Affiliations of authors: Departments of Epidemiology (H-CH, KJJ, FBH, DH, GAC, DS, WCW) and Nutrition (RJ, FBH, SASW), Harvard School of Public Health, Boston, MA; Department of Oral Health Policy and Epidemiology (H-CH, KJJ), Harvard School of Dental Medicine, Boston, MA; Channing Laboratory (DH, GAC, BR, WCW) and Department of Medicine, Brigham and Women's Hospital and Department of Biostatistics, Harvard Medical School (BR, DS), Harvard School of Public Health, Boston, MA; Institute of Health Care Management (H-CH), National Sun Yat-Sen University, Kaohsiung, Taiwan
Correspondence to: Walter C. Willett, MD, Department of Nutrition, Harvard School of Public Health, 651 Huntington Ave., Boston, MA 02115 (e-mail: walter.willett{at}channing.harvard.edu)
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ABSTRACT |
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INTRODUCTION |
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METHODS |
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The Nurses' Health Study (NHS) was established in 1976, with the recruitment of 121 700 female registered nurses between the ages of 30 and 55 from 11 states. The Health Professionals' Follow-up Study was initiated in 1986 and consisted of 51 529 male dentists, optometrists, pharmacists, osteopathic physicians, podiatrists, and veterinarians who were between 40 and 75 years of age.
At baseline, participants completed mailed questionnaires on lifestyle practices and medical history. Every 2 years, questionnaires were sent to update individual characteristics and behaviors and new occurrences of cancers, cardiovascular diseases, and other outcomes. The study was approved by the Institutional Review Boards of Harvard School of Public Health and Brigham and Women's Hospital, Boston, MA, and return of the questionnaire(s) constituted written informed consent.
Assessment of Dietary Intake
A semiquantitative food-frequency questionnaire was included with the general health questionnaire in 1980, 1984, 1986, 1990, and 1994 for the NHS and in 1986, 1990, and 1994 for the Health Professionals' Follow-up Study. The 1980 food-frequency questionnaire for the NHS contained 61 items, including six questions on fruit consumption, 11 on vegetable consumption, and three on potato consumption. The subsequent food-frequency questionnaire, used in 1984, was expanded to include at least 15 questions about fruit consumption, 28 about vegetable consumption, and three about potato consumption. The baseline (1986) food-frequency questionnaire for Health Professionals' Follow-up Study had 15 questions about fruit consumption, 30 about vegetable consumption, and three about potato consumption. In these dietary questionnaires, a commonly used unit or portion of each food (such as one tomato or one glass of fruit juice) was specified, and participants indicated how often, on average, they had consumed that food over the past year. The frequencies were reported in nine categories, ranging from less than once a month to six or more times per day. The dietary data from both cohorts have been validated by comparisons with multiple weighted 1-week dietary records (2528).
The average daily intakes of all fruit and vegetable items (not including potatoes) reported by each participant were added to assess the consumption of total fruits and vegetables. Average daily intakes of foods in specific groupscitrus fruits, green leafy vegetables, cruciferous vegetables, vitamin Crich fruits and vegetables (i.e., items with 30 mg of vitamin C per serving), legumes, and potatoes were also assessed. The definitions of these specific groups were modified from a report by Steinmetz et al. (29) to correspond with our questionnaires and hypotheses, as described previously (9). For questionnaires that were missing values for an individual food but were otherwise substantially complete, we assumed no intake of that item when aggregating items to calculate the total and specific groups of fruits and vegetables.
Ascertainment of Outcomes
The primary endpoint was major chronic disease, defined as cardiovascular disease, cancer, or nontraumatic death, whichever came first (30,31). Participants who reported cardiovascular disease or cancer on any biennial questionnaire were mailed letters to verify the reports and to request permission to review their medical records. Study investigators reviewed medical records without knowing the participants' risk factor status. Cardiovascular disease was defined as fatal or nonfatal myocardial infarction and fatal or nonfatal stroke. Myocardial infarction was confirmed based on World Health Organization criteria (32). Stroke was confirmed if there was a typical neurologic defect of sudden or rapid onset lasting 24 hours or more that was attributable to a cerebrovascular event (33).
