Research
Original Investigation
Association Between Dietary Whole Grain Intake and Risk of Mortality Two Large Prospective Studies in US Men and Women Hongyu Wu, PhD; Alan J. Flint, MD, ScD; Qibin Qi, PhD; Rob M. van Dam, PhD; Laura A. Sampson, RD; Eric B. Rimm, ScD; Michelle D. Holmes, MD, DrPH; Walter C. Willett, MD, DrPH; Frank B. Hu, MD, PhD; Qi Sun, MD, ScD
IMPORTANCE Higher intake of whole grains has been associated with a lower risk of major
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chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease (CVD), although limited prospective evidence exists regarding whole grains’ association with mortality. OBJECTIVE To examine the association between dietary whole grain consumption and risk of
mortality. DESIGN, SETTING, AND PARTICIPANTS We investigated 74 341 women from the Nurses’ Health Study (1984–2010) and 43 744 men from the Health Professionals Follow-Up Study (1986–2010), 2 large prospective cohort studies. All patients were free of CVD and cancer at baseline. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for total mortality and mortality due to CVD and cancer according to quintiles of whole grain consumption, which was updated every 2 or 4 years by using validated food frequency questionnaires. RESULTS We documented 26 920 deaths during 2 727 006 person-years of follow-up. After multivariate adjustment for potential confounders, including age, smoking, body mass index, physical activity, and modified Alternate Healthy Eating Index score, higher whole grain intake was associated with lower total and CVD mortality but not cancer mortality: the pooled HRs for quintiles 1 through 5, respectively, of whole grain intake were 1 (reference), 0.99 (95% CI, 0.95-1.02), 0.98 (95% CI, 0.95-1.02), 0.97 (95% CI, 0.93-1.01), and 0.91 (95% CI, 0.88-0.95) for total mortality (P for trend < .001); 1 (reference), 0.94 (95% CI, 0.88-1.01), 0.94 (95% CI, 0.87-1.01), 0.87 (95% CI, 0.80-0.94), and 0.85 (95% CI, 0.78-0.92) for CVD mortality (P for trend < .001); and 1 (reference), 1.02 (95% CI, 0.96-1.08), 1.05 (95% CI, 0.99-1.12), 1.04 (95% CI, 0.98-1.11), and 0.97 (95% CI, 0.91-1.04) for cancer mortality (P for trend = .43). We further estimated that every serving (28 g/d) of whole grain consumption was associated with a 5% (95% CI, 2%-7%) lower total morality or a 9% (95% CI, 4%-13%) lower CVD mortality, whereas the same intake level was nonsignificantly associated with lower cancer mortality (HR, 0.98; 95% CI, 0.94-1.02). Similar inverse associations were observed between bran intake and CVD mortality, with a pooled HR of 0.80 (95% CI, 0.73-0.87; P for trend < .001), whereas germ intake was not associated with CVD mortality after adjustment for bran intake. CONCLUSIONS AND RELEVANCE These data indicate that higher whole grain consumption is associated with lower total and CVD mortality in US men and women, independent of other dietary and lifestyle factors. These results are in line with recommendations that promote increased whole grain consumption to facilitate disease prevention. Author Affiliations: Author affiliations are listed at the end of this article.
JAMA Intern Med. 2015;175(3):373-384. doi:10.1001/jamainternmed.2014.6283 Published online January 5, 2015.
Corresponding Author: Qi Sun, MD, ScD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 ([email protected]).
(Reprinted) 373
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Research Original Investigation
Whole Grain Intake and Mortality
W
hole grains have been widely recommended in numerous dietary guidelines as a healthful food.1,2 Compared with refined carbohydrates, whole grains contain many beneficial nutrients and phytochemicals that primarily reside in the outer layers of grains that are removed during milling processes to produce refined grain products. In laboratory research and human feeding trials, whole grains, as well as constituents of whole grains, such as insoluble fiber, magnesium, and phytochemicals, consistently have beneficial effects on glucose metabolism,3-5 blood lipids,6 endothelial function,7 antioxidant activity,8 and inflammation.9,10 In addition, epidemiologic studies have consistently found inverse associations between whole grain intake and lower risk of type 2 diabetes mellitus11-13 and cardiovascular diseases (CVDs).12-14 Although these lines of evidence suggest beneficial effects of whole grain intake on overall health, data regarding whole grain intake and mortality were not entirely consistent. For instance, whole grain intake was significantly associated with lower total mortality risk in the Iowa Women’s Health Study,15,16 the Atherosclerosis Risk in Communities study,17 and the Norwegian County Study.18 In contrast, null associations were found among a healthy elderly population19 and among patients with diabetes.20 Regarding cause-specific mortality, an inverse association between whole grain intake and CVD mortality was consistently observed in previous studies,15,16,18-21 although only 3 studies15,16,18 evaluated cancer mortality and reported a nonsignificant reduced cancer mortality risk among whole grain eaters. The inconsistency of results may be explained in part by the heterogeneity in dietary assessments, baseline exclusion criteria, and population demographic and lifestyle characteristics. In particular, most previous studies17-20 only assessed the eating frequency of whole grain foods that may contain various proportions of actual whole grain contents. For example, some studies17,19 defined whole grain foods using the proportion of whole grain or bran of 25% or greater as the criterion and examined total servings per day of whole grain foods in relation to disease risk. This approach might bring in residual measurement error because the absolute amount of whole grain varies among the foods. Moreover, only one study,20 which was conducted among women with type 2 diabetes, explicitly examined the intake of added bran and germ in relation to total and cause-specific mortality. Therefore, in the current study, we investigated the association between whole grain intake and total and cause-specific mortality in 2 large cohort studies with repeated assessments of diet and extended length of follow-up: the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). We also evaluated the association between bran and germ consumption and total and cause-specific mortality.
