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.

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.

We have performed a large genome-wide association study in a few thousand ankylosing spondylitis patients and need to replicate several promising genetic associations. Although we have genotyped putatively associated SNPs in a new sample of cases, we need to obtain genotype data from a similarly sized european control sample on ~100 candidate SNPs. Since both cohorts have been genotyped on the Illumina 317K SNP chip, the ~1700 ALSPAC individuals for whom genome-wide SNP data is now available would be an obvious choice. Note that we are requesting a small number of candidate SNPs (i.e. ~100 SNPs) NOT the entire genome-wide dataset.

Recent advances in high-throughput genotyping technologies, coupled with the development of massive databases such as the International HapMap Project that catalogues millions of SNPs (single nucleotide polymorphisms), have set the stage for genome-wide association studies. Genome-wide association (GWA) studies are designed as two- or three phased studies. The first phase requires a dense set of hundreds of thousands of SNPs across the human genome, genotyped in a large sample of well-characterised individuals. The second and third phases aim to replicate and fine-map the most significant findings of the first phase in other large cohorts. Eventually, genome-wide association studies will identify new gene variants, previously unanticipated, that will contribute to a better understanding of the etiology of common disease and complex traits.

Our GWA study is designed for the identification of new, unanticipated gene variants that contribute to variation in obesity as well as BMI, and related traits, including age at menarche. This GWA study is undertaken as a collaboration between the MRC Epidemiology Unit and the WT Sanger Institute (Dr Ines Barroso) using a case-cohort design. The 1713 cases (defined as those with a BMI greater than 30kg/m2) and a random control cohort of 2200 individuals have been selected from the EPIC-Norfolk prospective cohort study, a population-based cohort of 25.663 men and women aged 40-79 years recruited in Norfolk, UK between 1993 and 1997. All 3913 individuals have been genotyped for two dense SNP-chips; i.e. the 500K GeneChip Mapping Sets of Affymetrix and the Sentrix HumanHap300 BeadChip of Illumina. We are currently analysing associations of this genome-wide data with obesity as a dichotomous outcome in the case-cohort study and with BMI, age at menarche and various metabolic variables as quantitative traits within the cohort study.

In order to increase the power to detect true positive signals Phase 1 will be expanded by performing a meta-analysis of two other cohorts with similar GWA phenotypic and data. We have recently established a long term collaboration with Vincent Mooser (GSK) and colleagues, who have performed a GWA study in the GSK-Lausanne cohort. The GSK-Lausanne population is comparable to the EPIC data as it is a cohort study of 6,205 Europid men and women from Lausanne, aged 35-75 years. This collaboration has a general aim to identify genes that contribute to various metabolic traits. The summary statistics from these GWA studies on these traits will be shared and meta-analysed at the MRC Epidemiology Unit.

Key to genomewide association studies is replication of the initial findings in more populations with similar characteristics. New genes identified by GWA will be taken forward for rapid confirmation studies in several large cohort studies. In addition to ALSPAC, these include a second equal sized case-cohort study within the EPIC cohort (n=3,900), the MRC-Ely study (n = 1,700), the MRC-Fenland study (currently n = 2,000), the Hertfordshire study (n = Outline 3,000), and the European Youth Heart study (n = 2,700).

Genetics, Speech and Language

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.

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.

This project looks to understand how genetic predisposition to coronary heart disease is manifest in early life. The idea here is that although young people have not yet presented with adult/mature disease, there may be metabolic signatures of later life disease risk which differ by genetic factors and are which mark carriers of these genotypes as different. Importantly, showing differences in metabolic profile at earlier ages may lead to the ability to target and modify these factors to aid later life disease risk.

Learning disabilities are common disorders characterized by unexpected difficulty with a specific mode of learning in the context of adequate intelligence and academic opportunity. The high prevalence of these disorders in the general population represents a costly burden to the educational system and affected individual are often at risk for long-term adverse psychological and socioeconomic outcomes. Intervention programs work, but are more effective when tailored to individuals and administered earlier in life. The pre-symptomatic detection of individual who are at risk of developing learning disabilities, and who are more likely to benefit from early intervention, is therefore an important diagnostic opportunity with major economic and societal implications. The objective of this project is to evaluate the diagnostic performance and predictive value of genetic variants associated with learning disabilities in the ALSPAC cohort.