Proposal summaries
B1096 - Characterisation of autistic-trait related visual processing Fellowship - 13/01/2011
There are a series of visual characteristics and visual processing impairments and abnormalities reported for children with autistic symptoms.
There is evidence for abnormal visual processing of colour informationin autistic children. This manifests as poor chromatic discrimination (Heaton, Ludlow, & Roberson, 2008)(Franklin, Sowden, Burley, Notman, & Alder, 2008)(Franklin et al., 2010) but good colour memory (Heaton et al., 2008). Although originally outlined as test of executive functioning, autistic children, children with autism also show less interference effects for colour naming compared with typically developing children on the classic Stroop test e.g. (Simmons et al., 2009), which is probably related to verbal information processing. Some theories suggest that there is an association between verbal ability and perceptual discrimination (Heaton et al., 2008) such that normally developing children apply verbal labels to colours, and are therefore distracted when presented with colours carrying non-typical labels. Children with language difficulties, as typically expressed in autism spectrum disorders (ASD), however are thought to remember colours perceptionally, in other words they do not encode colour verbally, and may therefore have less interference effects compared to typically developing children (Simmons et al., 2009). A considerable body of research reports that children with autism have also impairments in facial recognition and in the understanding of facial emotional expressions (Simmons et al., 2009). This might be related to the finding that ASD children appear to process and/or attend the eye region of faces less effectively than typically developing children e.g. (Rutherford, Clements, & Sekuler, 2007)(Spezio, Adolphs, Hurley, & Joseph Piven, 2007)(Simmons et al., 2009) and more likely fail to form view-invariant face representations (Wolf et al., 2008). In addition, the ability to perform face-eye region special discriminations might be coupled to verbal intelligence (Rutherford et al., 2007). Furthermore, several studies have observed an enhanced ability to perform visual search tasks in autistic patients such as the ability to disembed a target figures from a complex background in the "Embedded Figures Test". Likewise, autistic children show an superior performance in perceptional grouping as well as mental rotation tasks (e.g. Block-Design subtest of the WISC-III; (Shah & Frith, 1993)(Venter, Lord, & Schopler, 1992)(Goldstein, Beers, Siegel, & Minshew, 2001). Latter association was also observed for autistic-like traits (Stewart, Watson, Allcock, & Yaqoob, 2009).
Aim: Assuming the dimensionality of autism, the proposed fellowship aims to understand the mechanisms linkingvisual functioning to autistic symptoms using a general population sample in order to provide guidance for strategies aiming at intervention and treatment of autistic symptoms.
1) We aim to study chromatic information processing, interference processes between colour perception and colour naming, the understanding of facial expressions as well perceptional grouping and mental rotation tasks with respect to autistic symptoms. Findings will be used to create a profile of visual characteristics and impairments which are associated with specific autistic symptoms in the general population. We will use Growth mixture modelling for longitudinal measures of autistic traits and mixture modelling for cross-sectional autistic data to accomplish this task.
Required variables in ALSPAC:
Outcomes:
4 SCDC measures (8-17 years), CCC
Predictors:
Visual processing of chromatic information: L'Anthony desaturated D15, Stroop (8,11y)
Facial expression based tasks:DANVA (8y Happy, Sad, Angry, Fearful faces), CVI related "face recognition" items (13 y) (Williams, 2010)
Perceptional grouping tasks:CVI related "crowded scenes" items (13y) (Williams et.al, 2010)
Mental rotation tasks:WISC-III Block Design (8y)
Moderators: Verbal IQ (8 y); Colour Ishihara test (12y)
Sensitivity analysis:This will performed by adding less autism-specific visual characteristics like refractive error (7,10,11,12,15 y), strabismus (7y) and visual acuity (7, 11y) to the derived mixture models.
2) Given the genetic basis of autism and autism-specific visual tasks (e.g. h2 Stroop = 0.5, Stins et. al, 2009) we also aim to identify genetic variants which are related to both visual and autistic traits.
a. We propose genome-wide analyses using the Stroop test, the DANVA and the perceptional grouping items of the CVI. Replication will be sought internally within ALCPAC by dividing the sample into a discovery and a replication cohort and within independent samples such a QIMR (Faces task). Genome-wide analysis of the Block-Design test is performed within CHIC.
b. Selection of SNPs for functional network work construction will be enhanced through a second step of GWAS analyses where we combine each autistic symptoms score (i.e. CCC and SCDC) with each studied visual trait (Stroop test, the DANVA, the perceptional grouping items of the CVI, in addition to the WISC-block design) into a bivariate outcome to identify SNPs which preferentially affect both visual and autistic outcomes. For this analysis we will select preferentially trait combinations which have been supported through GMM and cross-sectional mixture modelling (see step 1).
c. Functional networks will be constructed with Ingenuity pathway analysis (http://www.ingenuity.com/products/answers.html).
B1095 - Epidemiological studies of human transgenerational responses TGR to paternal and ancestral exposures - 12/01/2011
Biological inheritance from one generation to the next is generally regarded as transmission of genes and other DNA variation from both parents, plus 'maternal effects' either carried within the egg cytoplasm or through the trans-placental passage of nutrients and metabolic signals. Biological inheritance is supplemented by 'cultural inheritance' (including nurturing behaviour and social patterning) from which it needs to be distinguished.
However, there is growing evidence in mammals (refs 1- 3,9 and references therein) that sperm carry information about the ancestral environment that can influence the development and health of the next generation(s) through enduring alterations in gene expression. How this information is transmitted is unknown, but epigenetic gametic inheritance is one candidate.
There are human epidemiological TGR data (predominantly male-line with mortality, diabetes, coronary heart disease and metabolic syndrome as outcomes) from three populations;Overkalix in Northern Sweden (4-6), ALSPAC (6) and Taiwan (7).A similar phenomenon could occur down the maternal line, complementing the known 'maternal effects', although the latter present a challenge in terms of confounding. Beyond the importance of enlarging our knowledge of human inheritance, understanding the nature and extent of these transgenerational responses is likely to bring medical and public health benefits.
This project will extend our ALSPAC work on TGR to include additional ancestral exposures and further exploration of sex-specific effects.
Background
The initial ALSPAC data (6) showed that paternal onset of smoking before puberty was associated with a greater BMI at 9 years in sons but not daughters. This triggered sex-specific analysis of the Overkalix data with dramatic results. The paternal grandfather's food supply in mid childhood was only linked to the mortality rate of grandsons, whilst paternal grandmother's food supply was only associated with the granddaughters' mortality rate (6). This was true in 2 of 3 independent cohorts and the TGR persists when the grandchild's early life circumstances were also taken into account (8). There are also father to son affects in the Overkalix data. Recent unpublished ALSPAC analysis shows paternal onset of smoking before puberty continues to be associated with greater BMI in (just) sons until age 15.
Since we published 5 years ago, animal studies have paid more attention to sex differences in TGR with varying results from exposed males linked to affected female offspring (2,3) or to affected offspring of both sexes (1) and with curious three generation male-line effects, namely exposed male, his male offspring (unaffected) and that male's male offspring who are affected (2). But some of these studies had altered diet throughout development of the exposed male ancestor. Other studies, e.g. with short term fasting at different ages of the exposed male, found predominantly affected male offspring (9).
Our collaborative work with Lars Olov (Olle) Bygren suggests humans have an exposure sensitive period in mid childhood (both sexes) and in the fetal/infant period (females), but there is no triggering of TGR in puberty in either sex. Thus we can expect to find different outcomes in descendants (analysed by sex) by comparing paternal or ancestral exposures during puberty with exposures at the above specific times before puberty.
The long-term plan is to; a) test the hypothesis that transmission across the generations in TGR is mediated by elements segregating with the Y(non pairing region) and X chromosome by (epi)genomic analysis, and b) to look for the downstream effects on gene expression in the offspring that are relevant to the outcomes using genome wide DNA methylation association studies. However, more epidemiological evidence of triggers of TGR and sex specific effects are needed to inform these future molecular studies. Meanwhile more understanding of the variables in methylome analysis will accumulate (e.g.10).
Planned studies
* Using the established TGR trigger of paternal smoking before puberty, explore outcomes relevant to metabolic syndrome throughout the development of sons and daughters.
* To test the exposure of the study father in utero (via his own mother smoking in pregnancy) on the outcomes as above in his sons and daughters, particularly in fathers who did not smoke themselves.
* To test the exposure of the study mother in utero (via her own mother smoking in pregnancy) on the outcomes as above in her sons and daughters, particularly in mothers who did not smoke themselves.
In line with animal data, explore 'traumatic events' as a TGR trigger for mental health and behavioural outcomes (as well as metabolic syndrome outcomes) in descendants. These will be of two kinds.
* Study fathers and mothers who suffered the death, separation or divorce of a parent before their own puberty.
* Paternal great grandmother's experience of husband being eligible to go to war in 1939-40 whilst the paternal grandmother was a fetus or infant. Outcomes measured in the children of the study fathers who did and did not have this ancestral exposure.
Look for potential TGR by detecting associations with exposures in the parental or grandparental generation for specific outcomes in the study child. [Unpublished analysis with respect to all childhood cancers reveals an association with the study father's early childhood traumatic circumstances.]
References
1. Carone BR et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084-1096.
2. Franklin TB et al (2010) Epigenetic transmission of the impact of early stress across generations. Biological Psychiatry 68, 408-415.
3. Ng SF et al (2010). Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963-966.
10. Robinson MD et al (2010). Evaluation of affinity-based genome-wide DNA methylation: effects of CpG density, amplification bias and copy number variation. Genome Res 20, 1719-29.
B1094 - Examining links between mental health problems and epilepsy in childhood and adolescence - 11/01/2011
Background
The point prevalence of epilepsy in childhood and adolescence has been estimated at between 0.3-0.6%. It has been known for many years from cross-sectional surveys that children with epilepsy have particularly high rates of psychiatric disorders (34.3-37%) when compared to children with other common chronic medical conditions (11-11.3%) and that depression rates especially are particularly high, with reports of upto 26% reported. Depression and depressive symptoms have a high impact on children and adolescents with epilepsy and on their families.
The reasons for the high rates of depression in children with epilepsy are not well understood. One of the most established associations for depression is the female preponderance in prevalence of depression which merges around the time of puberty. This female preponderance is however not found for individuals with epilepsy. A small study found marked differences in gender patterns in depression rates amongst adolescents with epilepsy compared to adolescents with other chronic diseases with adolescent males with epilepsy showed significantly higher rates of depression than males with asthma whereas females with epilepsy were at much lower risk than females with asthma. Moreover there is evidence that that the pattern of depressive symptoms for children and adolescents with epilepsy are also different from that found in the general population.
