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Russell R, Chung M, Balk EM, et al. Issues and Challenges in Conducting Systematic Reviews to Support Development of Nutrient Reference Values: Workshop Summary: Nutrition Research Series, Vol. 2. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Mar. (Technical Reviews, No. 17.2.)

Cover of Issues and Challenges in Conducting Systematic Reviews to Support Development of Nutrient Reference Values: Workshop Summary

Issues and Challenges in Conducting Systematic Reviews to Support Development of Nutrient Reference Values: Workshop Summary: Nutrition Research Series, Vol. 2.

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The Office of Dietary Supplements (ODS) requested the Tufts Medical Center Evidence-based Practice Center (EPC) to conduct an exercise to identify the issues and challenges of including evidence-based methods as a component of the process used to develop nutrient reference values (such as the Dietary Reference Intakes [DRI]) issued by the Institute of Medicine (IOM). This work was performed under a task order issued by the Agency for Healthcare Research and Quality (AHRQ) EPC program. The Tufts EPC assembled a group of nutrition experts from academic institutions and relevant federal government agencies, led participants in teleconferences and meetings, conducted exercises in formulating questions that would be amenable to systematic reviews of the scientific literature, and identified the challenges and limitations of applying this method to processes previously used to establish nutrient reference values. This report summarizes the impetus behind this project, approach taken, and the lessons learned.

Nutrient reference values have significant public health and policy implications. This type of dietary guidance is needed for planning diets, assessing the adequacy of diets in individuals and populations, developing nutrition education and guidance, and for setting reference values for nutrition labeling.1

An example of nutrient reference values is the IOM DRIs developed for healthy US and Canadian populations. The DRI values are established by ad hoc study committees convened by the IOM, National Academies of Science. The DRIs for each nutrient are in fact a set of nutrient reference values that typically include an Estimated Average Requirement (EAR), a Recommended Dietary Allowance (RDA), and a Tolerable Upper Intake Level (UL). When available evidence was considered to be inadequate to establish an EAR, the study committees developed a value known as the Adequate Intake (AI). EAR values reflect the median nutrient requirement for the particular life stage and gender group. The EAR was used to calculate RDA values, defined as the nutrient intake level that is sufficient to meet the nutrient requirements of nearly all (97 to 98 percent) individuals within that group. Available data were used to estimate a UL, defined as the highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population. AIs, when developed, were defined as “the recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake of a group (or groups) of apparently healthy people that are assumed to be adequate”.

The IOM Food and Nutrition Board has issued reports on the DRIs for a wide range of nutrients. Six reports have been published and are organized around groups of nutrients.27 Contents of the reports include a summary of what is known about the nutrient function in the human body, selection of indicators of adequacy of nutrient intakes or nutrient levels (for determining nutrient requirements), factors that may affect how the nutrients are utilized and that affect requirements, and how nutrients may be related to the prevention of chronic disease across age groups. Various study committees were convened to evaluate a body of available scientific evidence for specific nutrients. Primarily human studies were reviewed and selected animal studies were used when human data are absent or conflicting. Available evidence was weighted according to quality, peer review status, biological plausibility, and whether similar estimates would be derived from different indicators.1

However, the process of establishing DRIs has been variable and has evolved as experience accrued from study committees. Concern has been expressed that in some cases the methods used to determine DRIs have suffered from a lack of transparency and consistency.8 Moreover, differences in the reference values derived by various groups of nutrition experts worldwide have been noted for the same nutrient when all presumably have used the same body of available evidence. For example, three different organizations from the European Union (EU-SCF), UK (EVM), and the US (IOM) performing nutrient risk assessment proposed different upper levels of intake for vitamin A.9

Given the importance of defining reliable nutrient reference values, there is a need for an explicit, objective, and transparent process to set these values. Evaluating evidence is a major component of informing the process. Because new studies are constantly being published, it would also be desirable to have a framework that allows efficient updating when new information becomes available. Although the mandate to different committees around the world has previously been different (e.g., prevent nutrient deficiency, decrease chronic disease risk), with the globalization of the food supply and health risks it should be expected that evaluating similar evidence will result in similar recommendations.

