In this exercise, the EPC staff began by reviewing the literature cited for the vitamin A section in the DRI publication. A simple analytical framework was created as an approach to the process of systematic review to derive reference values for vitamin A. This “straw man” model was introduced to the workgroup members during a series of teleconferences. Based on the domain experts' input, the EPC staff refined the analytical framework for the systematic review process. A preliminary search of the literature was conducted and it yielded several thousand potentially relevant abstracts. EPC staff provided introductory training to the workgroup members in the methodology of conducting the systematic review during teleconferences and at the first workgroup meeting. This included familiarizing them with the systematic search strategy - drafting well focused key questions and establishing the PICO criteria, explicit descriptions of the population, interventions (or exposures), comparators, and outcomes. The expert panel created a set of key questions and systematically worked through the biological roles of vitamin A in the body. An abstract screening session led by EPC staff was conducted at the second meeting. All workgroup members participated in this exercise. A sample of 20 abstracts was selected using the PICO criteria. Through an iterative process, the PICO criteria were further refined and finalized by the workgroup members.

This short training exercise raised the workgroup members' awareness and appreciation of the methodological rigor and the transparency involved in the systematic review process. The need for systematic appraisal of the literature was apparent in their discussions and there was willingness to incorporate the systematic review methodology into future efforts to review and potentially revise nutrient reference values.


The published literature on vitamin A is large and its extent is likely similar to that of most other nutrients for which reference values have been or have yet to be established. The lesson learned from this exercise, focused on vitamin A, suggests that evidence-based methods, including systematic reviews, are applicable to the development of nutrient reference values, with appropriate nutrient specific modifications. When the volume of literature is large, rational and well-defined eligibility criteria must be applied in conducting a systematic review to manage the workload. Appropriate questions must be formulated so that the answers to those questions can be used to inform the derivation of a set of reference values and help to ensure transparency and reproducibility, and form the foundation for future updates as new data emerge.

In the past, the process to derive a set of reference values for a particular nutrient has been, to a large degree, dependent on the make up of the expert panel. Using this new approach, it would be not only important that the members of the expert panel represent a balanced range of scientific views but that they also are familiarized with the process of conducting a systematic review and interpreting its results.

It became apparent from this exercise that it would be desirable if nutrient reference values could be linked to specific health outcome(s). Although this issue presents challenges it should be considered in the future. The process in selecting specific health outcomes and intermediate outcomes (e.g., biomarkers, indicators) when specific health outcomes are not available for deriving of a reference value should be defined prior to starting systematic reviews.

Some of the issues in the existing literature that will need to be addressed directly when applying systematic reviews to the process of establishing nutrient reference values include: generalizability of well-controlled experiments but with few subjects (e.g., <10) or subjects selected from limited spectrum of the general population; applicability of findings of animal studies to humans; generalizability of early studies that employed methodologies that are not state of the art or directly comparable to contemporaneous data; and appropriate interpretation and integration of scientific evidence from observational studies. Contemporary issues such as the role of genomics, and en masse nutrient fortification will also need to be factored in when undertaking this process.