Methods Study Populations The study protocol was approved by the Human Research Committee of Brigham and Women's Hospital and the Harvard School of Public Health. The completion of the selfadministered questionnaire was considered to imply written informed consent. 374
The NHS is a prospective cohort study of 121 700 female registered nurses aged 30 to 55 years from 11 states initiated in 1976. The HPFS cohort was established in 1986 with an enrollment of 51 529 US male health professionals aged 32 to 87 years from all 50 states. Through 2010, a response rate that exceeded 90% has been achieved in both cohorts. For the current investigation, we excluded participants with cancer, stroke, or coronary heart disease (CHD) at baseline (1984 for the NHS and 1986 for the HPFS); those who had incomplete information for dietary data; and those who reported implausible total energy intake (3500 kcal/d for the NHS and 4200 kcal/d for the HPFS). After exclusions, a total of 74 341 women and 43 744 men remained in the analysis.
Ascertainment of Diet Intakes of whole grains and other foods were assessed using validated food frequency questionnaires (FFQs) every 2 to 4 years.22,23 The FFQs inquired about mean consumption of foods (with a prespecified portion size) during the previous year using 9 categories of intake frequency, ranging from less than 1 per month to 6 or more per day. Open-ended questions were included for breakfast cereal brand names and foods that were not listed on the FFQ. Intakes of whole grain were estimated from all graincontaining foods (rice, bread, pasta, and breakfast cereals) according to the dry weight of the whole grain ingredients in each food.24-26 Whole grain consumption from breakfast cereal was derived from more than 250 brand name cereals based on information provided by product labels and breakfast cereal manufacturers. In our study, whole grains included intact and pulverized forms that contained the expected proportion of bran, germ, and endosperm for the specific grain types. By definition, the following foods and ingredients were considered whole grains: whole wheat and whole wheat flour, whole oats and whole oat flour, whole cornmeal and whole corn flour, whole rye and whole rye flour, whole barley, bulgur, buckwheat, brown rice and brown rice flour, popcorn, amaranth, and psyllium. In the FFQ, we also asked the frequency of consuming added bran (oat bran and other bran) and added wheat germ. Intakes of bran and germ were derived directly from whole grain foods and those added to foods. Total bran and total germ are the sum of intakes from both sources.
Ascertainment of Mortality Deaths were reported by the next of kin or the postal authorities or identified by searching the National Death Index.27 More than 97% of deaths can be identified in these cohorts.27 For all deaths, we sought death certificates and, when appropriate, requested permission from the next of kin to review medical records. The underlying cause of death was assigned according to the International Classification of Diseases, 8th Revision (ICD-8). In this analysis we also specifically considered deaths due to CVD (ICD-8 codes 390.0-458.9 or 795.0-795.9) or cancer (ICD-8 codes 140.0-207.9).
