Proposal summaries
B525 - Determining the causal effect of vitamin D on perinatal metabolic vascular and bone health - 08/07/2007
This grant will be submitted as DA Lawlor's main MRC programme grant for 2008 as part of the MRC Centre for Causal Analyses in Translational Research. It is concerned with determining the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery), vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness), metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids) and skeletal health (variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC offspring and mothers other relevant studies that are linked to the MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE) will contribute to the programme. Our specific objectives are:
1. To use bioinformatics and genome wide association studies to identify genetic variants that are associated with vitamin D levels.
2. To replicate the association of these variants with vitamin D levels in ALSPAC mothers and offspring.
3. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery)using data from ALSPAC, Danish National Birth Cohort, the Norwegian Birth Cohort and the Born in Bradford Cohort.
4. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.
5. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.
6. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on skeletal outcomes(variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC mothers and offspring will be used for this objective.
B524 - Linkage of polymorphisms of PMCH with asthma and obesity - 08/07/2007
Th1 and Th2 cells are the two main subsets of CD4+ T helper cell and are defined by their cytokine expression patterns. The subsets have different roles in the clearance of pathogens, and their unregulated activation leads to distinct immune pathologies. Th1 cells express IFNgamma and are crucial for the phagocytic immune response against intracellular pathogens such as M. tuberculosis, but their aberrant activation is implicated in autoimmunity. Human Th2 cells express IL-4, IL-5 and IL-13 and orchestrate an immune response characterized by eosinophilia and IgE class-switching, in order to fight extracellular pathogens. Th2 cell activation is also central to the pathogenesis of allergic diseases such as asthma, in which the Th2 cytokines play important roles.
PMCH encodes a pro-hormone, pro-melanin concentrating hormone (PMCH) of 165 amino acids which is proteolytically processed to form several peptides including the orexigenic peptide melanin concentrating hormone (MCH). PMCH was first implicated in the regulation of appetite by the finding that the gene is upregulated in obese, leptin deficient mice. Further studies demonstrated that intracerebroventricular administration of MCH into rats increases feeding, and weight gain occurs after chronic infusion of the peptide into the lateral ventricle, strongly suggesting that the peptide stimulates appetite. In addition, mice deficient in MCH are lean and hypophagic, and animals overexpressing the gene are obese. Several groups cloned the G-protein coupled receptor for MCH termed MCHR1, and MCHR1 deficient mice are resistant to diet induced obesity. A second receptor, MCHR2, was later identified in humans by its homology to MCHR1. MCHR2 is not present in the rodent genomes, but orthologues have been identified in ferret, dog and rhesus monkey, in addition to the human gene. PMCH therefore has an important role in increasing appetite, and a small molecule antagonist of MCHR1 has been shown to reduce feeding and weight gain in rats fed a high fat diet ad libitum.
The prevalence of both asthma and obesity are increasing in the western world, and a link between the two conditions has been proposed and debated. Epidemiological evidence from several studies suggests a positive association between body mass index (BMI) and asthma, especially in females (1). Mechanisms to explain the association are unknown.
Utilizing microarray analysis of in vitro differentiated Th1 and Th2 cells to identify secreted proteins selectively expressed by human Th2 cells, we found for the first time that activated Th2 cells expressed the gene PMCH. Activated Th2 cells secreted MCH-containing proteins, and ex vivo Th2 but not Th1 cells also expressed the gene.
PMCH gene is located on chromosome 12q23.1, a region consistently shown to have linkage to asthma. We hypothesize that expression of PMCH by Th2 cells in vivo in the asthmatic lung may provide a mechanistic link between allergic inflammation, asthma and obesity. Asthmatic individuals are not necessarily obese, however, therefore we wish to test whether there are genetic polymorphisms of PMCH that are associated with both asthma and obesity. As expected, a positive association between BMI and asthma in girls at 7 years of age has been confirmed in ALSPAC (AJ Henderson, unpublished data).