We included all cancers except nonmelanoma skin cancer, in situ breast cancer in women, and organ-confined prostate cancer in men. Cardiovascular disease or cancers that were verified by letter or telephone interview but for which medical records or pathology reports were unavailable were defined as "probable" cases. The reported analyses used both confirmed cases (approximately 80% of total cardiovascular events and 90% of cancer events) and probable cases, but the analyses were also conducted separately for confirmed cases and showed similar results (data not shown).
Deaths were reported by next of kin, coworkers, or postal authorities or through the National Death Index (34). The causes of deaths were confirmed by examining medical records or autopsy reports. All deaths except those from external causes, such as accidents and suicides, were included. Nonresponding participants were assumed to be alive if not listed in the National Death Index.
Statistical Methods
We excluded participants who reported daily energy intake outside the plausible range of 800 to 4200 kcal/day for men and 600 to 3500 kcal/day for women or who left 70 or more dietary questions blank at baseline. Participants who reported cancer, diabetes, myocardial infarction, angina, stroke, and other heart diseases before 1984 for women or 1986 for men were also excluded. We used 1984 as the starting year for the NHS in the analyses because the NHS questionnaires from 1984 onward and the Health Professionals' Follow-up Study questionnaires from 1986 onward were similar with respect to the questions on fruits and vegetables. The analyses thus included 71 910 women and 37 725 men.
Person-time of follow-up was contributed by each eligible participant from the date of return of the baseline food-frequency questionnaire (1984 for women and 1986 for men) to the diagnosis of cardiovascular disease or cancer, death, or May 31, 1998, for women or January 31, 1998, for men, whichever came first. Those who reported cardiovascular disease or cancer or who died were excluded from subsequent follow-up. Thus, each participant could contribute only one endpoint, and the cohort at risk included only those free of the outcome. We recorded 9329 major chronic disease endpointsincluding 1964 cardiovascular diseases, 6584 cancers, and 781 non-traumatic deaths from causes other than cancer or cardiovascular diseaseamong women during 19841998 and 4957 endpointsincluding 1670 cardiovascular events, 2500 cancers, and 787 nontraumatic deaths from other causesamong men during 19861998. To increase power, we conducted additional separate analyses for cancer that did not exclude participants with cardiovascular disease during follow-up and for cardiovascular disease that did not exclude participants with cancer during follow-up; the results were similar to those for cancer excluding the participants with cardiovascular diseases during follow-up and for cardiovascular disease excluding participants with reported cancer during follow-up (data not shown). The associations of fruit and vegetable intake with cancer and cardiovascular mortality were also evaluated separately, and the findings were similar to those for cancer and cardiovascular disease incidence (data not shown).
To reduce within-person variation and to best represent long-term diet, we used the cumulative average intake of fruits and vegetables from all available questionnaires up to the start of each 2-year follow-up interval (35). If participants experienced angina, coronary artery bypass grafting, angioplasty, hypercholesterolemia, hypertension, or diabetes, we stopped updating diet at the beginning of the interval in which they developed the diagnosis. The nondietary variables were updated from the biennial questionnaires. We used Cox proportional hazards models with time-dependent variables to perform these analyses (36). Proportionality of hazards was evaluated by visual examination of associations across intervals of time.
Participants were grouped into equal-sized quintiles of fruit and vegetable intake using the updated cumulative average (35). For each outcome, the relative risks were calculated by dividing the incidence among participants in each quintile by that in the lowest quintile. Quintiles were used to avoid assumptions about the shape of the doseresponse relationship. We also assessed linear relationships, using the median values of intake for deciles to minimize the influence of outliers. The relative risk for the continuous measure indicates the change in risk associated with an increment of five servings per day for total fruits and vegetables, an increment of three servings per day for all fruits and for all vegetables, and an increment of one serving per day for the specific food groups. We also compared groups with intakes of 1.52.99, 3.04.99, 5.05.99, 6.07.99, and 8 or more servings per day against participants with fewer than 1.5 servings of total fruit and vegetable intake per day as the referent group to evaluate the association of major chronic disease across the range of fruit and vegetable consumption and to assess the potential optimal intake.
