Edward Yu

Understanding Nutritional Epidemiology and Its Role in Policy

Nutritional epidemiology has recently been criticized on several fronts, including the inability to measure diet accurately, and for its reliance on observational studies to address etiologic questions. In addition, several recent meta-analyses with serious methodologic flaws have arrived at erroneous or misleading conclusions, reigniting controversy over formerly settled debates. All of this has raised questions regarding the ability of nutritional epidemiologic studies to inform policy. These criticisms, to a large degree, stem from a misunderstanding of the methodologic issues of the field and the inappropriate use of the drug trial paradigm in nutrition research. The exposure of interest in nutritional epidemiology is human diet, which is a complex system of interacting components that cumulatively affect health. Consequently, nutritional epidemiology constantly faces a unique set of challenges and continually develops specific methodologies to address these. Misunderstanding these issues can lead to the nonconstructive and sometimes naive criticisms we see today. This article aims to clarify common misunderstandings of nutritional epidemiology, address challenges to the field, and discuss the utility of nutritional science in guiding policy by focusing on 5 broad questions commonly asked of the field.

Retinal Not Systemic Oxidative and Inflammatory Stress Correlated with VEGF Expression in Rodent Models of Insulin Resistance and Diabetes

PURPOSE To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes. METHODS Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers. Retinal expression of Nox2, Nox4, and p47phox mRNA levels were measured as oxidative stress markers. TNF-α, inter-cellular adhesion molecule-1 (ICAM-1), IL1β, and activation of nuclear factor κB (NF-κB) were used as retinal inflammatory markers. RESULTS Retinal VEGF mRNA and protein expression increased in Zucker diabetic fatty (ZDF(fa/fa)) rats and streptozotosin (STZ) induced diabetic Sprague-Dawley rats, after two months of disease, but not in Zucker fatty (ZF) rats. Systemic markers of oxidative stress and inflammation were elevated in insulin resistant and diabetic rats. Some oxidative stress and inflammatory markers (TNF-α, IL-6, ICAM-1, and IL1-β) were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after 4 months of disease. In contrast, activation of NF-κB in the retina was observed in high fat fed nondiabetic and diabetic cis-NF-κB(EGFP) mice, ZF, ZDF(fa/fa), and STZ-induced diabetic rats. CONCLUSIONS Only persistent hyperglycemia and diabetes increased retinal VEGF expression. Some markers of inflammation and oxidative stress were elevated in the retina and systemic circulation of obese and insulin resistant rodents with and without diabetes. Induction of VEGF and its associated retinal pathologies by diabetes requires chronic hyperglycemia and factors in addition to inflammation and oxidative stress.

Increases in Plasma Tryptophan Are Inversely Associated with Incident Cardiovascular Disease in the Prevención con Dieta Mediterránea (PREDIMED) Study

Background: During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.Objective: We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.Methods: We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up [mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m2): 29.7 ± 3.7]. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.Results: Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (P-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.Conclusions: An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score.

Objective measures are complementary to, rather than a replacement for, self-reported methods

Objective measures are complementary to, rather than a replacement for, self-reported methods

Race/ethnicity modifies the association between school prevalence of e-cigarette use and student-level use: Results from the 2014 US National Youth Tobacco Survey

Abstract This study assessed racial/ethnic moderation of the association between school prevalence of lifetime e‐cigarette use and students’ use. Using multilevel regression methods and data from the 2014 US National Youth Tobacco Survey, we found attending schools with high rates of e‐cigarette use was positively associated with students’ lifetime use of e‐cigarettes, especially for white students. A cross‐level interaction term indicated a weaker association between non‐Hispanic black race and attending high‐use schools (odds ratio [OR] =0.61, 95% confidence interval [CI] =0.39, 0.95). Results implicate race/ethnicity as an important effect modifier in the link between school contexts and teenage e‐cigarette use. HighlightsSchool level e‐cigarette use is highly predictive of later e‐cigarette initiation.Hispanics and students of other races reported the highest rates of e‐cigarette use.Among high prevalence schools, blacks had lower odds of trying e‐cigarettes compared to whites.Race is an important effect modifier in the link between school context and teen e‐cigarette use.

Dairy Products, Dairy Fatty Acids, and the Prevention of Cardiometabolic Disease: a Review of Recent Evidence

Purpose of ReviewTo examine recent literature on dairy products, dairy fatty acids, and cardiometabolic disease. Primary questions of interest include what unique challenges researchers face when investigating dairy products/biomarkers, whether one should consume dairy to reduce disease risk, whether dairy fatty acids may be beneficial for health, and whether one should prefer low- or high-fat dairy products.Recent FindingsDairy composes about 10% of the calories in a typical American diet, about half of that coming from fluid milk, half coming from cheese, and small amounts from yogurt. Most meta-analyses report no or weak inverse association between dairy intake with cardiovascular disease and related intermediate outcomes. There is some suggestion that dairy consumption was inversely associated with stroke incidence and yogurt consumption was associated with lower risk of type 2 diabetes. Odd chain fatty acids (OCFAs) found primarily in dairy (15:0 and 17:0) appear to be inversely associated with cardiometabolic risk, but causation is uncertain. Substitution analyses based on prospective cohorts suggested that replacing dairy fat with vegetable fat or polyunsaturated fat was associated with significantly lower risk of cardiovascular disease.SummaryCurrent evidence suggests null or weak inverse association between consumption of dairy products and risk of cardiovascular disease. However, replacing dairy fat with polyunsaturated fat, especially from plant-based foods, may confer health benefits. More research is needed to examine health effects of different types of dairy products in diverse populations.

