Toward more rigorous and informative nutritional epidemiology: The rational space between dismissal and defense of the status quo.

To date, nutritional epidemiology has relied heavily on relatively weak methods including simple observational designs and substandard measurements. Despite low internal validity and other sources of bias, claims of causality are made commonly in this literature. Nutritional epidemiology investigations can be improved through greater scientific rigor and adherence to scientific reporting commensurate with research methods used. Some commentators advocate jettisoning nutritional epidemiology entirely, perhaps believing improvements are impossible. Still others support only normative refinements. But neither abolition nor minor tweaks are appropriate. Nutritional epidemiology, in its present state, offers utility, yet also needs marked, reformational renovation. Changing the status quo will require ongoing, unflinching scrutiny of research questions, practices, and reporting-and a willingness to admit that "good enough" is no longer good enough. As such, a workshop entitled "Toward more rigorous and informative nutritional epidemiology: the rational space between dismissal and defense of the status quo" was held from July 15 to August 14, 2020. This virtual symposium focused on: (1) Stronger Designs, (2) Stronger Measurement, (3) Stronger Analyses, and (4) Stronger Execution and Reporting. Participants from several leading academic institutions explored existing, evolving, and new better practices, tools, and techniques to collaboratively advance specific recommendations for strengthening nutritional epidemiology.

The whole food beef matrix is more than the sum of its parts.

Foods are not simply a delivery vehicle for nutrients; they consist of a matrix in which nutrients and non-nutrient compounds are presented that induce physiologic effects different from isolated nutrients. Dietary guidance is often based on effects of single nutrients that are considered unhealthy, such as saturated fat in beef. The purpose of this paper is to propose a working definition of the whole food beef matrix whose consumption has health effects distinct from those of isolated nutrients. The beef matrix can be defined as: the collective nutritive and non-nutritive components of the beef food structure and their unique chemical and physical interactions that may be important for human health which are distinguishable from those of the single components in isolation. Background information supporting this approach is summarized on multiple components provided by beef, temporal changes in beef consumption, dietary guidance that restricts beef, and how the background diet determines healthfulness rather than a single food. Examples of research are provided on other whole foods that differ from their constitutive nutrients and lay the groundwork for studies of beef as part of a healthy dietary pattern.

Considerations for best practices in studies of fiber or other dietary components and the intestinal microbiome.

A 2-day workshop organized by the National Institutes of Health and U.S. Department of Agriculture included 16 presentations focused on the role of diet in alterations of the gastrointestinal microbiome, primarily that of the colon. Although thousands of research projects have been funded by U.S. federal agencies to study the intestinal microbiome of humans and a variety of animal models, only a minority addresses dietary effects, and a small subset is described in sufficient detail to allow reproduction of a study. Whereas there are standards being developed for many aspects of microbiome studies, such as sample collection, nucleic acid extraction, data handling, etc., none has been proposed for the dietary component; thus this workshop focused on the latter specific point. It is important to foster rigor in design and reproducibility of published studies to maintain high quality and enable designs that can be compared in systematic reviews. Speakers addressed the influence of the structure of the fermentable carbohydrate on the microbiota and the variables to consider in design of studies using animals, in vitro models, and human subjects. For all types of studies, strengths and weaknesses of various designs were highlighted, and for human studies, comparisons between controlled feeding and observational designs were discussed. Because of the lack of published, best-diet formulations for specific research questions, the main recommendation is to describe dietary ingredients and treatments in as much detail as possible to allow reproduction by other scientists.

An Overview of Reviews on the Association of Low Calorie Sweetener Consumption With Body Weight and Adiposity.