Assessment of Covariates In both cohorts, information on body weight, medical history, lifestyle characteristics (eg, cigarette smoking and physical activity), disease diagnoses (diabetes, hypertension, and hyper-
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Whole Grain Intake and Mortality
Original Investigation Research
cholesterolemia), and other characteristics was collected at baseline and in biennial validated questionnaires. Alcohol and other dietary information was assessed and updated by validated FFQs. Detailed descriptions on the validity and reproducibility of self-reported body weight, physical activity, and alcohol consumption have been published elsewhere.28-30 A modified Alternate Healthy Eating Index (AHEI) score was calculated based on intakes of 10 foods and nutrients predictive of chronic disease risk, including fruits, vegetables, nuts and legumes, red or processed meat, sugar-sweetened beverages, alcohol, sodium, trans fat, long-chain ω-3 fats, and other polyunsaturated fats.31
Statistical Analysis We calculated person-years of follow-up from the return date of the first FFQ to the date of death or January 31, 2010, for the HPFS or June 30, 2010, for the NHS, whichever came first. We calculated and used the energy-adjusted residuals of whole grain intakes to control for total energy intake. To better represent long-term or habitual intake and to minimize within-person variation, we created and used the cumulative mean of energyadjusted whole grain intake from all available dietary questionnaires from baseline through the end of follow-up.32 We replaced missing values in each FFQ with cumulative means based on prior assessments. To minimize the possibility of reverse causation bias, we stopped updating diet information after participants reported a diagnosis of diabetes, stroke, or CHD because diagnosis of these conditions led to changes in whole grain intake (eTable 1 in the Supplement). We then carried forward the cumulative means of dietary variables before the development of these diseases to represent diet for later follow-up.33 Because of differences in sex, follow-up time, and the questionnaires in the 2 cohorts, we conducted analyses separately for each cohort to facilitate better control of confounding. Cox proportional hazards models stratified on age (months) and calendar time (2-year intervals) were used to investigate the association of whole grain, bran, and germ consumption with total and cause-specific mortality. We used hazard ratios (HRs) to measure relative risks in higher intake quintiles compared with participants in the lowest quintiles, and 95% CIs were calculated for the HRs. In multivariate analysis, we controlled for age and ethnicity, as well as time-varying covariates, including body mass index (BMI; calculated as weight in kilograms divided by height in meters squared); smoking status; alcohol intake; physical activity; multivitamin use; aspirin use; a family history of heart disease, cancer, or diabetes; a history of hypertension, high cholesterol, or diabetes at baseline; total energy (in quintiles); and modified AHEI score (whole grain excluded). In the NHS, we also adjusted for menopausal status and postmenopausal hormone use. Proportional hazards assumption was tested by evaluating the significance of the interaction term between quintiles of whole grain consumption and period of follow-up, and no violation of the proportional hazards assumption was found (P = .17, .22, and .35 in the NHS and P = .29, .58, and .11 in the HPFS for total, CVD, and cancer mortality, respectively). Tests for trend were conducted by assigning the median value to each category and modeling this value as a continuous variable. In addition, we used restricted cubic spline regressions with 4 knots jamainternalmedicine.com
to examine the dose-response relationships between whole grain intake and risk of mortality. Tests for nonlinearity used the likelihood ratio test, comparing the model with only the linear term to the model with the linear and the cubic spline terms. We estimated the association of substituting whole grains for refined grains, red meat, and potato. The calculation of substitution effects was based on the differences of β coefficients between whole grains and a specific food, and their variances and covariance matrix were used to derive the 95% CI for the point estimate.34 The estimates of association across the 2 studies were pooled using a fixed-effects model. All analyses were performed using SAS statistical software, version 9.3 (SAS Institute Inc). All P values presented are 2-tailed, and P < .05 was considered statistically significant.
Results Table 1 presents baseline characteristics by quintiles of whole grain intake. Men and women with higher intake of whole grains were more likely to be physically active and have a history of high cholesterol levels, were less likely to be current smokers, and had lower alcohol intake. In addition, a higher whole grain intake was associated with a better diet quality as reflected by the higher AHEI score. In the NHS, during 26 years of follow-up (1 798 063 personyears), we documented 15 106 deaths, of which 2989 were CVD deaths and 5964 were cancer deaths (499 due to colorectal cancer, 1417 to lung cancer, and 895 to breast cancer). In the HPFS, with up to 24 years of follow-up (928 943 person-years), we documented 11 814 deaths, of which 3621 were CVD deaths and 3921 were cancer deaths (423 due to colorectal cancer, 739 to lung cancer, and 564 to prostate cancer). Table 2 gives the associations between whole grain consumption and total and causespecific mortality. In age-adjusted analyses, a higher intake of whole grain was significantly associated with lower total and cause-specific mortality. Further adjustment for other potential confounders, especially physical activity, smoking, and BMI, attenuated these associations, although the statistical significance remained for associations with total and CVD mortality. The pooled HRs comparing extreme whole grain intake levels were 