Proposal summaries
B687 - An FTO Gene Variant and Sedentary Behaviour in Children - 12/08/2008
An FTO Gene Variant and Sedentary Behaviour in Children
Purpose:
To examine any potential differences in the time spent sedentary at 11 and 13 years old in relation to a variant in the fat mass and obesity (FTO) gene. Secondly, to examine the changes in sedentary behaviour between 11 and 13 years old in relation to a variant in the FTO gene.
Background:
Genome-wide association studies have provided resounding evidence that variants in the FTO gene are associated with obesity. For instance, per A allele for the single nucleotide polymorphism (SNP) - rs9939609 - has been extensively associated with an increased odds of being obese, defined by several obesity phenotypes (1). The mechanisms whereby this gene induces the increased fat mass are now being investigated. Due to the FTO gene being highly expressed within the hypothalamus, hypotheses concerning energy intake have been developed and there is evidence that those with the risk allele may consume more energy (2). In terms of energy expenditure there have been contrasting reports with null (3) and positive (4) associations found between FTO gene variants and self-reported physical activity. While these initial reports are intriguing, the clinical measurements are far from robust. Specifically analysing the association between rs9939609 genotypes and sedentary behaviour, assessed by accelerometry, while adjusting for moderate-to-vigorous physical activity (MVPA), could reveal further insight into the role of the FTO gene in energy expenditure.
B686 - Follow-up of bone phenotype associated loci from ALSPAC GWA within the complete ALSPAC cohort - 11/08/2008
The aim of this proposal is to perform follow-up genotyping of top, bone phenotype related, genotypes within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. Our definition of "top" signals of interest will take into account a three sources of information, original ALSPAC genomewide association testing, bioinformatics analysis of highest scoring SNPs and from collaborative exchange between ALSPAC and an established study for genomewide association in extremes of bone mineral density. This, in combination with results available from the one available publication on this topic, should allow us to confidently generate a list of potentially replicating loci for further follow-up. Our current estimations as to the number of loci to be followed up are approximate, however (considering the power of our studies and budget constraints) are likely to include up to 20 loci.
In terms of the recognition and analysis of reliable genetic associates of bone mineral density, this use of the ALSPAC cohort marks an important step. Given the precision and diversity of the measures available in the ALSPAC cohort, this will mark the first comprehensive analysis of top genomewide association signals from available evidence in any cohort in this way and an encouraging first use of ALSPAC genomewide genotype data.
B685 - Is there a relation between Developmental Coordination Disorder at 7-8 years and physical activity at 11 years - 11/08/2008
Background:
Children with Developmental Coordination Disorder (DCD; 5-6% of children) form a large group at risk of a less active lifestyle, social isolation, obesity and mental health problems1-3 with a higher prevalence in boys (Boy:girl ratio of 4:1 to 7:10) 4. The relationship between movement skill in children with DCD and physical activity participation has not been established in a UK population. Mediating factors of generalised self efficacy and peer relations have been shown to influence physical activity in children with DCD in Canada and Australia respectively 1,5. Many of these children, due to their motor coordination difficulties, are unable to cycle or swim and thus may not be able to take advantage of government initiatives to boost fitness through school sport schemes. Furthermore, health fitness may be compromised in individuals with low motor competence3,6.
Reduced levels of physical activity participation in typically developing children are of a concern7,8 as well as considering the levels of physical activity energy expenditure during the day which contribute to overall health fitness9. Children with DCD may be at an additional, increased risk of reduced physical activity participation, in part due to a lack competence and confidence in their movement skill performance. This may contribute to exclusion by peers in PE and playground activities which results in social isolation, further reducing opportunities for exercise2,10-11. Lonliness and lowered life satisfaction of boys with DCD has been linked with reduced participation in team sports which may result in reduced participation in moderate to vigorous physical activity with incrased time engaged in activities with low levels of physical activity 5,12.
There is emerging evidence to suggest that children with DCD, particularly boys, may have a two-fold risk of obesity with 70% showing low cardio-vascular fitness1,3,6. Other studies have highlighted the social isolation experienced by these children along and additional risks of associated psychopathology 11,13. It is not known how these factors interact with a developmental history of poor movement skill to influence physical activity.
Current assessments and interventions for DCD tend to consider the short term amelioration of movement difficulties rather than participation and enjoyment in physical activities.
