Proposal summaries
B11 - The ALSPAC cell lines - 01/07/2001
The overall aim of this grant was to create a Lymphoblastoid Cell Line (LCL) collection from children and parents participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). The study has collected data on a scale and with a richness unprecedented in the field of epidemiological study and the generation of the cell line bank would provide material for further genetic, gene expression and metabolomic research.
Development of the resource initially involved establishing a cell culture facility with robotic cell maintenance systems, development of a bespoke Laboratory Information Management System (LIMS) and development of protocols for the transformation and growth of LCLs. Once these systems were in place LCL production would become a routine laboratory procedure enabling cell lines to be produced from all cohort members who consented to cell line production.
B10 - Blood pressure central obesity and insulin sensitivity in early childhood - associated with adrenal function birthweight and early growth - 01/07/2001
At UCLH we run a nationally used service for investigation of adrenal disease based on urine steroid analysis. We frequently get referred samples from children with early pubertal development which we attribute to adrenarche. From epidemiological studies we have conducted in collaboration with Professor Baker in Southampton we have examined changes in adrenal function in 9 year old children in Salisbury. In 24 hour urine collections both adrenal androgen and cortisol metabolites were quantified. Urinary androgen excretion was higher in children who had been light at birth. A 1 kg decrease in birthweight was associated with a 40% increase in androgen excretion. In contrast the relationship with urinary cortisol excretion was U-shaped with higher outputs at the extremes of birthweight. Birthweight was associated with metabolite output independent of current weight, gender and gestational age at birth, indicating that the HPA function was related to fetal growth rather than prematurity. A reduced birth size has also been associated with cardiovascular disease risk and insulin-dependent diabetes. High blood pressure and cardiac hypertrophy may be the consequence of the hyperactive adrenal secreting both cortisol and adrenal androgens from early puberty.
In children with asthma at 8 years of age there is absence of adrenal androgen output. This leads to a reduction in growth rate such that asthmatic children at this stage are shorter than their peers. As they go into puberty they catch-up on the lost height. Loss of adrenal androgens is a feature of many sytemic illnesses (severe burns, HIV and AIDS) and may be linked with states of immune suppression. Children with diabetes would be another group worth investigating.
In keeping with the objectives of the ALSPAC study these children would be worth studying in the same way with the aim of clarifying:
* Adrenal function in relation to birth weight
* Adrenal function in relation to parental adrenal function
* Adrenal function in asthmatic children
In addition to examining the balance of adrenal androgens and cortisol the urine data can be examined to establish whether changes would be due to increased circulating levels or due to changes in the degradative process for cortisol through it's metabolism to inactive cortisone. Thus metabolites of cortisol and cortisone will be examined along with the excretion rates of the free hormones themselves.
24 hour urine samples would be desirable from the children and their parents in order to assess cortisol and adrenal androgen productions.
B106 - Mannose binding lectin genotype and preterm labour and delivery - 01/06/2001
(No outline received).
B7 - Hearing - 01/06/2001
(No proposal form received).
B6 - Proximity to overhead power lines and depression - 01/06/2001
(No proposal form received).
B5 - Thiomersal in DTP immunisations and long term development of this child - 01/06/2001
N/A
B3 - An investigation into environmental influences on skeletal mineralisation during childhood - 01/06/2001
This project aimed to examine whether skeletal development in childhood is programmed by early life factors, by studying the relationship between maternal diet as assessed by food frequency questionnaire (FFQ), other determinants of maternal nutrition such as smoking and exercise, and bone mass acquisition in childhood. The latter was assessed by measuring total body bone mineral content (BMC), bone area and bone mineral density (BMD) by performing total body DXA scans in 7000 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort at age nine. Regional development at sites such as the spine, upper and lower limbs was also evaluated. In further studies, we aimed to explore the mechanisms involved in any such programming effect by examining the role of genetic factors by studying associations between DXA parameters and single nucleotide polymorphisms (SNPs) in different genes.