BACKGROUND: Numerous systematic reviews (SR) and meta-analyses (MA) on low calorie sweeteners (LCS) have been published in recent years, concluding that LCS have beneficial, neutral, or detrimental effects on various health outcomes, depending on the review. OBJECTIVES: The objective of this overview of reviews was to determine how the methodologies of SR investigating the association between LCS consumption and body weight (BW) influence their findings and whether MA results can provide a consistent estimated effect. METHODS: Systematic searches of PubMed, Scopus, and Cochrane Library were conducted in November 2022 to identify SR of randomized controlled trials (RCT) or non-randomized studies (NRS) investigating the association between LCS consumption and BW. The methods, MA results, and conclusions were extracted from each eligible SR. RESULTS: Of the 985 search results, 20 SR evaluated the association between LCS and BW, drawing from publications of 75 RCT, 42 prospective cohort studies, and 10 cross-sectional studies. There was a considerable lack of overlap of studies included within each SR attributed, in part, to the inclusion of studies based on design; thus, each SR synthesized results from distinctly different studies. Evidence synthesis methods were heterogeneous and often opaque, making it difficult to determine why results from certain studies were excluded or why disparate results were observed between SR. CONCLUSIONS: SR investigating the effect of LCS on BW implement different methodologies to answer allegedly the same question, drawing from a different set of heterogeneous studies, ignoring the basic assumptions required for MA, resulting in disparate results and conclusions. Previous MA show the large effects of study design, which results in inconsistent estimates of the effect of LCS on BW between MA of RCT and NRS. Given the availability of long-term RCT, these studies should be the basis of determining causal relationships (or lack thereof) between LCS and BW. This trial was registered at PROSPERO as CRD42022351200.

Toward a science-based classification of processed foods to support meaningful research and effective health policies.

Processed foods have been part of the American diet for decades, with key roles in providing a safe, available, affordable, and nutritious food supply. The USDA Food Guides beginning in 1916 and the US Dietary Guidelines for Americans (DGA) since 1980 have included various types of commonly consumed processed foods (e.g., heated, fermented, dried) as part of their recommendations. However, there are multiple classification systems based on "level" of food processing, and additional evidence is needed to establish the specific properties of foods classified as "highly" or "ultra"-processed (HPF/UPFs). Importantly, many foods are captured under HPF/UPF definitions, ranging from ready-to-eat fortified whole grain breakfast cereals to sugar-sweetened beverages and baked goods. The consequences of implementing dietary guidance to limit all intake of foods currently classified as HPF/UPF may require additional scrutiny to evaluate the impact on consumers' ability to meet daily nutrient recommendations and to access affordable food, and ultimately, on health outcomes. Based on a meeting held by the Institute for the Advancement of Food and Nutrition Sciences in May 2023, this paper provides perspectives on the broad array of foods classified as HPF/UPFs based on processing and formulation, including contributions to nutrient intake and dietary patterns, food acceptability, and cost. Characteristics of foods classified as UPF/HPFs are considered, including the roles and safety approval of food additives and the effect of food processing on the food matrix. Finally, this paper identifies information gaps and research needs to better understand how the processing of food affects nutrition and health outcomes.

Nutrition research to affect food and a healthy life span.

Proper nutrition offers one of the most effective and least costly ways to decrease the burden of many diseases and their associated risk factors, including obesity. Nutrition research holds the key to increasing our understanding of the causes of obesity and its related comorbidities and thus holds promise to markedly influence global health and economies. After outreach to 75 thought leaders, the American Society for Nutrition (ASN) convened a Working Group to identify the nutrition research needs whose advancement will have the greatest projected impact on the future health and well-being of global populations. ASN's Nutrition Research Needs focus on the following high priority areas: 1) variability in individual responses to diet and foods; 2) healthy growth, development, and reproduction; 3) health maintenance; 4) medical management; 5) nutrition-related behaviors; and 6) food supply/environment. ASN hopes the Nutrition Research Needs will prompt collaboration among scientists across all disciplines to advance this challenging research agenda given the high potential for translation and impact on public health. Furthermore, ASN hopes the findings from the Nutrition Research Needs will stimulate the development and adoption of new and innovative strategies that can be applied toward the prevention and treatment of nutrition-related diseases. The multidisciplinary nature of nutrition research requires stakeholders with differing areas of expertise to collaborate on multifaceted approaches to establish the evidence-based nutrition guidance and policies that will lead to better health for the global population. In addition to the identified research needs, ASN also identified 5 tools that are critical to the advancement of the Nutrition Research Needs: 1) omics, 2) bioinformatics, 3) databases, 4) biomarkers, and 5) cost-effectiveness analysis.