Dr Green is a post doctoral academic occupational theapist with a research interest in activity participation. This project will dovetail with the work of Dr Lingam and Professor Emond who have defined DCD within the ALSPACcohort and are looking at the long term psychosocial and health effects of this condition. ProfessorsNessand Riddoch have extensive research experience with ALSPAC exploring levels and patterns of physical activity and energy expenditure in children.
This study proposes to analyse data collected as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study.It will analyse the relationship between movement difficulities at age 7 to 8 years with later activity participation at age 11 years, adjusting for other physical health, psychosocial indicators and potential confounding factors.
B683 - An investigation of breastfeeding protection on obesity based on FTO genotypes - 04/08/2008
Background. Childhood obesity is considered to have reached epidemic levels in developed countries. A number of studies have reported remarkably strong, replicable associations with obesity indices for the FTO gene.
We investigated the prospect of breastfeeding protection from obesity markers on a genotype dependent way for the FTO rs9939609 and rs11075989 polymorphisms in the GENDAI cohort - 1138 children attending fifth and sixth grade living in the Attica region of Greece (53% girls; mean age: 11.2+/-0.7 years) recruited from randomly selected elementary schools.
For both SNPs, children homozygotes for the risk allele presented higher values of BMI, waist, waist to hip ratio, skinfolds (triceps and subscapular) body fatness and TNF-a levels. Multivariate analysis showed that, after controlling for age, sex, physical activity, Tanner stage and energy intake, the impact of both SNPs on body composition variables and on TNF-a levels remained statistically important. We looked then on breastfeeding variable and we found that the prevalence of any breastfeeding was 80.6% with the majority of breast feeders reporting duration of 2-4 months. Including breastfeeding as a covariant in the model we revealed that breastfeeding was inversely associated with waist to hip ratio (beta+/-SE: -0.075+/-0.016, p=0.0004). Additionally to that a strong interaction was observed with both SNPs for waist to hip ratio and for body fatness.
We want to use a sample of the ALSPAC cohort to replicate our findingds in the GENDAI cohort. For this purpose we are requesting data on children for which there is available information on breastfeading (see below) and genotypes for SNP rs9939609.
In the GENDAI study data on the method of infant feeding were obtained from self-completion questionnaires sent to each mother. Information on breastfeeding duration was available as a categorical variable, and for this study we had information on the exclusivity of breastfeeding and of breastfeeding and formula on the same time. A positive answer was recorded if the duration of breastfeeding exceeded one month.
We would like to request
Breastfeading Mother Questionnaire Birth to 6 months
Sex Child
Body weight Child Clinic at the age of 10-12 years
Height Child '' ''
Waist circumference Child '' ''
Waist to hip ratio Child '' ''
TNF-a (pg/ml) Child '' ''
skinfolds
triceps Child '' ''
subscapular Child '' ''
body fatness Child '' ''
Genotype rs9939609 Child
B682 - Risk Factors and outcomes associated with bedwetting daytime wetting and soiling in late childhood and early adolesence - 04/08/2008
Summary
The overall aim is to increase an understanding of the impact of nocturnal enuresis, day wetting and soiling in late childhood/early adolescence (9-13 years) and to examine risk factors for persistent wetting and soiling in a prospective cohort study - the Avon Longitudinal Study of Parents and Children (ALSPAC). The two main threads are:
(i) the impact of persistent wetting/soiling problems on the everyday life of young adolescents on outcomes,including mental health, education/school attainment, peer relationships, social activities and goals/aspirations for the future
(ii) the risk factors for wetting and soiling problems continuing through the period of late childhood and into early adolescence
Within these threads, the specific research questions of the proposed project are:
Impact of wetting and soiling
* Do children with persistent wetting/soiling at 13 years have a higher risk of problems with mental health, self concept / image, education/school attainment, peer relationships and leisure activities than those with delayed bladder/bowel control (wetting/soiling that resolved during the period 9-13 years)?
* Are there long lasting negative outcomes associated with experiencing a delay in attainment of bladder/bowel control, or do the problems improve/resolve following resolution of wetting/soiling?
* Does the impact of wetting/soiling problems become more acute or distressing in late childhood/early adolescence compared to earlier childhood?
* Are adolescents with combined problems (wetting and soiling) at increased risk of negative outcomes compared to those with wetting or soiling alone?
Risk factors
* What is the impact and timing of negative life events on trajectories of bladder/bowel control?
* Is there an increased vulnerability to negative outcomes in children with wetting/soiling who experience socioeconomic disadvantage
* Does onset of puberty have an impact on wetting/soiling problems? Is puberty associated with a resolution of wetting/soiling?)
