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Transcript
American Journal of Epidemiology
Copyright © 2004 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved
Vol. 159, No. 1
Printed in U.S.A.
DOI: 10.1093/aje/kwh010
PRACTICE OF EPIDEMIOLOGY
VITamins And Lifestyle Cohort Study: Study Design and Characteristics of
Supplement Users
Emily White1,2, Ruth E. Patterson1,2, Alan R. Kristal1,2, Mark Thornquist1, Irena King1, Ann L.
Shattuck1, Ilonka Evans1, Jessie Satia-Abouta1,3, Alyson J. Littman1,2, and John D. Potter1,2
1
Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
3 Department of Nutrition, School of Public Health, University of North Carolina, Chapel Hill, NC.
2
Received for publication April 22, 2003; accepted for publication July 11, 2003.
Vitamin and mineral supplements are among the most commonly used drugs in the United States, despite
limited evidence on their benefits or risks. This paper describes the design, implementation, and participant
characteristics of the VITamins And Lifestyle (VITAL) Study, a cohort study of the associations of supplement use
with cancer risk. A total of 77,738 men and women in western Washington State, aged 50–76 years, entered the
study in 2000–2002 by completing a detailed questionnaire on supplement use, diet, and other cancer risk
factors, and 70% provided DNA through self-collected buccal cell specimens. Supplement users were targeted
in recruitment: 66% used multivitamins, 46% used individual vitamin C, 47% used individual vitamin E, and 46%
used calcium, typically for 5–8 of the past 10 years. Analyses to identify confounding factors, the main study
limitation, showed that regular nonsteroidal anti-inflammatory drug use, intake of fruits and vegetables, and
recreational physical activity were strongly associated with supplement use (p < 0.001). The authors describe a
follow-up system in which cancers, deaths, and changes of residence are tracked efficiently, primarily through
linkage to public databases. These methods may be useful to other researchers implementing a large cohort
study or designing a passive follow-up system.
calcium; data collection; dietary supplements; epidemiologic research design; follow-up studies; vitamins
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; VITAL, VITamins And Lifestyle.
Consumers have little rigorous scientific information to
guide them in selecting types and dosages of supplements to
use for disease prevention or, specifically, cancer prevention. Many nutrients have shown cancer preventive properties in in vitro studies, animal studies, and human clinical
studies (2–4). Hundreds of epidemiologic studies on diet and
cancer have been conducted; an extensive review found
strong and consistent evidence that diets high in vegetables
and fruit reduce the risk of cancers of the mouth and
pharynx, esophagus, lung, stomach, colon and rectum, and
possibly breast and bladder; however, studies of dietary
intake of specific nutrients have been less consistent (5).
Vitamin, mineral, and other dietary supplements are
among the most commonly used drugs in the United States.
According to recent national surveys, 48–55 percent of US
adults use vitamin and/or mineral supplements regularly (1;
E. Slaughter, Princeton Survey Research Associates,
personal communication, 2002). Moreover, some supplements provide much higher levels of nutrients than can be
obtained from food. For example, median intake of vitamin
E from food is 7–8 mg of α-tocopherol for those aged 51–70
years (2), whereas the common dose in an individual supplement is 20 times this amount (400 IU or 180 mg αtocopherol equivalents).
Correspondence to Dr. Emily White, Cancer Prevention Program MP-702, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle,
WA 98109-1024 (e-mail: [email protected]).
83
Am J Epidemiol 2004;159:83–93
84 White et al.
TABLE 1. Disposition of questionnaires and response rates in the VITamins And Lifestyle
cohort study, Washington State, 2000–2002
Full mailing list
No.
%
364,418
100
Undeliverable questionnaire
6,900†
1.9
Deceased
7,300†
2.0
Duplicate questionnaire
4,700†
Age ineligible
Out of area at baseline
Total
Returned questionnaires Response
rate (%)
No.
%
79,300
100
1.3
73
0.1
4,000†
1.1
844
1.1
2,600†
0.7
402
0.5
3
0.0
Questionnaire completed by a
person to whom it was not mailed
163
0.2
Excess missing data‡
77
0.1
77,738
98.0
21.8*
Ineligible
Transsexual
Failed quality control checks
Eligible and passed quality control
338,918†
93.0
22.9§
* Percentage of questionnaires returned.
† Estimate based on counts within subsamples or external estimates.
‡ Failed two of three quality control checks: some items on every page of the food frequency
questionnaire were completed, at least half of the cancer risk factor questions were completed, at least
some items in the supplement section were completed.
§ Estimated response rate among eligible individuals.