B520 - An investigation into the relationship between growth and dental caries - 02/07/2007
Introduction:
The study planned is an analysis of existing data within the Avon Longitudinal Study of Parents and Children (ALSPAC). The aim is to examine the growth rates of children with and without dental caries from birth until the age of five years.
The hypothesis-generating observation that stimulated the proposed study was that weight and body mass index appeared to increase following removal of diseased teeth (1). The proposed study is required because in the original observational study it was not possible, for ethical reasons, to have a control group i.e. the ethical committee found it unacceptable to observe disease in children's mouths without offering a treatment service to them. Since funding to provide such a service was unavailable the study had to utilize population data for the reference group. The best reference population data available was the UK 90 growth reference data. However, the findings of the study have such profound policy implications that it is important to explore the hypothesis of a caries/growth association with high quality data such as ALSPACs as the weaknesses in the former study cast doubt upon the crucially important findings.
Method:
The growth measurements of the children will be converted to percentiles and SD scores. L grow software will then be used to calculate longitudinal norms and to judge the growth pattern of the participants. The average velocity of growth calculated from their height, weight and body mass index at 4, 8, 12 monthly and 6 monthly thereafter until the age of five for each individual will be correlated with their measured dmfts. The children's gender, maternal and partner social class, maternal education, maternal age, maternal and partner height, breast feeding, ethnic group on growth and their effect on caries rates will also be determined.
Thus the relationship between growth and dental caries can be established as well as the extent to which poor oral health is associated with either abnormal body mass index or acceleration/ deceleration in growth.
Sample Size: the number of children will be between 300 (with complete data) and 800 with data on some measurement occasions
Percentile curves on growth charts are spaced 0.67 of a SD apart. The sample size is therefore calculated for a change in SD score of 0.67 units (one percentile space) assuming a correlation between the SD measure on two occasions of 0.80.
A sample size of 20 in each of two groups would have 96% power to detect a difference in means of 0.67 assuming the common standard deviation was 0.63 using a two group t test with two sided significance. Thus in order to allow analysis and comparison of up to 5 sub groups, a sample size of 200 is suggested.
sample. (1) Childhood Growth and Dental Caries. Mohammadi M and Kay E Comm Dent Hlth (in press)
B530 - Early Growth genetic and environmental determinants of sex hormone and growth factor exposure during puberty - 01/07/2007
No outline received
B519 - Prediction of drinking outcomes in ALSPAC - 26/06/2007
Our goal is to add a limited number of additional variables to our current data analyses using the ALSPAC data. We currently have information on the level of response to alcohol and demography at age 12-13, know the outcome regarding a limited number of alcohol-related variables at age 14-15, and have models of how the level of response to alcohol relates to alcoholic outcomes in teenagers and adults from several additional studies (the Collaborative Study on Genetics of Alcoholism, the San Diego Prospective Study adults, and the San Diego Prospective Study adolescents). However, to date none of these structural equation models have been tested in subjects in their early teens. Therefore, if several additional areas of data can be made available to us within the next week or so, we will be able to test whether aspects of the structural equation models generated in late teenagers and adults apply to the ALSPAC population using predictors from age 12-13. The published structural equation models have utilized both the MPlus approach and the AMOS programs as described in the references offered below. To carry out these analyses, we would be grateful for any of the following variables.
1. Age 11 (KW file) and age 13 (TA file) for all SDQ scores. Of particular importance are summarizing scores for externalizing and internalizing symptoms. We do not need specific items. The variables we would like include KW6600a to KW6605c. NOTE: I could not locate the SDQ variables for the 13-year clinic (TA file).
2. Stop-Signal (SS Task Score) from the 10-year clinic. Specifically, we need the number of failures for the hard and easy inhibition items. The specific variable names are: FDCM210 to FDCM222 and FDCM230 to FDCM233.
3. Scores for the TEA-CH test of Sky Search, Sky Search Dual Task, and Opposite Worlds Task from the 11-year clinic. These include variables FEAT060 to FEAT065, FEAT141, FEAT146 to FEAT148, FEAT225, FEAT226, FEAT228, FEAT229.
