Grilling the data: application of specification curve analysis to red meat and all-cause mortality.

OBJECTIVES: To present an application of specification curve analysis-a novel analytic method that involves defining and implementing all plausible and valid analytic approaches for addressing a research question-to nutritional epidemiology. STUDY DESIGN AND SETTING: We reviewed all observational studies addressing the effect of red meat on all-cause mortality, sourced from a published systematic review, and documented variations in analytic methods (eg, choice of model, covariates, etc.). We enumerated all defensible combinations of analytic choices to produce a comprehensive list of all the ways in which the data may reasonably be analyzed. We applied specification curve analysis to data from National Health and Nutrition Examination Survey 2007 to 2014 to investigate the effect of unprocessed red meat on all-cause mortality. The specification curve analysis used a random sample of all reasonable analytic specifications we sourced from primary studies. RESULTS: Among 15 publications reporting on 24 cohorts included in the systematic review on red meat and all-cause mortality, we identified 70 unique analytic methods, each including different analytic models, covariates, and operationalizations of red meat (eg, continuous vs quantiles). We applied specification curve analysis to National Health and Nutrition Examination Survey, including 10,661 participants. Our specification curve analysis included 1208 unique analytic specifications, of which 435 (36.0%) yielded a hazard ratio equal to or more than 1 for the effect of red meat on all-cause mortality and 773 (64.0%) less than 1. The specification curve analysis yielded a median hazard ratio of 0.94 (interquartile range: 0.83-1.05). Forty-eight specifications (3.97%) were statistically significant, 40 of which indicated unprocessed red meat to reduce all-cause mortality and eight of which indicated red meat to increase mortality. CONCLUSION: We show that the application of specification curve analysis to nutritional epidemiology is feasible and presents an innovative solution to analytic flexibility.

Compliance with U.S. Government Nutrition Advice and Concurrent Obesity Trends Using Nurses' Health Study Data, 1980-2011.

BACKGROUND: Beginning in 1977, the U.S. Government began formally issuing dietary advice, a main objective of which was to reduce and prevent the prevalence of obesity in the American population. Concurrently, the Harvard School of Public Health began conducting dietary intake surveys and collecting body mass index (BMI) (kg/m2) data on female nurses in the Nurses' Health Study I (NHSI) and II (NHSII). OBJECTIVES: We aimed to assess whether compliance with the nutrition guidance from the U.S. Government to restrict dietary intake regarding total fat, saturated fat, and cholesterol was meaningfully associated with the prevalence of obesity. METHODS: We analyzed nutrition survey data from 1980 to 2011, grouping the sample into "compliers," those who complied with guidance on the intake of total fat, saturated fat, and cholesterol, and "noncompliers," those who did not. We then compared the means, medians, and distributions of BMI for compliers and noncompliers over the period for both the full survey population and an age-controlled sample. Finally, we plotted raw NHS data to examine respondents' Fat Proportion intake of energy and concurrent BMI. RESULTS: The mean and median BMI for both compliers and noncompliers increased throughout the sample period, and the BMI distributions shifted toward obese and severely obese overall and for an age-controlled subset compared with the 1980 NHSI and 1990 NHSII baselines. Compliers had slightly lower mean BMI increases than noncompliers but saw a relatively higher increase in the growth of the prevalence of those with BMI >30. We also found no linear relationship between Fat Proportion of energy intake and concurrent BMI. CONCLUSIONS: Guidance from the U.S. Government to limit fat, saturated fat, and cholesterol consumption was widely adopted by American female nurses during the study period. Our results show that compliance with this guidance had little if any effect in mitigating population-wide BMI increases during our study period.

Positive nutrition: shifting the focus from nutrients to diet for a healthy lifestyle.

