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OCR for page 1
- ~
Executive Summary
Diet is vital to health promotion and disease prevention. Several decades of
impressive evidence have documented that in addition to preventing nutrient
deficiency diseases like scurvy and rickets, dietary practices can also help to
prevent other diseases, including cardiovascular disease, diabetes, osteoporosis,
dental caries, birth defects, and potentially some types of cancer. Although con-
sumers, scientists, entrepreneurs, and policymakers want evidence on potential
new relationships between nutrients and chronic diseases as soon as possible,
conclusive evidence is typically elusive. Gathering sufficient knowledge to draw
conclusions about causal relationships, especially between a given nutrient and a
disease, remains a challenge.
Can the scientific method be accelerated by identifying patterns of evolving
evidence to yield confirmed findings for public policy? Can patterns of research
evidence be observed in identified nutrient~isease relationships that can be
applied to potential nutrient-disease relationships earlier in the research process
and benefit the public by enabling earlier application of such knowledge? Can
unpredictable elements be identified to provide caution to consumers? The
Committee on Examination of the Evolving Science for Dietary Supplements of
the Institute of Medicine's Food and Nutrition Board was convened to address
this topic.
OCR for page 2
2
EVOLUTION OF EVIDENCE
THE COMMITTEE'S APPROACH
The committee was directed to review, retrospectively, selected case studies
of diet and health relationships that were relevant to dietary supplements and
identified as important in the National Research Council report, Diet and
Health: Implications for Chronic Disease Risk (D&H) (NRC, 1989~. It was then
to determine the extent to which subsequent scientific evidence from the peer-
reviewed literature used in published reports from the Dietary Reference Intakes
(DRI) series (IOM, 1997, 1998, 2000a, 2001) either agreed with the preliminary
evidence used to support the relationship identified originally in the 1989 review
or significantly modified the original hypotheses and preliminary conclusions.
The committee's analysis was to include characteristics of research with appar-
ent high probability of predicting future confirmation by new science in support
of a diet and health relationship. It also was to consider characteristics of infor-
mation useful to consumers that would allow them to make scientifically in-
formed judgments about the role that a specific food component or nutrient
plays in health.
The committee based its analysis only on evidence cited in the D&H report
and in nutrient-specific DRI reports published by March 2001. The DRI reports
were: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin
D, and Fluoride (IOM, 1997~; Dietary Reference Intakes for Thiamin, Ribofla-
vin, Niacin, Vitamin B6, Folate, Vitamin By, Pantothenic Acid, Biotin, and Cho-
line (IOM, 1998~; Dietary Reference Intakes for Vitamin C, Vitamin E, Sele-
nium, and Carotenoids (IOM, 2000a); and Dietary Reference Intakes for
Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Man-
ganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc TOM, 2001~. The
committee was aware of, but did not include, evidence published since release of
the relevant DRI reports because that was not part of its charge.
Because the D&H and DRI reports were prepared for different purposes,
precise comparison of evidence was sometimes difficult. The D&H report was
an "in-depth analysis of the overall relationship between diet and the full spec-
trum of major chronic diseases" (D&H, p. 4~. It was intended to move beyond
assessment of dietary risk factors for single chronic diseases and address the
complex task of determining how these risk factors influence a number of
chronic diseases. The intended outcome of the assessment was recommendations
for dietary patterns that would reduce risk for chronic disease. The DRI reports
present "reference values that are quantitative estimates of nutrient intake to be
used for planning and assessing diets for apparently healthy people" (IOM,
2000a, p. 2~. In spite of differences in purpose, the D&H and DRI reports, sepa-
rated by a decade or more, are deliberative reviews of evidence about many nu-
trient~isease relationships, and the committee determined they could be used in
a qualitative description of selected case studies and an assessment of possible
patterns in relationships.
OCR for page 3
EXECUTIVE SUMMARY
3
To accomplish its task, the committee developed and applied a qualitative
approach to select nutrient-disease relationships (dyads), to determine the level
of confidence in a positive relationship (accepted, promising, uncertain, or no
relationship), and to examine differences in levels of confidence between the
two reports (increased, decreased, unchanged, or not in D&H). Fourteen dyads
were selected and classified, including three that were discussed only in a DRI
report (see Box ES-1~. The committee used the classification as a way to sum-
marize the evidence as described in each report. It is not intended as a recom-
mendation for or against increased consumption of a nutrient.