B285 - A national DNA control series for genetic case-control studies based on the British 1958 cohort NOT ALSPAC - 01/01/2001
The MRC / Wellcome Trust Expert Working Group on UK Population Biomedical Collections, in their final report dated March 2000 (section 1.9), suggested that there was a need for intensive genotyping of a "panel of controls ... representing various sectors of the UK population ... for comparison of SNP allele and genotype frequencies with case series." This application describes an expeditious and cost-effective approach to the creation of such a DNA control panel, by producing immortalised cell lines and banked DNA from specimens to be collected over the next two years from members of the British 1958 birth cohort. This fieldwork is already funded by the MRC and all biological material thus derived will be managed according to the MRC guidelines for use of human tissue and biological samples in research (1999), except that our MREC-approved consent forms extend only to non-commercial medical research studies of the causes, diagnosis, treatment or outcome of disease. This nationwide sample of adults followed from birth potentially offers much richer phenotypic information than a control group newly recruited in middle age. In particular, there is prospectively collected data on traits and diseases during childhood and adolescence which would be missed by creation of a de novo panel.
B13 - Lifestyle and changes in body composition through puberty a resource for a study of gene-environment interactions - 01/01/2001
Our proposal was to create a resource for the study of lifestyle and body composition through puberty bycollecting and calibrating data on diet, activity and body composition within the Avon Longitudinal Study ofParents and Children (ALSPAC). The specific aims of the proposal were to:
- Code dietary diaries collected at age 10+
- Code activity diaries collected at age 10+
- Perform total body dual energy X-ray absorptiometry (DXA) scans at age 11+
- Perform calibration studies using magnetic resonance imaging (MRI) and deuterium dilution at age 11+
- Collect and code dietary diaries at age 13+
- Collect and code activity diaries at age 13+
- Perform total DXA scans at age at age 13+
- Perform calibration studies using MRI and deuterium dilution at age 13+
- Calibrate the diet diary measures using repeat diaries, overnight urine collection and activity measures at age 13+
B287 - Antisocial behaviour in girls BAT Study - 01/06/2000
Though universally documented, sex differences in antisocial disorders remain poorly understood, and existing theory and evidence couses heavily on males. This proposal outlines an integrated programme of studies - spanning early childhood to the adult years - designed to test psychosocial influences on sex differences, and to provide the basis for a life-course perspective on antisocial behaviour in girls. Building on collaborations with three ongoing UK and US epidemiology/longitudinal studies the programme tests: (i) influences on the emergence of sex differences in early childhood; (ii) contrasting developmental models for the onset and persistance of girls' antisocial behaviour in childhood and adolescence, and for continuities to problems in psychosocial functioning in adult life; and (iii) biological and psychosocial risks for the development of depressive co-morbidity in early adolescence, and for the onset and recurrence of low mood in adult life.
B284 - Stepfamilies single parent families and childrens development and adjustment Sub-study supervised by Judy Dunn Institute of Psychiatry Avon Brothers and Sister Study - 01/01/2000
Children in single-parent and step-families have higher rates of problems in adjustment, education and health than those in non step-families, yet individual dfferences are marked. This programme of research is focused on the issue of which individuals are most vulnerable, to identify significant sources of risk and support in relation to the mental and physical health of children and parents.
B282 - Genetic and environmental influences on the atherogenic phenotype in the young a population based study - 01/01/2000
We have developed techniques to study endothellal function non-invasively in children and young adults. This programme of work will study how genetic and early enviromental factors affect endothellal function and other markers of early arterial disease (such as arterial stiffness) in a large population of pre-pubertal children undergoing long-term follow-up. Long-term follow-up will also show how these arterial changes progress during puberty and when later risk factors such as smoking are enocuntered.
B294 - To assess whether age at onset of puberty is influenced by intrauterine exposure to endocrine disrupting chemicals - 01/01/1999
HSB would like to purchase the data from the University after it has been collected.HSB would like to increase the amount of FY06 funds to increase the number of questionnaires (from 10,700 to 11,800) and the amount of work associated with pulling and shipping biologic samples from the University of Bristol to the NCEH lab for analysis.
In addition to the Tanner Scale questionnaire, from 2005, ALSPAC will supply biological samples; namely 150 maternal bloods, 150 maternal urines and 300 cord blood samples. This will be at an additional cost of $22,728 for 2007; $16,387 for 2008.
Background: The onset of puberty is difficult to ascertain using Tanner stages, which are subjective in nature. Especially when Tanner stages are self-reported by pre-teen children, questions of accuracy arise. The transition into puberty - represented by entry into Tanner Stage 2 - is especially difficult to determine. Since the outward sign of development reflect underlying changes in concentrations of reproductive hormones, an alternative method of detecting progression into puberty is to examine concentrations of relevant hormones. In pre-pubertal boys, testosterone levels are close of 0 nmol/L. It is only with the onset of puberty that blood concentrations rise and a distinctive pattern develops (Albertsson-Wikland 1997).