* Is there a higher rate of cognitive impairments in children with persistent wetting/soiling compared to delayed bladder/bowel control?
B781 - Interactions between early diet and filaggrin and FADS mutations on risk of eczema asthma and allergen sensitisation - 01/08/2008
Asthma, eczema and other allergic disorders are common among children in industrialized countries, and their frequency is increasing. Changes in diet provide one possible explanation for this increase, but the results of dietary intervention trials in older children have been disappointing, and it has been suggested that diet during pregnancy and infancy may be critical to the development of atopy(1). In particular it has been suggested that the age of introduction of solids, duration of breastfeeding, and the balance of n-3/n-6 PUFAs in the pregnancy and infant diet may be important. Traditionally, the advice given on feeding infants at high risk of atopy is that to minimize risk they should be breastfed for at least six months, and that solid foods should be avoided for at least 4-6 months, with possible further delays in the introduction of particularly allergenic foods such as egg and peanuts(2-4). However, the efficacy of all aspects of this advice is questionable. There are a number of mechanisms by which early diet could be associated with the development of atopy. There could be a causal relationship, whereby early introduction of solid foods either induces an allergic response, or alternatively induces immune tolerance and so reduces the risk of allergy/atopy. It is possible that atopic parents, or parents noticing early symptoms of allergy in their child might delay the introduction of solids, generating a spurious association between the early introduction of solids and allergy/atopy (reverse causation). It is also possible that prolonged breastfeeding or delayed introduction of solids might increase the rates of allergy/atopy by affecting the development of mature immune response mechanisms in the infant - either by a direct reduction in exposure to immune stimulants such as bacteria, or in the case of breastfeeding by passive transfer or immune responses from the mother (hygiene hypothesis). There are relatively few studies of the associations of early diet with eczema and asthma and the results are very variable. Some studies have found early introduction of solids to be associated with wheezing and eczema, others have found no association, and some have found later introduction of particular solids to increase the risk of eczema and food sensitization (5,6).
One possible reason for the variability in the results of these studies is interaction of these dietary factors with the child's genotype. Loss of function mutations in the filaggrin gene have been shown to confer a greatly increased susceptibility to eczema, eczema plus asthma, and allergic sensitisation(7). This genotype has been shown to interact with environmental factors, with exposure to cats only being a risk factor for infant eczema among FLG deficient infants(8) Filaggrin has been detected in both human oral cavity and pharynx and rodent gut (9), and indeed the gut has been characterised as a key site for peanut absorption and sensitisation (10). However, as far as we are aware there is no data on how filaggrin genotype might interact with early dietary factors to determine the risk of allergic and atopic disorders.
Atopic sensitisation and inflammation are related to plasma levels of the 2-series prostaglandins and 4-series leukotrienes, which are derived from arachidonic acid(9). Common polymorphisms in the fatty acid delta-5 delta-6 desaturase gene cluster FADS1 and FADS2 have been linked with both altered plasma levels of arachidonic acid and clinical symptoms of adult atopy(10). There is no data on how FADS genotype is associated with the risk of wheeze and eczema in children and infants, nor on how this genotype may interact with early dietary factors such as PUFA intake.
Proposed project:
We propose to investigate the relationship between early dietary factors and atopic outcomes in the ALSPAC cohort, considering possible interactions with filaggrin and FADS genotype. Statistical analyses will take account of the possibility of reverse causation.
Data requested
1. Outcome variables:
Wheeze in the first 3 years of life (assessed by questionnaire at 6m, 18m, 30m and 42m)
Wheeze at 7 1/2 years of life (self-reported)
Questionnaire data on doctor-diagnosed asthma at 7 years
Lung function by BHR at 8 years (clinic assessment)
Results of skin prick tests at 7 years (clinic assessment)
Eczema assessed by questionnaire at 6, 18, 39, 42, 57 and 81 months of age.
Flexural dermatitis assessed by observation annually from 7y to 11y (clinic assessment).
2. Infant dietary predictor variables (all assessed by questionnaire at 6m and 15m):
Duration of breastfeeding
Age of introduction of formula milk.
Age of introduction of any solids.
Number of solids introduced at 4m and 6m.