Over the past 15 years, the concept of evidence-based medicine (EBM) building upon the foundation of systematic reviews, meta-analyses and related methods as important tools for evidence-based practice, has gained widespread acceptance in the evaluation of medical evidence for healthcare decision-making.10 The application of this approach to evaluating the nutrition literature could provide for the transparent, comprehensive and objective evaluation of scientific evidence and could provide support for a framework for a consistent approach to establishing nutrient reference values for all dietary components. Systematic reviews offer a clear and detailed description of the method used to ensure completeness in identifying the available scientific evidence, rationale for the selection of studies, and method of analysis and interpretation. Systematic reviews also allow for an unbiased retrospective evaluation and could provide a starting point for updating and revising the reviews. They are particularly helpful in identifying research gaps for use in establishing research funding and priorities.

Organizations Conducting Systematic Reviews in Nutrition

Numerous investigators and organizations have published hundreds of systematic reviews on nutrition topics. Nutrition-related systematic reviews have been used by several organizations to develop clinical practice guidelines or recommendations. For example, in 2003, the United States Preventive Services Task Force concluded that the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease. The conclusion was based on several considerations including the findings of an evidence report produced by the Oregon EPC.11 A National Institutes of Health (NIH) State-of-the-Science Conference Panel on Multivitamin/Mineral Supplements and Chronic Disease Prevention reached similar conclusions, partly based on the results from an updated evidence report produced by the Johns Hopkins EPC.12 Furthermore, the Centers for Disease Control and Prevention's (CDC) Task Force on Community Preventive Services produced many systematic reviews and evidence-based recommendations for programs and policies to promote population health. Many nutrition-related topics were covered, including the effectiveness of school-based nutrition and physical activity programs, and community- or school-based obesity prevention (

In 2000, the American Dietetic Association (ADA) began carrying out evidence analyses on a wide range of nutrition-related diseases and conditions with the goal of enhancing dietetics practice in these areas. Evidence-based practice guidelines are available for some topics on the ADA evidence analysis library (EAL) ( These guidelines allow food and nutrition professionals to apply the best research knowledge available to their practice with the goal of improving patient outcomes and practitioner effectiveness.13

The Cochrane Collaboration (, established in 1992 and currently consisting of over 10,000 international volunteers, is the best known group worldwide conducting and disseminating systematic reviews of healthcare interventions. While it has about 5,000 systematic reviews completed or in progress in its Cochrane Library, currently there are relatively few nutrition titles. In 2005 a group of researchers proposed to establish a Diet and Nutrition subfield with the main goal of ensuring that the nutrition community is not left behind in the move towards the evidence-based approach.14 However, as of this writing this has not been implemented.

Impetus for the Current Report

While many concepts and methodologies of EBM could be applied directly to nutrition questions, there are importance differences between evaluations of medical interventions (e.g., drug therapies) and nutrient requirements.15 One of the aims of this project was to assess the feasibility of applying evidence-based methods to the process of developing nutrient reference values. By leading a workgroup through the systematic review process to formulate questions that a nutrient reference values panel might consider, the intent was to identify unanticipated issues and challenges.

The following sections briefly describe the methods of systematic review and the activities surrounding the two workgroup meetings. The bulk of the discussion is about integrating evidence-based methods to the process for deriving nutrient reference values. We focus on the process of identifying and reviewing evidence, which is only one aspect of setting nutrient reference values. We did not actually review the evidence identified in the literature searches, as this was beyond the scope of the current project. The intent of this exercise was not to make specific recommendations for reference values or propose how an expert panel should integrate the evidence into its decision-making process. Finally, this report does not recommend a specific approach for implementing the evidence-based methods for the development of nutrient reference values.

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