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Lichtenstein AH, Yetley EA, Lau J. Application of Systematic Review Methodology to the Field of Nutrition: Nutritional Research Series, Vol. 1. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Jan. (Technical Reviews, No. 17.1.)
Application of Systematic Review Methodology to the Field of Nutrition: Nutritional Research Series, Vol. 1.
Show detailsUnique Considerations When Conducting Nutrition-Related Systematic Reviews
There are a number of issues that need to be factored into systematic reviews of nutrition related topics that do not normally arise when systematic reviews of pharmaceuticals and related topics are conducted. These should in no way hamper the process. However, information relative to these issues often need to be captured in systematic reviews to facilitate interpretation of study results and the overall quality, applicability, and strength of the evidence. By accounting for them, their potential influence can be factored into the review.
Baseline Exposure
In contrast to pharmaceutical trials, for the most part, in nutrition related studies all persons have some level of background dietary exposure to the nutrient of interest, either from food and/or supplement intake or, in certain cases, endogenous synthesis (e.g., vitamin D, vitamin K). Background levels of exposures can be difficult to accurately determine due to limitations in currently available assessment methodologies of food intake, incomplete nutrient databases with which nutrient intake estimates are calculated, and temporal changes in exposure. Therefore information on background intakes and the methodologies used to assess them should be captured in the systematic review so that this level of uncertainty can be factored into data interpretation.
Nutrient Status
Nutrient status of an individual or population can affect the response to nutrient supplementation. An accurate approach to evaluate nutrient status is unique to each nutrient and dependent on the availability of nutrient specific tissue for sampling and homoeostatic mechanisms regulating plasma concentrations via storage depot accretion and release. For some nutrients, a relatively good assessment of nurture can be made; in other cases, the level of uncertainty of nurture is great because of uncertainties about the biological interpretation and/or methodological errors in measuring the indicator of interest that it is necessary to incorporate this information into the systematic review conclusions to facilitate appropriate data interpretation.
Bioequivalence of Different Chemical Forms of Nutrients
Many nutrients occur in multiple forms that differ in biological activity. The general approach to address this issue is to calculate ‘nutrient equivalents’, as was done when setting the Recommended Dietary Allowances for vitamin A (preformed vitamin A, carotenoids), folate (folate, folic acid), vitamin K (phylloquinone and menaquinone), and niacin (preformed niacin, tryptophan).(29–31) The challenge of determining accurate conversion factors for the calculation of nutrient equivalents has recently been demonstrated for beta-carotene.(29) Capturing information on nutrient forms of baseline diets and intervention products in summarized studies is therefore often essential for appropriate data interpretation.
Bioavailability of Nutrients
There are a number of factors which can alter the bioavailability of individual nutrients. These differences must be considered when estimating dietary intake and comparing response to dietary supplementation. Briefly, these include the chemical form of a nutrient (e.g., heme and non-heme iron), nutrient/nutrient interactions (e.g., vitamin C and non-heme iron), nutrient/drug interactions (e.g., isoniazid and vitamin B-6; coumadin and vitamin K; folate and metformin), nutrient/food interactions (e.g., fat soluble vitamins and dietary fat, zinc- and phytic acid/oxalic acid containing foods), form of inorganic mineral (e.g., calcium carbonate, citrate or malate), biological response to single versus multiple daily doses (e.g., calcium) and habitual intake effect on efficiency of absorption and excretion (e.g., iron, vitamin C). Other factors that may alter nutrient bioavailability include biological status (e.g., iron and pregnancy, achlorhydria and vitamin B-12), food processing (e.g., particle size and dietary fiber; lye treated corn and trytophan; heat treatment and carotenoids), and for dietary supplements factors which alter completeness or rate of release (e.g., coatings, excipients and surfactants). Bioavailability also differs among nutrients from biological stores. For example, vitamin A has a relatively high bioavailability from liver only when protein status is adequate. Release and deposition of nutrients from storage depots can be unrelated to biological needs. For example, fat soluble vitamin deposition or release from adipose tissue is altered by weight gain or loss, respectively. Again, capturing relevant information on baseline diet and intervention product bioavailability may be necessary for interpreting summarized results included in a systematic review.
Multiple and Interrelated Biological Functions of a Nutrient
Most nutrients have multiple biological functions. A critical point during the research question(s) development and refinement phase of the systematic review process is to clearly define the nutrient specific scope of the review. This often entails narrowing the range of the work. Some biological functions of nutrients are dependent on multiple nutrients (e.g., folate, vitamin B-12 and vitamin B-6; vitamin D and calcium). These relationships must be defined early in the review process and putative factors incorporated into formulating the questions.