Critical data at the crossroads: the National Health and Nutrition Examination Survey faces growing challenges.

NHANES needs urgent attention to ensure its future, which is facing emerging challenges associated with data collection, stagnant funding that has undercut innovation, and the increased call for granular data for subpopulations and groups at risk. The concerns do not rest merely on securing more funding but focus on the need for a constructive review of the survey to explore new approaches and identify appropriate change. This white paper, developed under the auspices of the ASN's Committee on Advocacy and Science Policy (CASP), is a call to the nutrition community to advocate for and support activities to prepare NHANES for future success in a changing nutrition world. Furthermore, because NHANES is much more than a nutrition survey and serves the needs of many in health fields and even commercial arenas, effective advocacy must be grounded in alliances among the survey's diverse stakeholders so that the full range of expertise and interests can engage. This article highlights the complicated nature of the survey along with key overarching challenges to underscore the importance of a measured, thoughtful, comprehensive, and collaborative approach to considering the future of NHANES. Starting-point questions are identified for the purposes of focusing dialog, discussion forums, and research. In particular, the CASP calls for a National Academies of Sciences, Engineering, and Medicine study on NHANES to articulate an actionable framework for NHANES going forward. With a well-informed and integrated set of goals and recommendations that could be provided by such a study, a secure future for NHANES is more readily achievable.

Perspective: Measuring Sweetness in Foods, Beverages, and Diets: Toward Understanding the Role of Sweetness in Health.

Various global public health agencies recommend minimizing exposure to sweet-tasting foods or beverages. The underlying rationale is that reducing exposure to the perception of sweet tastes, without regard to the source of sweetness, may reduce preferences for sweetness, added sugar intake, caloric intake, and body weight. However, the veracity of this sequence of outcomes has yet to be documented, as revealed by findings from recent systematic reviews on the topic. Efforts to examine and document the effects of sweetness exposure are needed to support evidence-based recommendations. They require a generally agreed-upon methodology for measuring sweetness in foods, beverages, and the overall diet. Although well-established sensory evaluation techniques exist for individual foods in laboratory settings, they are expensive and time-consuming, and agreement on the optimal approach for measuring the sweetness of the total diet is lacking. If such a measure could be developed, it would permit researchers to combine data from different studies and populations and facilitate the design and conduct of new studies to address unresolved research questions about dietary sweetness. This narrative review includes an overview of available sensory techniques, their strengths and limitations, recent efforts to measure the sweetness of foods and diets across countries and cultures, and a proposed future direction for improving methods for measuring sweetness toward developing the data required to support evidence-based recommendations around dietary sweetness.

Web-enabled and improved software tools and data are needed to measure nutrient intakes and physical activity for personalized health research.

Food intake, physical activity (PA), and genetic makeup each affect health and each factor influences the impact of the other 2 factors. Nutrigenomics describes interactions between genes and environment. Knowledge about the interplay between environment and genetics would be improved if experimental designs included measures of nutrient intake and PA. Lack of familiarity about how to analyze environmental variables and ease of access to tools and measurement instruments are 2 deterrents to these combined studies. This article describes the state of the art for measuring food intake and PA to encourage researchers to make their tools better known and more available to workers in other fields. Information presented was discussed during a workshop on this topic sponsored by the USDA, NIH, and FDA in the spring of 2009.

Serum retinol, retinol-binding protein, and transthyretin in children receiving dialysis.

