In the final session of the workshop, five speakers from a range of backgrounds presented closing remarks. John Suttie of the University of Wisconsin and chairperson of the workshop planning committee led off. He was followed by Dr. Molly Kretsch of the Agricultural Research Service (ARS) of the U.S. Department of Agriculture (USDA) and a co-chairperson of the Federal Dietary Reference Intakes (DRIs) Research Synthesis Subcommittee; Dr. Hasan Hutchinson from the Institute of Nutrition, Metabolism and Diabetes of the Canadian Institutes of Health Research; Dr. Catherine E. Woteki from Mars, Inc. and a former staff director of the Food and Nutrition Board and former chairperson of the Food and Nutrition Board; and Dr. Dennis Bier, an academic researcher from the USDA Children’s Nutrition Research Center at Baylor University, Texas.
COMMENTS BY DR. SUTTIE
This presentation included a series of points that address the question, What did we learn here today?:
Much research that related to the research recommendations has been conducted—more than some of us realized.
In some cases, sufficient new information is available to warrant reexamination of selected DRIs in the near future.
Some problems of the past DRI process have become apparent retrospectively and will require careful attention in the future. For example, in a number of cases the Recommended Dietary
Allowances (RDAs) and the Tolerable Upper Intake Levels (ULs) are not compatible.
Limitations of the Adequate Intake (AI) were raised by a number of speakers. In Dr. Suttie’s view, the AI is based on a concept that is useful in situations where data are insufficient to set an Estimated Average Requirement (EAR), but the usefulness of the AI has been limited by lack of a common definition. The AI was established in different ways for various nutrients, and the lack of consistency causes some problems. Over the course of 10 to 12 years, new challenges have arisen. For example, should the EARs now be based more on criteria that relate to health promotion? In many ways, the use of such criteria is much more difficult than focusing on biological assays.
One cannot underestimate the impact that the rapid move to genomics will have on the DRI process. Within a few years, it will be relatively inexpensive for people to have their genome searched and at least a few hundred markers identified. Some of those markers will identify rather drastic changes in nutrient metabolism or in the nutrient requirement. How should this type of information be incorporated in the DRI model? How do we make sure that we cover the subpopulations that have higher requirements without moving to higher recommendations that potentially could have some undesirable effects?
More information is available now on how the DRI process can be used for planning and how it is used by different agencies to develop different programs. Some problems have been identified that need to be addressed more explicitly than was done in the first reports.
Recommendations for infants and children definitely need attention. Problems with extrapolations are of concern. Since the methods to study nutrient requirements in adults typically have involved invasive techniques, studies of children pose difficulties. Therefore, addressing the requirements of infants and children will require much more thought in the future. One possibility would be to have a committee address the problem of establishing requirements for infants and children across the range of nutrients.
The difficulties in dealing with ULs need to be addressed, especially since ULs are expected to become more important in the future.
COMMENTS BY MOLLY KRETSCH
A new collaborative process between U.S. and Canadian government sponsors and with sponsors and the Institute of Medicine was initiated with this project. The U.S. Federal DRI Steering Committee is very pleased with the results of this new way of working. This presentation included a review of the goals of the project, progress made, next steps, and cross-cutting research needs.
Goals and Progress Made
Box 13-1 shows a summary of the goals and of progress made. Follow-up activities after this workshop involve the database, a report, and funding.
Goals of the DRI Research Synthesis Project and Progress Made
The Federal DRI Steering Committee would like to see the DRI Research Synthesis Database become a “living database”—one that would encompass not only the DRI research recommendations but also the progress made toward filling these research gaps. Toward this end, new software could make it possible to link these research recommendations to the research portfolios of federal agencies. Such a linkage would make it easier to identify progress and help coordinate research in the United States—and possibly between the United States and Canada as well. At this time, resources for maintaining a “living database” have not yet been secured, but this is a possibility to be explored.
The workshop summary should be available in October 2006. The workshop’s information will help inform the research planning process for the Federal DRI Steering Committee agencies. For example, this workshop and the database are very timely for the ARS, which does considerable research on human nutrient requirements. Planning for the next 5-year research cycle for the ARS Human Nutrition Program starts in January 2007. The workshop, together with other input from stakeholders, will help inform the research planning process.
Revising the DRIs must be continued. However, some perceive that the study of nutrient requirements is simply filling gaps and is of limited importance. Thus, not only is there a need for dedicated funding, but we need to change perceptions regarding the nature and importance of this research. How can we engender interest in this field by young researchers? Thought needs to be given to how we can boost funding for and interest in future DRI research.