Age of first introduction of egg, fish, meat, fruit, vegetables
Pregnancy dietary predictor variables (assessed by FFQ at 32 wks gestation):
PUFA intake in pregnancy
fish intake in pregnancy
3. Other predictor variables:
Fillagrin genotype
FADS genotype
4. Confounding variables:
Maternal education (assessed by questionnaire at 32 wks gestation)
Maternal age (assessed by questionnaire)
Smoking in pregnancy (assessed by quesitionnaire at 32 wks gestation)
Maternal parity (assessed by questionnaire)
Pet exposure (assessed by questionnaire)
Gestation (assessed by questionnaire)
Sex
ETS in first four years (assessed by questionnaire)
Crowding (assessed by questionnaire)
Child's BMI
Parental atopy (assessed by questionnaire)
References
1. Devereux G. The increase in the prevalence of asthma and allergy: food for thought. Nature Reviews Immunology 2006;6:869-874.
2. Pediatric Nutrition Handbook. 2004 Elk Grove, IL: American Academy of Pediatrics.
3. World Health Organisation. Fifty-Fourth World Health Assembly. WHA54.2 Agenda Item 13.1. Infant and Young Child Nutrition. 2004. Geneva, Switzerland: World Health Organization.
4. Murano A et al. Dietary prevention of allergic diseases in infants and small children: part III - critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatric Allergy and Immunology, 2004;15:291-307.
5. Tarini B et al. Systematic review of the relationship between early introduction of solid foods to infants and the development of allergic disease. Archives of Pediatric and Adolescent Medicine 2006;160:502-507.
6. Zutavern A. et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitisation at the age of 6 years. Results from prospective birth cohort study LISA. Pediatrics 2008;121:e44-e52.
7. Henderson J et al. The burden of disease associated with filaggrin mutations: A population-based longitudinal birth cohort study. Journal of Allergy and Clinical Immunology 2008 (In Press).
8. Bisgaard H et al. Gene-environment interaction in the onset of eczema in infancy: Filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PloS Med 2007;5:e131.
9. Makino T et al. Expression of hornerin in stratified squamous epithelium in the mouse: a comparative analysis with profilaggrin. J Histochem Cytochem 2003;51:485-492.
10. Anonymouse. Absorption of peanuts. N Engl J Med 1981;304:359-360.
11. Behrendt H et al. Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergen sensitization. Int Arch Allergy Immunol 2001;124:121-125.
12. Schaeffer L et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human Mol Gen 2006;15:1745-1756.
B680 - Molecular Phenotyping in the Avon Longitudinal Study of Parents and their Children A resource for understanding Molecular genetic pathways underlying phenotypic variation in humans - 30/07/2008
ObThe aim of this application is to develop a world-class resource for systems biology that elucidates the molecular pathways underlying genotype-phenotype associations in the UK's largest, most densely phenotyped, prospective cohort. Specifically, 1000 adolescents from the Avon Longitudinal Study of Parents and their Offspring (ALSPAC) who have been measured repeatedly in a prospective study across a wide range of biological, sociological and behavioural variables, and for whom pre-existing genome-wide SNP data and genome-wide expression levels in transformed lymphoblastoid cell lines are also available, will be assayed on a range of molecular phenotypes including: (a) level of small molecule metabolites, (b) serum protein concentrations, and (c) methylation profiles. This information will then be entered into a database and made available to bona fide researchers, through data sharing systems that already exist within ALSPAC and that facilitate rapid access with clear variable definitions. The database will not only comprise the world's largest collection of molecular phenotypes to date, but also the first publicly available resource for systems biology which allows users to integrate genetic and molecular data with end stage phenotypes.
B684 - Role of Growth Hormone pathway SNPs in childhood obesity - 28/07/2008
Aim:
We intend to analyse genetic variants in genes of the growth hormone pathway for their association with childhood fat mass and measures of obesity in adulthood.
Rationale:
This is a continuation of a project which has already identified an association between a genetic variant in the the growth hormone gene cluster and fat mass in ALSPAC children. We wish to expand this research to include other genes in the same pathway that may have additional effects on fat mass in order to determine (a) the importance of this pathway in childhood obesity and adult cardiovascular risk and (b) whether there is any potential for therapeutic developments. Genetic variants have been selected on the basis of functional candidacy and nominal association (pless than 0.01) with type II diabetes in the WTCCC genome-wide data. This combines the notion of prior biological knowledge with significance values in genome wide data, as typified for example by the appearance of key pharmacogenetically important genes such as PPARG in genome wide data. The growth pathway includes several drugged, druggable or possibly nutritionally modifiable targets and these may be lower down the order of hundreds of genes with modest effects in polygenic disease although potentially of more practical utility as targets..