OBJECTIVE: We investigated the relationships of retinol (ROH), retinol-binding protein (RBP), and transthyretin (TTR) in children with end-stage renal disease (ESRD). Our hypothesis was that levels of ROH and RBP would be elevated in children with ESRD. METHODS AND PATIENTS: We measured ROH, RBP, and TTR serum concentrations in a group of pediatric ESRD patients biannually. Children were grouped according to age and method of dialysis, i.e., hemodialysis (HD) or peritoneal dialysis (PD): HD1, aged <12 years (n = 8); PD1, aged <12 years (n = 19); HD2, aged >or=12 years (n =19); and PD2, aged >or=12 years (n = 29). RESULTS: No differences in ROH, RBP, TTR, or their ratios were found as a function of type of dialysis in groups PD2 and HD2. The ROH and TTR were significantly higher in PD1 than HD1 (P = .01 and P = .003, respectively). No correlations were evident between ROH and RBP or TTR with length of time on dialysis, serum calcium, or serum creatinine, except for group PD2, in which ROH was positively correlated with RBP (P = .025). There were no significant differences among any of the ratios in terms of age or method of dialysis. CONCLUSIONS: The data indicate that children with ESRD exhibit elevated levels of serum ROH, RBP, and TTR, in proportions similar to those reported in the adult ESRD literature. Further study is needed to clarify the consequences of increased ROH in uremic children.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches.

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids.

There is considerable interest in the impact of (n-3) long-chain PUFA in mitigating the morbidity and mortality caused by chronic diseases. In 2002, the Institute of Medicine concluded that insufficient data were available to define Dietary Reference Intakes (DRI) for eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), noting only that EPA and DHA could contribute up to 10% toward meeting the Adequate Intake for alpha-linolenic acid. Since then, substantial new evidence has emerged supporting the need to reassess this recommendation. Therefore, the Technical Committee on Dietary Lipids of the International Life Sciences Institute North America sponsored a workshop on 4-5 June 2008 to consider whether the body of evidence specific to the major chronic diseases in the United States--coronary heart disease (CHD), cancer, and cognitive decline--had evolved sufficiently to justify reconsideration of DRI for EPA+DHA. The workshop participants arrived at these conclusions: 1) consistent evidence from multiple research paradigms demonstrates a clear, inverse relation between EPA+DHA intake and risk of fatal (and possibly nonfatal) CHD, providing evidence that supports a nutritionally achievable DRI for EPA+DHA between 250 and 500 mg/d; 2) because of the demonstrated low conversion from dietary ALA, protective tissue levels of EPA+DHA can be achieved only through direct consumption of these fatty acids; 3) evidence of beneficial effects of EPA+DHA on cognitive decline are emerging but are not yet sufficient to support an intake level different from that needed to achieve CHD risk reduction; 4) EPA+DHA do not appear to reduce risk for cancer; and 5) there is no evidence that intakes of EPA+DHA in these recommended ranges are harmful.

A report of activities related to the Dietary Reference Intakes from the Joint Canada-US Dietary Reference Intakes Working Group.

The governments of the United States and Canada have jointly undertaken the development of the Dietary Reference Intakes (DRIs) since the mid-1990s. The Federal DRI committees from each country work collaboratively to identify DRI needs, prioritize nutrient reviews, advance work to resolve methodological issues that is necessary for new reviews, and sponsor DRI-related committees through the National Academies of Sciences, Engineering and Medicine. In recent years, the Joint Canada-US DRI Working Group, consisting of members from both Federal DRI committees, developed an open and transparent nomination process for prioritizing nutrients for DRI review, by which sodium, the omega-3 (n-3) fatty acids, vitamin E, and magnesium were identified. In addition, discussions during the nutrient nomination process prompted the Federal DRI committees to address previously identified issues related to the use of chronic disease endpoints when setting DRIs. The development of guiding principles for setting DRIs based on chronic disease risk reduction will be applied for the first time during the DRI review of sodium and potassium. In summary, the US and Canadian governments have worked collaboratively to adapt our approach to prioritizing nutrients for DRI review and to broaden the scope of the DRIs to better incorporate the concept of chronic disease risk reduction in order to improve public health.

Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives.

A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.

Thinking critically about whole-grain definitions: summary report of an interdisciplinary roundtable discussion at the 2015 Whole Grains Summit.

