The Development of DRIs 1994-2004 Lessons Learned and New Challenges: Workshop Summary (2008) / Chapter Skim
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2 Conceptual Framework for DRI Development: Session 1
2 Conceptual Framework for DRI Development: Session 1
Pages 11-62
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Food and Drug Administration (FDA) , explored considerations when applying the DRI framework to chronic disease endpoints.
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Dr. Elizabeth Yetley, a Senior Nutrition Research Scientist with the Office of Dietary Supplements at the National Institutes of Health, discussed whether risk assessment is a relevant organizing structure for the DRI development process.
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However, these major changes to the DRI development process have both pros and cons. Reference Values Expressed: EARs, RDAs, and AIs The Estimated Average Requirement (EAR)
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. The study committees encountered numerous data gaps.
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Applicability of the Framework to All Nutrient Substances The framework did not "fit" well for establishing reference values for fat and macronutrients. Such substances are not essential and have no beneficial role, except for essential fatty acids and amino acids.
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That is, the EER was based on energy balance (no weight gain) , not on reduction of disease risk -- a different type of paradigm than originally envisioned.
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While the science for setting DRI values takes precedence and should not be compromised because of real or perceived inconsistencies about what the population is eating, DRI reports may need to include more discussion about these problems when they occur. While decisions about the use of DRIs for nutrition labeling are outside the purview of the DRI development process, related issues raise interesting questions, such as what to do if there is no DRI (e.g., trans fat)
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Consistent guidelines should be developed for setting uncertainty factors and for rating the overall evidence for a DRI value, based on the strength of the data, the consistency, the public health relevance, and the applicability to the person or persons of interest. Usefulness of the DRI Framework and Conclusions The DRI framework has often been found not to be useful for planning for groups, such as WIC, primarily because too many assumptions have to
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CASE STUDY: APPLYING THE DRI FRAMEWORK TO CHRONIC DISEASE ENDPOINTS Presenter: Paula Trumbo The conclusion that the "reduction in risk of chronic disease is a concept that should be included in the formulation of future RDAs where sufficient data for efficacy and safety exist" (IOM, 1994) had a notable impact on the DRI development process.
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Setting EARs Based on Chronic Disease Endpoints Of the nutrients that were assigned reference values related to nutritional adequacy, only five were based on chronic disease endpoints. While the DRI study committees were encouraged to set an EAR rather than an AI because of the limited utility of the AI for assessment purposes, the reference values related to nutritional adequacy that were developed for nutrients based on chronic disease endpoints were all AIs.
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If the EAR is to be based on chronic disease risk reduction rather than reduction of the risk of nutrient inadequacy, then the definition of the EAR would be the nutrient intake level to reduce the risk of chronic disease in half the healthy individuals in a particular subpopulation, or to achieve an absolute risk reduction of 50 percent (where absolute risk is the probability of getting a disease over a certain time and is affected by the relative risk of a particular risk factor, such as intake of an individual nutrient)
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For instance, although one of the endpoints considered for calcium was fracture risk, the DRI study committee chose to reject the observational data on fracture risk because of the influence of confounding factors. One reason given for not setting an EAR for vitamin D was that it could not account for the contribution of sunlight exposure, which is affected by a wide variety of factors (this would also influence reference values related to nutritional adequacy based on essentiality)
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Therefore, the definition of an EAR does not allow for the use of chronic disease risk reduction in setting recommended intake levels, which is an opinion shared by many who have worked closely with the DRI process. Setting ULs Based on Chronic Disease Endpoints Chronic disease endpoints have also been used to set ULs.
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Implications for Reference Values Related to Nutritional Adequacy The challenges of setting reference values related to nutritional adequacy based on chronic disease risk reduction were recognized when the framework for revising the RDAs was being considered. A 1994 IOM report stated that "If reduction of risk of chronic disease is to become a criterion in the development of future RDAs, many questions must be faced" (IOM, 1994)
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. Along with that, the reference values related to nutritional adequacy based on chronic diseases would be expected to be greater than reference values related to nutritional adequacy based on the daily requirement for many essential nutrients (e.g., if an RDA for potassium had been set based on essentiality, it would have been much lower than the AI of 120 mmol/day based on chronic disease risk reduction)
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The study committee defined dietary antioxidant as a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans. In addition to vitamin C, vitamin E, and selenium the study committee examined data about β-carotene and other carotenoids (α-carotene, β-cryptoxanthin, lutein, lycopene, and zeaxanthin)
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The study committee wanted scientifically valid experiments. It was looking to measure relevant biomarkers that were significantly related to the disease endpoints, were based on in vivo experiments, and played a role in health.