0.91 (95% CI, 0.88-0.95; P for trend < .001) for total mortality and 0.85 (95% CI, 0.78-0.92; P for trend < .001) for CVD mortality. In contrast, the same multivariate adjustment abolished the associations for cancer mortality; the pooled HR was 0.97 (95% CI, 0.91-1.04; P for trend = .43) comparing extreme intake levels. Further analyses revealed that whole grain intake was not significantly associated with mortality due to major types of cancer, including colorectal cancer, lung cancer, breast cancer, or prostate cancer (eTable 2 in the Supplement). The association for non-CVD and noncancer mortality is given in eTable 3 in the Supplement. We further estimated that every serving (28 g/d) of whole grain consumption was associated with a 5% (95% CI, 2%-7%) lower total morality or a 9% (95% CI, 4%-13%) lower CVD mortality, whereas the same intake level was nonsignificantly associated with lower cancer mortality (HR, 0.98; 95% CI, 0.941.02). We consistently observed monotonic associations (Reprinted) JAMA Internal Medicine March 2015 Volume 175, Number 3
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375
Research Original Investigation
Whole Grain Intake and Mortality
Table 1. Baseline Characteristics of Study Participants by Intake Levels of Whole Grainsa NHS Quintile Characteristic No. of participants
1
HPFS Quintile
3
14 819
5
14 630
14 868
1
3
5
8724
8777
8776
Whole grains, g/d
4.3
14.7
35.6
5.8
21.8
52.6
Bran, g/d
0.4
2.2
8.7
0.5
3.8
11.7
Germ, g/d
0.1
0.6
1.8
0.2
0.9
2.7
Age, y
50.2
50.2
50.3
53.3
53.2
53.2
BMI
25.3
25.2
24.4
25.2
25.1
24.3
9.4
6.8
4.7
14.5
11.6
8.1
11.4
13.6
15.7
17.8
20.4
25.8
Alcohol, g/d Physical activity, METs Total energy, kcal/d
1711
1786
1653
1984
2060
1879
42.8
45.6
49.5
46.0
49.9
54.6
Never
36.3
44.6
50.2
41.9
50.6
56.1
Past
27.1
32.1
35.2
40.7
41.0
39.5
Current
36.6
23.3
14.6
8.4
4.3
Alternate Healthy Eating Index scoreb Smoking status
17. 5
Family history Diabetes mellitus
29.9
29.5
29.0
23.7
24.1
24.0
Cancer
14.3
15.2
16.6
34.9
34.7
36.7
MI
19.7
19.6
18.9
31.3
30.8
33.0
Diabetes
2.7
2.7
3.5
2.2
2.4
3.3
22.0
20.4
21.2
22.9
19.1
19.9
6.6
7.6
10.1
9.2
10.1
13.2
Aspirin use
66.3
67.4
64.8
25.3
27.8
26.5
Multivitamin use
30.2
37.0
44.9
34.7
41.0
50.3
Hypertension High cholesterol level
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HPFS, Health Professionals Follow-Up Study; MET, metabolic equivalent (hours per week); MI, myocardial infarction; NHS, Nurses’ Health Study. a
Whole grains were excluded when calculating the Alternate Healthy Eating Index scores.
Values are means for continuous variables and percentages for categorical
between whole grain consumption and total mortality (P for linearity = .047) and CVD mortality (P for linearity = .003), and no evidence of nonlinearity was observed (Figure). By using the same model adjustment, we further observed that each serving (28 g/d) of refined grains was associated with a small reduction in total mortality (pooled HR, 0.98; 95% CI, 0.97-0.99) but not with CVD mortality (pooled HR, 0.99; 95% CI, 0.97-1.01) or cancer mortality (pooled HR, 0.98; 95% CI, 0.97-1.00). In the substitution analyses, replacing 1 serving of refined grains or total red meat with 1 serving of whole grains daily was associated with lower CVD mortality: 8% (pooled HR, 0.92; 95% CI, 0.88-0.97) for replacing refined grains and 20% (pooled HR, 0.80; 95% CI, 0.75-0.86) for replacing red meat (eFigure in the Supplement). The corresponding substitution estimates were 4% and 10% for total mortality, respectively. Replacement of potato was not significantly associated with total or CVD mortality. Meanwhile, no significant associations were found for cancer mortality in substitution analyses (eFigure in the Supplement). The associations between whole grain intake and CVD mortality largely persisted among participants with various risk profiles defined by age, BMI, physical activity, 376
variables. All variables except age were age standardized. b
smoking status, and AHEI score (Table 3, all P for interaction ≥.21). In addition, whole grain without added bran or germ was also associated with lower total and CVD mortality to a similar extent (eTable 4 in the Supplement). In several sensitivity analyses, we updated participants’ diet throughout follow-up regardless of disease occurrence and applied a 4-year lag between exposure and the occurrence of deaths; further stopped updating diet information after intermediate (hypertension and hypercholesterolemia) diagnosis; adjusted for incidence of intermediate outcomes; used baseline whole grain intakes, which did not account for different trends of whole grain intakes over time; or used a multiple imputation procedure with 5 rounds of imputation to impute missing data of exposures and covariates and repeated the analyses. The association between whole grain intake and mortality did not change materially in these analyses (eTable 5 in the Supplement). The age-adjusted correlation coefficient for association between intake of whole grain and total bran was 0.87 for women and 0.85 for men, and these figures were both 0.79 for association of whole grain and total germ in men and women. Total bran consumption was significantly associated with lower total and
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Table 2. Total Mortality and Cause-Specific Mortality by Quintiles of Whole Grain Intake Quintile Variable
1
2
3
4
5
P Value for Trend
Total Mortality NHS Median of whole grain intake, g/d No. of cases No. of person-years
4.2
9.7
14.7
21.1
33.0
NA
4122
2990
2744
2550
2700
NA
356 895
359 688
359 945
361 086
360 449
NA
HR (95% CI) Model 1a
1 [Reference]
0.72 (0.69-0.76)
0.63 (0.60-0.66)
0.54 (0.51-0.57)
0.49 (0.47-0.51)
Original Investigation
Association Between Dietary Whole Grain Intake and Risk of Mortality Two Large Prospective Studies in US Men and Women Hongyu Wu, PhD; Alan J. Flint, MD, ScD; Qibin Qi, PhD; Rob M. van Dam, PhD; Laura A. Sampson, RD; Eric B. Rimm, ScD; Michelle D. Holmes, MD, DrPH; Walter C. Willett, MD, DrPH; Frank B. Hu, MD, PhD; Qi Sun, MD, ScD
