • Bertoia M.L.
      • Rimm E.B.
      • Mukamal K.J.
      • et al.
      Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years.
      ,
      • Mink P.J.
      • Scrafford C.G.
      • Barraj L.M.
      • et al.
      Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women.
      ]. Second, the flavonoid intake was measured only once at baseline, which might not reflect potential dietary changes during the follow-up. However, the associations of flavonoids and subclasses with CVD mortality remained stable after excluding CVD death events in the first five years of follow-up. Hence, a single measurement of flavonoid intake was unlikely to result in considerable bias to the risk estimates. Third, the contents of flavonoids and the subclasses depend on the ripeness, storage, and processing, thus introducing additional measurement bias to this study [
      • Bertoia M.L.
      • Rimm E.B.
      • Mukamal K.J.
      • et al.
      Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124,086 US men and women followed for up to 24 years.
      ]. Fourth, potential additive or synergistic interactions between flavonoids and other food components could contributed to the cardiovascular benefits of flavonoids [
      • Ma L.
      • Liu G.
      • Ding M.
      • et al.
      Isoflavone intake and the risk of coronary heart disease in US men and women: results from 3 prospective cohort studies.
      ]. Fifth, most participants in this study had a non-Hispanic ethnic background and received a college-level education or above, limiting the generalizability of our results to a broader population with more diverse socioeconomic background. Sixth, we cannot infer any causality for the relationships between flavonoid intake and CVD mortality and rule out unmeasured confounding due to the prospective cohort design.
      In conclusion, we demonstrated inverse associations between flavonoid intake and total and CVD mortality among older people from the NIH-AARP Diet and Health Study. Higher habitual consumption of flavonoids and flavonoid-rich fruits and vegetables might help reduce the risks of CVD death during aging.

      Financial support

      This research was supported by the National Key R&D Programmes of China (grant number 2019YFC2003401), the National Natural Science Foundation of China (grant number 82173499), and the High-performance Computing Platform of Peking University. The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

      CRediT authorship contribution statement

      Yimin Zhao: Conceptualization, Methodology, Software. Duo Li: Writing – review & editing. Tao Huang: Supervision, Software, Validation, Writing – review & editing.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We sincerely thank Zimin Song, Zhenhuang Zhuang, Wenxiu Wang, Yueying Li, Ninghao Huang, Wendi Xiao, Xue Dong, and Thi Ha Luu, all from Peking University, for their assistance in conducting this study.
      This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida) under contract with the Florida Department of Health, Tallahassee, Florida. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, The Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, Phoenix, Arizona. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Division of Public and Behavioral Health, State of Nevada Department of Health and Human Services, Carson City, Nevada.
      We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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