Methods:
Genetic analyses will be carried out by KBioscience according to the standard ALSPAC arrangements for SNP genotyping. Data analysis will be carried out in STATA using regression to test per allele genetic effects.
Genetic variants and phenotypes are listed below.
Expected value of results:
Understanding the genetic mechanisms underlying obesity is an important component of researching the obesity epidemic. We hope this project will direct us to genetic variants that are both important in childhood obesity and in predisposition to adult cardiovascular disease. This work will help clarify the role of a candidate genetic pathway and provide valuable information for future research.
B679 - Sedentary Behaviour and its Impact on Physical Fitness in Adolescents - 19/07/2008
Purpose:
To examine any potential, independent, association between sedentary behaviour and physical fitness among the ALSPAC adolescents at 13 years old
Background:
Cardiorespiratory fitness (CRF) is an important component of overall physical fitness and low CRF was found to increase the risk of mortality, in adults, independent of fat mass (1). Therefore improving physical fitness should perhaps be a priority, and may have a greater impact upon health outcomes than if weight reduction is solely targeted. Engaging in physical activity is of great benefit to CRF, especially vigorous physical activity (2). However, physical activity does not explain all the variance in CRF (2). Therefore, specifically reducing the time spent sedentary may be of importance. Previous studies involving adults and children have shown sedentary behaviour to be independently associated with various health outcomes (3, 4). However, there is a lack of research concerning the independent effects of sedentary behaviour upon CRF, and this information could potentially help ameliorate morbidity and mortality rates seen in later life (1).
Variables
- Dependent Variable:
? Physical Fitness (PWC 170; 13 year olds; clinical)
- Independent Variable:
? Sedentary Behaviour (hours per day, accelerometry; 13 years old; clinical)
- Covariates:
? Age, pubertal status (chronological and biological maturation; 13 years old; child-response questionnaire)
? Birth length, birth weight, gestation, TV viewing (38mo) and sleep patterns (30mo) (intrauterine factors and early life factors; parental/birth records, 30 and 38 month questionnaire)
? Parental height, parental BMI, social class, maternal smoking during pregnancy, maternal education at time of birth (parental and sociodemographic factors; 32 week questionnaire)
? Adolescents total fat mass (body composition measure; 13 years old; DXA)
? MVPA (physical activity, accelerometer; 13 years old; clinical)
B678 - Childhood negative early life events and pain in adolescence a birth cohort study - 16/07/2008
Aims and purpose of the proposed research
The proposed study will examine whether negative early life events in childhood predict pain in adolescence. To do so the study will examine the following hypotheses:
1) Negative early life events in childhood (pre-natal, birth and early childhood) predict musculoskeletal pain in adolescence
2) Negative early life events in childhood (pre-natal, birth and early childhood) predict chronic widespread pain in adolescence
3) These relationships are moderated by physiological and psychological factors including HPA axis dysfunction, sleep, anxiety and depression.
B677 - Physical activity in pregnancy and offspring neurodevelopment - 14/07/2008
Background
Physical activity has been associated with improvements in cognitive function in both animals and humans. In adult rats and mice, voluntary physical activity has been associated with neurogenesis in the hippocampus (1, 2) and with an increase in long-term potentiation of synaptic efficacy (2). In adult humans, cardiovascular fitness is associated with better performance on cognitive functioning tests (4). In rats and mice, maternal exercise during pregnancy appears beneficial to offspring neurodevelopment. In mice, voluntary wheel running during pregnancy led to differences in offspring's hippocampal cell proliferation (5). In rats, maternal swimming once a day for 10 minutes was associated with offspring having higher levels of neurogenesis in several regions of the hippocampus, higher levels of brain-derived neurotrophic factor, and better short-term memory (6).
The hippocampus may play a key role in the mechanism underlying these beneficial effects of physical activity. Traditionally, the hippocampus has been thought to preserve episodic memories (memories of events) while its role in memorization of facts (semantic memory) is less established. However, recent research has implicated the hippocampus in semantic memory potentially through its role in associative thinking (7, 8). As an example, the hippocampus was recently implicated in acquiring a unique and imaginary lexicon through visual images. Thus, language acquirement through associative learning, as is done in children, may be mediated by the hippocampus (9).