One possible factor that may explain some of these differences from the general populations is that epilepsy commonly coexists with other neurodevelopmental problems, notably intellectual disability(15-38% of individuals with intellectual disability affected by epilepsy) autistic spectrum disorders, ASD (epilepsy present in 8-28% of those with autism) and Attention Deficit Hyperactivity Disorder, ADHD (ADHD present in 38% of children with epilepsy) that are themselves associated with increased rates of depression. Thus depression risk could be better explained by the cluster of multiple brain/neurodevelopmental problems rather than by epilepsy alone. There are mixed findings from studies on whether it is the presence of other neurodevelopmental problems such as intellectual disability that indexes increased risk of depression amongst adolescents with epilepsy.
It is also not clear whether the association of increased risk of depression is only for those with epilepsy or extends to all those who have experienced non-febrile convulsions. Many children and adolescents experience non-febrile convulsions in a given year but only a minority are labelled as having epilepsy. For many of these children seizures are attributed to a specific cause but for others there is no cause noted and these are labelled as single unprovoked seizures. However there is little long term follow information on this non-epilepsy seizures group as most studies are cross sectional. Moreover detailed characterisation of this group (e.g. co morbidity, prognosis) is lacking although a high prevalence of psychological and social problems are found in individuals labelled as having non-epileptic seizures. Given that both misdiagnosis and underdiagnosis of epilepsy have been identified as issues better characterisation of the non-febrile non -epilepsy group to examine natural history and co morbidity would seem timely.
The overall aim of this proposal is to build on our previous work on adult epilepsy and begin a new programme of neuropsychiatric and psychology research on epilepsy in children and adolescents. The overall scientific aims are to better understand the clinical presentation and processes linking depression with paediatric epilepsy and identify which children are at greatest risk. Longitudinal assessments of epilepsy,non-epilepsy convulsions, asthma and depression across puberty and additional information on commonly co morbid disorders and other psychological and social covariates and outcomes will allow testing of our key hypotheses.
The specific aims of the proposal are
1. To explore whether in children with epilepsy the pattern of depression symptoms and pattern of associations (such as with age, gender, family adversity and social disadvantage) are similar 1) to those for children with asthma) and 2) and to children with non-febrile convulsions but no definite diagnosis of epilepsy
2. To examine the influence of puberty in depression rates for adolescents with depression as compared to adolescents with asthma and adolescents with no other chronic medical condition.
3. To examine the relationship between depression symptoms and adolescent epilepsy. Particularly 1) in temporal order of development of each problem (depression and epilepsy) 2) the effect of co-morbidity (ADHD, Intellectual disability) in explaining any associations uncovered 3) the role of seizure frequency, adjusting for the presence of other co morbid conditions, in predicting depression symptoms.
Practical importance of the topic
There is a paucity of community based mental health research on children with epilepsy particularly focusing on identifying those children at high risk of adverse outcomes. Depression is a key factor determining the quality of life of individuals and their families. This research will provide evidence to inform management strategies for children with epilepsy and should be of help to clinicians and families. For example if a sub-group of children at particular risk of adverse psychopathological outcomes are found this will enable development of appropriate interventions and targeting of clinical resources to this group. If risk pathways to depression in children with epilepsy are different from those in the general population, this would influence clinical management and prevention.
Research design
Samples
This consists of information from parents and children from 14 541 pregnancies. We will include information from children with epilepsy aged between 8 1/2 years and 15 years. Information on epilepsy related convulsions, non-epilepsy non-febrile convulsions, asthma and depression and anxiety are available at 4 data points and will be used for the analysis) We will include all children with epilepsy (31 at age 10) and social class, gender and severity match an equivalent number of children with asthma (selected out of 935 children with asthma) and individuals with non-epilepsy non-febrile convulsions.
Current data required:
Epilepsy: Mother questionnaire reports of convulsions (both attributed to epilepsy and non febrile non-epilepsy and frequency if available ) at ages 103 months, 128 months , 140 months, 157 months and 166 months (KS, KV, KW, TA, TB).
Asthma: Mother questionnaire reports of asthma at ages 103 months, 140 months, 157 months and 166 months (KS, KV, TA, TB)
Depression and anxiety : Mother questionnaire reported depression and anxiety using MFQ items 115 months(KU), 140 months (KW)
Child reported depression and anxiety using SMFQ items: 126 month(focus 10+), 150months (12.5years) (TF1), 13.5 years (TF2) and DAWBA interview 15.5 years (186 months(TF3)).
SDQ infirmation from KU(115 months) (includes information on peer problems (e.g. bullying), Hyperactivity symptoms)
Autism, Dyspraxia, Dyslexia- from KU questionnnaire 115 months
DAWBA interview ADHD diagnoses (91 months)
IQ scores
Age (child at assessment)
Gender
Social class
Family history of depression
Lifestyle factors: diet parent reported (KT (103m) KU(115m)) self reported CCM (156 months), sleep (KU 115 m, KV 128m, KW 140m TB 166m)
B1093 - Prenatal exposure to maternal obesity in utero and risk for behavioral problems in childhood - 05/01/2011
Aims and Objectives
To determine whether children of women who were overweight or obese at the time of pregnancy are more likely to receive high ratings of ADHD symptoms as compared to children of women who were normal weight. Importantly, use of the ALSPAC data will allow us to extend previous work by testing potential mechanisms, e.g. maternal dietary intake during pregnancy and child weight, as well as examining longitudinal associations across childhood.
Background
Overweight and obesity are significant public health concerns. Prevalence is continuously escalating and by 2030 it is estimated that as many as 2.16 billion and 1.12 billion adults world-wide will be overweight and obese, respectively (Kelly et al., 2008). Women entering pregnancy are more likely than ever to be overweight or obese, with well-documented deleterious health consequences for both mother and child. Less is, however, known about the possible consequences for child mental health.
The concept of maternal weight in programming of mental health problems in the offspring has been studied primarily from the perspective of underweight and low weight gain in pregnancy. Famine studies in the Netherlands and China show that low maternal weight at the beginning of pregnancy is a risk factor for neurodevelopmental disorders in the adult offspring. Fetal brain development is dependent on maternal energy supply (Hay & Sparks, 1985). Due to the obesity epidemic, recent work has examined mental health consequences for the offspring as a function of maternal overweight/obesity in pregnancy (Rodriguez, 2010a). We were first to report an association between maternal pre-pregnancy overweight/obesity and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in children (Rodriguez et al., 2008).
ADHD, a neurodevelopmental disorder, is very common and has an estimated world-wide prevalence of 5%. The core symptoms of inattention and hyperactivity are associated with impairment even at sub-clinical levels (Rodriguez et al., 2007). Thus, ADHD and its symptoms pose a public health concern due to the documented negative ramifications to the individual, family, and society.
Our first report showed an association between maternal pre-pregnancy overweight/obesity and core symptoms of ADHD combining data from three prospective cohorts from Sweden, Finland, and Denmark with a pooled sample size of over 12,000 children. The finding was confirmed in another Swedish prospective cohort of younger children using the full symptom description of ADHD (Rodriguez, 2010a). Further, this work also showed a significant association with child negative affect. It was possible to adjust for many confounding factors including maternal depression, stress, socio-demographics, as well as ADHD symptoms in both parents. One possibility that the Rodriguez (2010a) paper examined was whether the child's own weight accounted for the association. This is a plausible link because previous research has pointed to the contribution of maternal pre-pregnancy weight in the programming of child weight (Rodriguez, 2010b). Although the results did not show that child weight accounted for the association, the question remains opened because child weight was assessed as within or outside the normal range, thus it is unknown whether child body mass index (BMI) mediates or accounts for the association.
Hypotheses:
1) Children born to mothers who were overweight or obese at pregnancy will have higher risk of child behavior problems, specifically those related to ADHD according to teachers and mothers.
2) Children exposed to maternal obesity in utero will have consistent behavior problems across childhood.
3) Children's own weight will not mediate the association between prenatal exposure to maternal obesity and child behavior problems.
Methodology
Design: A longitudinal prospective study with contrast groups.
Participants: This study is based on data collected from the Avon Longitudinal Study of Parents and Children, ALSPAC (Golding et al., 2001). ALSPAC is a longitudinal birth cohort study, which enrolled all pregnant women living within Avon, England, due to give birth between the 1st April 1991 and 31st December 1992. It is estimated that approximately 85-90% of those eligible for inclusion chose to participate and the sample has been shown to be representative of the UK population. The core ALSPAC sample consists of 14,541 pregnancies, 69 of which had unknown birth outcomes. Data was obtained on the remaining 14,272 via postal questionnaires. For the purpose of this study women will be excluded if they did not respond to the 12 week questionnaire (2,019) or if they had multiple births (208).
Predictor: Prepregnancy maternal BMI will be calculated using the standard formula (weight in kg/height in m2) and rounded to nearest whole number. Maternal pre-pregnancy BMI will be analyzed as continuously and categorically according to the standard classification of the WHO guidelines for overweight and obesity: normal weight (20-24.99), underweight (15-19.99), overweight (25-29.99) and obese (>= 30).
Outcomes: The main outcome measures will be teacher reports of child behavior at ages 8 and 11 years using the Strengths and Difficulties Questionnaire (Goodman, 2000), a widely-used general screener for psychiatric disorders in community samples. One subscale is devoted to ADHD symptoms.
To assess whether children's own weight contributes to ADHD symptoms we will use data collected yearly on physical development (weight) up to the age of 11 years.
Confounders: Participants reported socio-demographic data, including age, occupation, marital status as well as smoking via self-report at 12 weeks gestation. We will also include psychosocial factors such as maternal anxiety and depression during pregnancy. Birth outcomes such as birth weight and gestational age will be included in the model.
Data Analysis: The hypotheses will be tested using linear and logistic regression analyses in which maternal pre-pregnancy BMI is used to predict behavioral outcomes in childhood. All of the central analyses will include covariates. Data available at several time-points will be initially analysed cross-sectionally; longitudinal and growth modelling will be used as a subsequent step. With the available sample sizes, small to moderate group differences in continuous outcomes can be detected with a power of 90% at the 5% test level. Analyses will take into account missing data.
The results offered by this study will not only provide an opportunity for replication in an independent sample in another geographical region, but more importantly will provide an opportunity for extension and examination of potential mediation by child weight as well as longitudinal analysis of child behavior problems across childhood.
REFERENCES
Golding J, Pembrey M, Jones R. ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatric and Perinatal Epidemiology 2001;15(1):74-87.