Purpose: Many of the boys in the study cohort have completed questionnaires indicating that they had reached puberty (Tanner Stage 2 or higher) as early as age 8. Using the blood hormone concentration, we will compare the self-reported pubertal stage to a more objective measure.
Description: We will examine testosterone concentrations measured by University of Bristol in 1000 (in total) previously collected blood samples of boys aged 7 through 10. Costs of this are included in Modified Line 005.
This sole-source contract is for the data collected during 2004 - 2008.
B2438 - Metabalomic profile of alcohol consumption in adolescents - 01/01/1900
Aims:
1) To assess the how alcohol consumption affects metabalomic profile
2) To identify a genetic instrument for metabolites that are associated with alcohol consumption
B989 - An item response theory analysis of the Childhood interview for DSM-IV Borderline Personality Disorders C1-BPD - 01/01/1900
We wish to investigate the measurement of borderline personality disorder (BPD) within the 11-12 year-old cohort of the ALSPAC data. Specifically, we intend to employ item response theory (IRT) methods on the BPD symptom criteria. IRT constitutes a latent trait approach to psychological measurement, modeling the probability of endorsing a given item (e.g., presence of affective instability) as a function of an individual's standing on the underlying construct (e.g., BPD).
The basic unit of IRT is the item characteristic curve (ICC), which depicts visually the relationship between the construct and a person's response to an item (Embretson & Reise, 2000). The shape of this curve is influenced by at least two parameters: difficulty and discrimination. The difficulty parameter represents the point at which the probability of endorsing an item is 50%. The discrimination parameter is the slope of the ICC at the value of the difficulty parameter. These parameters will provide important information for evaluating the performance of each BPD criterion, such as the level of BPD needed to meet the criterion and the degree to which it differentiates among higher and lower levels of BPD (Feske, Kirisci, Tarter, & Pilkonis, 2007).
Most applications of IRT require that the construct being measured is unidimensional. Several factor analytic investigations of the BPD criteria in adults have supported a unidimensional structure (Aggen, Neale, Roysamb, Reichborn-Kjennerud, & Kendler, 2009; Feske et al., 2007; Fossati, Maffei, Bagnato, Donati, Namia, & Novella, 1999), while others have reported a structure sufficiently unidimensional for IRT purposes (Johansen, Karterud, Pedersen, Gude, & Falkum, 2004; Sanislow et al., 2002), as evidenced by high factor intercorrelations (Embretson & Reise, 2000). To date, only one study (Becker, McGlashan, & Grilo, 2006) has conducted factor analysis of the BPD criteria in a youth sample, the results of which did not reveal a unidimensional structure. However, this study employed principle component analysis with orthogonal rotation and, thus, did not report the magnitude of factor intercorrelations. Taken together, these studies provide reason to believe that the BPD criteria may be sufficiently unidimensional to employ a traditional IRT-based model. However, in the event that the BPD criteria are not unidimensional in the ALSPAC data, multidimensional or categorical confirmatory factor analysis will be employed.
In order to investigate our aims, we will need the CI-BPD data that correspond to each of the 9 DSM-IV symptom criteria, including the questions used to inform judgment of whether the symptom was present.
B988 - Analysis of changes in fruit and vegetable intake as children get older in a UK cohort study - 01/01/1900
Title: analyse the evolution of fruit and vegetable intake frequency of children from infancy to 15 years, segmenting by household socioeconomic status (SES) and parental attitudes.
Specific objective: the aim of the analysis is to explore trends in intake (amount and frequency) across children's ages in years to evaluate the possibility of tracking of food habits (specifically fruit and vegetable intake), and any trends in changes in intake along the child's lifecycle (e.g. frequency of intake tends to drop/rise at the age of X). The idea is to construct different series of average intake by socioeconomic groups, and by mothers' attitudes to fruits and vegetables and eating in general. The analysis of segmentation by socioeconomic group and attitudinal variables will be helpful not only in illustrating any difference in starting points in fruit and vegetable intake when children are categorised according to these variables, but also any persistence and/or broadening of inequality as children grow older.
Broader objective: secondary data analysis of trends in children's fruit and vegetable intake by socioeconomic grades and mothers' attitudes as part of the research agenda for a PhD project on Consumer Behaviour and Associated Change Drivers and Barriers in the Consumption of Fruits and Vegetables by Children.
Methods: graph plotting average and median intake (y axis) against age (x axis) for categories by SES (quintiles or tertiles of SES) and mothers' attitudinal characteristics. Statistical analyses (paired t tests and correlations) to test for tracking of food habits (Skinner et al. 2002).