Far fewer human studies of cancer risk have explicitly
studied nutrients obtained from supplements. We have
published two critical reviews of this literature (6, 7). Key
findings are the adverse effects of β-carotene on lung cancer
(8, 9) and a probable reduction in risk of prostate cancer with
use of supplemental vitamin E (10) and selenium (11) (a
common component of multivitamins). There is also
supportive evidence that supplemental vitamin E (12–14),
supplemental calcium (15), and long-term multivitamin use
(16, 17) may reduce the risk of colorectal cancer.
Randomized trials are limited because they can test only
specific agents at specific doses for typically a small number
of years, and often in populations selected because of their
high risk of certain cancers. In contrast, cohort studies can be
an effective way to assess a wide range of supplements used
at varying dosages for long durations. We therefore designed
and implemented a cohort study with the overall aim of
investigating the associations of supplement use with cancer
risk. Specific goals focus on the associations of supplemental vitamin C, vitamin E, calcium, and multivitamins
with prostate, female breast, lung, and colorectal cancer incidence. The study is called the VITamins And Lifestyle
(VITAL) Study.
This paper describes the design and implementation of the
VITAL Study and presents baseline observations on factors
associated with supplement use. We describe the study
methods in detail, including recruitment of the cohort, data
collection methods, and our passive follow-up system. This
information provides a background for future reports from
this study and may provide practical information to aid
others who are implementing cohort studies. Description of
the characteristics of those who use the main supplements of
interest addresses the main limitation of this and other observational studies of supplement use—that factors associated
with supplement use need to be identified so they can be
controlled for as potential confounding factors.
MATERIALS AND METHODS
VITAL cohort recruitment
Men and women were eligible to join the cohort if they
were aged 50–76 years and lived in the 13-county area in
western Washington State covered by the Surveillance,
Epidemiology, and End Results (SEER) program cancer
registry. Using names purchased from a commercial mailing
list, we mailed 364,418 baseline questionnaires followed by
a postcard reminder after 2 weeks. To recruit supplement
users into the cohort, the cover letter described the study as
one on supplement use and cancer risk, but the study was not
restricted to supplement users. Recruitment was conducted
from October 2000 to December 2002, during which time
79,300 (21.8 percent) questionnaires were returned. Of
these, 77,738 questionnaires passed eligibility and quality
control checks. Disposition of the questionnaires is given in
table 1. We estimated that 93 percent of those persons on the
mailing list would have been eligible for the study (table 1),
yielding an estimated response rate of 22.9 percent among
those eligible.
Data and specimen collection
Data were collected at baseline by using a 24-page, selfadministered, sex-specific, optically scanned questionnaire
Am J Epidemiol 2004;159:83–93
VITamins And Lifestyle Cohort Study 85
that covered three content areas: supplement use, diet, and
health history and risk factors. We plan to update this information at 5 years postbaseline.
Measurement of supplement use. Supplement use was
the principal exposure in this study; therefore, our supplement questionnaire section was considerably longer (six
pages) and more detailed than typical supplement assessment forms used in large epidemiologic studies. This questionnaire was developed based on our earlier methodological
work in supplement assessment (18–20).
Respondents were asked about their use of supplements
during the 10 years prior to baseline. For current multivitamin use, participants either selected one of 16 common
brand names or provided dose information on each vitamin
and mineral in the brand they used. For those who had used
more than one brand over the 10 years or had used multivitamins only in the past, respondents selected from another list
of brand names (reflecting past market availability). For
analysis, the nutrient content of multivitamins was based on
information from the Physicians’ Desk Reference for
Nonprescription Drugs and Dietary Supplements (21) and
from direct inquiry to manufacturers to determine composition of multivitamins in the past 10 years.
Respondents then reported their intake of 10 vitamins and
six minerals from all other mixtures not classified as multivitamins (e.g., “stress”/B complex or antioxidant mixtures)
and single supplements and of 21 herbal and specialty
supplements. We used a closed-ended format to inquire
about current versus past use, frequency (times per week)
and duration of use over the previous 10 years, and usual
dose per day. For herbal and specialty supplements, questions on dose were not included because of a lack of accurate
information on their potency.
Average daily intake of supplemental vitamin E, C, and
calcium over the previous 10 years was estimated by
summing intake from individual supplements and intake
from multivitamins during the 10-year period; intake from
each nutrient was computed as number of years/10 × number
of days per week/7 × dose. For multivitamin use, 10-year
intake was expressed as daily pills over the 10 years (number
of years/10 × number of days per week/7).
In a study of 220 participants, the VITAL supplement
questionnaire showed excellent reliability/validity when
compared with a repeat administration of the questionnaire 3
months after baseline, to a detailed home interview and
supplement inventory, and to nutrient biomarkers (22) (table
2).