Goodman R, Ford T, Simmons H, Gatward R, Meltzer H. Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders in a community sample. Br J Psychiatry. 2000;177:534-9.
Hay WW, Jr., Sparks JW. Placental, fetal, and neonatal carbohydrate metabolism. Clin Obstet Gynecol. 1985;28(3):473-85.
Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes. 2008;32(9):1431-7.
Rodriguez A. Is prenatal exposure to maternal obesity linked to child mental health? In: Bagchi D, editor. Global View
on Childhood Obesity: Current Status, Consequences and Prevention: Elsevier; 2010, pp157-166.
Rodriguez A. Maternal pre-pregnancy obesity and risk for inattention and negative emotionality in children. J Child Psychol Psychiatry. 2010a;51(2):134-43.
Rodriguez A. Is prenatal exposure to maternal obesity linked to child mental health? In: Bagchi D, editor. Global View on Childhood Obesity: Current Status, Consequences and Prevention: Elsevier; 2010b.
Rodriguez A, Miettunen J, Henriksen TB, Olsen J, Obel C, Taanila A, et al.Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. Int J Obes (Lond). 2008;32(3):550-7.
B1089 - Ethical aspects of epidemiological research on young people involving linkage to routine individual data PEARL - PhD - 21/12/2010
The project is part of a 1+3 year MRC funded PhD at the University of Bristol. The first year has been dedicated to scoping the ethical issues pertinent to data linkage research and conducting a conceptual analysis of these. I plan to investigate the ethical aspects of data linkage research in relation to public health and research ethics, therefore examining the possible benefits and burdens of conducting this type of research and how these are balanced and distributed in both research procedure and outcomes.
Empirical ethics: integrating qualitative, in-depth interviews and grounded theory analysis with ethical analysis will be utilised to examine the Project to Enhance ALSPAC through Record Linkage (PEARL) as a case study.
Three groups of participants will be interviewed:
1. ALSPAC researchers who have utilised or are planning to utilise data linkage in their work
2. Members of the ALSPAC ethics and law Committee (ALEC)
3. Members of the eligible ALSPAC cohort including individuals from groups potentially less likely to consent to data linkage.
Participants will be purposively sampled and members of the eligible ALSPAC cohort will be recruited in consultation with the ALSPAC family liaison team. Approximately 10-15 individuals from each of the three participant groups will be interviewed.
Members of the eligible cohort will be sampled in two ways:
1. According to their previous participation in ALSPAC
2. Specific refusers to data linkage in the PEARL study
Within these two criteria variation according to sex, level of education and ethnicity will be aimed for with attention to individuals from social groups potentially less likely to consent to data linkage (such as individuals with low or high educational levels or from ethnic minorities).
The outcomes of this research will inform recommendations regarding the ethics of conducting data linkage research.
PhD Student: Mari-Rose Kennedy
Project Supervisors: Prof. John Macleod
Dr Ainsley Newson (currently on maternity leave)
Prof. Ruud ter Meulen (temporary supervisor)
Dr Catherine Heeney
Dr Amanda Owen-Smith
Please Note: This project will be collecting new qualitative interview data. Collection of new data from direct assessment was ticked in section 4 of this form as it seemed the most accurate description available in the form for what is intended in this study.
B1091 - Phenotypic Association of Squint Stereopsis and Phychosis - 20/12/2010
Stereoacuity
Stereoacuity describes the ability to visually perceive depth. It is a product of having two eyes facing in the same direction. Depth perception has an evolutionary advantage and is a feature shared by many successful predators. Stereoacuity allows for better hand-eye coordination and has been attributed with a role in the development of tools by primates and humans1. The ability to see in 3D confers an advantage in modern human life, allowing the performance of complicated manual tasks common to many occupations.
Requirements for stereoacuity are:
* Normal ocular and orbital anatomy
* Overlapping visual fields
* Equal sensory input
* Equal higher central processing
The most common cause of monocular vision in children is lack of overlapping fields caused by a misalignment of the eyes, known as strabismus or squint.
Strabismus
Strabismus (Squint) occurs when there is a failure to align the eyes. It is the most common paediatric ophthalmic condition occurring at a rate of aprox 3% in Caucasian populations.
A constant discrepancy of gaze has the suffix -tropia while an intermittent one is termed -phoria. Either may be convergent or divergent (prefixed by eso- or exo- respectively). Furthermore a squint may be catagorised as a concomitant or incomitant, a description of whether the angel of deviation is constant. These catagorisations lead to a collection of phenotypes and it is currently unclear whether these have disparate aetiologies.
There is a definite heritable element to strabismus and this has been displayed in ALSPAC2 for convergent squint (OR 2.39 for a positive family history of esotropia).
A previous (unpublished) analysis of genome wide associations of Single Nucleotide Polymorphims (SNP) with squint and stereo was conducted within ALSPAC (ref B711) to tease out the heritable element of the condition. The strongest association was with a SNP in a gene on Chromosome 1 - PDE4B.
PDE4B
PDE4B gene is located on chromosome 1p31. Its gene product is one of a family of enzymes that regulate intracellular pathways via cAMP. It has been proven to be expressed in brain tissue3.
Most significantly, in this context, PDE4B is a well characterised susceptibility locus for schizophrenia and bipolar affective disorder3-5.
Squint, Stereo and Schizophrenia
Minor Physical Anomalies scales such as the Waldrop scale have been identified as phenotypic markers to aid in the diagnosis of schizophrenia. Although the original Waldrop scale did not include squint, it has been modified to incorporate squint with more accurate predictive power6.
Squint has also been shown to be an independent risk marker for schizophrenia7,8.
Additionally, binocular depth perception has been shown to be reduced in psychiatric illness9.
PLIKSi
The Psychosis Like Symptoms Interview is an interview assessment of children reporting episodes of hallucinations, feelings of persecution, delusional symptoms and though disorder.
Children who report such symptoms have been shown to be at a higher risk of developing psychiatric illness9.
Questions Raised
Is there any association between squint/stereo and psychiatric illness?
How to Answer this Question
ALSPAC is uniquely placed as it has both phenotypic data on squint, stereo and psychiatric variables as well as genotypic data. As such we propose an investigation into the following
* Assoc squint & stereo phenotypes and schizophrenia phenotypes (PLIKSi)
1 Foundations of Binocular Vision, a clinical perspective, Steinman, 200
2 Williams, C., Northstone, K., Howard, M., Harvey, I., Harrad, R. A., & Sparrow, J. M. (2008). Prevalence and risk factors for common vision problems in children: Data from the ALSPAC study. Br J Ophthalmol, 92(7), 959-64.
3 Fatemi, S. H., King, D. P., Reutiman, T. J., Folsom, T. D., Laurence, J. A., Lee, S., et al. (2008). PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res, 101(1-3), 36-49.
4 Numata, S., Ueno, S., Iga, J., Song, H., Nakataki, M., Tayoshi, S., et al. (2008). Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the japanese population. J Psychiatr Res, 43(1), 7-12.
5 Millar, J. K., Mackie, S., Clapcote, S. J., Murdoch, H., Pickard, B. S., Christie, S., et al. (2007). Disrupted in schizophrenia 1 and phosphodiesterase 4B: Towards an understanding of psychiatric illness. J Physiol, 584(Pt 2), 401-5.
6 Yoshitsugu, K., Yamada, K., Toyota, T., Aoki-Suzuki, M., Minabe, Y., Nakamura, K., et al. (2006). A novel scale including strabismus and 'cuspidal ear' for distinguishing schizophrenia patients from controls using minor physical anomalies. Psychiatry Res, 145(2-3), 249-58.
7 Schiffman, J., Maeda, J. A., Hayashi, K., Michelsen, N., Sorensen, H. J., Ekstrom, M., et al. (2006). Premorbid childhood ocular alignment abnormalities and adult schizophrenia-spectrum disorder. Schizophr Res, 81(2-3), 253-60.
8 Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., et al. (2004). Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet, 13(5), 551-61.
9Gunawardana 2010 schizo research - in press.
B1090 - The diagnosis of childhood disorders clinical and social implications MERGED WITH B0521 - 20/12/2010
Core research question:
Does identification/diagnosis of children with attention deficit hyperactivity disorders in their communities help improve core symptoms?
Background to proposed research:
Biomedical research suggests that attention deficit hyperactivity disorder (ADHD) is partially genetically and neurologically determined, leading to recommendations that a clinical diagnosis should be made as early as possible to treat and manage this condition. Current clinical trends show diagnosis is given more frequently and at younger ages than previously. Although the evidence for the effectiveness of the pharmaceutical intervention methylphenidate is well established as an effective intervention for ADHD, its use is controversial, particularly in young children.
There is little evidence-base that early diagnosis confers an advantage. Specific early school-based screening and intervention programmes for ADHD have not consistently improved children's outcomes.My own previous work in collaboration with Jean Golding and Colin Steer has shown that children with autistic traits in the ALSPAC cohort who were diagnosed had worse outcomes as adolescents in core autistic symptoms than those who had equally severe symptoms as preschoolers, but remained undiagnosed. We were not able to follow the developmental trajectories of core autism symptoms in detail other than in measures prosocial behaviour, where diagnosis and subsequent interventions in the community apparently made no difference to the developmental trajectory of this trait.
The proposed research will extend the methodology used for autistic traits to examine ADHD. We will identify ADHD diagnoses from clinical medical records of children with SEN or parent and teachers reports of doctors diagnoses of ADHD, and the group of children in the cohort reported as having an ADHD diagnosis will be identified.
This will allow us to define a control group with similar ADHD symptoms levels to those with a diagnosis. - as recorded by parents, teachers and/or medical records- see above. We will then examine social and demographic factors that may be associated with lack of diagnosis, as well as comparing outcomes between the groups.
Methodology:
The main study will focus on four key areas, although there will be scope for flexibility to allow for new developments:
[A] Identifying behavioural traits most predictive of receiving a diagnosis.
Hypothesis:
There will be a group of impaired (but undiagnosed) children in the ALSPAC cohort.
This will involve backwards 2 stage logistic regression to find behavioural traits associated with receiving a clinical diagnosis, then defining a composite 'attention deficit, hyperactivity' trait with appropriate weightings, which matches diagnostic criteria as closely as possible. We will find the ADHD diagnoses from a combination of parent report, teacher report and the IDI data which reports ADHD diagnoses for children with SEN at school action plus or statement level. We may also utilise the DAWBA 'pseudo diagnoses' where children were rated as having ADHD, and determine what proportion were actually diagnosed with ADHD in their communities.