In humans, the effects of physical activity during pregnancy on the neurodevelopment of offspring have been inadequately studied. Three studies of the subject of three slightly different samples of women have been done by JF Clapp. In one study of healthy women with a history of engaging in regular physical activity, women who continued to exercise throughout pregnancy had neonates (N=34) who scored higher in terms of orientation behavior and their ability to regulate state at 5 days after birth as measured by the Brazelton Neonatal Behavioral Assessment Scales when compared to neonates born to women who did not exercise (N=31) (10). In a similar study design, infants of exercising mothers (N=52) at one year of age scored slightly (non-significantly) higher on the mental performance domain of the Bayley Scales of Infant Development when compared to infants of non-exercising mothers (N=52). For psychomotor score, however, infants of exercising mothers scored statistically significantly higher, though the effect was small (11). In the third study, 5 year-old children of women who exercised during pregnancy (N=20) were compared to women who did not exercise (N=20) using the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Peabody Picture Vocabulary Test, the Expressive One Word Picture Vocabulary Test, and the Clinical Evaluation of Language Fundamentals. The children of exercising mothers scored higher in the domains of general intelligence (p=0.01) and oral language skills (p=0.01) (12). The difference in language skills is particularly intriguing given the potential role of the hippocampus in vocabulary acquisition.
Investigation is needed on physical activity during pregnancy in relation to offspring neurodevelopment in humans. Animal evidence supports a biological mechanism for such an effect but the previous human studies suggest a positive association yet are not convincing.
Project Description
We propose an investigation of physical activity during pregnancy in relation to neurodevelopment in offspring using data from ALSPAC. This cohort is ideal for this project for several reasons. We expect that if physical activity influences neurodevelopment the effect may be small and the large sample size in ALSPAC will improve power. Physical activity was assessed by self-administered questionnaire at approximately week 18 of pregnancy for nearly 12,000 women. Of these, we expect over 4,000 will have had IQ measured at age 8 years.
Several questions in section G of the 18 week pregnancy questionnaire have questions on physical activity. Most importantly, question G19 ascertains the number of hours per week, at present, that the woman participated in any of 11 specific exercise-intensive activities.
With respect to outcome, ascertainment was of especially high quality at age 8 compared with other large cohorts that rely on parent-completed questionnaires only. We will follow the analytical plan as presented by Hibbeln et al. (13), in their recent paper on pregnancy seafood consumption in relation to neurodevelopmental outcomes in childhood (except with physical activity scale(s) as the main exposure variable). Their results were adjusted for 26 potentially confounding factors; we might also want to adjust for pregnancy seafood intake.
B676 - Long-term consequences of feeding problems in infancy and early childhood - 11/07/2008
Young infants spend between a half and a third of their waking time feeding, making the outcome of the feeding situation important, not just in terms of nutrition, but also in the establishment of the relationship between the caregiver and the child (Wolke, Skuse and Reilly, 2006). Feeding problems are common amongst infants and young children. The reported prevalence of feeding disorders is 5-10% (Lindberg et al, 2006), with 20-25% of parents reporting feeding problems at some time in the first two years (Wolke, 2003). Considering that there were 669,601 live births inEnglandandWalesin 2006 (Office of National Statistics) up to 167,000 will experience some form of feeding problem in their first two years of life. The most prevalent feeding problem is refusal to eat, with only 14% of cases being linked to some form of physicaldisorder (Wolke, 1994).
One serious consequence of feeding problems in young children can be failure to thrive, or growth faltering, as it is coming to be known. Failure to thrive has been defined as the rate of weight gain being significantly below the weight gain on population standards and persisting for more than three months (Wolke, Skuse and Reilly, 2006). The prevalence of failure to thrive is 3-5 % of the population in Western countries (Corbett and Drewett, 2004). A conditional weight gain criterion has been used to define growth faltering, which takes weight and gestational age at birth into account to identify the slowest 5% of infants to gain weight ( Drewett et al, 2004; Blair et al, 2004; Emond et al, 2007). Corbett and Drewett (2004) conducted a review and meta-analysis and concluded that "failure to thrive in infancy is associated with adverse intellectual outcomes sufficiently large to be of importance at a population level".
However, the majority of those with feeding disorders do not fail to thrive (Lindberg et al, 2006), and feeding problems and failure to thrive are separate phenomena (Rydell and Dahl, 2005). It is necessary to look at the long-term consequences of feeding problems where there is no failure to thrive as distinguished from any consequences that are the result of the severity of the effects on growth. There are a few studies that have looked at the long-term outcome of feeding problems with and without growth faltering (e.g. Lindberg et al, 2006; Dahl et al, 1994; Rydell and Dahl, 2005; Marchi and Cohen, 1990; Kotler et al, 2001). However, the community samples have been usually small and most studies are based on clinically referred populations more likely to suffer multiple regulatory problems (Wolke, 2003; Papousek et al, 2008).
