Sex and Race Differences in Obesity-Related Genetic Susceptibility and Risk of Cardiometabolic Disease in Older US Adults.

Importance: The fat mass and obesity-associated gene (FTO) is associated with obesity phenotypes, but the association is inconsistent across populations. Within-population differences may explain some of the variability observed. Objective: To investigate sex differences in the association between FTO single-nucleotide variants (SNVs) and obesity traits among self-identified non-Hispanic Black and non-Hispanic White US adults, to examine whether the SNVs were associated with cardiometabolic diseases, and to evaluate whether obesity mediated the association between FTO SNVs and cardiometabolic diseases. Design, Setting, and Participants: This cross-sectional study used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a US population-based cohort study with available genetic data (assayed in 2018) and phenotypic data at baseline (enrolled 2003-2007). Participants were aged 45 to 98 years at baseline. Data were analyzed from October 2021 to October 2022. Exposures: Eleven SNVs in the FTO gene present among both Black and White participants. Main Outcomes and Measures: Objectively measured obesity indicators (body mass index and waist-to-height ratio), objectively measured and/or self-reported cardiometabolic diseases (hypertension, stroke history, heart disease, and diabetes), and self-reported social-economic and psychosocial status. Results: A total of 10 447 participants (mean [SD] age, 64.4 [9.7] years; 5276 [55.8%] women; 8743 [83.7%] Black and 1704 [16.3%] White) were included. In the White group, 11 FTO SNVs were significantly associated with obesity, hypertension, and diabetes using linear models (eg, body mass index: ß = 0.536; 95% CI, 0.197-0.875), but none of the FTO SNVs were associated with obesity traits in the Black group. White males had a higher risk of obesity while White females had a higher risk of hypertension and diabetes. However, 1 FTO SNV (rs1121980) was associated with a direct increase in the risk of heart disease in Black participants not mediated by obesity (c' = 0.145 [SE, 0.0517]; P = .01). Conclusions and Relevance: In this cross-sectional study of obesity phenotypes and their association with cardiometabolic diseases, the tested FTO SNVs reflected sex differences in White participants. Different patterns of associations were observed among self-identified Black participants. Therefore, these results could inform future work discovering risk alleles or risk scores unique to Black individuals or further investigating genetic risk in all US residents.

Design, analysis, and interpretation of treatment response heterogeneity in personalized nutrition and obesity treatment research.

It is increasingly assumed that there is no one-size-fits-all approach to dietary recommendations for the management and treatment of chronic diseases such as obesity. This phenomenon that not all individuals respond uniformly to a given treatment has become an area of research interest given the rise of personalized and precision medicine. To conduct, interpret, and disseminate this research rigorously and with scientific accuracy, however, requires an understanding of treatment response heterogeneity. Here, we define treatment response heterogeneity as it relates to clinical trials, provide statistical guidance for measuring treatment response heterogeneity, and highlight study designs that can quantify treatment response heterogeneity in nutrition and obesity research. Our goal is to educate nutrition and obesity researchers in how to correctly identify and consider treatment response heterogeneity when analyzing data and interpreting results, leading to rigorous and accurate advancements in the field of personalized medicine.

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.

Relationship Between Food Security Status in a Caregiver's Family of Origin and Current Feeding Practices Among Low-Income, Single, Female Primary Caregivers.

A child's familial environment is paramount to the formation and maintenance of their health behaviors. Factors that influence a child's health behaviors include parental modeling, types of available food, timing of food availability, and characteristics of the home environment. Previous research has demonstrated an association between a caregiver's current food security status and feeding practices, but no studies have explored the association between food security in the caregiver's childhood and their current feeding practices. This study investigates the relationship between parental food insecurity (both current and childhood) and child feeding practices. The US Household Food Security Survey and the Child Feeding Questionnaire were completed by 103 low-income, single, female primary caregivers. Results indicated that caregivers who reported current food insecurity expressed greater tendency to pressure their children to eat. Caregivers who reported food insecurity during their childhood also expressed greater tendency to pressure their children to eat and a greater concern about their child's weight. These findings can serve in both research and clinical efforts as an early screening tool to indicate families most in need of accessible resources. Findings also help to highlight the transgenerational nature of food insecurity, including its residual effects on health behaviors.