[B] Defining an undiagnosed control group with equivalent symptoms to those with diagnosis.
The group will consist of children with impairment at the same levels as those with diagnosis (in the top 5%, of a composite 'attention deficit, hyperactivity' trait, for example) but who have not been given any Special Educational Needs (SEN) provision. We will examine the sensitivity and specificity of the composite ADHD trait in predicting diagnosis, and we will identify an impaired (control) group who did not receive SEN provision.
[C] Looking at social and demographic factors to see if any predict diagnosis.
Hypothesis:
Social and demographic factors will influence access to diagnosis.
Regression/association will be used to determine which factors in a child's background predict whether a diagnosis is applied or whether they fall into the control group. Gender, geographic region, measures of socio economic status, maternal age at birth, maternal mental health and other factors will be examined.
[D] Comparing outcomes in the two groups up to adolescence, and with the general population of the cohort.
Hypothesis addressing core research question:
Diagnosis of ADHD and subsequent intervention has an effect on clinical and social outcomes, compared with the undiagnosed group with similar symptoms.
We would hope that children receiving diagnosis of ADHD and receiving evidence based treatment (stimulant drugs and / or SEN provision) will have better outcomes than children who were not diagnosed and did not have SEN provision. This stage will compare measures of core symptoms, in diagnosed group, or not diagnosed control group, and in the general population. In addition, we will look at psychological measures such as well being, bullying, self esteem, friendships, and other salient measures such as impact on carers and children as the children reach adolescence. Trajectories of traits throughout the children's lifetimes will also be compared where data resolution allows.
The research proposed for this fellowship will take place at the host institution (Peninsula College of Medicine & Dentistry, Exeter), with an initial placement of one year at the University of Bristol Centre for Child and Adolescent Health, focusing on epidemiological and statistical techniques with ongoing collaboration on the qualitative project with the school of Social Science at Exeter University. A second period of up to one year (broken into short chunks) will be a placement at the international centre for epidemiological research with the larger longitudinal cohort in Denmark, depending on agreements and data availability. Preliminary enquiries have been made to The Danish National Birth Cohort (n=100,000+) who seem enthusiastic to collaborate.
The proposal as a whole responds to calls for community-based, multidimensional studies of outcome in childhood disorders so that current clinical practice can be robustly married with evidence based research. Please note that this research will be part of a larger fellowship proposal made to the Wellcome trust. The deadline for submission of this proposal is 21st January, so I am hoping to secure agreement with ALSPAC before submitting it.
B1092 - Childhood and early adolescent outcomes of early childhood grandparental care - 17/12/2010
As increasing numbers of women return to work in their child's first year of life, research and policy interest in the effects of non-maternal care has increased. To date, most attention has focused on group care, where evidence suggests some enhancement of aspects of children's cognitive development, but also (for some children at least) some increased risk of aggressive and disobedient behaviours.
Although a significant minority of very young children are cared for in group settings, in practice informal care from family and friends is much more common. In the Millennium Cohort Study (MCS), for example, although approaching a quarter of the babies of working mothers were in group care at 9 months of age, approaching 60% were receiving 'informal' care. Of these, by far the largest group (35% of all children of working mothers) were looked after by grandparents (Hansen & Hawkes, 2009). Followed at age 3, children cared for by grandparents in infancy showed superior vocabulary development by comparison with children in other non-maternal care settings, but higher levels of difficulties in relationships with peers (Hansen & Hawkes, 2009).
In a previous study (Fergusson et al, 2008) we used the extensive data available on child care arrangements in ALSPAC to identify children cared for by grandparents at 8, 15 and 24 months of age. As in MCS, we found that this pattern was common: 44% of ALSPAC children were regularly cared for by their grandparents at each age. We identified family and maternal characteristics associated with the use of grandparent care, and traced its associations with risk for emotional/behavioural difficulties (as assessed by the Strengths and Difficulties Questionnaire) at age 4. Children cared for by grandparents had somewhat elevated rates of both hyperactivity and peer difficulties, though these variations seemed at least partly attributable to variations in the types of families using grandparent care.
There has been some work looking at the longer-term outcomes of different types and quantities of early childcare (Belsky et al, 2007). In theUS, for example, there may be an association between extensive non-relative care and problem behaviours at 8 and 11 years. So far as we are aware, however, no studies have yet tracked the impact of early grandparent care beyond the preschool years. This study is designed to fill that gap. Specifically, we propose to examine (i) indicators of behavioural adjustment/psychiatric disorder across childhood and early adolescence; and (ii) indicators of early language development (not examined in our previous study), and later cognitive abilities and school progress. We will contrast children who did and did not receive early grandparent care on this range of outcomes, controlling for previously identified confounders/selection effects, and assess the extent to which early grandparent care is associated with long-term risks or advantages for children's development.
References
Belsky, J., Lowe Vandell, D., Burchinal, M., Clarke-Stewart, K.A., McCartney, K., & Tresch Owen, M. Are there long-term effects of early child care? Child Development, 78, 681 - 701
Fergusson, E., Maughan, B. & Golding, J. (2008). Which children receive grandparental care and what effect does it have? Journal of Child Psychology and Psychiatry 49, 161-169
Hansen, K., & Hawkes, D. (2009). Early childcare and child development. Journal of Social Policy 38, 211-239
B1088 - Molecular and life-course aspects of APOE and TOMM40 in cognition - 14/12/2010
The human APOE gene is located on chromosome 19 (19q13.2) and encodes the protein apolipoprotein E (ApoE).(1) There are 3 known APOE variants, epsilon2, epsilon3 & epsilon4 with single amino acid substitutions occurring at amino acid residue 112 (arginine for cysteine in epsilon4) or 158 (cysteine for arginine in epsilon3).(2) APOE is mainly expressed in the liver, with the brain having the second highest concentration.(2) ApoE is involved in lipid transport around the body, is a constituent of VLDL & HDL particles and of intestinally formed chylomicrons.(2) It also modifies binding of lipoprotein particles containing ApoE to LDL receptors(2) and in the brain is thought to be involved in lipid recycling, neuronal repair and maintenance, with E4 being the least efficient isoform.(3, 4)
Possession of an e4 allele is a strong genetic risk factor for the development of Alzheimer's disease (AD), although the mechanisms remain unclear.(5, 6) Cumulative inefficiences of repair and maintenance may contribute to the increased risk in e4 carriers. Early neuropathological changes of AD including deposition of amyloid-beta (Abeta), FDG PET abnormalities and cognitive changes have been found even in early middle age in e4 carriers, decades before AD is clinically evident.(7-9) Possession of e4 (without diagnosed dementia) is also linked to higher levels of Abeta and neurofibrillary tangles at autopsy,(10, 11) accelerated volume loss,(12) reduced synaptic protein concentration(13) and decreased PET glucose metabolism in areas affected in AD.
A meta-analysis identified that e4 carriage (in the absence of dementia) was associated with significantly poorer global cognitive functioning, episodic memory and executive functioning;(14) however, most of the studies were small, some used insensitive tests, several cognitive domains were less studied, information on confounding variables was frequently lacking and most examined the over-60s only. From the small number of studies of younger age groups there is evidence that e4 may be beneficial for early cognitive function although one study reported that young adult e4 carriers had a thinner entorrhinal cortex.(15-17)
In addition to the link with AD, APOE genotype has been shown to influence LDL-C levels and cardiovascular disease risk with e4 homozygotes having the highest risk and e2 homozygotes the lowest.(18, 19) A non-linear relationship between APOE genotype and stroke was recently reported in a meta-analysis to which members of our group contributed.(20)
Recently the hypothesis that mitochondrial dysfunction precedes the development of AD neuropathology has again gained support.(24) Roses et al recently demonstrated that a variable length polymorphism in TOMM40, a mitochondrial protein essential for protein import, "predicts the age of onset of late-onset Alzheimer's disease".(23, 25) TOMM40 is very close to the APOE gene on Chr19 and they are in linkage disequilibrium. Roses et al proposed that the APOE/AD link may actually be due to a haplotype including a long poly-T repeat in TOMM40.(23) Improving our understanding of the early neurobiological effects of APOE and TOMM40 may help in predicting AD and to enhance the effectiveness of lifestyle-based and targeted pharmacotherapeutic interventions.
Most of our current knowledge regarding APOE and cognition relates to older adults and the end-stage pathology seen in AD. It is currently unclear when the e4-related changes in brain structure and function begin and which changes occur first. There is a dearth of information on e4 effects in earlier adult life, although the existing evidence suggests that there are differences between e4 and non e4 carriers. Even less is known about TOMM40 and pre-dementia changes.
Many other studies in this area have been criticised for using insensitive neuropsychological tests or not examining specific cognitive areas. I intend to carry out a battery of validated, sensitive neuropsychological tests to avoid this problem. Neuropsychological testing using genotype based recall from ALSPAC gives the potential to have much greater numbers ofe4 homozygotes, thus improving statistical power. Few other studies have included such young participants, had access to such a high number of individuals with rare genotypes or sufficient information on potential confounders, e.g. cardiovascular variables, whereas the use of ALSPAC data would permit the inclusion a wealth of information on confounders in addition to greater statistical power.
B1087 - Identification of Epigenetic differences in MZ twins at birth using Dried Blood spots - 14/12/2010
One of the biggest challenges in complex disease epigenomics is distinguishing cause from consequence. Simply comparing disease-affected vs. unaffected individuals will not reveal whether disease-associated epigenetic variation is causative for, or induced by, the disease. In this respect, comparing epigenetic profiles before and after disease onset would be invaluable, but prospective longitudinal birth-cohort studies are extremely expensive, time-consuming, and hence uncommon.
A Guthrie (or Dried Blood Spot, DBS) card is filter paper spotted with neonatal blood and used to screen for various diseases. For ~20 years, DBSs have been routinely generated in many countries (since 2000, greater than 90% of all neonates in the USA had DBSs made) and often stored indefinitely. This led us to consider whether DBSs can be used to generate whole-genome DNA methylation profiles (DNA methylomes). This would permit large-scale systematic analyses to determine whether disease-associated methylation variants are present at birth i.e. prior to overt disease. Importantly, this retrospective approach could be done at a fraction of the cost and time investment required for prospective studies. But, it would require the development of DNA methylomics methods that work on small amounts of relatively old DNA present in archived DBSs.
We have developed two different high throughput sequencing-based methods for generating DNA methylomes using nanogram quantities of DNA from greater than 10 year old DBSs. First, we developed the mini-MeDIPseq method that allows immunoprecipitation-based DNA methylomics from only 200ng of DNA. Then, we adapted BSseq (bisulfite conversion-based single bp-resolution DNA methylomes) for 100ng of DBS DNA. A range of bioinformatic analyses and comparisons with independent external data confirm the quality of the mini-MeDIPseq and BSseq data.