The evolution of evidence is described in Chapter 2 of this report. The
committee prepared a tabular summary of types of evidence in the D&H and
DRI reports to assess whether there were patterns of evidence that predicted an
increased, decreased, or unchanged level of confidence in a positive relation-
ship. The committee's findings and conclusions were based in large part on its
review of the evidence as summarized in Table ES-1.
OCR for page 4
4
EVOL UTION OF EVIDENCE
TABLE ES-1 Change in Confidence in a Positive Relationship by Type of
Evidence for Nu~ient-Disease Dyads
Types of Evidence in D&H
and DRI Reportsa
Animal Mechanistic
Change in
Confidences
Increased
A ~ A+c
UP A
UP A
Decreased
P ~ No
P ~ U
UP N
Unchanged
US P ~ U
US U
US U
US U
US U
Dyad
Not in D&H
A
P
P
Fluoride and dental caries
Calcium and bone status
Vitamin D and bone status
carotene and lung cancer
Vitamin C and gastric cancer
Vitamin E and cancers
Vitamin E and CHDf
Vitamin C and colds
Folate and cervical dysplasia
Phosphorus and bone status"
Chromium and diabetes
Folate and neural tube defects
Folate and colorectal cancer
Vitamin E and prostate cancer
O
o
o
o
o
o
o
o
o
O
o
o
O
O
O
0 = Diet and Health: Implications for Reducing Chronic Disease Risk (D&H) report
(NRC, 1989), ~ = Dietary Reference Intakes (DRI) reports (IOM, 1997, 1998, 2000a,
2001~. See text for description of types of studies.
h A = accepted, P = promising, U = uncertain, N = no relationship. Some animal and
mechanistic studies may have been cited in review articles in the DRI reports.
c Indicates extension to include adults, not just children.
Confidence changes from promising to uncertain for diet and from uncertain to no
relationship for dietary supplements.
OCR for page 5
EXECUTIVE SUMMARY
Observational
Clinical Trials
Small Large
Case Control Cohort Randomized Randomized
Retrospective Prospective Nonrandomized ( 1,000)
O ~ O ~ O O
O ~ O ~ O ~ O
O ~ O O
O
o
O
o
O ~
O O
O ~ O
O
O
O ~ O
·
·
e Except prostate cancer.
f CHD = coronary heart disease.
g For phosphorus, the D&H and DRI reports did not include any studies that directly
assessed the effect of dietary intake of phosphorus on bone, but only on phosphorus
absorption or serum phosphorus. In the DRI report, for young children only, data on
measures of whole body bone mineral content were used to estimate accretion of
phosphorus in the body during growth
OCR for page 6
6
EVOLUTION OF EVIDENCE
FINDINGS
Confidence in nutrient—disease relationships can change, often in unex-
pected directions.
An important finding is that preliminary evidence in support of a nutrient-
disease relationship was often not confirmed. Neither promising relationship
from the D&H report (~-carotene and lung cancer, vitamin C and gastric cancer)
was subsequently accepted in a DRI report. Of eight uncertain dyads from the
D&H report, two were subsequently found to be accepted (calcium and bone
status, vitamin D and bone status), one was found not to be a relationship (vita-
min E and cancer [excluding prostate cancer]), and five remained uncertain (vi-
tamin E and coronary heart disease [CHD], vitamin C and colds, folate and cer-
vical dysplasia, phosphorus and bone status, chromium and diabetes). High-dose
Q-carotene and lung cancer in smokers is illustrative. An impressive body of
evidence, including numerous observational studies, suggested that increased
intake of foods rich in p-carotene might reduce the risk of developing lung can-
cer. This appealing hypothesis was evaluated by testing high-dose )-carotene
administration in three large-scale, long-term trials, two of which focused on
populations at high risk for lung cancer. In contrast to expectations, supplemen-
tation with Q-carotene significantly increased the incidence of lung cancer in the
two studies that enrolled persons from high-risk populations. In the third trial,
involving male physicians, Q-carotene supplementation had no significant effect.