Diet and other covariates. Diet was assessed by using a
food frequency questionnaire that captures intakes of 120
food and beverage items and includes adjustment questions
on types of foods and preparation techniques. It was adapted
from food frequency questionnaires we developed for the
Women’s Health Initiative and other studies (23–25), with
the addition of highly supplemented foods such as calciumsupplemented orange juice and fortified drinks and bars such
as Slim·Fast (Slim·Fast Foods Company, West Palm Beach,
Florida) and PowerBar (PowerBar Inc., Berkeley, California). The measurement properties of earlier versions of
this questionnaire were published previously (25). The food
frequency questionnaire analytic program, based on nutrient
Am J Epidemiol 2004;159:83–93
TABLE 2. Validity and reliability of supplement use from the
baseline questionnaire (n = 220),* VITamins And Lifestyle
cohort study, Washington State, 2000–2002
Questionnaire
10-year dose
test-retest ICC†
Questionnaire
current dose
vs. interview/
transcription
r‡
Questionnaire
current dose vs.
biomarker§
r‡,¶
Vitamin C
0.85
0.77
0.29
Vitamin E
0.87
0.81
0.69
Calcium
0.77
0.69
–0.07
Multivitamins
0.81
NA†
NA
Nutrient
* Satia-Abouta J, Patterson RE, King IB, et al. Reliability and
validity of self-report of vitamin and mineral supplement use in the
Vitamins and Lifestyle study. Am J Epidemiol 2003;157:944–54.
† ICC, intraclass correlation; NA, not applicable.
‡ Pearson correlation coefficient.
§ Plasma vitamin C, serum α-tocopherol, and spot urinary
calcium, respectively.
¶ Adjusted for age, sex, race, and current smoking. In addition,
plasma vitamin C was adjusted for dietary vitamin C; serum αtocopherol was adjusted for serum total cholesterol, body mass
index, and dietary α-tocopherol; and urinary calcium was adjusted
for urinary creatinine and dietary calcium.
values from the Minnesota Nutrient Data System (26), yields
estimated intakes of over 50 nutrients.
The remaining parts of the questionnaire covered personal
identifiers for tracking purposes, demographic characteristics, health history, drug use with emphasis on nonsteroidal
anti-inflammatory drugs, physical activity over the 10 years
prior to baseline, cancer screening practices, and other
potential confounders of supplement-cancer associations.
Health complaints, such as fatigue and joint pain, were also
assessed because such nonmedically diagnosed health conditions may be the “indication” that led subjects to select
certain supplements.
Questionnaire quality control. Questionnaires were reviewed before scanning; correction tape was used on
crossed-out answers, and written comments were read and
coded. The data entry and scan (ScanTools; Pearson NCS,
Bloomington, Minnesota) software we used contain editcheck capabilities (e.g., value ranges). We developed extensive postentry programmed edit checks, including
comparing names from the questionnaire and the mailing
lists to determine whether the correct person had completed
the questionnaire, comparing questionnaire identifiers to
spot duplicate questionnaires from the same person,
checking that subjects completed the appropriate sexspecific questionnaire (if not, a subject was interviewed by
telephone to ascertain the missing information), interpreting
duplicate marks, and conducting extensive consistency
checks between variables.
Collection of buccal cells. Buccal cells were collected as
a source of DNA for future gene-nutrient studies. To select
the best procedures, we conducted a small study (n = 24) to
compare DNA quality, DNA quantity, and costs of cytobrush and mouthwash methods (27). The cytobrush method
86 White et al.
TABLE 3. Supplement use over 10 years prior to baseline by participants in the VITamins
And Lifestyle cohort study, Washington State, 2000–2002
Supplement
(units)
Individual use
of supplement
(%)
Median
dose
per day
Median no.
of years
of use
High-dose
supplement
use* over 10
years (%)
Multivitamin (no. of pills/day)
65.5
1
8
53.9
Vitamin C (mg)
45.8
500
8
34.1
Vitamin E (mg of dl α-tocopherol)
47.2
400
5
30.6
Calcium (mg)
45.2
500
5
22.6
* High-dose use was defined as an average intake over 10 years of ≥5 multivitamin pills per
week, ≥180 mg of vitamin C per day, ≥150 mg of vitamin E per day, or ≥350 mg of calcium per
day.
yielded sufficient DNA quality and quantity (12.0 µg, sufficient for an estimated 150–225 polymerase chain reactions
requiring short- and intermediate-length DNA fragments)
at a cost acceptable for this large-scale study ($8.50 per
participant).
Three months after the completed baseline questionnaire
was received, a DNA kit was mailed containing a cover
letter; three sterile cytology brushes, each packaged in a
separate bar-coded tube; detailed instructions with pictures;
and a consent form. A second mailing was sent to nonresponders approximately 1 year later. When returned, buccal
brushes were logged into the specimen tracking system and
were linked to the participant’s identity, and the name on the
consent form was entered to ensure that the correct person
provided specimens. The three brushes were stored in separate –80°C freezers. The response rate was 70 percent.