DBSs are already available for millions of people, of whom tens of thousands are disease-affected, and these numbers are increasing. DBS storage is also becoming more formalized. It is worth noting that spotting blood on filter paper is not limited to neonatal screening, but also used in home/field-based settings, and our methods can be applied to such samples. In summary,DBS-based DNA methylomics will help determine whether methylation variants in disease-affected individuals are present at birth, thus forming the basis of a novel retrospective longitudinal strategy for complex disease epigenomics.
Now, we would like to demonstrate, using the methods we have developed, that MZ twins are born epigenetically different, and that these differences are stable. To do this, we will need Guthrie cards from an MZ twin pair and then a follow up samples take any time between 1 - 13 years after birth. The sex, ethnicity, current age, disease-discordance etc. are of no relevance to this project. It would be good to have information on the chorionicity if available, and as many we would also be very grateful if you could provide samples for 2-3 different MZ pairs.
B1086 - Parental depression and child development assessing the moderating effects of temperament and specific genotypes - 14/12/2010
Aim
To assess the potential moderating effects of reactive temperament and 5-HTTLPR genotype on the association between parental depression and child behavioural and emotional outcomes.
Background
Parental depression is a consistent and strong predictor of adverse outcome for children. Work within ALSPAC has established that maternal anxiety during pregnancy, and maternal depression both pre- and post-natally, predict an increased risk of behavioural problems in children. These effects have been shown to persist until at least age 7 years. Paternal depression in the postnatal period has also been shown to be independently associated with similar adverse risks for children.
There has been considerable interest in recent years in the hypothesis that some children are differentially susceptible to environmental influence, for better or for worse. According to this conception, the same group of children (usually identified as having reactive temperament, and sometimes by genotype) show worse outcomes in adverse environments compared to non-reactive children, but also better outcomes in response to positive environmental exposures. We have previously explored this hypothesis in collaboration with ALSPAC in relation to paternal influence on children's behaviour (forthcoming publication in Family Science by Ramchandani, Bakermans-Kranenberg and van IJzendoorn). Findings from other studies have also supported the notion that differential susceptibility may occur in relation to reactive temperament, and also in relation to genes related to serotonergic and dopaminergic functioning (notably 5-HTTLPR and DRD4) (van IJzendoorn & Bakermans-Kranenberg, in press; Pluess et al, 2010).
Work undertaken by Professor Michael Meaney with the MAVAN cohort study has found preliminary evidence of a moderating effect of the serotonin transporter gene on the association between maternal prenatal depression and child outcome. We have come together to propose a further investigation with the ALSPAC team to investigate specific candidate genotype by environmental risk factors, focussing on parental depression. The MAVAN cohort could act as a second confirmatory cohort for any findings emerging from these analyses.
We would like to develop this further, using a conservative approach and testing the serotonergic candidate genes, namely:
1) Serotonin Transporter Gene- Promoter Region Polymorphism (5-HTTLPR)
If evidence of interaction and clear differential susceptibility is found, then we would seek to take a biologically informed approach and confirm findings in other relevant functional polymorphisms in genes related to serotonergic neurotransmission.
Resources required
We do not anticipate significant resource being required, as we have an existing dataset containing the key variables needed, with the main exception of the genotype classifications. The lead applicant (Paul Ramchandani) would undertake the analyses in collaboration with the other applicants.
This proposal is deliberately brief, but we are happy to answer any questions and provide further detail as required.
B1085 - Accelerometer measured sedentary behaviour and time spent in self-reported daily activities - 10/12/2010
Background: It is estimated that children spent 6 to 9 hours per day in sedentary behaviour, as assessed by accelerometry (1). This has important public health implications since sedentary behaviour has been associated with poor metabolic health in children and adults, and early mortality in adults (2-4). While accelerometry provides an objective estimate of total sedentary behaviour, this measure of sedentary behaviour does not provide details on how that time is spent. This is a limitation from a preventive standpoint as it is unknown what behaviours need to be specifically targeted to reduce time spent in sedentary behaviour. It is known from self-reported diaries that there is within and between gender variability regarding sedentary behaviour profiles (5, 6). However it is unknown if sedentary behaviour profiles are associated with more or less total sedentary behaviour as assessed by accelerometry.
Aim 1: To determine if spending time in specific sedentary behaviours associate with total sedentary behaviour, MVPA and adiposity at 14-years-old
Aim 2: To determine if spending time in specific sedentary behaviours at 14-years-old associate with changes in total sedentary behaviour, MVPA and fat mass from 14- to 16-years-old.
Cluster Analysis: Cluster analysis will be used to determine if children belong to similar groups based on their self-reported sedentary behaviours (separately for boys and girls). The time spent in 14 sedentary activities on a typical day was self-reported by the children: none, less than 1hr, 1-2hrs or 3 or more hrs.
Dependent Variable 1: Total sedentary behaviour (accelerometry less than 200cpm, mins/d)
Dependent Variable 2: Total MVPA (accelerometry(cubed)3600cpm, mins/d)
Dependent Variable 3: Fat mass (DXA, kg)
Independent Variable: Sedentary cluster group
Covariates: Maternal education, maternal obesity, birth weight, and length of gestation.
Statistical Analysis: Cross-sectional analysis at 14-years using analysis of covariance (ANCOVA) and Tukey adjustment for multiple comparisons. Longitudinal analysis between 14- and 16-years using linear mixed models to determine if sedentary cluster group is associated with change in total sedentary behaviour, MVPA and fat mass over time. All analyses will be conducted separately for boys and girls.
Model Building:
Model 1 - adjusted for age
Model 2 - adjusted for age + maternal factors
Model 3 - adjusted for age + maternal factors + birth factors
Target Journals: American Journal of Preventive Medicine or MSSE
References:
1. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors in the United
States, 2003-2004. Am J Epidemiol. Apr 1 2008;167(7):875-881.
2. Ekelund U, Brage S, Froberg K, et al. TV viewing and physical activity are independently associated with metabolic risk in children: the European Youth Heart Study. PLoS Med. Dec 2006;3(12):e488.
3. Healy GN, Dunstan DW, Salmon J, et al. Breaks in sedentary time: beneficial associations with metabolic risk. Diabetes Care. Apr 2008;31(4):661-666.
4. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc. May 2009;41(5):998-1005.
5. Biddle SJ, Gorely T, Marshall SJ. Is television viewing a suitable marker of sedentary behavior in young people? Ann Behav Med. Oct 2009;38(2):147-153.
6. Gorely T, Marshall SJ, Biddle SJ, Cameron N. Patterns of sedentary behaviour and physical activity among adolescents in the United Kingdom: Project STIL. J Behav Med. Dec 2007;30(6):521-531.
B1084 - Cortisol in middle childhood associations with genetic and early environmental risk PhD - 09/12/2010
Individual differences in the hypothalamic-pituitary-adrenal (HPA) axis are important contributing factors for mental and physical health throughout the lifespan (e.g. Fan et al., 2009; Weber-Hamann et al., 2002; Whiteford, Peabody, Csernansky, Warner, & Berger, 1987). Because many individual differences that are important for health are believed to emerge in early childhood, research has focused on identifying individual and environmental variables that may impact basal and stress-reactive HPA axis activity. Elements of the early home environment such as financial strain, family turmoil, exposure to violence, and maternal depression have emerged as reliable predictors of basal cortisol (the primary hormonal product of the HPA axis) in childhood (Essex, Klein, Cho, & Kalin, 2002; Evans 2003; Flinn & England, 1997; Saridjan et al., 2010). However, prior research has primarily used concurrent or retrospective designs and therefore the longitudinal effects of early environmental risk on basal cortisol are relatively unknown. Although some important individual differences in HPA axis activity and development are likely due to genetic differences, studies examining genetic contributions to basal cortisol have found inconsistent results. Some studies suggest that genes such as SLC6A4, COMT, and MAOA may contribute to HPA axis regulation in adults (Brummett et al., 2008; Jabbi et al., 2007, Wust et al., 2009). Developmental research has also found main effects for SLC6A4 on basal cortisol in 9-14 year olds (Chen, Joormann, Hallmayer, & Gotlib, 2009). Interestingly, published work (including papers utilizing ALSPAC data) examining associations among these polymorphisms and mental health in children has often reported null results (Araya et al., 2008; Evans et al., 2008; Haberstick et al., 2005; Munafo, Durrant, Lewis, & Flint, 2009). Both theoretical models and limited prior research suggest that early effects of these polymorphisms on health may occur via a meditational process, such as through differences in HPA axis regulation. Thus genetic and early environmental risk may contribute to HPA axis dysregulation in childhood, which may then contribute to poorer health outcomes. However this meditational model needs to be assessed more thoroughly to extend environmental findings and replicate genetic associations.
Toward that end I have been examining genetic and environmental associations with cortisol in early childhood (2-6 years). This research was for my masters degree and related presentations. In our small sample of children (N = 59) I found that environmental risk (a composite of income, financial strain, life events exposure, maternal age, maternal education, and current maternal depression symptoms) did predict basal cortisol, but genetic risk (according to 5-HTTLPR, COMT, DAT, DRD2, and DRD4) did not (Pikovsky & Watamura, 2010). This suggests that although the early environment exerts its influence on basal cortisol patterns fairly early, effects of the above genetic variations may emerge later, and/or be too small to detect in a sample of this size. Because effect sizes are known to be small and effects likely emerge in middle childhood or later, it would be most useful to assess cortisol in a large sample of children more than six years old, as was done in the ALSPAC study.
The proposed study would examine relationships among genetic risk, early environmental risk, and basal cortisol in middle childhood. I would like to examine polymorphisms in the COMT gene (Val158Met - rs4680, rs2097603, rs6269, rs4818, rs165599), the MAOA promoter VNTR (AJ004833), and the serotonin transporter SLC6A4 (5-HTTLPR and rs25531). These polymorphisms will be used to define genetic risk, which along with environmental risk and their interaction will be used to predict basal cortisol. According to the ALSPAC documentation of child biological samples, cortisol was assessed in 889 participants at approximately 7.5 years of age.