Previous work using ALSPAC
Motion et al (2001) reported on persistent early feeding difficulties and subsequent growth and early development outcomes using the ALSPAC data. Persistent difficulties were defined by reference to weak sucking at 4 weeks and great difficulties feeding at 4 weeks, 6 months and 15 months of age. Persistent feeding difficulties were associated with significant developmental impairments in motor, language and behaviour at 18 months, with weight gain being a continuing problem. Behavioural outcomes were temper tantrums and frequent meal refusal at 18 months.
Emond et al (2005) investigated the relationship between feeding symptoms and early growth faltering in ALSPAC. They reported that growth faltering between birth and 8 weeks was associated with infant sucking problems regardless of the type of milk, and after 8 weeks of age the most significant post-natal influences on growth were the efficiency of feeding, the ability to successfully take solids, and the duration of breastfeeding. A subsequent study (Emond et al 2007) found that growth faltering in infancy was associated with persisting deficits in IQ at 8 years. Multivariate analysis showed that reduction in IQ was linked with growth faltering before 8 weeks and associated feeding problems.
There is a surprising paucity of investigations of the long-term consequences of feeding problems on behavioural outcome and continued eating disorder in childhood (Micali, 2005). Little is known about whether the chronicity of feeding problems increases the risk for other behavioural maladaptations. No previous study has taken into account whether any long-term consequences of feeding difficulties may be impacted by co-morbidity with other infant problems such as crying or sleeping problems (Wolke et al. 1995; Wolke et al., 2002;Von Hofacker & Papousek, 1998). ALSPAC provides an excellent dataset for investigating the longitudinal trajectories of feeding problems, and the interaction with other problems, both those intrinsic to the infant and factors in the family and wider environment.
The research questions to be addressed by the proposed project are:
- What is the impact of feeding problems in infancy and the toddler years on the development of behavioural and psychiatric problems in childhood? Do early feeding problems predict later eating disorder?
- Are the long-term consequences due to feeding problem behaviour, or are these a consequence of multiple regulatory problems in infancy (i.e. crying, sleeping problems) or social and family problems?
B675 - Cardiovascular Health During Growth Hormone Therapy in Transition - 10/07/2008
No outline received
B258 - The functional study of preterm birth - 06/07/2008
We wish to investigate the associations between birth outcomes, (primarily gestational age and birth weight) and SNPs with proven roles in biochemical phenotypes. Key pathways include the inflammatory response and vascular function, which has important implications for utero-placental function. We have recently performed a genome wide assocaition study of mulitple biochemistry phenotypes in the InCHIANTI study (Melzer et al PloS Genetics, May 08), that has identified, or taken to GWAS significance, many variants altering biochemical traits. This study and other recent genome-wide and large-scale association studies have provided robust evidence (P values less than 5 x 10-8) that common genetic variants, marked by key SNPs, influence the levels of various inflammatory cytokines, clotting factors, and susceptibility to aneurysm. This makes them excellent candidates for altering fetal growth and or gestational age and greatly increases the prior odds that they will influence genetic susceptibility to preterm birth through these pathways. In addition, SNPs have been identified which alter the circulating serum levels of various nutrients, hormones and growth factors, including Vitamin A, each of which is also a potential candidate for influencing susceptibility to preterm birth. In the case of Vitamin A , a known teratogen, the SNP that alters Vitamin A may alter risk of miscarriages or fetal abnormalities.
In this study we propose to test the hypothesis that each selected "functional" SNP is associated with fetal growth and or gestational age.
We wish to genotype the selected SNPs in all ALSPAC mothers and children in order to assess associations between fetal growth gestational age and both maternal and fetal genotypes.
ALSPAC is the largest and best UK study for investigating the genetics of fetal growth and perinatal outcomes as it is well-powered to detect small genetic effects, it has the availability of both maternal and fetal DNA and has detailed clinical data on birth size and pregnancy outcomes as well as other relevant maternal phenotypes. RAINE in collaboration with Lyle Palmer, and NFBC with Mark McCarthy, Leena Peltonen and Marjo-Riita Jarvelin are other potential sources of replication/meta-analysis for fetal effects.