Follow-up methods for cancer and censoring
After discounting rates to account for a possible “healthy
volunteer effect,” we expect approximately 1,000 cancers to
be diagnosed in the cohort in each of the next 5 years,
including an estimated 220 prostate, 155 breast, 130 lung,
and 90 colorectal cancers. The censoring date (the last date
for follow-up) for each participant will be the earliest of the
date of death, date on which the participant moved out of the
SEER catchment area, date on which he or she asked to be
removed from the study, or most recent date that endpoints
were ascertained. Information on cancers, deaths, and moves
out of the area are obtained primarily from passive follow-up
by using linkages to public databases.
Cancer incidence. Incident cancer cases are ascertained
by linking the study cohort to the western Washington SEER
program cancer registry, maintained by the Fred Hutchinson
Cancer Research Center under contract to the National
Cancer Institute. Data are collected on all newly diagnosed
cancers (except nonmelanoma skin cancers) occurring in
residents of the 13 counties of the Seattle-Puget Sound area.
Cases are ascertained through all hospitals in the area;
offices of pathologists, oncologists, and radiotherapists; and
state death certificates. Extensive quality control procedures
ensure that registry data are accurate and complete.
Linkage methods. We link the VITAL cohort to the
SEER file annually. We have designed and implemented a
comprehensive linkage system, which is largely automated,
by using data items common to both sets of data. First,
potential matches are identified based on linking the two
files by nine increasingly broad (i.e., less specific) sets of
matching criteria. Examples follow: 1) full social security
number (provided by 33 percent of our cohort); 2) last four
digits of the social security number (provided by 36 percent
of our cohort), first five characters of the last name, and date
of birth; and 3) “sounds like” (based on phonetic sound) last
name and date of birth. Second, each potential match is
ranked electronically to determine whether it is “good”
(enough data items in common to be considered a match),
“bad” (too few data items in common to be considered a
match), or “needs visual inspection” (some data items in
common). The ranking criteria are based on the type and
number of other data items that match (name, sex, date of
birth, street address, zip code, telephone number, marital
status, and birthplace), with the criteria more stringent for
the less specific linkage criteria. Third, matches requiring
visual inspection are reviewed by staff using screens that
display all relevant information from VITAL and SEER.
This inspection allows the use of human judgment for
matches not made electronically because of misspellings of
names, nicknames, transposition of numbers, and so forth.
Finally, for records for which the visual match is still uncertain, the participant is telephoned directly.
Mortality. Deaths occurring in the cohort in Washington
State are ascertained by linkage to the state death file and by
using other methods. Our linkage system to the death file is
almost identical to the system described above for linkage to
the SEER file. In addition, unconfirmed deaths will be ascertained from annual linkage to the Social Security Death
Index, from tracking those lost to follow-up, from the US
Postal Service as a result of the 5-year mailings, and from
family members who receive the 5-year mailings. We will
link the unconfirmed deaths and all 5-year questionnaire
nonresponders to the National Death Index. Confirmed or
unconfirmed date of death will be the censoring date.
Moves out of area. Subjects who move out of the 13county area are tracked by electronic linkage to the National
Am J Epidemiol 2004;159:83–93
VITamins And Lifestyle Cohort Study 87
TABLE 4. Herbal and specialty supplement use in the VITamins
And Lifestyle cohort study, Washington State, 2000–2002
Prevalence of use* (%)
Type of supplement
Men
Women
Glucosamine
14.0
19.0
Fiber
10.6
14.1
Chondroitin
8.7
13.0
Saw palmetto†
8.0
Ginkgo biloba
6.5
Fish oil/EPA‡/omega-3/cod liver oil
6.4
7.4
Garlic pills
7.3
6.8
7.9
* Use at least once a week for a year.
† Asked of men only.
‡ EPA, eicosapentaenoic acid.
Change of Address system. All change of address data
submitted by people who relocate across the entire country
are entered into this system. The resulting file is provided to
licensed private companies and is updated every 2 weeks.
We link the VITAL cohort to the National Change of
Address file annually by using a vendor who contracts with
the US Postal Service. If a name and address match exactly
(last name for family moves and first and last names for individual moves), the new address and move date are provided.
If a new address is not known, a move date is provided along
with information about the move (e.g., moved, no
forwarding address). If a record does not match exactly but
enough data items are common to suggest the possibility of a
move, codes are returned to indicate a “possible” move, but
no new address is given. This system is estimated to identify
about 65 percent of moves.