To assess early environmental risk I would like to examine cumulative exposure to a variety of risk factors from approximately 2.5 - 6 years of age. The first of these risk factors is exposure to upsetting events. This was assessed with section D of the child-based questionnaires administered at 42, 57, and 69 months. Additionally, because maternal exposure to stressful events has implications for the child's environment, I would also like to examine mother's recent events exposure assessed at 47, 61, and 73 months. Together, cumulative exposure to upsetting events (child) and stressful recent events (mother) will provide a more comprehensive picture of financial strain, family turmoil, and exposure to violence. Finally, prior research in our lab and others suggests that maternal depression during early childhood is a risk factor for physiologic dysregulation (Essex et al., 2002; Pikovsky & Watamura, 2010), therefore I would like to look at the Edinburgh Postnatal Depression Scale assessed at 33, 61, and 73 months. Information from all three sets of risk factors will be combined via structural equation modelling into a latent Environmental Risk variable that will be used in subsequent analyses.
In addition to the aforementioned study variables, I would also like to look at the following variables as possible controls. Information about illness, medication, and diagnoses is especially important as these may impact cortisol concentrations. Therefore I would like to look at several sections of the child-based questionnaires administered at 91 months. Section A provides detailed information about health and medications. Section N provides information about special needs that may indicate underlying physiologic conditions. Finally, variables KR800 - KR832a provide information about DSM IV diagnoses.
Thank you for considering this data request. If accepted, these dissertation analyses will be supervised by my co-applicants: Sarah Watamura and Julia Dmitrieva. By examining the ALSPAC variables described above I hope to more thoroughly examine the links from genetic and early environmental risk to basal cortisol in early childhood. In doing so I will contribute to the literature on physiologic mechanisms leading to variability in mental and physical health.
B1082 - The impact of fathers age on offspring intelligence development and health - 09/12/2010
Changing patterns in education, employment and marriage along with improved reproductive technologies mean that the average age of childbearing in men and women is increasing while the average family size is falling. Although there are potential advantages to these trends, particularly in terms of financial security, there are also disadvantages, many of which are poorly understood at present. The detrimental effect of increasing maternal age on the health and development of offspring is widely recognised but the effect of increasing paternal age remains largely unexplored. However, there is emerging evidence that pregnancies conceived to older men are more likely to end in spontaneous abortion and that their children may be less intelligent, and be at higher risk of adverse outcomes and developmental disorders independent of the age of their mother.1-2 Moreover, these increased risks are not confined to childhood and advanced paternal age has also been reported to be associated with a number of adverse outcomes in adult offspring, most notably schizophrenia and certain cancers (principally breast, prostate and leukaemia).3-5 It is hypothesised that these associations may be due to the accumulation of chromosomal aberrations and mutations during the maturation of male germ cells.6 Later reproduction is also leading to a trend towards smaller families. While it is known that morbidity and mortality often rise with increasing number of siblings, there is also evidence to suggest that children from smaller families, and in particular only children, have a health experience that is out of line with anticipated gradients with number of siblings, specific examples being high blood pressure and asthma.7-8
Although the individual risks from having an older father or fewer siblings may be low, current trends in childbearing mean that these will increase at a population level and it is important that the risks are fully understood to allow appropriate education and to inform social policy changes. The aim of this project is to systematically investigate the effects of increasing paternal age and decreasing family size on the health and development of offspring throughout the life course. Systematic reviews of the available evidence will be carried out along with original research utilising a wide range of existing datasets.
Research plan
The project will involve a diverse range of existing large, good quality prospective datasets that cover the whole of the life-course, in different populations, over a range of calendar periods. These data sets include: ALSPAC, ProtecT, Swedish record linkage studies, Midspan Family Study, Glasgow Students Cohort, Caerphilly Cohort, and Boyd Orr Cohort. Parental age is available in all cohorts, along with a wealth of additional relevant data such as: mortality (Swedish, Midspan, Glasgow Students), cancer (ProtecT, Swedish, Midspan, Glasgow Students), offspring IQ (ALSPAC, Swedish), other mitogenic exposures (ALSPAC, Midspan), and details of family formation (ALSPAC, Swedish, Midspan, Glasgow Students).
This wide range of studies will form a consistent and complementary body of evidence on the short and longer-term effects of paternal ageing and smaller family size on offspring intelligence, development and health, and will also allow identification of critical periods in the life-course and investigation of how these interact with other risk factors. Examples (not an exhaustive list) of some specific hypotheses of interest include:
- Is greater paternal age associated with an increased risk of neuro-developmental markers of future mental disorder such as low intelligence or delay in obtaining motor milestones? How important is intelligence in setting an individual's life-course in terms of education, future financial attainment and long-term health? These questions will be explored using ALSPAC, Swedish and other datasets.
- Is increasing paternal age is associated with an increased risk of cancer? This will be examined in ProtecT (prostate cancer), Swedish (leukaemia, lymphoma and testicular cancer), and other datasets.
- How do offspring risks from mitogenic exposures in the father, e.g. smoking, alcohol, diet and occupation, combine with those from advancing paternal age? This will be explored using ALSPAC, Midspan and other datasets.
* It has been suggested that poorer health in only children may be a result of a more sedentary lifestyle. However, there are alternative hypotheses: Are only children more likely to be born to older parents and have a poorer health experience as a result? Or are only children the result of poor reproductive experience with hereditary factors responsible for poorer health? (e.g. high blood pressure in pregnancy is associated with high blood pressure in offspring; if a negative experience in pregnancy (e.g. eclampsia) results in a decision not to have any further children then this could explain the apparent pattern of increased blood pressure in only children) These hypotheses will be investigated using ALSPAC and other data on maternal health in pregnancy.
* To what extent are paternal age and family size associations confounded with each other and with other factors, in particular, parental intelligence, maternal age and changing social class? The availability of a wide range of datasets from across the life-course will allow a thorough investigation of the impact of these inter-correlated confounding variables through direct statistical analysis, appropriate simulation work and alternative study designs, e.g. in the Swedish studies data are available on both biological and step-fathers; if associations are restricted to biological father's age then, assuming that parents tend to be similar in age, this will provide evidence that the relationship is independent of maternal age.
The specific assemblage of different cohorts provides additional strength and value to the proposal. For example, the use of cohorts, some historical, from a range of calendar periods will allow a comparison of associations over time and insight into the impact of changing attitudes and societal trends in the reasons for delayed parenthood. In addition, several cohorts (e.g. ALSPAC, Glasgow Students) have repeated sweeps of data collection and these will be used to explore the impact of missing data on the results and conclusions of the analyses.
References
1. Bray I, et al. Advanced paternal age: How old is too old? J Epidemiol Community Health 2006;60:851-3
2. Cannon M. Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence The clock ticks for men too. PLos Med 2009;6
3. Sipos A, et al. Paternal age and schizophrenia: a population based cohort study. BMJ 2004;329:1070-3
4. Zhang Y, et al. Parental Age at Child's Birth and Son's Risk of Prostate Cancer. Am J Epidemiol 1999;150:1208-12
5. Hemminki K, Kyyronen P. Parental age and risk of sporadic and familial cancer in offspring: Implications for germ cell mutagenesis. Epidemiology 1999;10:747-51.
6. Crow JF. The origins patterns and implications of human spontaneous mutation. Nat Rev Genet 2000;1:40-7
7. Okasha M, et al. Determinants of adolescent blood pressure: findings from the Glasgow University student cohort. J Hum Hypertens 2000;14:117-24
8. Rona RJ, et al. Association between asthma and family size between 1977 and 1994. J Epidemiol Community Health 1999;53:15-9
B1083 - Is pet ownership associated with childhood asthma - 02/12/2010
We propose to examine the association between pet ownership, allergic sensitization and asthma, within a cohort of children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). On the basis of the findings of previous studies, we hypothesise that childhood household pet ownership will be associated with childhood asthma and asthma/atopy symptoms, and that these associations will be moderated by a number of factors including child genotype, time and duration of exposure, species of exposure (cats, dogs, other pets), and associated parental behaviours (domestic hygiene practices). By making use of an existing large-scale database, which has detailed records of pet keeping in the prenatal and early-to-middle childhood period, as well as extensive information concerning potential confounding factors, we propose to conduct the most rigorous study to date of the relationship between pet keeping and childhood asthma morbidity.
5.2. Hypotheses
We hypothesise that household ownership of cats, dogs and other pets, prenatally, in infancy and in early-to-middle childhood will be associated with:
1. Sensitisation to aeroallergens at 84 months (7 years);
2. Wheezing illnesses during early childhood up to 81 months of age (6 years 9 months);
3. Doctor-diagnosed asthma by 96 months(8 years);
4. Lung function and bronchial responsiveness at age 96 months (8 years).
We additionally hypothesise:
1. that pet ownership effects on sensitisation to aeroallergens, wheezing illness and asthma are independent of other social and lifestyle variables;
2. age and duration of pet exposure, number and types of pets owned (e.g. cats & dogs, cats only, dogs only, other furry pets., etc.) will moderate these associations;
3. parental hygiene practices (e.g. cleaning frequency and use of household cleaning products) will moderate these associations.
5.3. The study population - The Avon Longitudinal Study of Parents and Children (ALSPAC):
Child health questionnaires: Maternal reports of their children's health were collected using questionnaires issued six months after birth and at annual intervals thereafter. Mothers were asked if, during the preceding 12 months (6 months for the initial questionnaire), their child had 'wheeze with whistling on his/her chest when s/he breathed'. If they answered, "Yes," they were asked to complete a number of supplementary questions detailing the frequency of wheezing episodes, duration of wheezing, associated symptoms of breathlessness or fever, and what (if anything) provoked the wheezing. At 91 & 103 months of age (7 1/2 & 8 1/2 years approximately) they were also asked to report if a 'doctor had ever diagnosed (their) child as having asthma'. From responses to these questions, we reported differences in the epidemiological associations of wheezing illnesses in young children (Sherriff et al., 2001) and we have been able to map these symptoms to early wheezing phenotypes reported from the Tucson Children's Respiratory Study (Martinez et al., 1995).
Household pet ownership questionnaires: Details of pets kept in the household of the child were reported by mothers within the same questionnaires used to obtain details concerning child and maternal health. Respondents were asked "Do you have any pets?" and "How many of the following pets do you have?". Pet types listed included cats, dogs, rabbits, rodents (mice, hamster gerbil, etc.), birds (budgerigar, parrot etc.) and 'other' pets. Two additional categories of pet type (fish and turtles/tortoises/terrapins) were added when the cohort children were 2 years of age and onwards. Pet questions were asked prenatally (when the mother was between 8 and 32 weeks pregnant), at 8 months, and at 21, 33, 47, 85 and 97 months (approximately 2, 3, 4, 7 and 8 years).
