GWAS for BMI: a treasure trove of fundamental insights into the genetic basis of obesity.

Muller et al. [1] have provided a strong critique of the Genome-Wide Association Studies (GWAS) of body-mass index (BMI), arguing that the GWAS approach for the study of BMI is flawed, and has provided us with few biological insights. They suggest that what is needed instead is a new start, involving GWAS for more complex energy balance related traits. In this invited counter-point, we highlight the substantial advances that have occurred in the obesity field, directly stimulated by the GWAS of BMI. We agree that GWAS for BMI is not perfect, but consider that the best route forward for additional discoveries will likely be to expand the search for common and rare variants linked to BMI and other easily obtained measures of obesity, rather than attempting to perform new, much smaller GWAS for energy balance traits that are complex and expensive to measure. For GWAS in general, we emphasise that the power from increasing the sample size of a crude but easily measured phenotype outweighs the benefits of better phenotyping.

Generalized lambda distribution for flexibly testing differences beyond the mean in the distribution of a dependent variable such as body mass index.

BACKGROUND/OBJECTIVES: Conventional statistical methods often test for group differences in a single parameter of a distribution, usually the conditional mean (for example, differences in mean body mass index (BMI; kg m-2) by education category) under specific distributional assumptions. However, parameters other than the mean may of be interest, and the distributional assumptions of conventional statistical methods may be violated in some situations. SUBJECTS/METHODS: We describe an application of the generalized lambda distribution (GLD), a flexible distribution that can be used to model continuous outcomes, and simultaneously describe a likelihood ratio test for differences in multiple distribution parameters, including measures of central tendency, dispersion, asymmetry and steepness. We demonstrate the value of our approach by testing for differences in multiple parameters of the BMI distribution by education category using the Health and Retirement Study data set. RESULTS: Our proposed method indicated that at least one parameter of the BMI distribution differed by education category in both the complete data set (N=13 571) (P<0.001) and a randomly resampled data set (N=300 from each category) to assess the method under circumstances of lesser power (P=0.044). Similar method using normal distribution alternative to GLD indicated the significant difference among the complete data set (P<0.001) but not in the smaller randomly resampled data set (P=0.968). Moreover, the proposed method allowed us to specify which parameters of the BMI distribution significantly differed by education category for both the complete and the random subsample, respectively. CONCLUSIONS: Our method provides a flexible statistical approach to compare the entire distribution of variables of interest, which can be a supplement to conventional approaches that frequently require unmet assumptions and focus only on a single parameter of distribution.

Social status and energy intake: a randomized controlled experiment.

While the inverse association between socioeconomic status (SES) and obesity in high gross domestic product countries is well established using observational data, the extent to which the association is due to a true causal effect of SES and, if so, the mechanisms of this effect remain incompletely known. To assess the influence of social status on obesity via energy intake, we randomized individuals to a higher or lower social status and observed subsequent energy intake. College students between the ages of 18 and 25 were randomized to social status and were operationalized as being a leader or follower in a partner activity as purportedly determined by a (bogus) test of leadership ability. Investigators were blinded to treatment assignment. Immediately after being told their leadership assignment, paired participants were provided with platters of food. Energy intake was objectively measured in kilocalories (kcal) consumed, and paired t-tests were used to test for significant differences in intake between leaders and followers. A total of 60 participants were included in the final analysis (males = 28, females = 32). Overall, no difference in energy intake was observed between leaders and followers, consuming an average of 575.3 and 579.8 kcal, respectively (diff = 4.5 kcal, P = 0.94). The null hypothesis of no effect of social status, operationalized as assignment to a leadership position in a small-group activity, on energy intake was not rejected.

The development of scientific evidence for health policies for obesity: why and how?

Potential obesity-related policy approaches have recently been receiving more attention. Although some have been implemented and others only proposed, few have been formally evaluated. We discuss the relevance, and in some cases irrelevance, of some of the types of evidence that are often brought to bear in considering obesity-related policy decisions. We discuss major methods used to generate such evidence, emphasizing study design and the varying quality of the evidence obtained. Third, we consider what the standards of evidence should be in various contexts, who ought to set those standards, as well as the inherent subjectivity involved in making policy decisions. Finally, we suggest greater transparency from both academics and policymakers in the acknowledgment of subjectivities so they can distinguish and communicate the roles of empirical evidence and subjective values in the formulation of policy.

