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OCR for page 12
4 EpidemiologicalMethods
The investigation of diet and cancer in human populations has been
complicated by concerns about the adequacy of the various methods of
assessing exposure. The following list summarizes the approaches that
have been used to measure dietary exposure in epidemiological studies:
Methods Based on
Group Data
National per-capita
intakes
Household food use
Methods Based on
Individual Data
Food intake records
or diaries
Recent (24-hour or
7-day) diet recalls
Diet histories
Biochemical markers of
exposure
Anthropometric measure-
ments
These approaches and their respective strengths and limitations were
described in detail in Chapter 3 of the first report by the Committee
on Diet, Nutrition, and Cancer (National Research Council, 1982~. The
following paragraphs summarize methodological problems that character-
ize epidemiological studie s of diet and cancer and provide suggestions
for research.
Assessment of dietary intakes can be based either on group data or
on data collected directly from individuals The most frequently used
method in the first category is the estimation of per-capita intakes
from national food disappearance data; however, because of the rudimen-
tary nature of such data, these estimates may not be very accurate indi-
cators of actual consumption levels. Assessment of household food use
can be based on recall histories of consumption, collected from the
chief food-preparers, or on the availability of food supplies in the
home, recorded by a household member or a trained nutritionist. Since
thi s me thod require s contact wi th individual household s without produc-
ing individual consumption data, it is not often used. These so-called
"group" methods have proved useful for aggregate correlation analyses,
which are often the basis for generating new hypotheses. Such aggregate
correlations, however, do not control for confounding factors, nor do
they necessarily reflect associations at the individual level.
The second type of method is based on data collected directly from
individuals. These data are obtained by a variety of mechanisms, par-
ticularly through diet recall s and the contemporaneous recording of
12
OCR for page 13
Epidemiological Methods 13
weights or volumes of foods consumed. The collection of data from food
records necessarily focuses on current intake. Because this method re-
quires meticulous attention to detail, it is practical only in studies
involving small, selected samples. Diet recalls, on the other hand,
can be collected from much larger and more representative samples.
In contrast to recent recalls, which are focused on specified brief
periods close to the time of interview, diet histories, which are also
based on recall, assess usual intakes over a longer period in the past.
Thus, diet histories can be used to study intakes prior to the onset of
disease in cancer cases, even allowing for relatively long induction
periods. Therefore, this method has been used most frequently in in-
vestigations of the etiology of disease.
The use of biochemical markers of exposure, such as components of
body fluids or tissues, represents a somewhat different approach to
dietary assessment. Unfortunately, few markers that reflect long-
term dietary exposures have yet been identified, since the concentra-
tions of substances in biological fluids such as serum and urine are
usually related to recent exposures or to the functioning of ho~eo-
static control mechanisms rather than to long-term intakes and body
stores. In another method, certain anthropometric measures known to be
correlated with obesity (including indices based on height and weight
or skinfold thickness) have sometimes been used as indirect indicators
of nutritional status. Since past weight, for example, can be obtained
by interview, these measures are not necessarily limited to the assess-
ment of current nutritional status.
For studies involving large samples, the diet history is the most
practical and useful method. Although many investigators have expressed
reservations about approaches that rely on long-term memory, there have
been few studies on the validity and reproducibility of any of the
diet recall methods used in epidemiological studies. Because dietary
habits do not remain constant throughout life, even diet histories must
be focused on a particular period. In some instances, as in studies of
putative promoters, relatively recent intakes are of interest, whereas
in studies of initiators, early dietary habits are likely to be rele-
vant.
It is important to recognize that recall errors tend to be random
and apply equally to the comparison groups (e.g., cases and controls).
Thus, they will contribute to a reduction in the estimate of relative
risk and tend to lead to a false negative conclusion. Therefore, in
the interpretation of data from studies using the diet history method,
a finding of a significant association is likely to be considered valid,
whereas a negative finding (i.e., lack of an association) would not be
assigned as much weight.
The collection of diet histories requires consideration of a wide
array of variables, since eating reflects complex social, behavioral,
and cultural patterns. Thus, food preferences, the temporal pattern of
OCR for page 14
14 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
eating, portion sizes, use of condiments, and methods of food prepara-
tion (such as frying) and storage (which can affect nutrient content
and provide opportunities for contamination) should all be considered,
since any of these factors might have important influences on cancer
risk. In few studies have investigators elected or been able to con-
sider these many factors simultaneously. Moreover, current approaches
to dietary data collection are generally based on the subjects' recol-
lection of food items consumed, not their constituents, whereas most of
the hypotheses being tested pertain to nutritive or nonnutritive food
components. Since all foods are collections of such components, it has
not been possible to relate the findings in epidemiological studies
specifically to single constituents of foods.