Additional Questionnaire information: Measures of numerous potential confounds and moderators of pet ownership-asthma associations were collected using the same and additional maternal questionnaires administered both before birth and at yearly intervals thereafter. ALSPAC variables that have previously been found to be associated with variations in pet ownership include: gender of child, number of people in household, presence of older sibling, type of dwelling, maternal age, maternal and paternal social class, presence of other species of pet and maternal and paternal education (Westgarth et al 2010). ALSPAC variables that have previously been found or are thought to be to be associated with childhood asthma include: maternal and paternal smoking (including total number of hours of exposure to tobacco smoke per week in home), environmental pollution, use of household cleaning products, maternal anxiety during pregnancy, maternal and child diet, child activity levels (Shaheen et al 2002, 2004, 2005; Sherriff et al 2005, 2010; Cookson et al 2009).
Child clinic assessments: A range of clinical and behavioural data were collected between 91 and 103 months of age (approx. 7-8 years), including skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus), and mixed grass pollen. A subsample of the clinic population (approx 2500 children) was also assessed by skin prick test responses to other animals commonly kept as domestic pets (dog, horse, mouse, rabbit, guinea pig and hamster). For genetic analyses, DNA was extracted from maternal blood and from infant cord blood samples at birth, and later supplemented by blood samples drawn at approx. 91 months; such samples are currently available for approximately 10,000 mothers and 10,000 children.
The ALSPAC population is broadly representative of the rest of the British population based on 1991 census data, although participants in the study were more likely to live in owner-occupied accommodation and less likely to have a non-white mother (ALSPAC 2.6%; population of Avon 1970 4.1%; UK census 1991 7.6%). In common with all population-based longitudinal studies, there has been incomplete retention of the cohort with attrition biased towards the more socially disadvantaged groups. However, over 11,000 children actively participated in the study to age 96 months (8 years), providing a large dataset with which to assess antenatal and early life effects on the development of childhood asthma and wheeze.
5.4. Health outcomes (see Hypotheses):
1. Sensitisation to aeroallergens was assessed by skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus) and mixed grass pollen at the age of 91 months (approx. 7 years). A positive skin prick test response (greater than 2mm weal) to any of these three allergens identifies over 95% of atopic children in our population (i.e., positive skin test to any allergen).
2. Doctor diagnosed asthma at approx. 96 months (8 years) was assessed from response to questionnaires completed by the mother.
3. Wheezing illness during early childhood is based on a novel approach to wheezing phenotype characterisation developed by our group from longitudinal analyses of wheeze data using latent class models (Henderson et al 2008). This analytical approach defines the minimum number of wheezing trajectories (classes) that best describe the data and is robust to missing data, providing wheeze phenotype classifications for 11,625 of the study population from birth through 81 months. The best fitting model to our data suggested the presence of 6 classes (5 wheezing classes plus non-wheezers). We have named these five wheezing trajectories Transient Early, Prolonged Early, Intermediate-onset, Late-onset and Persistent Wheezing as shown in the legend. These include classes that have been suggested to be associated with abnormalities of early (including intrauterine) airway development (Stocks and Dezateux, 2003). Our analyses showed strong associations between intermediate and late onset wheezing with bronchial hyper-responsiveness and of intermediate onset and persistent wheezing with allergy to cat and house dust mite. Therefore, it appears that these classes are representative of discrete wheezing phenotypes in early childhood that may have differing natural histories and aetiology (Henderson et al 2008).
4. Lung function and bronchial responsiveness were assessed at a research clinic at approximately 103 months. Spirometry was performed according to American Thoracic Society criteria for acceptability and reproducibility (American Thoracic Society, 1995). Measurements were quality controlled to ensure appropriate selection of the optimal curve from which lung function variables (FEV1, FVC, MMEF, FEF50, FEF75) were derived. Each variable was converted to a scale of gender- age- and height-adjusted standard deviation units based on log-linear regression against age and height, for boys and girls separately and then combined across genders (Chin and Rona, 1992). After completion of satisfactory baseline lung function measurements, bronchial responsiveness to methacholine was measured in consenting children (n=5000) according to the rapid method of Yan et al, (1983) using hand-operated glass nebulisers. For each participant, we measured forced expiratory volume (FEV1) post-saline inhalation (baseline) and 1 minute after each of a sequence of cumulative doses of methacholine.
B1078 - Early Adversity Psychological Functioning and Cardiovascular Risk in Youth Fellowship - 22/11/2010
An expanding literature has documented that adverse childhood experiences are associated with increased risk for a broad range of chronic diseases later in life, including cardiovascular diseases (CVD) (Felitti, Anda et al. 1998; Galobardes, Lynch et al. 2004). There is growing interest in clarifying the physiological mechanisms that link early experiences to health later in life (Taylor 2010); however, the majority of existing studies on this topic are retrospective and have a large window of time between the time of exposure and assessment of cardiovascular risk factors or health outcomes (Miller, Chen et al. 2009). Recent improvements in our understanding of atherosclerosis, and technologies to detect early indicators of CVD, have made it possible to identify risk factors among children and adolescents (Groner, Joshi et al. 2006). However, few studies have examined the association between early life adversity and CVD risk factors that emerge during the child and adolescent period. And, among existing studies, the majority have focused on socioeconomic factors (Batty and Leon 2002; Howe, Galobardes et al. 2010) to the exclusion of other types of stress exposures (e.g., family conflict, abuse, or acute stressful events). A related short-coming is that we have a limited understanding of the role of psychological health in the relationship between early adversity and development of CVD risk factors, despite substantial evidence that exposure to adversities negatively affects child mental health (Repetti, Taylor et al. 2002). The goal of the research described in our proposal is to address these gaps in knowledge by considering a range acute and chronic family-level adversities in relation to pro-inflammatory markers (CRP and IL-6) and blood pressure (BP) measured during childhood and adolescence, and to examine the potential role of child mental health within this relationship.
B1076 - The relationship between autistic spectrum traits and psychotic symptoms in the ALSPAC birth cohort - 15/11/2010
The social disabilities described in autism are often reminiscent of classic descriptions of social disinterest and emotional coldness of schizoid personality types. Clinicians often report encountering brief psychotic episodes in people with autism spectrum disorders (ASDs) additionally many adults with ASD have had a 'misdiagnosis' of schizophrenia, particularly before the 1980s when autism was introduced in classification systems. Both disorders are defined by deficits in interpersonal relationships, and social skills1;2 frequently displayed as active and passive social withdrawal. Also it has been suggested that both disorders may be considered as existing on a continuum ranging from mild symptoms to clinical disorder3;4. Mild symptoms of both disorders are prevalent in community samples3;5 Theoretically it has been suggested by Crespi & Badcock6 that autism and psychosis are diametrically opposite disorders of the social brain, (the areas of the brain that are associated with social information processing). They suggest that austim is characterised by hypo-development of of social cognitive skills and that psychosis is characterised by hyper-development of these skills. There is reliable evidence for social cognitive deficits in both disorders7;8. There have been a few previous studies on social cognition9-11 12which have compared small clinical samples of both groups. These studies have been cross-sectional and some have included healthy comparison groups. The findings of these studies have been mixed with some studies suggesting similar deficits and others finding differences. There have been no previous studies using longitudinal or cohort data.
If there is a true overlap between autistic spectrum and psychosis spectrum disorders one would expect to find an association between autistm spectrum traits and psychotic symptoms. This study aims to investigate these links in the ALSPAC birth cohort using previously identified autistic spectrum traits, a diagnosis of autism taken from medical records, and later experience of psychotic symptoms.
Method
Sample
ALSPAC birth cohort
Study sample
Cohort members who have contributed to the data used to identify autistic spectrum traits and who have participated in the clinical interview to detect psychotic symptoms.
Measures
Primary Outcome
PLIKSi. Information on experience of 12 core psychotic symptoms was collected from cohort members who attended an ALSPAC clinic at the age of approximately 12 years. For the purposes of this study the variable is dichotomously coded as; experience of suspected or definite symptoms over the previous 6 months (yes), and no experience of symptoms over the previous 6 months (no).
Exposure
Four of the seven autistic spectrum traits identifed by Steer & Golding13; verbal ability, language acquisition, social understanding, semantic-pragmatic skills.
A confirmed diagnosis of autism taken from medical records
Other Measures
Demographic measures from the ALSPAC database
Statistical Analysis
Multivariate logistic regression models will be used to examine the association between autistic spectrum traits and later experience of psychotic symptoms
Implications
This analysis will confirm or otherwise any overlap between autism and psychosis in a large community sample. It will generate new information on whether people with autism may be more likely to develop a later psychotic illness, and if so, which autistic traits may be most strongly associated.
Reference List
(1) Green J, Gilchrist A, Burton D, Cox A. Social and psychiatric functioning in adolescents with Asperger syndrome compared with conduct disorder 1. J Autism Dev Disord 2000; 30(4):279-293.
(2) Bora E, Eryavuz A, Kayahan B, Sungu G, Veznedaroglu B. Social functioning, theory of mind and neurocognition in outpatients in with schizophrenia; mental state decoding may be a better predictor of social functioning than mental state reasoning. Psychiatry Research 2006; 145:95-103.
(3) Baron-Cohen S. Two new theories of autism: hyper-systemising and assortative mating. Arch Dis Child 2006; 91(1):2-5.
(4) van Os J, Linscott Ra, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness?persistence?impairment model of psychotic disorder. Psychological Medicine 2009; 39(02):179-195.
(5) Horwood J, Thomas K, Duffy L, Gunnell D, Hollis C, Lewis G et al. Frequency of psychosis-like symptoms in a non-clinical population of 12 year olds: Results from the Alspac birth cohort. European Psychiatry 2008; 23:S282.
(6) Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences 2008; 31(03):241-261.
(7) Muris P, Steerneman P, Meesters C, Merckelbach H, Horselenberg R, van den HT et al. The TOM test: a new instrument for assessing theory of mind in normal children and children with pervasive developmental disorders 1. J Autism Dev Disord 1999; 29(1):67-80.
(8) Sprong M, Schothorst P, Vos E, Hox J, van Engeland H. Theory of mind in schizophrenia-metanalysis. British Journal of Psychiatry 2007; 191:5-13.
(9) Bolte S, Poustka F. The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives 6. Psychol Med 2003; 33(5):907-915.
(10) Craig JS, Hatton C, Craig FB, Bentall RP. Persecutory beliefs, attributions and theory of mind: comparison of patients with paranoid delusions, Asperger's syndrome and healthy controls. Schizophrenia Research 2004; 69(1):29-33.
(11) Pilowsky T, Yirmiya N, Arbelle S, Mozes T. Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children. Schizophrenia Research 2000; 42:145-155.