PURPOSE AND METHODS: This summary is based on a scientific symposium organized by the Mediterranean Diet Roundtable and the American Italian Food Coalition titled, 'Positive Nutrition: shifting focus from nutrients to diet for a healthy lifestyle.' It was held at the Embassy of Italy in Washington DC in September of 2022. The panel of experts discussed how science can inform policy, what insights may be gleaned from different countries' approaches to healthy eating and what principles of the Mediterranean diet will inform strategies for a healthy future. Recognizing that isolated actions have limited impact on the complex relationship between diet and obesity, the panel discussed the importance of a system approach. In particular, the panel emphasized that focusing on single ingredients, isolated food categories and narrow approaches to policy have had limited success across the globe. RESULTS AND CONCLUSION: The panel agreed that there is a need for change of perspective that embraces complexity and emphasizes more positive nutrition messaging and policies. LEVEL OF EVIDENCE: V, Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

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 ultra-processed foods hypothesis: a product processed well beyond the basic ingredients in the package.

The NOVA classification of food items has become increasingly popular and is being used in several observational studies as well as in nutritional guidelines and recommendations. We propose that there is a need for this classification and its use in the formulation of public health policies to be critically discussed and re-appraised. The terms 'processing' and 'ultra-processing', which are crucial to the NOVA classification, are ill-defined, as no scientific, measurable or precise reference parameters exist for them. Likewise, the theoretical grounds of the NOVA classification are unclear and inaccurate. Overall, the NOVA classification conflicts with the classic, evidence-based evaluation of foods based on composition and portion size because NOVA postulates that the food itself (or how much of it is eaten) is unimportant, but rather that dietary effects are due to how the food is produced. We contend that the NOVA system suffers from a lack of biological plausibility so the assertion that ultra-processed foods are intrinsically unhealthful is largely unproven, and needs further examination and elaboration.

An analysis of the recent US dietary guidelines process in light of its federal mandate and a National Academies report.

The US Dietary Guidelines for Americans is an enormously influential policy that has guided US nutrition programs since 1980. During these last 40 years, some researchers have expressed concern that the guidelines are based on an insufficiently rigorous assessment of the scientific evidence, a view that was largely substantiated by a Congressionally mandated 2017 report by the National Academies of Sciences, Engineering, and Medicine, which identified a need for enhanced transparency, greater scientific rigor, and updates to the scientific methodology for the DGA process. This paper traces the history of these ideas and contextualizes the DGA within the law and regulations that govern its process. The paper also discusses how recent iterations of the Dietary Guidelines have not fully adhered to these guiding documents, which has resulted in diminished independence of the expert committee in charge of evaluating the science for the DGA and a continued lack of a fully rigorous scientific process for producing consistent and trustworthy guidelines for the public.

Dietary Saturated Fats and Health: Are the U.S. Guidelines Evidence-Based?

The last decade has seen nearly 20 papers reviewing the totality of the data on saturated fats and cardiovascular outcomes, which, altogether, have demonstrated a lack of rigorous evidence to support continued recommendations either to limit the consumption of saturated fatty acids or to replace them with polyunsaturated fatty acids. These papers were unfortunately not considered by the process leading to the most recent U.S. Dietary Guidelines for Americans, the country's national nutrition policy, which recently reconfirmed its recommendation to limit saturated fats to 10% or less of total energy intake, based on insufficient and inconsistent evidence. Continuation of a cap on saturated fat intake also fails to consider the important effects of the food matrix and the overall dietary pattern in which saturated fatty acids are consumed.

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults.

Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality and mental self-assessment. At low dosages, minor changes in serum electrolytes and plasma non-essential amino acids glutamine and aspartic acid concentrations were observed. Serine increased its plasma concentrations at high supplemental dosages (9 and 12 g/day), and phenylalanine increased plasma tyrosine concentrations at 12 g/day, but those changes were not considered toxicologically relevant. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of phenylalanine and serine supplementation in healthy adult males was determined to be 12 g/day.

Challenges in the design, interpretation, and reporting of randomized controlled clinical studies on the health effects of whole foods.