Associations between human breast milk hormones and adipocytokines and infant growth and body composition in the first 6 months of life.

BACKGROUND: Much is to be learnt about human breast milk (HBM). OBJECTIVES: The purpose of this study is to extend our knowledge of HBM by investigating the role of maternal body mass index (BMI), sex and stage of lactation (month 1 vs. 6) on HBM insulin, glucose, leptin, IL-6 and TNF-α and their associations with infant body composition. METHODS: Thirty-seven exclusively breastfeeding infants (n = 37; 16♀, 21♂), and their mothers (19-47 kg m-2 ) were studied at 1 and 6 months of lactation. Infants had body composition measured (using dual-energy X-ray absorptiometry) and HBM collected. RESULTS: A significant interaction between maternal BMI and infant sex on insulin levels (p = 0.0322) was observed such that insulin was 229% higher in obese mothers nursing female infants than in normal weight mothers nursing female infants and 179% higher than obese mothers nursing male infants. For leptin, a significant association with BMI category was observed (p < 0.0001) such that overweight and obese mothers had 96.5% and 315.1% higher leptin levels than normal weight mothers, respectively. Leptin was also found to have a significant (p = 0.0004) 33.7% decrease from months 1 to 6, controlling for BMI category and sex. A significant inverse relationship between month 1 leptin levels and infant length (p = 0.0257), percent fat (p = 0.0223), total fat mass (p = 0.0226) and trunk fat mass (p = 0.0111) at month 6 was also found. No associations or interactions were observed for glucose, TNF-α or IL-6. CONCLUSIONS: These data demonstrate that maternal BMI, infant sex and stage of lactation affect the compositional make-up of insulin and leptin.

Changes in pediatric waist circumference percentiles despite reported pediatric weight stabilization in the United States.

BACKGROUND: Obesity is a global health concern but the United States has reported a leveling in obesity rates in the pediatric population. OBJECTIVE: To provide updated waist circumference (WC) percentile values, identify differences across time and discuss differences within the context of reported weight stabilization in a nationally representative sample of American children. METHODS: Percentiles for WC in self-identified African Americans (AA), European Americans (EA) and Mexican Americans (MA) were obtained from 2009-2014 National Health and Nutrition Examination Survey data (NHANES2014). Descriptive trends across time in 10th, 25th, 50th, 75th and 90th percentile WC distributions were identified by comparing NHANES2012 with previously reported NHANESIII (1988-1994). RESULTS: WC increased in a monotonic fashion in AA, EA and MA boys and girls. When compared with NHANESIII data, a clear left shift of percentile categories was observed such that values that used to be in the 90th percentile are now in the 85th percentile. Differences in WC were observed in EA and MA boys during a reported period of weight stabilization. CONCLUSION AND RELEVANCE: WC has changed in the US pediatric population across time, even during times of reported weight stabilization, particularly among children of diverse racial/ethnic backgrounds.

The effects of experimentally manipulated social status on acute eating behavior: A randomized, crossover pilot study.

Both subjective and objectively measured social status has been associated with multiple health outcomes, including weight status, but the mechanism for this relationship remains unclear. Experimental studies may help identify the causal mechanisms underlying low social standing as a pathway for obesity. Our objective was to investigate the effects of experimentally manipulated social status on ad libitum acute dietary intakes and stress-related outcomes as potential mechanisms relating social status and weight. This was a pilot feasibility, randomized, crossover study in Hispanic young adults (n=9; age 19-25; 67% female; BMI ≥18.5 and ≤30kg/m(2)). At visit 1, participants consumed a standardized breakfast and were randomized to a high social status position (HIGH) or low social status position (LOW) in a rigged game of Monopoly™. The rules for the game differed substantially in terms of degree of 'privilege' depending on randomization to HIGH or LOW. Following Monopoly™, participants were given an ad libitum buffet meal and energy intakes (kcal) were estimated by pre- and post-weighing foods consumed. Stress-related markers were measured at baseline, after the game of Monopoly™, and after lunch. Visit 2 used the same standardized protocol; however, participants were exposed to the opposite social status condition. When compared to HIGH, participants in LOW consumed 130 more calories (p=0.07) and a significantly higher proportion of their daily calorie needs in the ad libitum buffet meal (39% in LOW versus 31% in HIGH; p=0.04). In LOW, participants reported decreased feelings of pride and powerfulness following Monopoly™ (p=0.05) and after their lunch meal (p=0.08). Relative to HIGH, participants in LOW demonstrated higher heart rates following Monopoly™ (p=0.06), but this relationship was not significant once lunch was consumed (p=0.31). Our pilot data suggest a possible causal relationship between experimentally manipulated low social status and increased acute energy intakes in Hispanic young adults, potentially influenced by decreased feelings of pride and powerfulness. Increased energy intake over time, resulting in positive energy balance, could contribute to increased risk for obesity, which could partially explain the observed relationship between low social standing and higher weight. Larger and longitudinal studies in a diverse sample need to be conducted to confirm findings, increase generalizability, and assess whether this relationship persists over time.