We conducted the initial analyses adjusting for age (5-year categories) and smoking status (never, past, current, 114, 1524, and 25 cigarettes/day) only. In the multivariable model, we also adjusted for total energy intake (continuous variable), alcohol (0, >0 to 5, >5 to 10, >10 to 30, and
30 g/day for women and 0, 0 to <5, 5 to <15, 15 to <30 and
30 g/day for men), body mass index (<21, 21 to <23, 23 to <25, 25 to <29 and
29 for women and <21, 21 to <23, 23 to <25, 25 to <30, and
30 for men), multivitamin supplement use (yes/no) and vitamin E supplement use (yes/no), physical activity (five categories), first-degree family history of myocardial infarction before age 60 (yes/no), first-degree family history of colon cancer (yes/no), personal history of hypertension, hypercholesterolemia, or diabetes (yes/no). In addition, for women, we adjusted for first-degree family history of breast cancer (yes/no), menopausal status (premenopausal/postmenopausal), and hormone replacement therapy use (current, past, and never).
We also carried out several subgroup analyses. In one subgroup analysis, we evaluated associations separately among users and nonusers of multivitamins. Nonusers of multivitamins who took other supplements such as vitamin E, B6, B12, and calcium were excluded from these subgroup analyses. We also conducted analyses separately for current, past, and never smokers to determine whether smoking modifies the association of fruit and vegetable intake with risk of major chronic disease. Interactions of fruit and vegetable consumption with smoking status and multivitamin use were tested separately in the two cohorts.
To increase the statistical power, we combined the results from both cohorts by using the random-effects model to pool the two relative risks. Tests for homogeneity between the two cohorts were conducted using the DerSimonian and Laird Q statistic (37).
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RESULTS |
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DISCUSSION |
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Consumption of five or more servings of fruits and vegetables per day has been recommended in the National 5 A Day for Better Health Program (2,3) for cancer prevention, but the protective effect of fruit and vegetable intake may have been overstated (38). Indeed, most of the evidence supporting this recommendation is based on casecontrol studies, which are potentially affected by methodological biases such as recall bias and selection bias. Selective reporting and publication may also explain some of these statistically significant findings, because the authors of studies in which only one or a few items among many fruits and vegetables examined were statistically significantly related to cancer incidence may present their findings as positive, even though they may actually have been due to chance. Moreover, recent findings from Health Professionals' Follow-up Study, the NHS, and other cohort studies have reported weak or no associations between total fruit and vegetable intake and incidence of specific cancers (12,14,1621).
Our findings are consistent with results from a study of a cohort of 9608 adults, in which high frequency of fruit and vegetable intake was associated with lower risk of cardiovascular disease and all-cause mortality but not with noncardiovascular disease mortality, which should consist mainly of cancer deaths (39). To evaluate whether fruit and vegetable intake is associated with cancer mortality, we conducted further analyses using cancer mortality instead of cancer incidence as the outcome and also found no association between consumption of fruits and vegetables and death from cancer.
There are several possible explanations for why we did not observe an association between fruit and vegetable intake and cancer in this analysis, if one exists. One possibility is that cancer risk is elevated only in individuals with low intake of fruits and vegetables (11). If an increased risk of cancer were associated only with a fruit and vegetable intake lower than that in our population, we would have been unable to detect a protective association with fruit and vegetable intake. In our population, the median fruit and vegetable intake in the lowest quintile was similar to the average intake of the U.S. population, i.e., approximately 0.7, 1.5, and 0.7 servings per day for fruits, vegetables including salad and potato, and vegetables excluding salad and potato, respectively (40). However, even in analyses in which we used a referent group of intake below 1.5 servings per day (Fig. 1), we still did not observe a protective association with fruit and vegetable intake. Further exploration of associations with intake lower than 1.5 servings per day is not feasible in this study population. The higher intake in our population is likely to reflect their being health professionals and having a higher socioeconomic status than the general U.S. population. It is also possible that the participants in our studies overestimated intake because of the relatively large number of questions for assessing intake of fruits and vegetables (approximately 15 questions for fruits and 30 questions for vegetables) on our questionnaires compared with national surveys, which contain seven such questions (41,42). However, even if there was some overestimation of fruit and vegetable intake, such overestimation, which would alter the responses of all participants, is unlikely to bias the relative risk estimates.