4. Scores from the Counting Span Task at the 10-year clinic. These variables are FDCM110, FDCM111, FDCM130 to FDCM133.
5. The mother's alcohol, nicotine, and cannabinol use at 18 weeks gestation, as well as the alcohol and nicotine use at 32 weeks gestation. It would also be valuable to have the mother's use of heroin, cocaine, amphetamines, or other drugs at 18 weeks gestation. The variable names for these items include B650 to B679, B700 to B714, B720 to B724, B752 to B760, B767 to B769, C361 to C373, C490, C491, C492.
6. From the puberty questionnaire (including Tanner) scores at the 11-year and 13-year clinics. Specific names include PUB407 to PUB497. NOTE: I could not locate the puberty variables for the 13-year clinic.
7. From the Arnett Sensation Seeking data, variables would include: FESS020 to FESS039, FESS050, FESS051.
B517 - Qualitative survey of use of cannabis and tobacco among adolescents in ALSPAC - towards assessing feasibility of developing and extending a tobacco peer-led intervention ASSIST to preveting cannabis and tobacco use - 25/06/2007
No outline received
B516 - Maternal thyroid levels and development outcome of offspring - 25/06/2007
Specific Aims:
1. To determine the levels of maternal thyroid function tests which result in impaired development of the offspring.
a. To determine the levels of TSH, free thyroxine, thyroglobulin, and thyroid peroxidase antibody in the sera of pregnant women at known times in the pregnancy
b. To compare maternal thyroid function with the neurodevelopment of the child at age 8 years, and determine the association between maternal thyroid levels and specific effects in domains of IQ, attention, behavior, speech and language skills, social cognition, gender behavior, executive function, and manual dexterity in the ALSPAC dataset, controlling for potential confounders such as maternal smoking status and socioeconomic status.
c. To determine which maternal factors (e.g. age, antibody status) and offspring factors (e.g. gender) modify the relationship between trimester-specific thyroid status and development of the offspring.
2. To determine the levels of maternal thyroid function tests which result in fetal demise.
3. To develop trimester-specific normative ranges for thyroid hormone levels during pregnancy, based on the relationship with impaired development and fetal loss.
B515 - Risk factor modelling of the devlopment of atelectasis and retraction of the tympanic membrane usign the ALSPAC dataset - 25/06/2007
No outline received
B506 - The effects of dietary factors on bone development in children and their mothers The Avon Longitudinal Study of Parents and Children - 22/06/2007
We propose to examine the following research question:
What aspects of the child's diet are related to bone structure in children either before and/or during puberty (depending on when the measures were made)?
Aspects of the diet will include:
- Overall assessment of the diet using dietary patterns
- Individual nutrients
- Individual foods and food groups
- Longitudinal measures of dietary effects (from prenatal to the current time)
Aspects of the bone structure to be examined will include:
- Bone size (assessed by area of the whole skeleton derived from total body DXA scans, width of the femoral neck derived from DXA scans of the hip, and cross sectional area of the tibia derived from pQCT scans).
- Bone shape (reflected by the ratio of length and width of the humerus based on a novel method we have recently developed19).
- Cortical thickness (based on hip DXA scans and tibial pQCT scans).
- Trabecular bone mass (based on bone mineral density (BMD) of the spine obtained from sub-regional analysis of total body DXA scans).
- Bone strength (reflected by cross sectional moment of inertia derived from hip DXA scans and tibial pQCT scans).
B511 - Infant feeding rapid weight gain and obesity - 11/06/2007
No outline received
B509 - Adverse clinical risk identification and utilisation for bespoke eye health strategies - 08/06/2007
No outline received
B510 - Do anxiety and depression associated with previous miscarriage resolve following the birth of a health child - 06/06/2007
No outline received
B547 - CCR5 delta 32 mutation and immune related outcomes Is there a link - 05/06/2007
The aim of this study is to investigate whether the CCR5 ?32 mutation is associated with immune related phenotypic outcome. It was proposed that abrogation of CCR5 bias the immune system toward a T-helper-2-driven response(Lucotte and Mercier, 1998). As a consequence we hypothesize that the presence of a CCR5?32 mutation is negatively correlated with the incidence of viral childhood infections and positively correlated with atopic disorders. Corresponding phenotypic outcomes will be obtained from the child-based questionnaires completed by a parent at different ages as well as from biological samples (e.g. skin prick test, IgE). Effect modification by environmental exposure will be investigated. The data will be analyzed using established statistical methods for genetic studies, primarily via regression models adjusted for potential confounding factors. Potential population admixture will be allowed for in the analysis.