Cross-Cutting Research Needs
One cross-cutting research need that has been emphasized during the workshop is continued work on food and dietary supplement composition databases. Two of the speakers acknowledged clear research advances stemming from advances in food composition data, specifically with regard to choline and vitamin K. On the other hand, two other speakers indicated that research is lagging because of deficiencies in food composition data, especially for vitamins E and D. Also, the application of metabolomics methodology to food composition analyses, which was mentioned by Dr. Ordovas, has been initiated by the USDA Food Composition Laboratory at Beltsville, Maryland. Other cross-cutting research needs include methodologies for the assessment of dietary intake, physical activity, and biomarkers of exposure. All these cross-cutting research needs fall in the area of methods, and frequently this area receives limited funding.
In her closing comments, Dr. Kretsch acknowledged the efforts of the members of the Workshop Planning Committee, the Federal DRI Research Synthesis Subcommittee and its Canadian counterparts, and the federal sponsors who provided funding for this project.
COMMENTS BY HASAN HUTCHINSON
This presentation included a review of objectives for the DRI Research Synthesis, types of knowledge gaps in general and for Canada, and selected uses of the DRI Research Synthesis in Canada.
The Canadian Institutes of Health Research’s top three objectives for the DRI Research Synthesis project were essentially the same as those presented by Dr. Kretsch. In addition, it is anticipated that the project would inform future iterations of the DRIs, methods of organizing research recommendations in future reports, and the prioritizing of future
research related to nutrient requirements. Certainly, prioritization is going to occur at the agency level, with consideration given to mandates and stakeholders.
Knowledge Gap Themes
Dr. Hutchinson highlighted the following knowledge gap themes:
Requirements of children, pregnant and lactating women, and the elderly—all of which are vulnerable population groups
Individual variation of requirements caused by genetics/epigenetics, lifestyle, environment, and geography
The need for biomarkers that are able to predict functional outcomes and chronic diseases
The need to improve dietary assessments and planning methods, including survey methodology and the food composition tables and databases
Interactions among nutrients
Research gaps that are especially important in Canada include information on how geographical variables affect the vitamin D needs of Canadians, vitamin B12 requirements of the elderly and how they can be met (Canada has no vitamin B12 fortification of foods), and nutrient requirements of children—a need voiced throughout the workshop.
Uses of the Research Synthesis in Canada
The workshop and database have facilitated the identification of research needs and promising future studies. The database is expected to be a very useful tool for researchers and for planning by agencies. Health Canada uses the research gap information to address in-house research needs. Its research program primarily supports the department's policy and risk assessment work. The Canadian Institutes of Health, like the ARS in the United States, is about to enter its next planning phase. Given the importance of this type of research and its application toward policy work and risk work, Dr. Hutchinson anticipates that nutrition research relevant to the DRIs will move forward in the institutes’ priorities. Dr.
Hutchinson expressed support for the idea of coordinating Canadian approaches with those of American colleagues. This might take the form of common funding calls or at least complementary funding calls in the future.
COMMENTS BY CATHERINE E. WOTEKI
This presentation reemphasized some of the points made during the introductory session to provide the context for her discussion of the DRI research recommendations. In particular, the presentation covered selected aspects of the evolution of the DRIs, key questions relative to research priorities, challenges, perspectives on funding, and responsibility for leading the research agenda.
Evolution of the DRIs
As conceived, the DRIs are an evolutionary and iterative scientific synthesis. The conceptual approach that was used for the DRIs was set out in the publication called “How Should the Recommended Dietary Allowances Be Revised?” (IOM, 1994). Key points from that publication are summarized as follows:
Reference values to be included: deficient, estimated average requirement (EAR), recommended dietary allowance (RDA), and an upper safe range of intake
Substances to be included: essential nutrients and what was called “important food components”
The incorporation of aspects from the report Dietary Reference Values for Food Energy and Nutrients for the United Kingdom (COMA, 1991)
The Food and Nutrition Board sought scientific review of its conceptual report through symposia, requests for public comments, and discussions at meetings of scientific societies. The process of developing the DRIs was intended to (1) be a much more open and participatory process than previously had been the case; (2) include a more transparent exposition of the principles, scientific evidence, and derivation of the values; (3) provide more flexibility to address the many uses of the nutrient val-
ues; and (4) develop research recommendations to identify knowledge gaps.
The Food and Nutrition Board had discussed extensively how it could be possible to revise and update selected DRIs and/or other information when new research evidence showed the need for such action. As pointed out in this workshop, such revisions or updates have not occurred. This matter merits much consideration.
Key Questions Relative to Research Priorities
Based on the presentations and discussions of the DRI Research Synthesis Workshop, addressing the following key questions would help to define what the priorities should be for research to be undertaken immediately. They relate to the question: Is the DRI paradigm “right”? That is,
Are the EAR, the RDA, the establishment of AIs and ULs the right values? Conceptually, are these values appropriate for the purposes for which they are being used or need to be used?
Are the methods used to derive these values appropriate with respect to extrapolations and other statistical adjustments, and are they equally applicable to nutrients and to other food substances that have received little attention to date?