Hence, not only was confidence in the putative benefit of p-carotene reduced,
but also the direction of the relationship changed because the available evidence
suggested that Q-carotene supplementation may increase the risk of lung cancer
in high-risk populations.
No pattern of evidence clearly predicts change in the confidence of relation-
ships, particularly those initially deemed uncertain or promising.
The evidence cited for each nutrient-disease dyed was heterogeneous. The
committee could not identify any pattern of evidence that consistently predicted
subsequent change in the level of confidence. The committee observed three
instances in which confidence in a relationship decreased from the D&H report
to the DRI report (~-carotene and lung cancer, vitamin C and gastric cancer,
vitamin E and cancer [except prostate cancers. In each instance, a common
characteristic was an absence of trial citations (even a small trial of less than
1,000 participants) in the D&H report and the presence of trial citations in a DRI
report. The case studies suggest that there is a tendency for large trials to be de-
veloped when smaller trials are promising, but the outcome of larger trials re-
mains unpredictable. Even the citation of small clinical trials in the D&H report
did not predict the nature of the relationship in a DRI report.
OCR for page 7
EXECUTIVE SUMMARY
7
Large randomized trials have the greatest impact in changing the level of
confidence in a nutrient~isease relationship.
Not surprisingly, large clinical trials were cited for only two dyads in the
D&H report (fluoride and dental caries, vitamin C and colds) and nine dyads in
the DRI reports (fluoride and dental caries, calcium and bone status, vitamin D
and bone status, Q-carotene and lung cancer, vitamin C and gastric cancer, vita-
min E and cancer [except prostate], vitamin E and CHD, folate and neural tube
defects [NTDs], vitamin E and prostate cancer). The latter two were not men-
tioned in the D&H report. For a dyed considered accepted in either the D&H or
DRI reports, a large clinical trial was cited. In those instances with an increase
or a decrease in the level of confidence in a positive relationship, a large clinical
trial typically was cited in the DRI report. For vitamin E and CHD, considerable
interest developed as a result of prospective observational studies published after
the D&H report that suggested the relationship to be promising. However, large
clinical trials published prior to issuance of the corresponding DRI report failed
to demonstrate a beneficial effect of vitamin E on CHD. On the other hand, large
clinical trials confirmed a role for folate in reducing the risk for NTDs.
The examples of vitamin E and CHD and of vitamin C and gastric cancer
highlight the difficulty in conducting large-scale trials to investigate potential
beneficial effects of single nutrients in reducing the risk for a chronic disease
like CHD or cancer, especially when compared with a condition that develops
over a relatively short time period, like NTDs. Chronic diseases develop over a
long period, typically over decades, and may be affected by various factors at
different times in the disease process. Nutrient trials have been more successful
in establishing causality for conditions that develop over a much shorter time,
such as was the case for trials aimed at preventing NTDs and caries.
Using a case study approach, the committee looked for patterns in types of
studies that could streamline the scientific process and bring useful recommen-
dations and information to consumers more rapidly. It did not find a "pattern
express train." The committee's review of differences in evidence available at
the time of the D&H report (1989) and at the time of the DRI reports (1997-
2001) suggests a skeptical approach to statements about beneficial effects of
single nutrients based on animal, mechanistic, or observational studies alone,
and argues against premature claims of benefit. For consumers, policymakers,
and regulators, the committee's assessment is as follows:
· Large, randomized controlled studies play an important role in establish-
ing the relationship between nutrient intake and the risk of disease. Ideally, con-
sumers should base decisions to change intake of specific nutrients on evidence
from trials. Likewise, regulators and policymakers should rely heavily upon
such evidence to guide nutrient recommendations.
OCR for page 8
8
~ Caution should be exercised in using presuming evidence Tom non-
con~olled studies as the bask far recommendations tar increased intakes of
Varied.
~ Claims Bog nu~ien~isease relationships He more easily made than
scientifically suppoded. Because the implications far public beaRb me so
impodanC camion is urged prior to accepting such claims about supportive
evidence Mom propriety designed, Epically large, clinical Dials.
Representative terms from entire chapter:
bone status