Tracking those lost to follow-up. Participants considered
“lost to follow-up” are determined primarily from 1) linkages to the National Change of Address system returned as a
match for a move without a forwarding address or as a
“possible move” but not an exact match, and 2) mailed data
collection instruments returned by the US Postal Service as
“undeliverable” or “moved, no forwarding address.” Intensive tracking procedures are conducted for these cohort
members by using 1) public databases and directories owned
by the Fred Hutchinson Cancer Research Center (e.g., Wash-
TABLE 5. Odds ratios† for 10-year high-dose supplement use‡ by participants in the VITamins And
Lifestyle cohort study, by participant characteristics (n = 76,072),§ Washington State, 2000–2002
Characteristic
%
Multivitamins
Vitamin C
Vitamin E
Calcium
Age (years)
50–59
46.0
Reference
Reference
Reference
Reference
60–69
34.7
1.29
1.28
1.64
1.65
≥70
19.3
1.39
1.34
1.81
1.94
0.001
0.001
0.001
0.001
p for trend
Sex
Male
48.3
Reference
Reference
Reference
Reference
Female
51.7
1.44***
1.30***
1.42***
4.79***
Education
High school or less
20.2
Reference
Reference
Reference
Reference
Some college
38.3
1.30
1.29
1.17
1.25
College degree
24.5
1.39
1.40
1.26
1.47
Advanced degree
17.0
1.45
1.51
1.36
1.50
0.001
0.001
0.001
0.001
p for trend
Race/ethnicity
White
93.2
Reference
Reference
Reference
Reference
Hispanic
0.9
0.64***
0.71**
0.85
0.78*
Black
1.3
0.64***
0.65***
0.54***
0.44***
American Indian/Alaska Native
1.5
0.92
1.05
0.95
0.98
Asian/Pacific Islander
2.5
0.67***
0.63***
0.63***
0.65***
* p < 0.05; ** p < 0.01; *** p < 0.001 for categorical variables. For ordinal variables, p for trend is given.
† Based on logistic regression models adjusted for other characteristics in the table.
‡ High-dose use was defined as an average intake over 10 years of ≥5 multivitamin pills per week, ≥180 mg of
vitamin C per day, ≥150 mg of vitamin E per day, or ≥350 mg of calcium per day.
§ Omitted were 114 late responders and 1,552 subjects for whom data on adjustment factors (education or race)
were missing.
Am J Epidemiol 2004;159:83–93
88 White et al.
TABLE 6. Odds ratios† for 10-year high-dose supplement use‡ by participants in the VITamins And Lifestyle cohort
study, by factors putatively associated with breast or prostate cancer, Washington State, 2000–2002
Risk factor
%
Multivitamins
Vitamin C
Vitamin E
Calcium
Risk factors for breast cancer in women (n = 39,301)§
Family history of breast cancer
No
83.9
Reference
Reference
Reference
Reference
Yes
16.1
1.02
1.02
1.08*
1.03
Mammogram in the past 2 years
No
9.0
Reference
Reference
Reference
Reference
Yes
91.0
1.52*
1.26*
1.43*
1.60*
≤24
58.6
Reference
Reference
Reference
Reference
25–29
19.6
0.95
0.92
0.88
1.01
≥30
8.9
0.82
0.80
0.71
0.90
Age at first birth (years)
No births
12.9
p for trend
1.05
1.17
1.10
1.11
0.61
0.03
0.62
0.08
Hormone replacement therapy
Never/former use
52.9
Reference
Reference
Reference
Reference
Current use
47.1
1.34*
1.25*
1.29*
1.41*
Normal (<25)
41.1
Reference
Reference
Reference
Reference
Overweight (25–<30)
33.5
0.92
0.86
0.90
0.79
Body mass index (kg/m2)
Obese (30–<35)
15.5
0.88
0.76
0.79
0.69
Very obese (≥35)
10.0
0.80
0.70
0.73
0.58
0.001
0.001
0.001
0.001
p for trend
Alcohol intake (no. of drinks/
week)
None
50.8
Reference
Reference
Reference
Reference
1–2
18.4
0.97
0.97
0.99
1.00
3–6
14.2
0.97
1.10
1.13
1.09
≥7
16.6
0.91
1.02
1.13
1.06
0.003
0.10
0.001
0.01
p for trend
Table continues
ington State Department of Licensing), 2) public records
offices (e.g., county tax assessors’ offices), and 3) Internet
sources and online database services (e.g., Autotrack;
ChoicePoint Asset Company, Boca Raton, Florida).