Genotyping will be done until end of July. Subsequently the analysis will be performed. The results will published in a scientific journal.
B528 - 1958 DNA distribution - 01/06/2007
The British 1958 birth cohort1 is based on all persons born in Britain during one week in March in 1958. Participants have been followed throughout their lives and biomedical information has been collected at various time points. Biological samples were collected from the cohort during medical examinations between Sept 2002 and March 2004. Funding for creation of a blood derived DNA bank was provided by the MRC (strategic project grant G0000934). Funding for creation of lymphoblastoid cell lines, cell line derived DNA extraction, banking and distribution was funded by the Wellcome Trust (grant no 068545).
DNA and cell line banks were created in the ALSPAC Laboratory. Blood derived DNA is available from 8018 individuals and has been used successfully in several genotyping studies.
Cell lines from 2288 individuals were created at ECCAC, Porton and a further 5239 in the ALSPAC laboratory. DNA has been extracted from all of these samples and has been organised into geographically representative subgroups of samples specifically for use as control samples in case control studies. Samples have been distributed to over 20 collaborators and were used as control samples by the Wellcome Trust Case Control Consortium2.
Further funding was obtained in 2006 for management of the cell line and DNA banks and distribution of samples (grant details). This funding will end on 31st August 2007 and we are therefore applying for additional funds to continue these functions.
B512 - Vigorous physical activity increases fracture risk in children independently of bone mass - 31/05/2007
No outline received
B502 - The impact of domestic violence during pregnancy on child development - 30/05/2007
Background: Domestic violence may start or increase in severity during pregnancy (Gazmararian et al 1996; Bowen et al, 2005). The main health effect specific to domestic violence during pregnancy is the threat to health and risk of death of the mother, foetus, or both, from trauma (El Kady et al, 2005; Pearlman et al, 1990). Domestic violence is also associated with depression, anxiety, insomnia, alcohol and drug abuse, and suicide attempts (Campbell 2002). However, the impact of domestic violence during pregnancy on the risk ofchild development has not been previously investigated to our knowledge. A recent study has reported, though, on the significant impact of postnatal domestic violence on child development, which, with postnatal depression, had a cumulative effect, leading to worse child outcome (Whitaker et al, 2006). There is increasing evidence that prenatal stress and major depression during pregnancy are associated with increased concentrations of corticotrophin releasing hormone (O'Keane et al, submitted); this increase in pituitary-adrenal activity may explain the association of domestic violence during pregnancy with poor obstetric outcomes (low birthweight and preterm pregnancy) . Domestic violence may therefore adversely affect child development independent of the effect of antenatal psychiatric morbidity or subsequent psychiatric morbidity, but any effects on child development may also be partly mediated by antenatal psychiatric morbidity.
B508 - Social cognition and PLIKS - 29/05/2007
Objectives:
1. Investigate the association between measures of social cognition and social functioning in the children and PLIKS and whether a particular measure of social cognition is particularly associated with PLIKS
2. Investigate the relationship between social cognition in the parents and these same measures in the children
3. Investigate the relationship between measures of social functioning and PLIKS and how this progresses over time
Social cognition has been the focus of much recent interest and is has been defined by social psychologists as a domain of cognition that involves the perception, interpretation and processing of social information (Ostrum, 1984). Social cognition involves stimuli which are more complex and labile than non- social stimuli. To process a social stimulus, the perceiver must draw upon a larger body of stored information (knowledge, attitudes, biases etc). Furthermore, the relationship between the perceiver and the stimulus is usually interactive. The definition can be broad and a number of abilities such as emotion perception, social perception, social knowledge and attributional bias are included (Brune, 2005). Theory of mind, the cognitive capacity to represent one's own and another person's mental states for instance, in terms of thinking, believing or pretending has also been classified as a social cognitive ability.