B674 - Biobank methods proposal - 30/06/2008
No outline received
B673 - Provision of demographic variables from ALSPAC cohort to link with CDR gathered variables during TF2 - 27/06/2008
The collaboration between Cognitive Drug Research (CDR) Ltd and the Avon Longitudinal Study of Parents And Children (ALSPAC) involved the measurement of attention in ALSPAC participants using the laptop-based CDR computerised assessment system. This collaboration was to be based around our generic collaboration agreement, a copy of which is attached, but owing to oversights, was not signed for this particular data gathering exercise.
The central dataset we use at CDR will include the CDR variables collected, and require demographic information from the ALSPAC study (gender and age required; handedness and race if available).
In keeping with the spirit of the standard CDR Collaborative Research Programme agreement (example attached), it is proposed that both parties have shared access to the data by holding identical copies.
Intended use
CDR hold a large in-house normative database of cognitive data. We propose to add the ALSPAC data to this database. Data will be anonymised, and reference to the source of the data in relation to our norms will not be made. The CDR normative database is used internally for reference and not published or sold externally.
Publication
If publication or presentation of the work occurs, both CDR and the Collaborating Group must agree the content of the publication or presentation. The 'Cognitive Drug Research computerised assessment system' must be mentioned in any publication or presentation. Representatives from both CDR and the Collaborating Group must be on the author list of any publication or presentation.
The publication policy of the ALSPAC study will be adhered to.
Generally, with any publications or conference presentations, the ALSPAC will take senior authorship, and one or more members of the CDR team who has been involved in the research will receive junior authorship.
If there are any questions relating to this proposal, Paul Snell would be happy to address them in the first instance.
B668 - Adiponectin as a biomarker in pharmacoepidemiology and as a biomarker in the wide human clinical phenome - 26/06/2008
Adiponectin is the most highly expressed adipocyte protein and is readily measurable in serum. It
has been extensively studied in the context of obesity, diabetes and metabolic syndrome and has
been clearly shown to have a direct role in the pathogenesis of diabetes. Being negatively
correlated with fat mass and acting as an insulin sensitizer, it represents one critical link between
fat mass and diabetes. It also has directly anti-inflammatory actions. Vascular disease and other
consequences of diabetes are among the most major diseases of our era in the developed and
developing worlds. This then states the general prominence of the protein. This proposal concerns
the biomarker potentials of adiponectin ranging beyond its pathogenic role in diabetes. We focus
on its potential as a pharmacoepidemiological marker and on its relationships to many other
facets of the clinical phenome.
B665 - The Epidemiology of Balance Problems in Childhood the affect of alcohol consumption during pregnancy - 26/06/2008
05.07.2010
E-mail from Rachel - 5/7/10
I'm doing this project for my PhD - have done nearly three years, another 12 - 18 months to go I think. I've had one paper rejected, and am about to send the exec a new version. Another paper is also nearly ready for the exec.
B667 - Long-Term Outcomes of Information Processing in Infancy - 25/06/2008
Long-Term Outcomes of Information Processing in Infancy
(From data on "Children in Focus")
From data on "Children in Focus" collected from 4 months to 11 years, we aim to investigate the following research questions:
Prediction from habituation to later information processing/memory as well as to attention measures.
Prediction from habituation to later cognitive tests and language /speech.
Stability of information processing and short term memory tasks.
Stability of IQ/cognitive tests.
Stability of Language/Speech.
Stability of individual differences in children's performance across age will be evaluated by Pearson correlation coefficients. To assess the predictive validity of habituation on later child outcomes, structural equation modeling will be conducted to obtain both direct and indirect effects as well as take into consideration a variety of control variables. To increase the precision of the within-child cognitive stability findings and to obtain the unique predictve validity of infant habituation on childhood outcomes, we will take into consideration (as we have done previously) child temperament, gender, birth-order, maternal education, and home environment.
B666 - Using Lifecourse analyses to predict axial length changes and myopia in the ALSPAC cohort - 25/06/2008
Study Plan
In this 3-year study, the named applicant (SS) will spend 2 years working on life course models to develop and test causal pathways for myopia using the 15-year data. At the same time, data on myopic progression will be collected from cohort members who attend the 17+ clinic (estimated as 4,500?). In the third and final year, the most robust models derived from years 1 and 2 will be used to analyze the newly acquired myopia progression data (i.e. change in axial length). Outputs will include papers on both the methodologies employed, with recommendations for use in other contexts and on the predictive power of eye growth over the lifecourse analyses to predict myopia.