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. For children 1–3 years, an iodine balance study on nutritionally rehabilitated children 1.5–2.5 years of age (Ingenbleek and Malvaux, 1974)
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Conclusion The major challenges experienced in setting reference values using non-chronic disease endpoints result from the existence of a continuum of adequate levels of intake reflective of the possible endpoints that could be selected. This continuum is different for different nutrients.
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The initial focus included macronutrient recommendations, the target population for DRIs, the ability to achieve DRI intake levels through typical diets, and the value in constituting a single study committee to develop both EARs/RDAs and ULs. Macronutrients One participant noted that quantitative reference values were not given in the reports on macronutrients; rather, advice such as "intake should be as low as possible while consuming a nutritionally adequate diet" was provided.
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The discussion continued, focusing on supplementation as a solution, noting specifically the possible role of targeted supplementation. These comments led one participant to remark on the value of tasking a single study committee with responsibilities for both EAR/RDA and UL development because these reference values at some point become highly related.
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He also noted the need to focus on the way changes in nutrient intake impact biomarkers as well as nutrient interactions. Another participant preferred the use of physiological endpoints rather than chronic disease endpoints.
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The DRI process should not attempt to provide derived reference values for all applications. Only the core values that are absolutely needed should be derived.
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Based on NHANES III protein intake data as used in the DRI reports to describe distributions of usual intake, I conducted dietary assessments using the methods provided as guidance for users. When the prevalence of apparently inadequate protein intakes as grams per kilogram body weight per day were considered by age, gender, and usable protein (taking into account likely digestibility and amino acid score, both of which fall as vegetable source protein increases in the diet [IOM, 2002/2005]
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We are left with three different estimates of the apparent adequacy of protein intakes among adults in the United States. These range from the inference of the existence of a major public health problem in an identifiable subgroup of the population, to satisfaction that protein intakes are adequate for nearly all persons.
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bCV = coefficient of variation. cUL = tolerable upper intake level.
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We must always remember that the whole purpose of any DRI process must be to come up with evidence-based information that can be applied to real life. Perspective II Presenter: Janet King My perspectives on the DRIs come from two experiences: as chair of the FNB in 1994 and as chair of the Dietary Guidelines Advisory Committee in 2005.
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2-8.eps Several implications of incorporating chronic disease prevention into the DRIs were unanticipated: • It immediately expanded the science base. We learned that endpoints for reducing the risk of chronic disease have multiple dietary deter minants, that the relationship between specific nutrients and disease endpoints varies widely in a population, and that the quantitative information needed to relate nutrients, foods, or food patterns to chronic disease is extremely limited.
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No data were available on upper protein intake levels; the value was actually derived from the AMDRs for carbohydrates and fat, which led to two different sets of protein recommendations. It is becoming apparent that the DRIs and the Dietary Guidelines for Americans have different primary purposes.
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Lichtenstein The formal use of SEBRs as part of the DRI development process is intended to supplement, rather than displace the efforts of the IOM study committees and in many cases allow them to focus their limited time on interpreting the available data rather than identifying and collating the information. Therefore, it is helpful to first address general issues about what SEBR can and cannot be expected to do.
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An example would be: What is the efficacy or association of omega-3 fatty acids in preventing incident CVD outcomes in people without known CVD (primary prevention) and with known CVD (secondary prevention)
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Differences Between SEBR for Clinical Medicine and SEBR Needed for DRI Development The data available to answer clinical medicine questions tend to be more straightforward than issues related to nutrient requirements. For drugs (e.g., statins)
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Finally, we are just learning how to deal with genetic polymorphisms in nutrient metabolisms, as well as how to address nutrient requirements for essential versus nonessential nutrients and energy-containing versus non-energy-containing nutrients. These are likely to require different approaches to the SEBR process.
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4.8 g/d * Abbreviations: N = number of subjects; RR = relative risk; CI = confidence interval; g/d = grams per day; nd = no data.