Oxidative costs of reproduction: Oxidative stress in mice fed standard and low antioxidant diets.

Lactation is one of the most energetically expensive behaviours, and trade-offs may exist between the energy devoted to it and somatic maintenance, including protection against oxidative damage. However, conflicting data exist for the effects of reproduction on oxidative stress. In the wild, a positive relationship is often observed, but in laboratory studies oxidative damage is often lower in lactating than in non-breeding animals. We hypothesised that this discrepancy may exist because during lactation food intake increases many-fold resulting in a large increase in the intake of dietary antioxidants which are typically high in laboratory rodent chow where they are added as a preservative. We supplied lactating and non-breeding control mice with either a standard or low antioxidant diet and studied how this affected the activity of endogenous antioxidants (catalase, superoxide dismutase; SOD, and glutathione peroxidise; GPx) and oxidative damage to proteins (protein carbonyls, PC) in liver and brain tissue. The low antioxidant diet did not significantly affect activities of antioxidant enzymes in brain or liver, and generally did not result in increased protein damage, except in livers of control mice on low antioxidant diet. Catalase activity, but not GPx or SOD, was decreased in both control and lactating mice on the low antioxidant diet. Lactating mice had significantly reduced oxidative damage to both liver and brain compared to control mice, independent of the diet they were given. In conclusion, antioxidant content of the diet did not affect oxidative stress in control or reproductive mice, and cannot explain the previously observed reduction in oxidative stress in lactating mammals studied in the laboratory. The reduced oxidative stress in the livers of lactating mice even under low antioxidant diet treatment was consistent with the 'shielding' hypothesis.

Rigorous control conditions diminish treatment effects in weight loss-randomized controlled trials.

BACKGROUND: It has not been established whether control conditions with large weight losses (WLs) diminish expected treatment effects in WL or prevention of weight gain (PWG)-randomized controlled trials (RCTs). SUBJECTS/METHODS: We performed a meta-analysis of 239 WL/PWG RCTs that include a control group and at least one treatment group. A maximum likelihood meta-analysis framework was used to model and understand the relationship between treatment effects and control group outcomes. RESULTS: Under the informed model, an increase in control group WL of 1 kg corresponds with an expected shrinkage of the treatment effect by 0.309 kg (95% confidence interval (-0.480, -0.138), P=0.00081); this result is robust against violations of the model assumptions. CONCLUSIONS: We find that control conditions with large WLs diminish expected treatment effects. Our investigation may be helpful to clinicians as they design future WL/PWG studies.

The importance of prediction model validation and assessment in obesity and nutrition research.

Deriving statistical models to predict one variable from one or more other variables, or predictive modeling, is an important activity in obesity and nutrition research. To determine the quality of the model, it is necessary to quantify and report the predictive validity of the derived models. Conducting validation of the predictive measures provides essential information to the research community about the model. Unfortunately, many articles fail to account for the nearly inevitable reduction in predictive ability that occurs when a model derived on one data set is applied to a new data set. Under some circumstances, the predictive validity can be reduced to nearly zero. In this overview, we explain why reductions in predictive validity occur, define the metrics commonly used to estimate the predictive validity of a model (for example, coefficient of determination (R(2)), mean squared error, sensitivity, specificity, receiver operating characteristic and concordance index) and describe methods to estimate the predictive validity (for example, cross-validation, bootstrap, and adjusted and shrunken R(2)). We emphasize that methods for estimating the expected reduction in predictive ability of a model in new samples are available and this expected reduction should always be reported when new predictive models are introduced.