Randomization, design and analysis for interdependency in aging research: no person or mouse is an island.

Investigators traditionally use randomized designs and corresponding analysis procedures to make causal inferences about the effects of interventions, assuming independence between an individual's outcome and treatment assignment and the outcomes of other individuals in the study. Often, such independence may not hold. We provide examples of interdependency in model organism studies and human trials and group effects in aging research and then discuss methodologic issues and solutions. We group methodologic issues as they pertain to (1) single-stage individually randomized trials; (2) cluster-randomized controlled trials; (3) pseudo-cluster-randomized trials; (4) individually randomized group treatment; and (5) two-stage randomized designs. Although we present possible strategies for design and analysis to improve the rigor, accuracy and reproducibility of the science, we also acknowledge real-world constraints. Consequences of nonadherence, differential attrition or missing data, unintended exposure to multiple treatments and other practical realities can be reduced with careful planning, proper study designs and best practices.

Experimentally Manipulated Low Social Status and Food Insecurity Alter Eating Behavior Among Adolescents: A Randomized Controlled Trial.

OBJECTIVE: This randomized trial experimentally manipulated social status to assess effects on acute eating behavior and 24-hour energy balance. METHODS: Participants (n = 133 Hispanics; age 15-21 years; 60.2% females) were randomized to low social status ("LOW") or high social status ("HIGH") conditions in a rigged game of Monopoly (Hasbro, Inc.). Acute energy intake in a lunchtime meal was measured by food scales. Twenty-four-hour energy balance was assessed via summation of resting metabolic rate (metabolic cart), physical activity energy expenditure (accelerometer), thermic effect of food, and subtraction of twenty-four-hour energy intake (food diary). RESULTS: In the total sample, no significant differences were observed by study condition at lunchtime. LOW females consumed a greater percent of lunchtime daily energy needs (37.5%) relative to HIGH females (34.3%); however, this difference was not statistically significant (P = 0.291). In males, however, LOW consumed significantly less (36.5%) of their daily energy needs relative to HIGH males (45.8%; P = 0.001). For 24-hour energy balance, sex differences were nearly significant (P = 0.057; LOW females: surplus +200 kcal; HIGH males: surplus +445 kcal). Food-insecure individuals consumed a nearly significant greater lunchtime percent daily energy than those with food security (40.7% vs. 36.3%; P = 0.0797). CONCLUSIONS: The data demonstrate differential acute and 24-hour eating behavior responses between Hispanic male and female adolescents in experimentally manipulated conditions of low social status.

Youth Subjective Social Status (SSS) is Associated with Parent SSS, Income, and Food Insecurity but not Weight Loss Among Low-Income Hispanic Youth.

OBJECTIVE: Subjective social status (SSS), perceived rank in the social ladder, is associated with weight, but determinants of SSS in youth remain unknown. Relationships between youth SSS and income, food insecurity, parent SSS, and BMI change were investigated during an obesity intervention. METHODS: Data came from a family-centered, community-based obesity intervention for low-income families. Parent and youth SSS were assessed using a validated, age-appropriate SSS scale. Food insecurity and socioeconomic factors were assessed in parents; child and parent weight-related data were measured at baseline and post intervention. RESULTS: Participants included 110 primarily Hispanic (97%) low-income youth and their parents. Food insecurity was reported in 66.4% of families. Youth SSS was positively associated with parent SSS (P = 0.0014). In both parents and children, the association between income and SSS was moderated by food insecurity such that lower income was more strongly associated with lower SSS among food-insecure households (P = 0.0286 and P = 0.0327, respectively). Youth SSS was not associated with youth BMI reduction. CONCLUSIONS: Youth SSS was not predictive of weight loss in this intervention. Intriguingly, the association between income and SSS was modified by food insecurity, suggesting that food insecurity shapes the contribution of socioeconomic factors to one's perceived social status.

Randomization to randomization probability: Estimating treatment effects under actual conditions of use.