Definitions for whole grain (WG) have been published by governments, the food industry, and grain organizations and generally fall into 2 categories: WG and WG food. WG definitions focus on the principal components of the WGs and their proportions, whereas WG-food definitions describe the quantity of WGs present in food. In the United States, widespread agreement exists on the main parts of a definition for a WG, with a definition for a WG food still in its early stages; a standard definition that has been universally accepted does not exist. Furthermore, nutrition policy advises consumers to eat WGs for at least one-half of their total grain intake (2010 and 2015 Dietary Guidelines for Americans), but confusion exists over which foods are considered WGs and how much is needed to achieve health benefits. In December 2014, a workshop sponsored by the subcommittee on collaborative process of the US Government's Interagency Committee on Human Nutrition Research convened in Washington, DC, and recognized WG definitions as a key nutrition and public health-related issue that could benefit from further collaboration. As a follow-up to that meeting, an interdisciplinary roundtable meeting was organized at the Whole Grains Summit on 25 June 2015 in Portland, Oregon, to help resolve the issue. This article summarizes the main opportunities and challenges that were identified during the meeting for defining WGs and WG foods internationally. Definitions of WGs and WG foods that are uniformly adopted by research, food industry, consumer, and public health communities are needed to enable comparison of research results across populations.

Night eating syndrome: evaluation of two screening instruments.

The purpose of the present study was to determine whether night eating syndrome was associated with treatment outcomes during a brief weight loss intervention for self-identified night snackers, and to evaluate the diagnostic utility of a screening question and the Night Eating Syndrome Questionnaire (NESQ) for the detection of night eating syndrome. Participants enrolled in a 4-week randomized clinical trial for obese and overweight persons who self-identified as night snackers were administered a structured clinical interview, a night eating screening question, and the NESQ. Treatment outcomes included adherence and weight loss. Results showed that night eating syndrome diagnoses were not associated with treatment outcomes. The screening question had adequate sensitivity but poor specificity. The night eating questionnaire was positively correlated with increasingly stringent definitions of night eating syndrome. Night eating syndrome is not the equivalent of night snacking. The definition of night eating syndrome must be expanded to include a sleep disturbance component accompanied by night eating.

Research gaps in evaluating the relationship of meat and health.

Humans evolved as omnivores and it has been proposed that cooking meat allowed for evolution of larger brains that has led to our success as a species. Meat is one of the most nutrient dense foods, providing high-quality protein, heme iron, zinc, and vitamins B6 and B12. Despite these advantages, epidemiologic studies have linked consumption of red or processed meat with obesity, type 2 diabetes, cardiovascular diseases, and cancers of multiple organs. Most observational studies report small, increased relative risks. However, there are many limitations of such studies including inability to accurately estimate intake, lack of prespecified hypotheses, multiple comparisons, and confounding from many factors - including body weight, fruit/vegetable intake, physical activity, smoking, and alcohol - that correlate significantly either positively or negatively with meat intake and limit the reliability of conclusions from these studies. The observational studies are heterogeneous and do not fulfill many of the points proposed by AB Hill in 1965 for inferring causality; his most important factor was strength of the association which in dietary studies is usually <1.5 but is not considered adequate in virtually all other areas of epidemiology outside nutrition. Accepting small, statistically significant risks as "real" from observational associations, the field of nutrition has a long list of failures including beta-carotene and lung cancer, low-fat diets and breast cancer or heart disease that have not been confirmed in randomized trials. Moderate intake of a variety of foods that are enjoyed by people remains the best dietary advice.

Achieving a transparent, actionable framework for public-private partnerships for food and nutrition research.

Officers and other representatives of more than a dozen food-, nutrition-, and health-related scientific societies and organizations, food industry scientists, and staff of the USDA, the CDC, the Food and Drug Administration, and the NIH convened on 8 December 2014 in Washington, DC, to reach a consensus among individuals participating on guiding principles for the development of research-oriented, food- and nutrition-related public-private partnerships. During the daylong working meeting, participants discussed and revised 12 previously published guidelines to ensure integrity in the conduct of food and nutrition research collaborations among public, nonprofit, and private sectors. They agreed to reconvene periodically to reassess the public-private partnership principles. This article presents the guiding principles and potential benefits, outlines key discussion points, and articulates points of agreement and reservation.