B935 - Antioxidant gene modification of the effect of prenatal paracetamol on asthma - 01/01/1900
Having identified a possible interaction between a maternal Nrf2 SNP and prenatal paracetamol exposure on asthma risk, we would like to carry out further genotyping to confirm additional gene*paracetamol interactions.These include an additional Nrf2 SNP; GCL (relevant to glutathione synthesis); Melatonin receptor MTNR1b (melatonin is a powerful antioxidant linked to paracetamol toxicity); CYP2E1 (relevant to paracetamol toxicity).
B929 - Bladder Control in Bilateral Cerebral Palsy a Population-based Study - 01/01/1900
With regards to children with cerebral palsy, very little information about attainment of urinary continence is available. The long-term physical, psychosocial and financial burden of incontinence in the cerebral palsy patient is considerable and in order for the paediatrician to begin addressing these important issues further information regarding the normal attainment of bladder control in children with cerebral palsy has to be established. This is the aim of this study.
METHODS
The original study:
The data in this study originate from a previously published population based study (Scrutton and Baird 1997) which established a cohort of children with bilateral cerebral palsy born from 1989 to 1992 (inclusive) to mothers resident at the time of birth within the geographically defined area of the South East Thames Regional Health Authority (SETRHA) in south east England in order to monitor the children's hip development up to the age of 5 years using serial hip X-rays. It is for this reason that children with hemiplegic cerebral palsy are not included. The South East Thames Health Region at the time had a population of 3.65 million with 205 958 live births during the study period. A comparison of epidemiological data between SETRHA and England and Wales showed similarities between the two. For original methods of recruitment, details of ethical permission and consent, and diagnosis of cerebral palsy the reader is referred to the original paper (Scrutton and Baird 1997).
Present study:
For the purposes of this study, a questionnaire containing details of the child's attainment of bowel and bladder control by day and night, as well as parental concerns or presence of abnormal bladder and bowel symptoms, was used. This questionnaire was administered by physiotherapists to the parents of the children sometime after their third birthdays together with other information required for the original study at that time. The parents/carers were asked to post the questionnaire back to the investigators in a self-addressed envelope. Almost all were returned between the third and fourth birthdays, although one was returned at 5 years. After 5 years of age, a visit was carried out by the original authors, mostly in the child's home together with the parents. A number of parameters were obtained during this visit including confirmation of the diagnosis of cerebral palsy, the nature of the motor disorder including distribution (quadriplegia, diplegia, double hemiplegia and paraplegia) and type (hypertonia, ataxia, involuntary movements, hypotonia and ataxic diplegia after Hagberg 1985), learning level (as ascertained from other medical or educational sources), severity of disability and the age of attainment of bladder and bowel control by day and night. For funding and practical reasons these visits were carried out between 7 to 9 years of age. A closing visit questionnaire, including further continence data was completed some time after the age of 14 years (up to age 19 years) in this cohort, in a similar manner to the above. Whilst the stated aim of this study is to establish the age of attainment of bladder control in subjects with cerebral palsy, data on bowel control have been analysed simultaneously for two reasons: availability and therefore ease of analysis together with bladder data, and the fact that bowel and bladder control are physiologically and developmentally linked, and have been shown by previous authors to follow each other sequentially (Stein and Susser 1967, Largo and Stutzle 1977, Crawford 1989).
Definitions:
Cerebral palsy has been taken to mean all non-progressive disorders of movement and posture caused by a defect or lesion in the brain by 15 months chronological age, and not part of another syndrome which has a motor component. Those with syndromes including a high risk of skeletal or joint anomalies and children whose disorder had no clinical trunk or lower-limb involvement were also excluded. Each child's paediatrician provided written confirmation of the diagnosis at 5 years of age.
Bladder and bowel control was defined as being reliably continent with socially acceptable toileting even if help was required.
Definitions of learning level, severity of disability and type (Hagberg 1989)/distribution of motor disorder are defined and classified according to the Gross Motor Function Classification System (GMFCS).
RESULTS
The results of bladder and bowel continence attainment will be presented in a longitudinal manner together with details of any abnormal patterns which will be discussed. The data collected at three years and eight years of age have already been analysed and analysis of the data available at 16-19 years of age is currently awaited. The only available control comparison group is a series of international studies which are for the large part retrospective, cross-sectional and not population based and neither are they collected from a British population with a similar birth date.