Blinded randomized controlled trials (RCT) require participants to be uncertain if they are receiving a treatment or placebo. Although uncertainty is ideal for isolating the treatment effect from all other potential effects, it is poorly suited for estimating the treatment effect under actual conditions of intended use-when individuals are certain that they are receiving a treatment. We propose an experimental design, randomization to randomization probabilities (R2R), which significantly improves estimates of treatment effects under actual conditions of use by manipulating participant expectations about receiving treatment. In the R2R design, participants are first randomized to a value, π, denoting their probability of receiving treatment (vs. placebo). Subjects are then told their value of π and randomized to either treatment or placebo with probabilities π and 1-π, respectively. Analysis of the treatment effect includes statistical controls for π (necessary for causal inference) and typically a π-by-treatment interaction. Random assignment of subjects to π and disclosure of its value to subjects manipulates subject expectations about receiving the treatment without deception. This method offers a better treatment effect estimate under actual conditions of use than does a conventional RCT. Design properties, guidelines for power analyses, and limitations of the approach are discussed. We illustrate the design by implementing an RCT of caffeine effects on mood and vigilance and show that some of the actual effects of caffeine differ by the expectation that one is receiving the active drug. (PsycINFO Database Record

Future Research Directions for the Insurance Hypothesis regarding Food Insecurity and Obesity.

This commentary discusses Nettle et al.'s "The Insurance Hypothesis" linking food insecurity to a high body mass index (BMI). Discussion about how the relationship between race/ethnicity and obesity in the United States is consistent with this hypothesis is presented. Potential ways forward to elucidate the validity of this hypothesis in humans through rigorous controlled trials is highlighted.

Social Relationships, Gender, and Recovery From Mobility Limitation Among Older Americans.

OBJECTIVES: Evidence suggests social relationships may be important facilitators for recovery from functional impairment, but the extant literature is limited in its measurement of social relationships including an over emphasis on filial social support and a paucity of nationally representative data. METHODS: Using data from Waves 4-9 (1998-2008) of the Health and Retirement Study (HRS), this research examines the association between social relationships and recovery from severe mobility limitation (i.e., difficulty walking one block or across the room) among older Americans. Using a more nuanced measure of recovery that includes complete and partial recovery, a series of discrete-time event history models with multiple competing recovery outcomes were estimated using multinomial logistic regression. RESULTS: Providing instrumental support to peers increased the odds of complete and partial recovery from severe mobility limitation, net of numerous social, and health factors. Having relatives living nearby decreased the odds of complete recovery, while being engaged in one's neighborhood increased the odds of partial recovery. The influence of partner status on partial and complete recovery varied by gender, whereby partnered men were more likely to experience recovery relative to partnered women. The effect of neighborhood engagement on partial recovery also varied by gender. Disengaged women were the least likely to experience partial recovery compared with any other group. DISCUSSION: The rehabilitative potential of social relationships has important policy implications. Interventions aimed at encouraging older adults with mobility limitation to be engaged in their neighborhoods and/or provide instrumental support to peers may improve functional health outcomes.

Packet randomized experiments for eliminating classes of confounders.

BACKGROUND: Although randomization is considered essential for causal inference, it is often not possible to randomize in nutrition and obesity research. To address this, we develop a framework for an experimental design-packet randomized experiments (PREs), which improves causal inferences when randomization on a single treatment variable is not possible. This situation arises when subjects are randomly assigned to a condition (such as a new roommate) which varies in one characteristic of interest (such as weight), but also varies across many others. There has been no general discussion of this experimental design, including its strengths, limitations, and statistical properties. As such, researchers are left to develop and apply PREs on an ad hoc basis, limiting its potential to improve causal inferences among nutrition and obesity researchers. METHODS: We introduce PREs as an intermediary design between randomized controlled trials and observational studies. We review previous research that used the PRE design and describe its application in obesity-related research, including random roommate assignments, heterochronic parabiosis, and the quasi-random assignment of subjects to geographic areas. We then provide a statistical framework to control for potential packet-level confounders not accounted for by randomization. RESULTS: Packet randomized experiments have successfully been used to improve causal estimates of the effect of roommates, altitude, and breastfeeding on weight outcomes. When certain assumptions are met, PREs can asymptotically control for packet-level characteristics. This has the potential to statistically estimate the effect of a single treatment even when randomization to a single treatment did not occur. CONCLUSIONS: Applying PREs to obesity-related research will improve decisions about clinical, public health, and policy actions insofar as it offers researchers new insight into cause and effect relationships among variables.