Another possible explanation for the lack of an association of fruit and vegetable intake with cancer incidence in our study is that the induction period for some cancers may be longer than for cardiovascular disease and than the follow-up period in these cohorts. In other words, because the development of cancer is a multistage process that takes place over several decades, we might need a longer follow-up period than for cardiovascular disease to detect whether fruit and vegetable intake are associated with changes in the early stages of cancer development.
Although cancer risk may be directly related to intake of a specific dietary factor, such as folic acid or lycopene (4346), analyses based on overall fruit and vegetable intake may not be sufficiently specific to detect such associations. Also, the use of vitamin supplements and intake of fortified foods by the participants in our study might attenuate an effect of fruit and vegetable intake on the incidence of cancers if the nutrients in these supplements are associated with reduced cancer risk, because participants would have sufficient intake from sources other than fruits and vegetables. Indeed, in subgroup analyses, we did find a moderate benefit of fruit and vegetable intake among nonsupplement users. Failure to find an expected association can also be due to low variation in the factors being studied or to an inability to measure the exposure well. The homogeneity of socioeconomic status among our populations might limit the variation in the amount of fruit and vegetable intake; on the other hand, it would reduce potential bias from unmeasured confounders. In addition, the nondifferential misclassification of information inherent in any dietary data would further attenuate a statistically significant association. However, the clear inverse relation between fruit and vegetable consumption and risk of cardiovascular disease indicates that exposure misclassification cannot account for the lack of an overall association with cancer incidence.
Finally, our findings do not preclude benefits of specific foods or food groups for prevention of specific cancers. We observed that intake of cruciferous vegetables was inversely associated with total cancer incidence among current smokers and nonmultivitamin supplement users in men, although not in women, and we earlier reported an inverse association between cruciferous vegetable intake and bladder cancer incidence in men (29). The difference between men and women may reflect the fact that the major cancers are different for men and women, but chance is also a possible explanation.
In our analyses, we adjusted for confounding variables by using updated measurements collected in the followed-up questionnaire to better control for confounding compared with using only the baseline measurements. Some of these factors, such as obesity, hypertension, and hypercholesterolemia, may mediate the causal pathway between fruit and vegetable intake and cancer risk; overcontrolling for these factors could, therefore, mask a true association. However, the association was already attenuated to the null in the model adjusting for age and the amount of smoking. Comparing participants in the highest quintile with those in the lowest quintile, relative risk for total fruits and vegetables and cancer incidence was 0.92 (95% CI = 0.86 to 0.98) adjusted for age only and 0.97 (95% CI = 0.90 to 1.04) adjusted for age and smoking. Hence, overadjustment for potential mediators is unlikely to account for our null findings.
Our findings for cardiovascular disease still support the recommendations of the American Heart Association (4) of consuming at least five servings of fruits and vegetables per day, as in our earlier reports (9,10). Participants in our study eating at least five servings of fruits and vegetables daily had a 28% lower risk of cardiovascular disease than participants eating fewer than 1.5 servings per day, probably due to higher intake of multiple nutrients, including folic acid, potassium, and possibly glucosinolates, diallyl sulfides, and flavonoids (4750). Fruits were associated with a greater reduction in risk of cardiovascular disease than vegetables. Among the specific groups of fruits and vegetables examined, green leafy vegetables were most strongly associated with a reduction in risk of cardiovascular disease; an increment of one serving was associated with an 11% lower risk of cardiovascular disease. In subgroup analyses, the association between fruit and vegetable intake and cardiovascular disease was stronger among current smokers and nonvitamin users than among nonsmokers and multivitamin users, respectively. Although a stronger association among smokers might be due to a need for higher intake of antioxidants among persons subjected to greater oxidative stress (51,52), we cannot exclude the possibility of residual confounding of amount and type of cigarette use among smokers.
In conclusion, our results provide further evidence that high intake of fruits and vegetables is associated with a modest reduction in major chronic disease risk and support the recommendation of consuming five or more servings of fruits and vegetables daily. However, the benefit of increasing intake of fruits and vegetables appears to be due primarily to a lower risk of cardiovascular disease, not cancer.
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NOTES |
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Manuscript received April 3, 2004; revised August 26, 2004; accepted September 1, 2004.
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