Given the challenges with nutrition research, the Canadian Nutrition Society and Intertek Health Sciences Inc held an expert consultation in late 2019 to discuss the development and implementation of best practices for clinical trials on whole foods. Key challenges in the design, interpretation, and reporting of clinical efficacy studies on whole foods and opportunities for the future development of best practices are reported. Novelty: Outlines existing tools, resources, and checklists for clinical nutrition trials and provides clear and tangible steps to develop best practices for studies on whole foods.

Science dialogue mapping of knowledge and knowledge gaps related to the effects of dairy intake on human cardiovascular health and disease.

Dairy has been described as everything from a superfood to a poison; yet, arguments, assumptions, and data justifying these labels are not always clear. We used an issue-based information system, "dialogue mapping™," to summarize scientific points of a live panel discussion on the putative effects of dairy on cardiovascular diseases (CVD) from a day-long session among experts in nutrition and CVD. Dialogue mapping captures relations among ideas to explicitly, logically, and visually connect issues/questions, ideas, pro/con arguments, and agreements, even if discussed at different times. Experts discussed two propositions: for CVD risk, consumption of full-fat dairy products 1) should be minimized, in part because of their saturated fat content, or 2) need not be minimized, despite their saturated fat content. The panel discussed the dairy-CVD relation through blood lipids, diabetes, obesity, energy balance, blood pressure, dairy bioactives, biobehavioral components, and other putative causal pathways. Associations and effects reported in the literature have varied by fat content of dairy elements considered, study design, intake methods, and biomarker versus disease outcomes. Two conceptual topics emerged from the discussion: 1) individual variability: whether recommendations should be targeted only to those at high CVD risk; 2) quality of evidence: whether data on dairy-CVD relations are strong enough for reliable conclusions-positive, negative, or null. Future procedural improvements for science dialog mapping include using singular rather than competing propositions for discussion.

Dietary Sugars: Not as Sour as They Are Made Out to Be.

Over the course of evolution, Mother Nature preserved the ability of humans to make every sugar they need for metabolic functions. Glucose is the almost exclusive fuel preferred by the human brain. Human infants are born with sweet taste receptors, sugars are a significant energy source in human milk, and mammals have a direct gut-to-brain sugar-sensing system that enhances development of a preference for sugars. If sugars are as toxic as many postulate, what species advantage was conferred by this evolutionary progression? Observational studies have reported that sugar consumption is associated with various adverse health risks. However, observational studies can never prove causality, dietary intake records are known to be highly problematic, and the huge number of correlation interdependencies among environmental "exposome" variables makes it impossible to attribute causality to individual dietary components. Additionally, these studies overall have been graded as low quality, and many reported the small effect sizes are likely within the propagated methodological "noise." With several exceptions, data from randomized controlled trials that ensured isocaloric energy intakes have failed to confirm the causal implications of the observational data. Likewise, the comprehensive UK Scientific Committee on Nutrition Report on Carbohydrates and Health also failed to confirm the vast majority of widely postulated detrimental effects of sugar consumption per se. Current data on intakes of sugar-sweetened beverages and on the risks associated with high intakes of dietary fructose remain under debate.

Proposals for Upper Limits of Safe Intake for Methionine, Histidine, and Lysine in Healthy Humans.

Based on research presented during the 10th Amino Acid Assessment Workshop, no observed adverse effect levels (NOAELs) for supplemental methionine at 46 mg/(kg·d) (∼3.2 g/d), for supplemental histidine at 8.0 g/d, and for supplemental lysine at 6.0 g/d have been proposed. These NOAELs are relevant to healthy adults and are applicable only to high-purity amino acids administered in fortified foods or dietary supplements. Because individuals are exposed to the above supplemental amino acids in the context of complex combinations of essential amino acids or individually in dietary supplements for various physiologic benefits, such as body fat reduction, skin conditioning, mental energy increase, or herpes simplex treatments, the above safety recommendations will make an important contribution to regulatory and nutritional practices.

Saturated Fats and Health: A Reassessment and Proposal for Food-Based Recommendations: JACC State-of-the-Art Review.