IMPORTANCE Higher intake of whole grains has been associated with a lower risk of major
Supplemental content at jamainternalmedicine.com
chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease (CVD), although limited prospective evidence exists regarding whole grains’ association with mortality. OBJECTIVE To examine the association between dietary whole grain consumption and risk of
mortality. DESIGN, SETTING, AND PARTICIPANTS We investigated 74 341 women from the Nurses’ Health Study (1984–2010) and 43 744 men from the Health Professionals Follow-Up Study (1986–2010), 2 large prospective cohort studies. All patients were free of CVD and cancer at baseline. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for total mortality and mortality due to CVD and cancer according to quintiles of whole grain consumption, which was updated every 2 or 4 years by using validated food frequency questionnaires. RESULTS We documented 26 920 deaths during 2 727 006 person-years of follow-up. After multivariate adjustment for potential confounders, including age, smoking, body mass index, physical activity, and modified Alternate Healthy Eating Index score, higher whole grain intake was associated with lower total and CVD mortality but not cancer mortality: the pooled HRs for quintiles 1 through 5, respectively, of whole grain intake were 1 (reference), 0.99 (95% CI, 0.95-1.02), 0.98 (95% CI, 0.95-1.02), 0.97 (95% CI, 0.93-1.01), and 0.91 (95% CI, 0.88-0.95) for total mortality (P for trend < .001); 1 (reference), 0.94 (95% CI, 0.88-1.01), 0.94 (95% CI, 0.87-1.01), 0.87 (95% CI, 0.80-0.94), and 0.85 (95% CI, 0.78-0.92) for CVD mortality (P for trend < .001); and 1 (reference), 1.02 (95% CI, 0.96-1.08), 1.05 (95% CI, 0.99-1.12), 1.04 (95% CI, 0.98-1.11), and 0.97 (95% CI, 0.91-1.04) for cancer mortality (P for trend = .43). We further estimated that every serving (28 g/d) of whole grain consumption was associated with a 5% (95% CI, 2%-7%) lower total morality or a 9% (95% CI, 4%-13%) lower CVD mortality, whereas the same intake level was nonsignificantly associated with lower cancer mortality (HR, 0.98; 95% CI, 0.94-1.02). Similar inverse associations were observed between bran intake and CVD mortality, with a pooled HR of 0.80 (95% CI, 0.73-0.87; P for trend < .001), whereas germ intake was not associated with CVD mortality after adjustment for bran intake. CONCLUSIONS AND RELEVANCE These data indicate that higher whole grain consumption is associated with lower total and CVD mortality in US men and women, independent of other dietary and lifestyle factors. These results are in line with recommendations that promote increased whole grain consumption to facilitate disease prevention. Author Affiliations: Author affiliations are listed at the end of this article.
JAMA Intern Med. 2015;175(3):373-384. doi:10.1001/jamainternmed.2014.6283 Published online January 5, 2015.
Corresponding Author: Qi Sun, MD, ScD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 ([email protected]).
(Reprinted) 373
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Iowa User on 05/27/2015
Research Original Investigation
Whole Grain Intake and Mortality
W
hole grains have been widely recommended in numerous dietary guidelines as a healthful food.1,2 Compared with refined carbohydrates, whole grains contain many beneficial nutrients and phytochemicals that primarily reside in the outer layers of grains that are removed during milling processes to produce refined grain products. In laboratory research and human feeding trials, whole grains, as well as constituents of whole grains, such as insoluble fiber, magnesium, and phytochemicals, consistently have beneficial effects on glucose metabolism,3-5 blood lipids,6 endothelial function,7 antioxidant activity,8 and inflammation.9,10 In addition, epidemiologic studies have consistently found inverse associations between whole grain intake and lower risk of type 2 diabetes mellitus11-13 and cardiovascular diseases (CVDs).12-14 Although these lines of evidence suggest beneficial effects of whole grain intake on overall health, data regarding whole grain intake and mortality were not entirely consistent. For instance, whole grain intake was significantly associated with lower total mortality risk in the Iowa Women’s Health Study,15,16 the Atherosclerosis Risk in Communities study,17 and the Norwegian County Study.18 In contrast, null associations were found among a healthy elderly population19 and among patients with diabetes.20 Regarding cause-specific mortality, an inverse association between whole grain intake and CVD mortality was consistently observed in previous studies,15,16,18-21 although only 3 studies15,16,18 evaluated cancer mortality and reported a nonsignificant reduced cancer mortality risk among whole grain eaters. The inconsistency of results may be explained in part by the heterogeneity in dietary assessments, baseline exclusion criteria, and population demographic and lifestyle characteristics. In particular, most previous studies17-20 only assessed the eating frequency of whole grain foods that may contain various proportions of actual whole grain contents. For example, some studies17,19 defined whole grain foods using the proportion of whole grain or bran of 25% or greater as the criterion and examined total servings per day of whole grain foods in relation to disease risk. This approach might bring in residual measurement error because the absolute amount of whole grain varies among the foods. Moreover, only one study,20 which was conducted among women with type 2 diabetes, explicitly examined the intake of added bran and germ in relation to total and cause-specific mortality. Therefore, in the current study, we investigated the association between whole grain intake and total and cause-specific mortality in 2 large cohort studies with repeated assessments of diet and extended length of follow-up: the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). We also evaluated the association between bran and germ consumption and total and cause-specific mortality.