RESULTS
Supplement use in the cohort
We successfully recruited a cohort in which the level of
supplement use was high and of long duration. Of multivitamins and the 16 individual vitamin and mineral supplements
we inquired about, 21 percent of the cohort used none, 26
percent used one or two, 21 percent used three or four, and
32 percent used five or more. Of the main exposures of
interest, 66 percent of participants used multivitamins, 46
percent used individual vitamin C, 47 percent used individual vitamin E, and 46 percent used calcium—each typically for 5–8 of the previous 10 years (table 3). The most
common daily doses were 500 mg of vitamin C, 400 mg of
vitamin E, and 500 mg of calcium. The last column of table
3 gives the percentage of the cohort whose 10-year average
level of use of each supplement was high, defined as higher
than could be obtained by 10-year daily use of common
formulations of multivitamins. By identifying such users, we
will be able to consider separately the effects of specific
supplemental nutrients and the effects of multivitamins.
According to this definition, 34 percent of our subjects
used high doses of vitamin C (≥180 mg, or about twice the
Recommended Dietary Allowance of 90 mg for men and 75
mg for women (3)), 31 percent used high doses of vitamin E
(≥150 mg of dl α-tocopherol (150 IU), or five times the
Recommended Dietary Allowance of 30 IU (4)), and 23
percent used high doses of calcium (≥350 mg, or about one
third the adequate calcium intake of 1,200 mg (28)). Multivitamins generally contain 100 percent of the Recommended
Dietary Allowance for those micronutrients for which there
Am J Epidemiol 2004;159:83–93
VITamins And Lifestyle Cohort Study 89
TABLE 6. Continued
Risk factor
%
Multivitamins
Vitamin C
Vitamin E
Calcium
Risk factors for prostate cancer in men (n = 36,771)¶
Family history of prostate cancer
No
86.3
Reference
Reference
Reference
Reference
Yes
13.7
1.02
1.04
1.00
0.96
No
26.6
Reference
Reference
Reference
Reference
Yes
73.4
1.43*
1.37*
1.50*
1.32*
Normal (<25)
27.5
Reference
Reference
Reference
Reference
Overweight (25–<30)
48.8
0.97
0.91
0.98
0.90
Obese (30–<35)
17.7
0.89
0.83
0.88
0.88
Very obese (≥35)
6.0
0.81
0.68
0.80
0.82
0.001
0.001
0.001
0.002
Prostate-specific antigen
screening in the past 2
years
Body mass index (kg/m2)
p for trend
Diet
Energy from fat (%)
>40
23.8
Reference
Reference
Reference
Reference
36–40
25.4
1.13
1.14
1.18
1.00
31–35
24.4
1.35
1.31
1.47
1.18
≤30
26.4
1.63
1.65
1.87
1.26
0.001
0.001
0.001
0.001
p for trend
Fruit/vegetables (no. of
servings/day)
0–2
28.1
Reference
Reference
Reference
Reference
>2–3
24.7
1.27
1.29
1.26
1.28
>3–5
25.2
1.31
1.48
1.50
1.47
>5
22.0
1.60
1.86
1.89
1.93
0.001
0.001
0.001
0.001
p for trend
* p < 0.001 for categorical variables. For ordinal variables, p for trend is given.
† Based on logistic regression models adjusted for age, education, and race/ethnicity.
‡ High-dose use was defined as an average intake over 10 years of ≥5 multivitamin pills per week, ≥180 mg of vitamin C per
day, ≥150 mg of vitamin E per day, or ≥350 mg of calcium per day.
§ Omitted were 38 late responders and 1,006 subjects for whom data on adjustment factors (education or race) were missing.
Those subjects for whom data for the risk factor of interest were missing (range, 0.6–6.1%) were also omitted.
¶ Omitted were 76 late responders and 546 subjects for whom data on adjustment factors (education or race) were missing.
Those subjects for whom data for the risk factor of interest were missing (range, 1.4–7.4%) were also omitted.
are recommendations, except for calcium and certain other
minerals. On average, men and women consume about the
Recommended Dietary Allowance of most nutrients from
food (29), so the 54 percent who met our definition of use of
high doses of multivitamins (≥5 pills per week for 10 years)
had about twice the intake of many nutrients compared with
nonusers of supplements.
The VITAL participants also commonly used other
supplements. Of the 13 other individual vitamins and
minerals of interest, use was highest for folate and other B
vitamins (14–17 percent), zinc (14 percent), and selenium
(14 percent). Overall, about one third of participants used at
least one herbal or specialty supplement. The most
frequently used other supplements are given in table 4.
Am J Epidemiol 2004;159:83–93
Participant characteristics and their association with
supplement use
The cohort is 52 percent female, the median age is 61
years, 42 percent of the participants are college graduates,
and 93 percent are White (table 5). To identify factors that
may confound supplement use-cancer relations in this observational study, we examined associations of demographic
factors and cancer risk factors with supplement use. Table 5
shows associations of demographic factors with 10-year
high-dose use (as defined above) of four specific supplements of initial major interest (multivitamins, vitamin C,
vitamin E, and calcium). High-dose use of each supplement
increased with age and education, and women were more
90 White et al.
likely to be high-dose users of each supplement, particularly
calcium. Whites showed higher levels of use of each supplement than other racial/ethnic groups except for Native Americans, who were similar to Whites in this regard.