A systematic review and meta-analysis of randomized controlled trials of the impact of sleep duration on adiposity and components of energy balance.

Recent epidemiological and ecological trends in humans indicate a possible causal relationship between sleep duration and energy balance. We aimed to find experimental evidence that has tested this relationship between sleep duration and measures of body composition, food intake or biomarkers related to food intake. We conducted a systematic literature review using six databases throughout 7 August 2014. We sought reports of randomized controlled trials where sleep duration was manipulated and measured outcomes were body weight or other body composition metrics, food intake, and/or biomarkers related to eating. We found 18 unique studies meeting all criteria: eight studies with an outcome of body weight (4 - increased sleep, 4 - reduced sleep); four studies on food intake; four studies of sleep restriction on total energy expenditure and three of respiratory quotient; and four studies on leptin and/or ghrelin. Few controlled experimental studies have addressed the question of the effect of sleep on body weight/composition and eating. The available experimental literature suggests that sleep restriction increases food intake and total energy expenditure with inconsistent effects on integrated energy balance as operationalized by weight change. Future controlled trials that examine the impact of increased sleep on body weight/energy balance factors are warranted.

Predicting adult weight change in the real world: a systematic review and meta-analysis accounting for compensatory changes in energy intake or expenditure.

BACKGROUND: Public health and clinical interventions for obesity in free-living adults may be diminished by individual compensation for the intervention. Approaches to predict weight outcomes do not account for all mechanisms of compensation, so they are not well suited to predict outcomes in free-living adults. Our objective was to quantify the range of compensation in energy intake or expenditure observed in human randomized controlled trials (RCTs). METHODS: We searched multiple databases (PubMed, CINAHL, SCOPUS, Cochrane, ProQuest, PsycInfo) up to 1 August 2012 for RCTs evaluating the effect of dietary and/or physical activity interventions on body weight/composition. INCLUSION CRITERIA: subjects per treatment arm ≥5; ≥1 week intervention; a reported outcome of body weight/body composition; the intervention was either a prescribed amount of over- or underfeeding and/or supervised or monitored physical activity was prescribed; ≥80% compliance; and an objective method was used to verify compliance with the intervention (for example, observation and electronic monitoring). Data were independently extracted and analyzed by multiple reviewers with consensus reached by discussion. We compared observed weight change with predicted weight change using two models that predict weight change accounting only for metabolic compensation. FINDINGS: Twenty-eight studies met inclusion criteria. Overfeeding studies indicate 96% less weight gain than expected if no compensation occurred. Dietary restriction and exercise studies may result in up to 12-44% and 55-64% less weight loss than expected, respectively, under an assumption of no behavioral compensation. INTERPRETATION: Compensation is substantial even in high-compliance conditions, resulting in far less weight change than would be expected. The simple algorithm we report allows for more realistic predictions of intervention effects in free-living populations by accounting for the significant compensation that occurs.

Energy balance measurement: when something is not better than nothing.

Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health-care policies, future research and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance.

Randomized controlled trial examining expectancy effects on the accuracy of weight measurement.

BACKGROUND: Researchers and participants' expectations can influence treatment response. Less is known about the effects of researchers' expectations on the accuracy of data collection in the context of a weight loss trial. METHODS: Student raters (N = 58; age = 20.1 ± 2.3 years) were recruited to weigh individuals who they thought were completing a 12-month weight loss trial, although these 'participants' were actually standardized patients (SPs) playing these roles. Prior to data collection, student raters were provided information suggesting that the tested treatment had been effective. Each student rater received a list of 9-10 'participants' to weigh. While the list identified each person as 'treatment' or 'control', this assignment was at random, which allowed us to examine the effects of non-blinding and expectancy manipulation on weight measurement accuracy. We hypothesized that raters would record the weights of 'treatment participants' as lower than those of 'control participants'. RESULTS: Contrary to our hypothesis, raters recorded weights that were 0.293 kg heavier when weighing 'treatment' vs. 'control' SPs, although this difference was not significant (P = 0.175). CONCLUSIONS: This pilot study found no evidence that manipulating expectancies about treatment efficacy or not blinding raters biased measurements. Future work should examine other biases which may be created by not blinding research staff who implement weight loss trials as well as the participants in those trials.