Are the risk assessment approaches used to set the UL the most appropriate?
Does the establishment of AIs and Acceptable Macronutrient Distribution Ratios (AMDRs) imply that the paradigm does not fit all nutrients?
Under the current DRI paradigm, the EAR has great importance: exposition of the end point selected is clear, data sets that were used are identified, the EAR is used in establishing the RDA, and the EAR has multiple uses in assessment and planning. This degree of importance may be greater than initially recognized.
If the DRI paradigm is correct, the research agenda priorities are clear. They relate to (1) identifying the valid nutritional status end points for nutrients that have public health importance and that lack an EAR, and (2) collecting sufficient data to set the EAR. If the paradigm is not correct, however, the same questions would remain; but there would be a different emphasis in establishing the priorities.
Assuming that the paradigm is correct, challenges remain. Workshop presenters addressed many of them: methodological issues, studies in infants and children, and incorporating genetic polymorphisms as they relate to nutrient requirements. Additional challenges relate to aspects of evidence-based reviews that are appropriate to setting DRIs and considering important food components that have not been part of this process.
Funding the Research Agenda
Two major factors will affect funding for the nutrition research agenda: the perceived need to address other topics within the research agenda and, even more importantly, all other priorities in the agency budgets and in the federal government budgets in both the United States and Canada. Consequently, an enormous amount might be gained from coordination among the U.S. and Canadian agencies to
establish a mechanism to set priorities,
determine types of research appropriate for the intramural agencies to fund (some research priorities will not be funded by extramural programs),
plan the content of future dietary surveys with an eye toward the future needs for the DRIs, and
develop the food composition analytical methods and data that are essential in establishing DRI values.
Incentives or disincentives for private sector research merit some consideration. Clearly, food companies have provided valuable food composition data. Working relationships have been especially good when a particular company or group of companies has had a special interest in a nutrient. Thus, there can be very good incentives for developing more food composition data and including the private sector in that effort.
Legislation has led to some disincentives, especially as related to dietary supplements. Perhaps, with a different set of incentives, there might be more reason for pharmaceutical companies to invest in answering some of the fundamental nutrition research questions.
As a follow-up to points raised during the workshop, consideration might be given to incentives for developing software both for professional use and for educational purposes and to incentives for formula companies to address some of the questions raised that pertain to requirements of infants.
Responsibility for Leading the Research Agenda
In moving forward, who has responsibility for leading this research agenda? Dr. Woteki stated that, without question, the government agencies do; and the coordinating body that involves research and action agencies in both Canada and the United States holds promise. The Food and Nutrition Board continues to have important roles in the development of the type of research synthesis that has led to the DRIs, as a body for strategic planning in the areas of food and nutrition, and in convening groups that can move the questions forward. Nonetheless, Dr. Woteki takes the position that the major responsibility for implementation of the agenda rests with the funding agencies.
From her current perspective with a major food company, Dr. Woteki reemphasized the importance of the DRIs for public health and for policy applications, and she reemphasized how extremely important it is that the research base be defensible. Quoting Dr. Lindsay Allen, “This is serious stuff, and it deserves investment.”
COMMENTS BY DENNIS M. BIER
This presentation addressed research opportunities, highlighting those related to new techniques. In addition, it briefly covered biomarkers for foods, ethical issues, and a systematic approach for setting ULs. In his opening remarks, Dr. Bier spoke about the logo of the Children’s Nutrition Research Center at Baylor College of Medicine. That logo shows happy children eating. The joys of food provide a reason to solve some of the research questions raised—to allow people to enjoy what they eat.
To move the research forward, there is a need to communicate the excitement. For example, what is the real relevance of finding the answers to the questions? How can the research questions be framed in a way that gets agencies and researchers interested in them?
One approach would be to use the new tools (genomics, epigenomics, proteomics, and metabolomics) to capture the excitement in the questions and bring young people into the field. There is an urgency to determine the relevance to human health of some of the epigenetic regulation issues with dietary intake. At the time the recommendation was made to fortify grains with folic acid, for example, the epigenetic effects of methyl donors were unknown and did not enter the discussion at all.
Another approach to generate interest is to build on the experience of the clinical pharmacology specialty and to develop a new specialty called clinical nutricology. For example, clinical pharmacologists showed that (1) pharmacokinetics had relevance to direct human health and behavior in the use of drugs, (2) genotypes altered the metabolism of drugs in a way that was relevant to human beings, and (3) the interaction among drugs was important to their effects in human beings—in fact, components of diet such as grapefruit juice were important to the metabolism of drugs. The parallel content of clinical nutricology can be seen simply by changing the word drug to nutrient in the example above.