Plasma trimethylamine-N-oxide and related metabolites are associated with type 2 diabetes risk in the Prevención con Dieta Mediterránea (PREDIMED) trial

Background The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.

Cardiovascular Disease Prevention by Diet Modification: JACC Health Promotion Series

Reduction in excess calories and improvement in dietary composition may prevent many primary and secondary cardiovascular events. Current guidelines recommend diets high in fruits, vegetables, whole grains, nuts, and legumes; moderate in low-fat dairy and seafood; and low in processed meats, sugar-sweetened beverages, refined grains, and sodium. Supplementation can be useful for some people but cannot replace a good diet. Factors that influence individuals to consume a low-quality diet are myriad and include lack of knowledge, lack of availability, high cost, time scarcity, social and cultural norms, marketing of poor-quality foods, and palatability. Governments should focus on cardiovascular disease as a global threat and enact policies that will reach all levels of society and create a food environment wherein healthy foods are accessible, affordable, and desirable. Health professionals should be proficient in basic nutritional knowledge to promote a sustainable pattern of healthful eating for cardiovascular disease prevention for both healthy individuals and those at higher risk.

Association of Tryptophan Metabolites with Incident Type 2 Diabetes in the PREDIMED Trial: A Case–Cohort Study

BACKGROUND Metabolites of the tryptophan-kynurenine pathway (i.e., tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic) may be associated with diabetes development. Using a case-cohort design nested in the Prevención con Dieta Mediterránea (PREDIMED) study, we studied the associations of baseline and 1-year changes of these metabolites with incident type 2 diabetes (T2D). METHODS Plasma metabolite concentrations were quantified via LC-MS for n = 641 in a randomly selected subcohort and 251 incident cases diagnosed during 3.8 years of median follow-up. Weighted Cox models adjusted for age, sex, body mass index, and other T2D risk factors were used. RESULTS Baseline tryptophan was associated with higher risk of incident T2D (hazard ratio = 1.29; 95% CI, 1.04-1.61 per SD). Positive changes in quinolinic acid from baseline to 1 year were associated with a higher risk of T2D (hazard ratio = 1.39; 95% CI, 1.09-1.77 per SD). Baseline tryptophan and kynurenic acid were directly associated with changes in homeostatic model assessment for insulin resistance (HOMA-IR) from baseline to 1 year. Concurrent changes in kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine/tryptophan ratio were associated with baseline-to-1-year changes in HOMA-IR. CONCLUSIONS Baseline tryptophan and 1-year increases in quinolinic acid were positively associated with incident T2D. Baseline and 1-year changes in tryptophan metabolites predicted changes in HOMA-IR. Tryptophan levels may initially increase and then deplete as diabetes progresses in severity.

Changes in Arginine are Inversely Associated with Type 2 Diabetes: A Case‐Cohort Study in the PREDIMED Trial

The associations between arginine‐based metabolites and incident type 2 diabetes (T2D) are unknown. We employed a case‐cohort design, nested within the PREDIMED trial, to examine six plasma metabolites (arginine, citrulline, ornithine, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine [SDMA] and N‐monomethyl‐l‐arginine [NMMA]) among 892 individuals (251 cases) for associations with incident T2D and insulin resistance. Weighted Cox models with robust variance were used. The 1‐year changes in arginine (adjusted hazard ratio [HR] per SD 0.68, 95% confidence interval [CI] 0.49, 0.95; Q4 vs. Q1 0.46, 95% CI 0.21, 1.04; P trend = 0.02) and arginine/ADMA ratio (adjusted HR per SD 0.73, 95% CI 0.51, 1.04; Q4 vs. Q1 0.52, 95% CI 0.22, 1.25; P trend = 0.04) were associated with a lower risk of T2D. Positive changes of citrulline and ornithine, and negative changes in SDMA and arginine/(ornithine + citrulline) were associated with concurrent 1‐year changes in homeostatic model assessment of insulin resistance. Individuals in the low‐fat‐diet group had a higher risk of T2D for 1‐year changes in NMMA than individuals in Mediterranean‐diet groups (P interaction = 0.02). We conclude that arginine bioavailability is important in T2D pathophysiology.