Cross-over studies underestimate energy compensation:The example of sucrose-versus sucralose-containing drinks

AbstractThe vast majority of preload-test-meal studies that have investigated the effects on energy intake of disguised nutrient or other food/drink ingredient manipulations have used a cross-over design. We argue that this design may underestimate the effect of the manipulation due to carry-over effects. To test this we conducted comparable cross-over (n = 69) and parallel-groups (n = 48) studies testing the effects of sucrose versus low-calorie sweetener (sucralose) in a drink preload on test-meal energy intake. The parallel-groups study included a baseline day in which only the test meal was consumed. Energy intake in that meal was used to control for individual differences in energy intake in the analysis of the effects of sucrose versus sucralose on energy intake on the test day. Consistent with our prediction, the effect of consuming sucrose on subsequent energy intake was greater when measured in the parallel-groups study than in the cross-over study (respectively 64% versus 36% compensation for the 162 kcal difference in energy content of the sucrose and sucralose drinks). We also included a water comparison group in the parallel-groups study (n = 24) and found that test-meal energy intake did not differ significantly between the water and sucralose conditions. Together, these results confirm that consumption of sucrose in a drink reduces subsequent energy intake, but by less than the energy content of the drink, whilst drink sweetness does not increase food energy intake. Crucially, though, the studies demonstrate that study design affects estimated energy compensation

No evidence of flavour-nutrient learning in a two-week ‘home exposure’ study in humans

Flavour-nutrient learning is robust in animals but remains elusive in humans. Recent evidence suggests flavour-nutrient learning may be more likely to occur with beverages that contain relatively few calories (compared to no calories), while others show that learned associations can influence satiation, without an effect on preference. The objective of this research was to determine whether acquired liking for a caloric drink could be observed in a ‘home learning’ context over 2 weeks, and whether it is impacted by viscosity. In combination, we also explored changes in learning relating to fullness and expected satiety. In a double-blind study, participants (N = 83; BMI = 23.3 kg/m2) were randomly allocated to one of four groups differing in either calories (0 kcal vs. 112.5 kcal) or viscosity (low vs. high) and consumed a novel-flavoured drink over 15 days. Measures of flavour (10 ml sample) and beverage liking, grip force (a measure of beverage reward value), fullness, and expected satiety were taken at the start and the end of the study. While the high-viscous beverages were less liked (M = 40.3 mm, SD = 24.7) than the low viscous beverages (M = 64.4 mm, SD = 15.3; p = .022), there was no evidence that repeated exposure to a calorie-containing beverage impacted subsequent liking for the flavour (p = .115) or for the beverage (p = .448), grip force (ps > .26), fullness, and expected satiety (ps > .12). Accordingly, we conclude that we found no evidence of flavour-nutrient learning and flavour-satiety learning. This null finding accords with previous observations indicating that humans do not acquire flavour-nutrient associations as readily as some non-human animals

In search of flavour-nutrient learning:A study of the Samburu pastoralists of North-Central Kenya

Much of our dietary behaviour is learned. In particular, one suggestion is that ‘flavour-nutrient learning’ (F-NL) influences both choice and intake of food. F-NL occurs when an association forms between the orosensory properties of a food and its postingestive effects. Unfortunately, this process has been difficult to evaluate because F-NL is rarely observed in controlled studies of adult humans. One possibility is that we are disposed to F-NL. However, learning is compromised by exposure to a complex Western diet that includes a wide range of energy-dense foods. To test this idea we explored evidence for F-NL in a sample of semi-nomadic pastoralists who eat a very limited diet, and who are lean and food stressed. Our Samburu participants (N = 68) consumed a sensory-matched portion (400 g) of either a novel low (0.72 kcal/g) or higher (1.57 kcal/g) energy-dense semi-solid food on two training days, and an intermediate version on day 3. Before and after each meal we measured appetite and assessed expected satiation and liking for the test food. We found no evidence of F-NL. Nevertheless, self-reported measures were very consistent and, as anticipated, expected satiation increased as the test food became familiar (expectedsatiation drift). Surprisingly,we observed insensitivity to the effects of test-meal energy density on measures of post-meal appetite. To explore this further we repeated a single training day using participants (N = 52) from the UK. Unlike in the Samburu, the higher energy-dense meal caused greater suppression of appetite. These observations expose interesting cross-cultural differences in sensitivity to the energy content of food. More generally, our work illustrates how measures can be translated to assess different populations, highlighting the potential for further comparisons of this kind

So Many Brands and Varieties to Choose from:Does This Compromise the Control of Food Intake in Humans?

The recent rise in obesity is widely attributed to changes in the dietary environment (e.g., increased availability of energy-dense foods and larger portion sizes). However, a critical feature of our “obesogenic environment” may have been overlooked - the dramatic increase in “dietary variability” (the tendency for specific mass-produced foods to be available in numerous varieties that differ in energy content). In this study we tested the hypothesis that dietary variability compromises the control of food intake in humans. Specifically, we examined the effects of dietary variability in pepperoni pizza on two key outcome variables; i) compensation for calories in pepperoni pizza and ii) expectations about the satiating properties of pepperoni pizza (expected satiation). We reasoned that dietary variability might generate uncertainty about the postingestive effects of a food. An internet-based questionnaire was completed by 199 adults. This revealed substantial variation in exposure to different varieties of pepperoni pizza. In a follow-up study (n= 66; 65% female), high pizza variability was associated with i) poorer compensation for calories in pepperoni pizza and ii) lower expected satiation for pepperoni pizza. Furthermore, the effect of uncertainty on caloric compensation was moderated by individual differences in decision making (loss aversion). For the first time, these findings highlight a process by which dietary variability may compromise food-intake control in humans. This is important because it exposes a new feature of Western diets (processed foods in particular) that might contribute to overeating and obesity

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Expected Satiety: Application to Weight Management and Understanding Energy Selection in Humans

Recent advances in the approaches used to quantify expectations of satiation and satiety have led to a better understanding of how humans select and consume food, and the associated links to energy intake regulation. When compared calorie for calorie some foods are expected to deliver several times more satiety than others, and multiple studies have demonstrated that people are able to discriminate between similar foods reliably and with considerable sensitivity. These findings have implications for the control of meal size and the design of foods that can be used to lower the energy density of diets. These methods and findings are discussed in terms of their implications for weight management. The current paper also highlights why expected satiety may also play an important role beyond energy selection, in moderating appetite sensations after a meal has been consumed, through memory for recent eating and the selection of foods across future meals