Tables 6 and 7 present associations of selected cancer risk
factors for the four most common cancers with 10-year highdose use of the four main supplements of interest. Of the
selected risk factors for breast cancer (table 6), prostate
cancer (table 6), colorectal cancer (table 7), and lung cancer
(table 7), all were statistically significantly associated with
all four supplements except for family history of cancer and
a woman’s age at first birth. Associations were particularly strong (odds ratios close to 2) for nonsteroidal antiinflammatory drug use (which includes low-dose aspirin
commonly used for heart disease prevention), physical
activity, and fruit and vegetable intake
DISCUSSION
A large and increasing number of Americans are using
dietary supplements, despite limited scientific information to
guide them. Therefore, we designed and implemented a
cohort study to test the associations of supplement use with
cancer risk. One advantage of this study is that participants’
use of supplements is considerably greater (more types,
higher doses, and longer durations) than for those subjects in
earlier cohorts (30, 31) because the present cohort was
recruited recently and targeted supplement users. We also
collected more detailed information on supplement use than
has been collected for most other cohorts, and our validation
study demonstrated good measurement properties of the
supplement questionnaire (22). We will be able to examine
cumulative dose over a long period of time (the 10-year
period ending at baseline), which is critical considering the
likelihood that 5–15 years of supplement use is needed to
affect cancer risk (16, 17).
The estimated response rate in the VITAL study was 23
percent. This low rate was probably due to the length of the
questionnaire (24 pages), use of only a single mailing, and
use of a recruitment letter that targeted supplement users to
participate. Our cross-sectional analyses on correlates of
supplement use (to identify confounding factors in this
cohort) would not be generalizable because of this low
response rate, although our findings are consistent with those
from past studies (see below). However, selection bias is not
a major concern in prospective studies, such as our future
studies of supplement-disease associations, because participation generally cannot be jointly related to supplement use
and to the participants’ unknown, future disease status.
This study is limited, as are all observational studies, by
possible confounding. Specifically, supplement users may
be more health conscious and therefore more likely to practice other disease prevention behaviors (32). We therefore
evaluated whether cancer risk or prevention factors were
associated with long-term, high-dose use of each of the four
main supplements of interest (multivitamins, vitamin C,
vitamin E, and calcium) in our population. Most associations
were in the direction that those participants with a possibly
lower risk of cancer (those with a lower body mass index,
lower dietary fat intake, higher fruit and vegetable intake,
regular use of nonsteroidal anti-inflammatory drugs, greater
recreational physical activity, and not a current smoker)
were more likely to use each supplement. High-dose supplement use was also associated with cancer screening, which
increases diagnoses of some cancers (e.g., prostate) and
decreases diagnoses of others (e.g., colorectal) and with
current use of hormone replacement therapy, which
increases the risk of breast cancer but reduces the risk of
colorectal cancer (33). To our knowledge, our finding that
use of nonsteroidal anti-inflammatory drugs is associated
with supplement use has not been reported previously. The
remainder of our findings are consistent with those from
earlier studies, even though our population is highly selfselected (34–42)..
Conversely, supplement users may be less healthy; certain
diseases or minor health complaints may have prompted
them to use supplements. Failure to control for these factors
may lead to “confounding by indication” (43). Gray et al.
(40) found that supplement users were more likely to have
multiple health care visits in the past year. We previously
reported associations of supplement use with 21 health
conditions assessed at baseline (44). However, in our study,
only one cancer-related condition was found to be associated
with supplement use: reflux disease with calcium supplements (44).
To account for these health behaviors and medical conditions that may be confounding factors in future analyses
from this study, we will statistically control for them in the
analyses. In addition, we will assess the dose-response
gradient of supplement use on the cancer outcome among
users of only that supplemental nutrient. For example, users
of supplemental vitamin C will be compared only with other
users, by dose of vitamin C, reducing bias caused by
comparing nonusers with users (45).
This study uses the cost-effective approach of ascertaining
endpoints and censoring dates by linkages to available
cancer registry, death, and change-of-address files rather
than by active contact with participants. Systems such as
ours, with computerized linkage to identify close matches
(rather than exact matches) and final decisions arrived at by
human judgment, are considered the most efficient and reliable (46, 47). Other cohort studies also use a primarily
passive follow-up system (48, 49).