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CONCEPTUAL FRAMEWORK FOR DRI DEVELOPMENT 45 Cardiac Death Sudden Death Non-Fatal MI All Strokes Control Control Control Control Group Group Group Group Event Event Event Event Rate RR Rate RR Rate RR Rate RR (%)
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Yetley This presentation considers whether it would be useful to extend the risk assessment framework from its current use as an approach for deriving ULs to future use in deriving the EARs as well as the AIs and AMDRs. Risk assessment is not a specific methodology, but rather an organizing framework for scientific assessments.
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Second, as it developed the risk assessment framework, the NRC recognized that it would usually have incomplete data, and that uncertainties would need to be dealt with through documentation and use of expert scientific judgment. This need for dealing with evidentiary uncertainties is also true in deriving nutrient reference values.
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The scientific assessment would be equivalent to a DRI study committee. The risk assessment process differentiates between the roles and responsibilities of the risk assessment study committee and the sponsors who have requested the risk assessment.
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For example, the committee would describe the nature of the risks associated with inadequate or excessive intakes and the percentage of the population exceeding the UL or failing to meet the reference value of adequacy. The risk characterization step also describes the public health implications of these deviations.
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It is recognized that the evaluations may have public health implications, although they often need to be made with evidentiary uncertainties. Risk assessment focuses on user needs by clarifying the information needs, documenting decisions, and describing the public health implications of population deviations from reference values in the risk characterization step.
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Thus, the terminology would need to be revised to apply risk assessment approaches to derivation of reference values for nutrient adequacy. For example, for nutrient risk assessment purposes, the terminology might be changed to "identification of indicators of adequacy (or inadequacy)
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Uncertainty assessments are a critical component in the dose–response assessment step of a risk assessment framework. Derivations of reference values for both inadequate and excessive intakes must deal with uncertainties in the available evidence and describe the nature and seriousness of those uncertainties in their texts.
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Establishing reference values for both inadequate and excessive intakes also often involves extrapolations from a studied group (e.g., adults) to an unstudied group (e.g., children)
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Miller opened with the general observation that although it seems we are asking the same questions from years ago, we are learning to ask better questions. He noted that it is not surprising that study committees appeared to derive their own approach to the problems they faced given the lack of experience, structure, or formal guidance when the DRI process began.
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Thus, SEBRs would not be used to derive DRI reference values; rather, they would be used as one source of data for deriving the reference values. A commenter remarked that SEBRs can be carried out by either paid panel members or unpaid volunteers who "work outside of their day jobs." She then inquired about the professional expertise needed for these SEBR panels as opposed to the DRI study committees, and about the rewards for unpaid volunteers.
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One person noted that death from disease had not been mentioned as a marker for chronic disease risk in the DRI process, even though there may be a reduction in death from disease associated with some nutrients. A participant responded that in the case of DRIs, death is probably not a preferable measure as compared with appropriately validated biomarkers for the advent of the disease state.
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Finally, she pointed out that to apply the values effectively, regulators and government agencies need to understand the process and the approach to decision making used by the study committees. Conversely, sponsoring government organizations bear the responsibility of defining the general questions to be answered through the process of DRI development if the end result is to be useful.
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Furthermore, she suggested that nutrient requirements and chronic disease prevention could be dealt with in separate reports because of the multiple factors that affect the chronic disease endpoints compared with the nutrient requirement endpoints. She agreed with the conclusion that a single endpoint should be used for age/gender groups.
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Assuming this hurdle is passed, the "biology of the nutrient" is the next component to consider, because the inability to specify the biological workings of the nutrient would be limiting in establishing meaningful reference values. From this point, the instruments and organizing approaches we have at our disposal to address the tasks become the focus.
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One participant expressed concern that numbers developed in the face of limited data appear to take on the same level of significance and credibility as other more well-founded reference values. He recalled that when AIs were first discussed, there was some mention of adding table footnotes or color codes or using faint print as a way of communicating the level of confidence associated with the numbers.
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If the approach for deriving these could be harmonized, different countries could, within the context of their own public health protection considerations, derive their own relevant reference values. Also with respect to harmonization, an audience member suggested that more international expertise should be included in the DRI process so countries could learn from each other, share information, and reduce costs.
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62 THE DEVELOPMENT OF DRIs 1994–2004 apparent lack of an overall framework for the DRIs. While recognizing the value of collaboration, participants disagreed with the intimation that there was no overall framework for the North American DRI process.
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