Undefined Nature of Nutrient Intervention
Food based nutrient interventions, in contrast to nutrient supplement based interventions, present unique challenges in accurately quantifying the absolute change in intake. For example, one approach to increasing very long chain (n-3) fatty acid intake (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) intake is to instruct study subjects to increase fish intake. However, there is considerable variability in the level of EPA and DHA in different fish, within species of fish, (32) time of year the fish were caught and animal husbandry practices for farm raised fish. Similarly, assessing EPA and DHA intake from nutrient supplement data is not without challenges due to the wide variability in fatty acid contents of available fish oil supplements and potential changes in supplement potency during prolonged storage or exposure to heat. Documentation of nutrient intake assessment is important to record.
Uncertainties in Assessing Dose Response Relationships
Measurement and assay procedures can alter apparent dose-response relationships between nutrient intake or dietary pattern and health outcomes. This can be particularly important for systematic reviews where absolute intake/response relationships rather than relative intake response relationships are needed to assess the public health importance of a particular intervention or to identify dose-response relationships to inform the establishment of recommendations. In general, dietary intake methodologies underestimate energy and protein intakes with greater biases for food frequency than 24-h recall methodologies.(33) Potential biases for other nutrient intake estimates are not adequately documented but likely exist. Assay procedures for biomarkers of nutritional status can also significantly affect the mean and distribution of reported values and need to be factored into data interpretation. (34, 35)
Strengths and Limitations of Systematic Review Approach for Nutrition Applications
The systematic review approach brings a number of strengths to the evaluation of evidence in nutrition applications. One of the most compelling strengths is the transparent, objective, and rigorous nature of the process. A clearly defined and unambiguous system is put in place to define the scope of the review, refine the question(s) to be addressed, and identify and select studies prior to reviewing the data. Evidence available to address each question is summarized and critically appraised. This transparency is particularly critical when the systematic reviews are subsequently used by expert panels in developing program or policy guidelines and recommendations.
The ability to combine small studies with meta-analysis increases the statistical power available to address specific questions. This is particularly useful for systematic reviews of nutrition topics where the availability of large trials is relatively limited or lacking. Meta-analyses may have potential usefulness in simulating dose-response curves across intervention studies that individually evaluated only one or two intake levels.
Inherent in the systematic review process is its flexibility for addressing wide variations in the nature of the questions of interest and available amounts and types of data to answer them, while simultaneously ensuring a consistency among topics. This has been particularly challenging for the nutrition community, as the scope of issues has gone beyond those traditionally addressed (from making recommendations for preventing deficiency to minimizing risk of developing chronic disease or nutrient excess). The methodologies of systematic reviews assure an objective assessment of the available body of literature and minimize biases often encountered in narrative reviews.
When systematic reviews are conducted for the purpose of informing policy and program decisions, an important by-product of a systematic review is the identification of gaps in available data. This information can be used to assist the formulation of research agenda and funding priorities. Equally important is the ability of systematic reviews to identify needed improvements in the quality and nature of reporting. For example, a commonly identified problem in nutrition-related systematic reviews has been that even for topics for which there are a number of published trials, incomplete reporting of basic study design and conduct, as well as poor characterizations of baseline, placebo and intervention characteristics, limits the ability to make definitive conclusions about the outcome of interest. To avoid commonly observed study documentation deficiencies, CONSORT guidelines for the reporting of randomized trials (16, 17) and trials of complex herbal interactions (36) have been proposed. Their use by publishers of nutrition studies is encouraged.
Lastly, the detailed documenting of search strategies and summarizing of the data associated with generating systematic reviews facilitates the updating/revising process as new data become available by providing a comprehensive foundation on which to build. This has the benefits of maximizing the use of limited resources and decreasing the time necessary for generating topic updates.
Notwithstanding these strengths there are clear limitations of using the systematic review approach in the field of nutrition. By definition the systematic review process is most effective when limited to addressing targeted questions of limited scope. This may include the population of interest (e.g., age, sex, health status), intervention, comparator, outcome measure and duration of intervention. Questions that require a broad-based exploratory search approach would better be served by using the systematic review approach after an initial literature search has been conducted and domain experts have narrowed and refined the questions of interest.
Systematic reviews are limited by the quality and availability of data. No approach to analyzing the data can adjust for poor study design, missing data or publication bias in the area of interest. Multiple systematic reviews addressing what appear to be the same topic can result in different conclusions, causing considerable confusion.(37, 38) For the most part discordant results are due to differences in study inclusion and/or exclusion criteria, temporal evolution of available data and subtle differences in the actual questions addressed that are not initially obvious. By clearly documenting review decisions, comparisons of different reviews can be made and reasons for differences become apparent.
- Unique Considerations When Conducting Nutrition-Related Systematic Reviews
- Baseline Exposure
- Nutrient Status
- Bioequivalence of Different Chemical Forms of Nutrients
- Bioavailability of Nutrients
- Multiple and Interrelated Biological Functions of a Nutrient
- Undefined Nature of Nutrient Intervention
- Uncertainties in Assessing Dose Response Relationships
- Discussion - Application of Systematic Review Methodology to the Field of Nutrit...Discussion - Application of Systematic Review Methodology to the Field of Nutrition
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