Data collection is only the first step in the assessment of dietary
exposure in epidemiological studies of cancer. The food intake data
have to be classified in a meaningful manner and, in many instances,
converted into nutrient equivalents. Useful data on food composition
have been published by the U.S. Department of Agriculture (1975), and
many investigators have assembled additional information from a variety
of specific sources. Unfortunately, the data base is not uniform
or complete, and the composition of a particular food item is not fixed
and consistent; it may vary by the location and the season of its growth
and by the method of its processing. Thus, the average or representa-
tive values in the food composition tables may be relatively inaccurate
indicators of nutrient intakes for discrete population subgroups and
may contribute to false negative conclusions, as explained above for
diet histories. In addition, many nutrients and all nonnutritive com-
ponents of foods (e.g., naturally occurring flavones or food additives)
are not included in these tables, although they may be factors of
interest in the testing of certain dietary hypotheses.
Epidemiology provides the only direct approach to the assessment
of risk for human beings. However, because dietary measurements are
not precise, estimates of risk or benefit tend to be less than the
true effect. Furthermore, because small increments in risk might be
accounted for by chance variation or by uncontrolled confounding fac-
tors, a relative risk (i.e., incidence of the disease in those exposed
divided by the incidence in those not exposed) of less than 2.0 is
rarely concluded to be meaningful. Other difficulties arise because of
the latent period that must elapse between the initial exposure and the
development of the disease--a period that could well encompass a number
of decades and be affected by a multitude of modifying factors. Impre-
cision in measuring dose also results in imprecision in assessing the
relationship between dose level and response, an important indicator
for establishing causality, especially when the dose response is linear.
Nonetheless, the advantages of direct measurements of risk in epidemio-
logical studies are likely to outweigh advantages inherent in laboratory
studies.
These are only a few of the methodological issues that the com-
mittee considered in relation to the needs for future epidemiological
research on diet and cancer. In making research recommendations, the
committee placed its major emphasis on trying to rectify the weaknesses
OCR for page 15
Epidemiological Methods 15
in methods that precluded the
studies reviewed in the first
RESEARCH RECOMMENDATIONS
Assessment of Dietary Exposures
formulation of firm conclusions from the
report.
~ New approaches to improving the quality of dietary intake data,
especially in relation to long-term dietary patterns, should be ex-
plored. Research in this area should include a search for new aids
to facilitate individual recalls and should enlist the participation of
specialists in human behavior and psychometric measurement, who might
be able to identify the best ways to elicit accurate information and to
provide new insight into the factors that influence the responses of
people asked to describe their diets. In addition, a search should be
conducted for biochemical markers that reflect relevant dietary expo-
sures some time in the remote past. Where direct measurements of
exposure are unsuitable (e.g., in examining serum for a nutrient under
homeostatic control), indirect markers, such as serum-binding proteins
or enzyme levels, may be appropriate substitutes. Because rates of
absorption and metabolism of nutrients may vary among subjects, how-
ever, individuals ingesting the same diet may differ in their ultimate
exposure because of individual differences in metabolism and, thus, may
differ in their degree of risk for cancer. These biochemical differ-
ences among individuals should be studied in relation to observed
differences in cancer risk.
o More effort should be spent in evaluating the validity of
dietary methods. One approach, which has not been widely used in epi-
demiological research, would be to compare suitable biochemical mea-
surements with information derived concurrently from food records or
diet recalls. Although this strategy is generally useful only for
assessing the validity of very recent recalls, a high degree of
agreement among the different forms of measurement suggests that the
recall approach applied to a more remote time period may also yield
relatively accurate results. This approach could be further validated
if stored biological samples from the same period were available, but
the limitations for the use of stored samples described on page 17
would also apply here.
~ Food composition data bases should be improved with respect to
information on both nutritive and nonnutritive constituents and on
regional and seasonal variations in composition. The current data base
lacks information on the components of fiber, essential trace elements
(e.g., selenium), nonessential trace elements (e.g., cadmium), and food
additives.
o In future studies, greater attention should be given to food
preparation and storage. These two processes can result in the produc-
tion or modification of the nature and amount of a variety of dietary
components that present a potential risk for cancer (e.g., aflatoxin
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16 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
contamination during storage of grain or production of mutagens during
cooking).
· Better data are needed on long-tern trends in the composition of
average national diets. On a regular basis, cross-sectional infonma-
tion should be collected from representative samples of the U.S. popu-
lation through surveys such as the annual Health and Nutrition Examina-
tion Surveys conducted by the National Center for Health Statistics,
Department of Health and Human Services. The accumulated data can then
be correlated with trends in cancer incidence. Information on such
trends can also be obtained by repeated measurements of intake at well-
spaced intervals among the subjects in prospective cohort studies. The
resultant data will provide information not only on the changing pat-
terns of eating during a lifetime but also on the reproducibility of
the dietary assessment method used.