Two concerns about our passive follow-up system are
possible selection biases from 1) censoring participants
when they move out of the catchment area of the western
Washington State SEER program cancer registry and 2)
erroneously including some out-of-area subjects as in-area
because of our inability to identify all moves. Censoring
those who move out of the area is significantly cheaper than
tracking the outcomes of those who have moved. The effect
of outmigration is expected to be a 4 percent loss of personyears (50). Failure to capture all out-of-area moves with our
tracking efforts would lead to a small error (an estimated 1
percent of person-years) in that we will include some
subjects who moved out of the area as contributing personyears of observation. Censoring subjects when they move
out of the area or erroneously including some out-of-area
subjects as in-area would bias the relative risk to only a small
degree, because these events are not likely jointly dependent
Am J Epidemiol 2004;159:83–93
VITamins And Lifestyle Cohort Study 91
TABLE 7. Odds ratios† for 10-year high-dose supplement use‡ by participants in the VITamins And Lifestyle
cohort study, by factors putatively associated with colorectal or lung cancer (n = 76,072),§ Washington State,
2000–2002
Risk factor
%
Multivitamins
Vitamin C
Vitamin E
Calcium
Risk factors for colorectal cancer
Family history of colorectal cancer
No
88.5
Reference
Reference
Reference
Reference
Yes
11.5
1.03
1.00
1.00
1.01
No
42.9
Reference
Reference
Reference
Reference
Yes
57.1
1.29*
1.23*
1.32*
1.39*
No
73.5
Reference
Reference
Reference
Reference
Yes
26.5
1.67*
1.81***
2.14*
1.68*
Normal (<25)
34.4
Reference
Reference
Reference
Reference
Overweight (25–<30)
41.0
0.94
0.88
0.93
0.82
Obese (30–<35)
16.6
0.88
0.79
0.82
0.74
Very obese (≥35)
8.0
0.81
0.70
0.76
0.62
0.001
0.001
0.001
0.001
Reference
Reference
Reference
Reference
Sigmoidoscopy in the past 10 years
Regular use of NSAIDs¶ in the past
10 years#
Body mass index (kg/m2)
p for trend
Physical activity (MET¶-hours/week)
None
15.0
1st tertile (0–<4.4)
28.3
1.36
1.32
1.36
1.27
2nd tertile (4.4–<13)
28.3
1.61
1.62
1.69
1.63
3rd tertile (≥13)
28.4
1.77
1.99
2.10
1.94
0.001
0.001
0.001
0.001
p for trend
Fruit/vegetables (no. of servings/day)
0–2
22.8
Reference
Reference
Reference
Reference
>2–3
22.1
1.24
1.30
1.29
1.31
>3–5
25.1
1.34
1.51
1.45
1.47
>5
30.1
1.63
1.89
1.84
1.96
0.001
0.001
0.001
0.001
p for trend
Risk factors for lung cancer
Smoking
Never
47.4
Reference
Reference
Reference
Reference
Former
44.3
1.08*
1.10*
1.12*
1.11*
Current
8.3
0.75*
0.79*
0.76*
0.67*
* p < 0.001 for categorical variables. For ordinal variables, p for trend is given.
† Based on logistic regression models adjusted for age, sex, education, and race/ethnicity.
‡ High-dose use was defined as an average intake over 10 years of ≥5 multivitamin pills per week, ≥180 mg of
vitamin C per day, ≥150 mg of vitamin E per day, or ≥350 mg of calcium per day.
§ Omitted were114 late responders and 1,552 subjects for whom data on adjustment factors (education or race)
were missing. Those subjects for whom data for the risk factor of interest were missing (range, 0.5–8.9%) were also
omitted.
¶ NSAIDs, nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, or naproxen); MET, metabolic equivalent.
# Regular use was defined as ≥4 times per week for ≥4 years.
on exposure and outcome in a cohort study. Furthermore, the
error in terms of person-years is sufficiently small so that
even a nonindependent association would bias the relative
risk by a small degree (51). Note that we retain the ability to
identify cancers and deaths of subjects who move within the
Am J Epidemiol 2004;159:83–93
catchment area whether or not we have tracked their current
address correctly.
Future results of this study on supplement-cancer associations may have scientific and public health implications. It
has been suggested that cohort studies may be the most
92 White et al.
rational way to choose specific agents to test in future clinical trails (52). The results of this study may also help guide
persons who choose to use supplements toward those that
have benefits. In addition, if some supplements are found to
have no effect or to be harmful, this information will be
important to the approximately 100 million US adults who
use them.
13.
14.
15.
ACKNOWLEDGMENTS
This study was supported by a grant (R01CA74846) from
the National Cancer Institute.
The authors thank Anne Oswald and Melissa Mouton for
their contributions to data collection for the study and Kayla
Stratton for the statistical analyses for this report.
16.
17.
18.
19.
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