There is a great deal of cross-sectional data that finds that people with schizophrenia are much more likely to have deficits in social cognition. However, there are very few longitudinal studies that have been able to investigate such an association. The psychotic like symptoms (PLIKS) measures in ALSPAC provide an opportunity to investigate social cognition in relation to this intermediate outcome.
We propose to use the following measures of social cognition available in ALSPAC:
Emotion recognition - the Diagnostic Analysis of Non Verbal Accuracy (DANVA-2-CF), a test of the recognition of facial emotions through the presentation of photographs of 24 children's facial expressions (12 female and 12 male participants showing an equal number of high and low intensity, happy, sad, angry and fearful faces) (Nowicki & Carton, 1993; Nowicki & Duke, 1994) was completed by the child at aged 8. The test was also completed by the childs parents
Theory of mind/Emotion attribution - A computerized test designed by Blakemore and colleagues (Boraston et al, 2006) was completed by the child aged 13 and the parent. The task consisted of series of short (5s) animations. These featured an "emotional" triangle, interacting with a circle. They were designed to evoke an attribution of emotion to the triangle, which was rated in terms of anger, happiness, sadness or fear from its pattern of movement and how animate ("living") it appeared to be.
Although classical measures of social functioning such as employment fail to apply to this age group, measures of social behaviour are also available in the cohort. These include:
Social communication - the Social and Communication Disorders Checklist (SCDC) (Skuse & Scourfield, 2005) has 12 questions measuring social communication and was completed by the parent with regard to the child at age 8
Social functioning - the number and satisfaction with friends (child rated) and teacher ratings of social interaction at school (available at age 8, 10 and 11).
B505 - Waist to height ratio and metabolic outcome in young people - 25/05/2007
The long term health outcomes for young people with different amounts of total body fat are unknown as most large scale studies examining the effects of childhood obesity have not used measures of body fat, but proxies such as body mass index (BMI). However, BMI may not indicate the level of central adiposity which is also associated with clustering of cardiovascular disease risk factors including dyslipidaemia, hypertension and insulin resistance. Clusters of risk factors are fairly stable characteristics that tend to track from adolescence to adulthood, hence the early identification of children who are likely to develop an elevated risk profile is of interest.1
Waist circumference has been recommended as a means of identifying young people at metabolic risk.2 Yet, there are several studies that indicate that waist circumference measurements have a similar performance to BMI in identifying dyslipidaemia and screening for the metabolic syndrome.3,4,5 These results are not unexpected, BMI and waist circumference are highly correlated.6
However, the waist to height ratio has been shown to more readily identify young people with adverse cardiovascular risk factors (cross-sectionally) when compared to BMI7 and may be an accurate indicator of change over time in fat distribution as it accounts for both waist circumference and height.8
Anecdotally there has been much interest expressed in the waist to height ratio by clinicians. Recent evidence suggests that the waist to height ratio, unlike BMI and waist circumference, does not require specification of sex or age and a ratio cut-point of 0.5 has been proposed as a simple means of indicating whether the amount of central adiposity is excessive in both children8 and adults.9 The concept of an increased waist girth relative to height may be easier to understand by patients and families compared to BMI percentiles, particularly if the message is 'keep your waist circumference to less than half your height'.8 However, to our knowledge use of the 0.5 ratio has not been validated at predicting metabolic risk in young people.
Aim: Examine the effectiveness of the waist to height ratio in identifying young people at risk of metabolic risk clustering.
B495 - Cleft gene bank pilot studies - 24/05/2007
The overall aim of the Healing Foundation UK Centre for cleft research supported by the VTCT (Vocational Training Charitable Trust) based in Bristol will be to generate important new knowledge to advance our understanding of the causes of cleft lip and/or palate, inform treatment and ultimately improve the lives of children, adolescents and adults born with cleft lip and/or palate.
B497 - Variation in DNA methylation profiles during childhood blood EBV cell line comparisons - 21/05/2007
No outline received