Biomarkers for Foods
Although the workshop gave much attention to the need for biomarkers and status indicators, Dr. Bier emphasized that there is also a need for biomarkers in foods. Food biomarkers could make it possible to know, for example, whether someone ate broccoli or not. Developing biomarkers in food could lead to a better independent assessment of dietary intake.
Participants raised a number of ethical issues during the workshop. Addressing them is extremely important to make it possible to conduct experiments related to the nutritional needs of children. For children, Dr.
Bier views the issue of safe study design to be of greater importance than developing the justification for the research. For studies relating to the ULs, developing the justification appears to be more important than the study design. Citing a specific example related to research relevant to ULs for amino acids, Dr. Bier indicated that, despite being given specific instructions on information needs for a symposium on amino acid science, only a small proportion of the invited scientists provided information on why they need to do specific studies.
Systematic Approach to a Decision Tree for Setting ULs
As his final comment, Dr. Bier stated that a systematic approach to a decision tree for setting ULs, as proposed by Dr. Sanford Miller, would be very helpful in improving the process for setting ULs.
No formal discussion occurred at the end of the session. However, earlier in the workshop, discussants raised points pertinent to the appropriateness of the DRI paradigm and methods for obtaining answers to research questions. These points are summarized below. These comments are not to be interpreted as consensus comments or recommendations.
The General Model
The model suggests a level of precision that we are unlikely to have.
The model is only as good as the indicators being measured. EARs were based on indicators having acceptable data, not on optimum nutrition. The model poses problems when an aim is chronic disease prevention.
A new DRI committee may be helpful to address methods for setting DRIs for infants and children.
The paradigm needs to be enlarged to include adaptations for DRIs for people who are ill. The DRIs are useful as long as illness does not change the requirement, but there has not been a
systematic examination of conditions for which changes in DRIs would be advisable. Considerable work has been done in medicine to determine the effects of specific conditions on nutrient requirements.
The appropriateness of the model was questioned for food components that have not yet been addressed (e.g., phytochemicals).
Method Used for Setting the RDA
Several discussants pointed out that variability in requirements is assumed rather than known for most nutrients. Setting the RDA at four rather than two standard deviations above the EAR, as suggested by Dr. Hathcock, would cover a higher percentage of the population and might make sense from the viewpoint of not missing 2 to 3 percent of the population. In some cases, however, a higher RDA could make it unrealistic to achieve the RDA using traditional foods. The people who are most likely to take multivitamin-mineral supplements are the people with the highest nutrient intakes, leading to intakes that might be high enough to be of concern (see third bullet in this set).
Considerable discussion centered on approaches to cover a substantial proportion of the population with a polymorphism: (1) increase the RDA or (2) recommend genetic testing and individualize the requirement? Dr. Stover clarified that individualization of requirements based on results from genetic testing probably would not be necessary as long as there is enough room between the RDA and the UL. In setting the RDA, one would include consideration of the genetic variance, similar to what was done in setting the vitamin B12 RDA for persons age 50 years and older. In theory, there is no need to individualize requirements unless one person's requirement is another person's UL. Dr. Rosenberg commented that bimodal distributions associated with the presence of polymorphisms, if not embedded in the population, might result in a need to change the model. He believes however, that the variability may be embedded in the variability of the population.
Dr. Zeisel believes that the measurement of single nucleotide polymorphism (SNPs) will be relatively inexpensive (perhaps $100 to obtain 50,000 SNPs) and widely available within 5 years. Information about SNPs is valid over one’s lifetime. Thus, the practice of nutrition may well involve telling individuals that they have certain SNPs that increase their requirements. Dr. Zeisel would like the DRI process to consider
setting the RDA at a level that covers essentially everyone but also noting that the RDA would be lower for people without the SNPs. Several discussants expressed concern about possible side effects from recommending too high an intake. For example, if the nutrient affects perinatal programming, there could be unforeseen adverse consequences of treating everyone with a large dose.
Discussants mentioned a variety of ways in which the DRIs can lead to communication problems, such as the following:
Lack of coverage of a large number of people in a country assuming that the RDA covers 97 to 98 percent of the population—the RDA may be viewed as too low
Needs of a given individual may be much lower than the RDA— the RDA may be viewed as too high
High percentages of the population who have intakes of selected nutrients that fall below the EAR—the EAR may be viewed as too high
Different meanings of the AI
Lack of correspondence between the carbohydrate RDA and AMDR
Finding Answers to Questions
Dr. Joanne Guthrie of the Economic Research Service (ERS) of the USDA commented that resources are available for testing some of the methods proposed in the DRI Assessment Report (IOM, 2000a) and the DRI Planning Report (IOM, 2003a). Relevant databases are available. The Food Assistance and Nutrition Research Program of the ERS and grants programs in some other agencies support research of this type. Dr. Guthrie encouraged researchers to collaborate with new partners, such as biostatisticians, to make use of the databases. Understanding distributions by analyzing existing data, for example, would be a good first step.