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- ~ 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.
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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.
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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.
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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.
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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
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6 EVOLUTION OF EVIDENCE FINDINGS Confidence in nutrientódisease 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.
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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.
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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.
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