Methods Study Populations The study protocol was approved by the Human Research Committee of Brigham and Women's Hospital and the Harvard School of Public Health. The completion of the selfadministered questionnaire was considered to imply written informed consent. 374
The NHS is a prospective cohort study of 121 700 female registered nurses aged 30 to 55 years from 11 states initiated in 1976. The HPFS cohort was established in 1986 with an enrollment of 51 529 US male health professionals aged 32 to 87 years from all 50 states. Through 2010, a response rate that exceeded 90% has been achieved in both cohorts. For the current investigation, we excluded participants with cancer, stroke, or coronary heart disease (CHD) at baseline (1984 for the NHS and 1986 for the HPFS); those who had incomplete information for dietary data; and those who reported implausible total energy intake (3500 kcal/d for the NHS and 4200 kcal/d for the HPFS). After exclusions, a total of 74 341 women and 43 744 men remained in the analysis.
Ascertainment of Diet Intakes of whole grains and other foods were assessed using validated food frequency questionnaires (FFQs) every 2 to 4 years.22,23 The FFQs inquired about mean consumption of foods (with a prespecified portion size) during the previous year using 9 categories of intake frequency, ranging from less than 1 per month to 6 or more per day. Open-ended questions were included for breakfast cereal brand names and foods that were not listed on the FFQ. Intakes of whole grain were estimated from all graincontaining foods (rice, bread, pasta, and breakfast cereals) according to the dry weight of the whole grain ingredients in each food.24-26 Whole grain consumption from breakfast cereal was derived from more than 250 brand name cereals based on information provided by product labels and breakfast cereal manufacturers. In our study, whole grains included intact and pulverized forms that contained the expected proportion of bran, germ, and endosperm for the specific grain types. By definition, the following foods and ingredients were considered whole grains: whole wheat and whole wheat flour, whole oats and whole oat flour, whole cornmeal and whole corn flour, whole rye and whole rye flour, whole barley, bulgur, buckwheat, brown rice and brown rice flour, popcorn, amaranth, and psyllium. In the FFQ, we also asked the frequency of consuming added bran (oat bran and other bran) and added wheat germ. Intakes of bran and germ were derived directly from whole grain foods and those added to foods. Total bran and total germ are the sum of intakes from both sources.
Ascertainment of Mortality Deaths were reported by the next of kin or the postal authorities or identified by searching the National Death Index.27 More than 97% of deaths can be identified in these cohorts.27 For all deaths, we sought death certificates and, when appropriate, requested permission from the next of kin to review medical records. The underlying cause of death was assigned according to the International Classification of Diseases, 8th Revision (ICD-8). In this analysis we also specifically considered deaths due to CVD (ICD-8 codes 390.0-458.9 or 795.0-795.9) or cancer (ICD-8 codes 140.0-207.9).