The recommendation to limit dietary saturated fatty acid (SFA) intake has persisted despite mounting evidence to the contrary. Most recent meta-analyses of randomized trials and observational studies found no beneficial effects of reducing SFA intake on cardiovascular disease (CVD) and total mortality, and instead found protective effects against stroke. Although SFAs increase low-density lipoprotein (LDL) cholesterol, in most individuals, this is not due to increasing levels of small, dense LDL particles, but rather larger LDL particles, which are much less strongly related to CVD risk. It is also apparent that the health effects of foods cannot be predicted by their content in any nutrient group without considering the overall macronutrient distribution. Whole-fat dairy, unprocessed meat, and dark chocolate are SFA-rich foods with a complex matrix that are not associated with increased risk of CVD. The totality of available evidence does not support further limiting the intake of such foods.

The Philosophy of Evidence-Based Principles and Practice in Nutrition.

The practice of evidence-based nutrition involves using the best available nutrition evidence, together with clinical experience, to conscientiously work with patients' values and preferences to help them prevent (sometimes), resolve (sometimes), or cope with (often) problems related to their physical, mental, and social health. This article outlines the 3 fundamental principles of evidence-based practice as applied to the field of clinical nutrition. First, optimal clinical decision making requires awareness of the best available evidence, which ideally will come from unbiased systematic summaries of that evidence. Second, evidence-based nutrition provides guidance on how to decide which evidence is more or less trustworthy-that is, how certain can we be of our patients' prognosis, diagnosis, or of our therapeutic options? Third, evidence alone is never sufficient to make a clinical decision. Decision makers must always trade off the benefits with the risks, burden, and costs associated with alternative management strategies, and, in so doing, consider their patients' unique predicament, including their values and preferences.

Nutrition from the Inside Out.

Nearly 50 years ago, I set out to investigate the clinical problem of hypoglycemia in children with illnesses that limited their food intake. My goal was to gather accurate and precise measurable data. At the time, I wasn't interested in nutrition as a discipline defined in its more general or popular sense. To address the specific problem that interested me required development of entirely new methods based on stable, nonradioactive tracers that satisfied the conditions of accuracy and precision. At the time, I had no inclination of the various theoretical and practical problems that would have to be solved to achieve this goal. Some are briefly described here. Nor did I have the slightest idea that developing the field would result in a fundamental change in how human clinical investigation was conducted, with the eventual replacement of radiotracers with stable isotopically labeled ones, even for adult clinical investigation. Additionally, I had no inclination that the original questions would open avenues to much broader questions of practical nutritional relevance. Moreover, only much later as the editor of The American Journal of Clinical Nutrition did I appreciate the policy implications of how nutritional data are presented in the scientific literature. At least in part, less accurate and precise measurements and less than full transparency in reporting nutritional data have resulted in widespread debate about the public policy recommendations and guidelines that are the intended result of collecting the data in the first place. This article provides a personal recollection (with all the known faults of self-reporting and retrospective memory) of the journey that starts with measurement certainty and ends with policy uncertainty.

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.

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group.

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.

Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly.

On the basis of research presented during the 9th Amino Acid Assessment Workshop, a No Observed Adverse Effect Level (NOAEL) for diet-added arginine (added mostly in the form of dietary supplements) of 30 g/d and an upper limit of safe intake (ULSI) for diet-added tryptophan (added mostly in the form of dietary supplements) of 4.5 g/d have been proposed. Both recommendations apply to healthy young adults. The total dietary leucine ULSI proposed for elderly individuals is 500 mg · kg-1 · d-1 All 3 recommendations are relevant only to high-quality amino acid-containing products with specifications corresponding to those listed in the US Pharmacopeia Because the above amino acids are extensively utilized as dietary supplements for various real or perceived benefits, such as vasodilation, spermatogenesis, sleep, mood regulation, or muscle recovery, the above safety recommendations will have an important impact on regulatory and nutritional practices.