Types of Epidemiological Study
Each of the several epidemiological study designs offers particular
advantages in certain circumstances (e.g., rare cancers can be examined
in case-control studies but seldom in cohort studies). On the other
hand, each of these designs has inherent limitations, as noted in the
first report (National Research Council, 1982~. For this reason, stud-
ies of all types, if appropriately applied, will be of value in further
investigations of diet and cancer in human populations.
· Correlation studies, if well designed, can continue to provide
useful information on the relationship between diet and cancer. When-
ever possible, these studies should be based on exposure data collected
directly from individuals rather than on per-capita consumption esti-
mates. When sufficient information is available, they should also be
based on morbidity rather than on mortality data, since the latter are
influenced by survival patterns and can be misleading (National
Research Council, 1982~.
O Consideration should be given to carrying out case-control
studies in populations such as those with unusual dietary habits or
levels of exposure as well as those at unusual risk for specific
cancers. International, collaborative case-control studies should be
encouraged, but the sample size in each geographical area should be
sufficiently large to permit separate analysis of the data. This would
enable investigators to replicate the findings in diverse settings
using a common methodology. To the greatest extent possible, the
determination of sample sizes in all case-control studies should allow
for meaningful examination of particular subgroups, statistical control
of all important confounding factors, and the examination of interac-
tions between separate dietary components or between dietary and
nondietary factors. In estimating sample size requirements, investi-
gators need to recognize that errors in measurement of exposure
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Epidemiological Methods 17
necessitate an increase in the sample size to demonstrate statistically
significant associations. Case-control studies have limited value for
investigations based on biochemical indicators of exposure, since these
markers may be altered by the disease in the cases. However, clues to
the possible biochemical markers of exposure may be obtained from such
studies.
~ More cohort studies of diet and cancer are needed. This is the
most suitable approach for investigations based on biochemical indi-
cators of dietary exposures. Cohort studies are best carried out in
populations at high risk for diet-associated cancers, where representa-
tive dietary data can be readily obtained and where long-term follow-
up can be aided by population-based cancer registries and good vital
statistics data for end points. Whenever possible in such studies,
biological samples (such as serum, urine, and feces) should be col-
lected and stored for later biochemical analysis of specimens from
controls and from subjects who subsequently develop cancer. Long-term
storage also enables the investigators to incorporate newer hypotheses
or analytical procedures into the study at a later time. However, the
utility of stored biological samples is limited because the samples
reflect only one or possibly a few finite periods in the individual's
life and because the samples may deteriorate during storage and han-
dling. Because cohort studies are expensive and of very long dura-
tion, a search should continue to be made for existing cohorts for
which there is relevant information on dietary exposures. In designing
cohort studies, the sample size should be sufficiently large to ensure
that an adequate number of cases will be identified, and their selec-
tion should be based on considerations discussed above for case-control
studies.
· Intervention studies (trials) have many advantages, but they
should be considered only when supporting evidence from other types of
studies is strong and only after the risks involved have been carefully
weighed. For ethical reasons, these studies will have to be limited to
examinations of putative protective factors or of the effects from
reduced exposure to risk factors. Several trials of specific microcon-
stituents (e.g., 6-carotene) have recently been initiated. There is
also a great need to study the effects of specific foods and food
groups (e.g., dark green and deep yellow vegetables, and those of the
genus Brass~ca--members of the cabbage family), since the biological
effectiveness of a food component is probably affected by the presence
of other constituents in the diet, and since the effects observed in
epidemiological and experimental studies may be due to a mixture of
different inhibitors of carcinogenesis. To obtain more definitive
data, the randomization procedure in these studies should 1oe based on
individuals rather than on groups, whenever possible.
Analysis of Data
· Analysis of data from epidemiological studies should include
examinations of specific foods and food classes, even when the hypothe-
OCR for page 18
18 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH
sis pertains to nutrients. Relationships involving nutrients from
selected groups of foods or involving nonnutritive components of foods
might be uncovered by thi s approach.
· Studies should be conducted to determine the limitations of the
logistic regression model for the analysis of epideraiological data on
diet and cancer. The extent to which the actual data in a study can
deviate from the theoretical distribution and still yield meaningful
results should be defined. Moreover, since many of the dietary and
nondietary factors in studies on cancer are highly intercorrelated,
efforts should be made to explore statistical methods that are less
sensitive to collinearity than is multiple logistic regression analysis.
Fi nally, statistical techniques need to be developed to describe snore
accurately the various forms of interaction among dietary variables.
Representative terms from entire chapter:
dietary exposures