Assessment of Covariates In both cohorts, information on body weight, medical history, lifestyle characteristics (eg, cigarette smoking and physical activity), disease diagnoses (diabetes, hypertension, and hyper-
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Whole Grain Intake and Mortality
Original Investigation Research
cholesterolemia), and other characteristics was collected at baseline and in biennial validated questionnaires. Alcohol and other dietary information was assessed and updated by validated FFQs. Detailed descriptions on the validity and reproducibility of self-reported body weight, physical activity, and alcohol consumption have been published elsewhere.28-30 A modified Alternate Healthy Eating Index (AHEI) score was calculated based on intakes of 10 foods and nutrients predictive of chronic disease risk, including fruits, vegetables, nuts and legumes, red or processed meat, sugar-sweetened beverages, alcohol, sodium, trans fat, long-chain ω-3 fats, and other polyunsaturated fats.31
Statistical Analysis We calculated person-years of follow-up from the return date of the first FFQ to the date of death or January 31, 2010, for the HPFS or June 30, 2010, for the NHS, whichever came first. We calculated and used the energy-adjusted residuals of whole grain intakes to control for total energy intake. To better represent long-term or habitual intake and to minimize within-person variation, we created and used the cumulative mean of energyadjusted whole grain intake from all available dietary questionnaires from baseline through the end of follow-up.32 We replaced missing values in each FFQ with cumulative means based on prior assessments. To minimize the possibility of reverse causation bias, we stopped updating diet information after participants reported a diagnosis of diabetes, stroke, or CHD because diagnosis of these conditions led to changes in whole grain intake (eTable 1 in the Supplement). We then carried forward the cumulative means of dietary variables before the development of these diseases to represent diet for later follow-up.33 Because of differences in sex, follow-up time, and the questionnaires in the 2 cohorts, we conducted analyses separately for each cohort to facilitate better control of confounding. Cox proportional hazards models stratified on age (months) and calendar time (2-year intervals) were used to investigate the association of whole grain, bran, and germ consumption with total and cause-specific mortality. We used hazard ratios (HRs) to measure relative risks in higher intake quintiles compared with participants in the lowest quintiles, and 95% CIs were calculated for the HRs. In multivariate analysis, we controlled for age and ethnicity, as well as time-varying covariates, including body mass index (BMI; calculated as weight in kilograms divided by height in meters squared); smoking status; alcohol intake; physical activity; multivitamin use; aspirin use; a family history of heart disease, cancer, or diabetes; a history of hypertension, high cholesterol, or diabetes at baseline; total energy (in quintiles); and modified AHEI score (whole grain excluded). In the NHS, we also adjusted for menopausal status and postmenopausal hormone use. Proportional hazards assumption was tested by evaluating the significance of the interaction term between quintiles of whole grain consumption and period of follow-up, and no violation of the proportional hazards assumption was found (P = .17, .22, and .35 in the NHS and P = .29, .58, and .11 in the HPFS for total, CVD, and cancer mortality, respectively). Tests for trend were conducted by assigning the median value to each category and modeling this value as a continuous variable. In addition, we used restricted cubic spline regressions with 4 knots jamainternalmedicine.com
to examine the dose-response relationships between whole grain intake and risk of mortality. Tests for nonlinearity used the likelihood ratio test, comparing the model with only the linear term to the model with the linear and the cubic spline terms. We estimated the association of substituting whole grains for refined grains, red meat, and potato. The calculation of substitution effects was based on the differences of β coefficients between whole grains and a specific food, and their variances and covariance matrix were used to derive the 95% CI for the point estimate.34 The estimates of association across the 2 studies were pooled using a fixed-effects model. All analyses were performed using SAS statistical software, version 9.3 (SAS Institute Inc). All P values presented are 2-tailed, and P < .05 was considered statistically significant.
Results Table 1 presents baseline characteristics by quintiles of whole grain intake. Men and women with higher intake of whole grains were more likely to be physically active and have a history of high cholesterol levels, were less likely to be current smokers, and had lower alcohol intake. In addition, a higher whole grain intake was associated with a better diet quality as reflected by the higher AHEI score. In the NHS, during 26 years of follow-up (1 798 063 personyears), we documented 15 106 deaths, of which 2989 were CVD deaths and 5964 were cancer deaths (499 due to colorectal cancer, 1417 to lung cancer, and 895 to breast cancer). In the HPFS, with up to 24 years of follow-up (928 943 person-years), we documented 11 814 deaths, of which 3621 were CVD deaths and 3921 were cancer deaths (423 due to colorectal cancer, 739 to lung cancer, and 564 to prostate cancer). Table 2 gives the associations between whole grain consumption and total and causespecific mortality. In age-adjusted analyses, a higher intake of whole grain was significantly associated with lower total and cause-specific mortality. Further adjustment for other potential confounders, especially physical activity, smoking, and BMI, attenuated these associations, although