(12) Couture SM, Penn DL, Losh M, Adolphs R, Hurley R, Piven J. Comparison of social cognitive functioning in schizophrenia and high functioning autism: more convergence than divergence 1. Psychol Med 2010; 40(4):569-579.
(13) Steer CD, Golding J, Bolton PF. Traits contributing to the autistic spectrum 2. PLoS One 2010; 5(9):e12633.
B1074 - ARIES - A multigenerational prospective resource for integrating genetic epigenetic and dense phenotypic measures from birth to 18 - 15/11/2010
We will obtain genome-wide white blood cell methylation data on 1000 mother-child pairs in the Avon Longitudinal Study of Parents and Children. Mothers' DNA was obtained during pregnancy and 18 years later and offspring DNA from cord blood, at age 7 and age 15-18. Genome-wide SNP data are available on all participants and the children of the 1000 mother-child pairs taken included in the present proposal have CNV analysis and genome-wide gene expression data available and whole genome exon sequencing is in progress. 2000 of the offspring will have whole genome exon sequencing, CNV analysis and genome-wide gene expression data. Dense phenotyping on the mothers and their offspring has been completed, with exposure and outcome measures relevant to cognitive development, growth, behavioural patterns, metabolic health and detailed functional, physiological and biochemical assessments. The generation of DNA methylation data will provide unparalleled opportunities for the integration of multi-dimensional biological data in human samples for the benefit of the scientific community. Stored samples of blood, hair, teeth, placentas, umbilical cords and urine are available for further analysis. These data will be curated and made fully available to the scientific community. The resource will address the issue of healthy human development (the cohort are currently in early adulthood) and, in the mothers, the avoidance of age-related decline.
Due to the poor accessibility and availability of DNA from human tissues we will complement the proposed resource with tissue-specific methylation and gene expression analysis in animal (rodent) models (incuding those with diet-induced altered ageing trajectories) which will include WBC DNA methylation to facilitate a direct comparison of WBC epigenetic signatures to those of target tissues. Rodent tissues will be banked and available to undertake fine mapping methylation analysis and gene expression studies of differentially methylated regions identified through analysis of ALSPAC data.
Resource development will be complemented by an overarching bioinformatics arm that will ensure the integration of respective data sets and the development of accessible data formats.. We will also integrate the resource with the Human International Epigenome Consortium (IHEC) to ensure maximal utilisation and added value for the data.
1. Strategic Relevance
Epigenetic studies of readily obtainable material are becoming a central focus of biological research internationally. Epigenetic profiles can serve as exposure markers and as prognostic or predictive biomarkers. ALSPAC is a unique resource in having two-generational data and cord blood samples available, allowing for intrauterine influences, intergenerational transmission, change in methylation from birth through to pre-pubertal and post-pubertal age, and investigation of how methylation patterns predict and change with development. This resource, coupled with studies of the relationship between white cell and other tissue methylation, would be unequivocally world leading.
This resource provides an excellent match with the current "BBSRC Priorities" document. Under "Ageing Research: Lifelong Health and Wellbeing" it is stated that "Evidence increasingly suggests that impaired growth in utero especially when followed by rapid post-natal growth can seriously impair many aspects of health and may influence ageing. The mechanisms by which these early life exposures are mediated are poorly understood. There is a need to encourage research that investigates how early developmental factors may influence health during ageing. Specifically, the challenges are to understand i) how nutritional (and other) exposures are recorded and transmitted through subsequent generations of cells and ii) how this "memory" is translated into altered function in later life." Our study will directly allow these issues to be addressed. In "The Age of Bioscience: Strategic Plan 2010-2015" the 3rd strategic research priority is "Basic Bioscience underpinning health", which the proposed resource will directly address, including the "key research goal [which] is to develop a better understanding of the role of diet and physical activity and the mechanisms by which they affect development and health" and the key priority to "establish greater understanding of how diet affects health throughout life, including epigenetic effects".
B1073 - Beverage consumption and adiposity in childhood and adolescence - 08/11/2010
Currently there is intense interest in the possible role of beverages in increases in childhood obesity, particularly sugar-sweetened beverages (SSB) and artificially-sweetened beverages (ASB). Observational and intervention studies in adults have linked the consumption of SSB to weight gain, insulin resistance and dyslipidaemia [1], and CVD incidence in women [2]. Less research has been conducted on children and adolescents. However, limited evidence suggests that SSB and ASB are associated with weight gain and have metabolic effects in young people [3]. Whereas, fruit juice and milk consumption have not been associated with weight gain in children [4].
There have been concurrent increases in obesity prevalence and sweetened beverage consumption in the UK (as well as Australia and USA) over the past two decades. Therefore, the possible association between sweetened beverage (caloric and non caloric) consumption and the development of adiposity during childhood and adolescence deserves investigation.
Hypotheses to be examined in ALSPAC cohort:
1. SSB intake at an early age (7 yrs) predicts SSB intake throughout middle childhood and adolescence, i.e. SSB intake tracks modestly from early childhood into adolescence.
2. Greater intakes of SSB (sugar-sweetened fizzy drinks, squashes, fruit drinks) are independently associated with the longitudinal development of excess adiposity (fat mass, fat mass index) between the ages of 9 and 15 years.
3. Greater intakes of ASB are independently associated with the longitudinal development of excess adiposity between the ages of 9 and 15 years.
4. Greater intakes of fruit juice are not associated with the longitudinal development of excess adiposity between 9 and 15 years of age.
The following will be considered as potential confounding variables in longitudinal models: sex, age, height, baseline fat mass/fat mass index, pubertal stage, physical activity levels. To investigate whether associations with beverage intake are independent of overall diet quality, we will also adjust for score for an energy dense, high fat, low fibre dietary pattern measured at the same time points as beverages.
Data required -
1. 3 day food diary data collected at 7, 10 and 13 years of age (foods and nutrients)
2. Fat mass measured at 9, 10 and 13 years of age
3. Height, weight and BMI at 7 through 15 years
4. Pubertal development (Tanner Stage) from 9 through 15 years
5. Physical activity (accelerometer data) at 11 and 13 years
6. Age (months) from 7 year follow up through to 15 y follow up
Note that the applicants have the data required for this project'- data were obtained for another ALSPAC analyses being conducted by the applicants examining 'Dietary determinants of fat mass in adolescents' (WCRF funded).
References
[1] Malik VS, Popkin BM, Bray GA, Despres J-P, Hu FB. Sugar-sweetened beverages, obesity, Type 2 Diabetes Mellitus, and cardiovascular disease risk. Circulation. 2010;121(11):1356-64.
[2] Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89(4):1037-42.
[3] Brown RJ, de Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obesity. 2010;5(4):305-12.
[4] Fiorito LM, Marini M, Francis LA, Smiciklas-Wright H, Birch LL. Beverage intake of girls at age 5 y predicts adiposity and weight status in childhood and adolescence. Am J Clin Nutr. 2009;90(4):935-42.
B1072 - Co-morbidity of autistic traits - 08/11/2010
Autism spectrum disorder (ASD) is associated with a range of comorbid psychopathology, with 70% of children with ASD meeting criteria for at least one other mental disorder 1. Furthermore, in the general population even the presence of subtle, sub-clinical ASD traits predicts the presence of additional internalising and externalising difficulties2. This suggests that mildly elevated ASD traits may be implicated in the onset and maintenance of a range of common psychological and behavioural difficulties that carry a significant cost to the individual and those around them. For example, it has recently been shown that the majority of 'severely disruptive' pupils in one UK inner city area have undetected ASD traits3.
The relationship between ASD traits and other internalising and externalising psychopathology has not been delineated in any detail, and a number of areas for investigation exist. Firstly, the cross-sectional analyses used so far cannot address the question of whether ASD traits precede the development of additional psychopathology. There is some evidence that 'social competence' in early childhood does predict later externalising and internalising problems4, but it is unclear to what extent the narrower, ASD-relevant construct of 'social-communication' (measured in ALSPAC by the Social Communication Disorders Checklist [SCDC]) precedes later psychopathology. This issue is relevant to whether or not ASD traits play a causal role in the development of non-ASD psychopathology. Secondly, nothing is known about what factors might moderate the risk conferred by elevated ASD symptomatology. Given the impact of age and gender on the type and degree of risk posed by other types of psychopathology5, it will be useful to consider these variables as potential moderators of the relationship between ASD traits and additional psychopathology. Thirdly, it is unknown whether ASD social-communication traits moderate well known pathways to psychopathology, such as the transition from oppositional defiant disorder to conduct problems6.
Data collected in the ALSPAC study offer a unique opportunity to address these issues, which are of clinical and theoretical importance. We propose using ALSPAC data for the following:
1/. An investigation of the moderating effects of gender and age on the relationship between social communication deficits and additional psychopathology. We will use SCDC data to identify individuals with consistently elevated social communication difficulties in middle and late childhood. We predict males in this group will experience an increase in their externalising psychopathology during adolescence. In addition we predict that females will experience increased internalising difficulties in adolescence.
2/. An investigation of whether social-communication abilities moderate the relationship between earlier oppositional behaviour and later conduct disorder symptoms. We aim to test this hypothesis using a cross-lagged panel design, modelling the relationships between DAWBA-measured oppositional behaviour, hyperactivity and conduct disorder symptoms at 7 and 10, and testing whether these are moderated by an individual's social-communication abilities at 7 years.
1Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008 Aug;47(8):921-9.
2Skuse DH, Mandy W, Steer C, Miller LL, Goodman R, Lawrence K, et al. Social communication competence and functional adaptation in a general population of children: preliminary evidence for sex-by-verbal IQ differential risk. J Am Acad Child Adolesc Psychiatry 2009 Feb;48(2):128-37.
3Donno R, Parker G, Gilmour J, Skuse DH. Social communication deficits in disruptive primary-school children. Br J Psychiatry 2010 Apr;196:282-9.
4Bornstein MH, Hahn CS, Haynes OM. Social competence, externalizing, and internalizing behavioral adjustment from early childhood through early adolescence: developmental cascades. Dev Psychopathol 2010 Nov;22(4):717-35.
5Zahn-Waxler C, Shirtcliff EA, Marceau K. Disorders of childhood and adolescence: gender and psychopathology. Annu Rev Clin Psychol 2008;4:275-303.
6Rowe R, Maughan B, Pickles A, Costello EJ, Angold A. The relationship between DSM-IV oppositional defiant disorder and conduct disorder: findings from the Great Smoky Mountains Study. J Child Psychol Psychiatry 2002 Mar;43(3):365-73.