the statistical significance remained for associations with total and CVD mortality. The pooled HRs comparing extreme whole grain intake levels were 0.91 (95% CI, 0.88-0.95; P for trend < .001) for total mortality and 0.85 (95% CI, 0.78-0.92; P for trend < .001) for CVD mortality. In contrast, the same multivariate adjustment abolished the associations for cancer mortality; the pooled HR was 0.97 (95% CI, 0.91-1.04; P for trend = .43) comparing extreme intake levels. Further analyses revealed that whole grain intake was not significantly associated with mortality due to major types of cancer, including colorectal cancer, lung cancer, breast cancer, or prostate cancer (eTable 2 in the Supplement). The association for non-CVD and noncancer mortality is given in eTable 3 in the Supplement. We further estimated that every serving (28 g/d) of whole grain consumption was associated with a 5% (95% CI, 2%-7%) lower total morality or a 9% (95% CI, 4%-13%) lower CVD mortality, whereas the same intake level was nonsignificantly associated with lower cancer mortality (HR, 0.98; 95% CI, 0.941.02). We consistently observed monotonic associations (Reprinted) JAMA Internal Medicine March 2015 Volume 175, Number 3
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375
Research Original Investigation
Whole Grain Intake and Mortality
Table 1. Baseline Characteristics of Study Participants by Intake Levels of Whole Grainsa NHS Quintile Characteristic No. of participants
1
HPFS Quintile
3
14 819
5
14 630
14 868
1
3
5
8724
8777
8776
Whole grains, g/d
4.3
14.7
35.6
5.8
21.8
52.6
Bran, g/d
0.4
2.2
8.7
0.5
3.8
11.7
Germ, g/d
0.1
0.6
1.8
0.2
0.9
2.7
Age, y
50.2
50.2
50.3
53.3
53.2
53.2
BMI
25.3
25.2
24.4
25.2
25.1
24.3
9.4
6.8
4.7
14.5
11.6
8.1
11.4
13.6
15.7
17.8
20.4
25.8
Alcohol, g/d Physical activity, METs Total energy, kcal/d
1711
1786
1653
1984
2060
1879
42.8
45.6
49.5
46.0
49.9
54.6
Never
36.3
44.6
50.2
41.9
50.6
56.1
Past
27.1
32.1
35.2
40.7
41.0
39.5
Current
36.6
23.3
14.6
8.4
4.3
Alternate Healthy Eating Index scoreb Smoking status
17. 5
Family history Diabetes mellitus
29.9
29.5
29.0
23.7
24.1
24.0
Cancer
14.3
15.2
16.6
34.9
34.7
36.7
MI
19.7
19.6
18.9
31.3
30.8
33.0
Diabetes
2.7
2.7
3.5
2.2
2.4
3.3
22.0
20.4
21.2
22.9
19.1
19.9
6.6
7.6
10.1
9.2
10.1
13.2
Aspirin use
66.3
67.4
64.8
25.3
27.8
26.5
Multivitamin use
30.2
37.0
44.9
34.7
41.0
50.3
Hypertension High cholesterol level
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HPFS, Health Professionals Follow-Up Study; MET, metabolic equivalent (hours per week); MI, myocardial infarction; NHS, Nurses’ Health Study. a
Whole grains were excluded when calculating the Alternate Healthy Eating Index scores.
Values are means for continuous variables and percentages for categorical
between whole grain consumption and total mortality (P for linearity = .047) and CVD mortality (P for linearity = .003), and no evidence of nonlinearity was observed (Figure). By using the same model adjustment, we further observed that each serving (28 g/d) of refined grains was associated with a small reduction in total mortality (pooled HR, 0.98; 95% CI, 0.97-0.99) but not with CVD mortality (pooled HR, 0.99; 95% CI, 0.97-1.01) or cancer mortality (pooled HR, 0.98; 95% CI, 0.97-1.00). In the substitution analyses, replacing 1 serving of refined grains or total red meat with 1 serving of whole grains daily was associated with lower CVD mortality: 8% (pooled HR, 0.92; 95% CI, 0.88-0.97) for replacing refined grains and 20% (pooled HR, 0.80; 95% CI, 0.75-0.86) for replacing red meat (eFigure in the Supplement). The corresponding substitution estimates were 4% and 10% for total mortality, respectively. Replacement of potato was not significantly associated with total or CVD mortality. Meanwhile, no significant associations were found for cancer mortality in substitution analyses (eFigure in the Supplement). The associations between whole grain intake and CVD mortality largely persisted among participants with various risk profiles defined by age, BMI, physical activity, 376
variables. All variables except age were age standardized. b
smoking status, and AHEI score (Table 3, all P for interaction ≥.21). In addition, whole grain without added bran or germ was also associated with lower total and CVD mortality to a similar extent (eTable 4 in the Supplement). In several sensitivity analyses, we updated participants’ diet throughout follow-up regardless of disease occurrence and applied a 4-year lag between exposure and the occurrence of deaths; further stopped updating diet information after intermediate (hypertension and hypercholesterolemia) diagnosis; adjusted for incidence of intermediate outcomes; used baseline whole grain intakes, which did not account for different trends of whole grain intakes over time; or used a multiple imputation procedure with 5 rounds of imputation to impute missing data of exposures and covariates and repeated the analyses. The association between whole grain intake and mortality did not change materially in these analyses (eTable 5 in the Supplement). The age-adjusted correlation coefficient for association between intake of whole grain and total bran was 0.87 for women and 0.85 for men, and these figures were both 0.79 for association of whole grain and total germ in men and women. Total bran consumption was significantly associated with lower total and
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Whole Grain Intake and Mortality
Original Investigation Research
Table 2. Total Mortality and Cause-Specific Mortality by Quintiles of Whole Grain Intake Quintile Variable
1
2
3
4
5
P Value for Trend
Total Mortality NHS Median of whole grain intake, g/d No. of cases No. of person-years
4.2
9.7
14.7
21.1
33.0
NA
4122
2990
2744
2550
2700
NA
356 895
359 688
359 945
361 086
360 449
NA
HR (95% CI) Model 1a
1 [Reference]
0.72 (0.69-0.76)
0.63 (0.60-0.66)
0.54 (0.51-0.57)
0.49 (0.47-0.51)
