Proposal summaries
B1118 - Dopamine Function Cognitive Flexibility and Emotion Regulation - 09/02/2011
Existing research has shown the relevance of the dopamine pathway in the development and maintenance of cognitive traits. Efforts to tease out the functional role of specific elements of this pathway, however, have struggled to yield reliable assertions as to the causal relationship between dopamine function, cognitive flexibility and emotion regulation The use of genetically-influenced variation in this system to examine functional/behavioural inter-individual differences has the potential to delivery causal statements about the role of dopamine in behaviour.
Here we propose to use a genotype reliably associated with functional variation in prefrontal cortex dopamine neurotransmission (Lachman et al., 1996) to examine the causal role of the dopamine pathway in cognitive flexibility and emotion regulation. Evidence suggests that the COMT Val158Met polymorphism influences prefrontal function (in particular maintenance aspects of working memory and cognitive flexibility) and emotion regulation. This polymorphism has been reported to be a risk factor for anxiety-related psychopathology, although the mechanism of this association remains unclear. One possibility is that this genotype influences cognitive flexibility, in particular with respect to emotional material, which in turn influences risk of anxiety-related psychopathology.
COMT Met/Met status has been linked to increased incidence of emotional disorder, including anxiety (Enoch et al., 2003), panic (Woo et al., 2004), depression (Ohara et alk. 1998), bipolar disorder (Mynett-Johnson et al., 1998; Papolas et al., 1998) and obsessive compulsive disorder (Karayiorgou et al., 1999), although there have also been failures to replicate these associations (e.g., Ohara et al., 1998; Domschke 1998). Met/Met homozygotes show less top-down regulation when having to ignore emotional distracters, while Val/Val homozygotes show a general enhancement in the processing of aversive stimuli, such as rapid disengagement of cortical circuits (e.g., Heinz & Smolka 2006; Xu et al., 2006; Tunbridge et al., 2006). Passive viewing of emotional images cause increase in prefrontal cortex (PFC) and limbic activation in Met/Met homozygotes as compared to Val/Val (Smolka et al., 2006).
COMT Met/Met homozygotes appear to show advantages on working memory tasks that especially tap "maintenance" aspects of working memory. For example, they show enhanced performance on the N-back working memory task (Egan et al., 2001; Goldberg et al.2003), the Wechsler Memory Scale (Bilder et al., 2002), the dots-mixed tasks which requires the online maintenance of two rule sets (Diamond et al., 2004) and they are able to acquire an initial rule as part of a cognitive task more quickly (Nolan et al., 2004). However, these benefits in the maintenance aspects of working memory come at the expense of cognitive flexibility, and it is argued that this is where Val/Val homozygotes tend to excel. For example, Val/Val homozygotes perform better at reversal learning and regulation of response competition (e.g., Fossella et al., 2002; Nolan et al., 2004). Furthermore, although Met/Met homozygotes can acquire an initial rule more quickly, Val/Val homozygotes can switch to a subsequent rule more easily (Nolan et al., 2004). In other words they are more able to inhibit a prepotent response.
To explain these findings it has been suggested that Met/Met homozygotes have increased tonic dopamine (DA) neurotransmission in the PFC and decreased phasic neurotransmission (and vice versa for Val/Val homozygotes). Having higher tonic DA neurotransmission in the PFC improves performance on a number of working memory tasks (particularly those that require a maintenance aspect). However, having stronger phasic neurotransmission (as with Val/Val homozygotes) means an enhanced performance on tasks requiring cognitive flexibility. It is argued that the differing effects on emotional information processing may be due to the inflexibility of the cortical networks in Met/Met homozygotes. For example, Drabant et al., (2006) argue that Met/Met homozygotes are "more easily locked into an affective processing set, reverberating emotional information through this re-entrant loop." They argue that this leads to biases in information processing that could remain dormant but lead to increased vulnerability to affective disorders.
Furthermore, the relationship between DA levels in the PFC and performance can be thought of as following an inverted-U relationship. Met/Met homozygotes are thought to be at the peak of the inverted-U, which conveys benefits on certain aspects of working memory tasks. However, any further increase in dopamine will push them onto the downwords slope, reducing performance. Val/Val homozygotes however, are thought to be on the upwards slope of the inverted-U, so that increases in dopamine should cause improved performance on working memory tasks. Research investigating amphetamine-induced shifts in dopamine levels supports this theory (Mattay et al., 2003). In addition, when under stress Met/Met homozygotes show deficits in working memory performance on tasks that they usually excel on as compared to Val/Val homozygotes (Bishop et al., 2008).
In a sample selected for a balanced representation of genotypes at COMT(rs4680)*, we therefore wish to test the following prediction:
Cognitive retraining, designed to modify cognitive response to emotional cues, should be more effective in individuals with lower PFC dopamine levels.
Translated to a "natural experiment", where genetic variation acts as a proxy measure for dopamine neurotransmission, we hypothesise that participants with Val/Val homozygotes will be more receptive to cognitive retraining in this model when compared to Val/Met heterozygotes or Met/Met homozygotes.
We will measure cognitive flexibility in response to emotional cues, using an emotional working memory modification task. This is a variant of the widely-used N-back working memory task, designed to experimentally induce temporary changes in the cognitive processing of emotional material.
This behavioural challenge to the dopamine system is expected to amplify effects of genotype on task performance. We propose to freely recruit 150 mothers from the ALSPAC study (i.e., not pre-selected on the basis of any specific characteristic), on whom demographic and COMT genotype data already exist, in a recall design. Participants would be invited through the ALSPAC study team, and if interested in the study invited to attend a single testing session in the School of Experimental Psychology. COMT genotype frequencies are approximately evenly distributed in samples of European ancestry, which will maximise statistical power.
Testing would consist of completion of a retraining task (described below), followed by three assessment tasks to assess the transfer of any effects of retraining to other measures. We will use existing genotype data to test for associations between COMT genotype and performance on the retraining task, adjusted for age, socioeconomic status, and educational status / IQ.
B1117 - Does genetic variation of mitochondrial DNA contribute to the risk of developing common disease phenotypes - 09/02/2011
Mitochondria are small organelles present within every nucleated mammalian cell. They are the principal source of intracellular energy, in the form of adenosine triphosphate (ATP), which is generated by oxidative phosphorylation (OXPHOS). Mitochondria contain their own DNA- mtDNA - which codes for 13 essential components of the OXPHOS system, along with 22 RNAs required for intra-mitochondrial protein synthesis. Highly deleterious mutations of mtDNA lead to a defect of ATP synthesis and cause multi-system mitochondrial diseases in humans, which typically involve skeletal muscle, the heart, endocrine organs, and the brain. The description of these diseases led to the idea that more subtle variation of mtDNA in the general population might contribute to the aetiology of complex common human disease because of the shared clinical features.
There is emerging evidence that naturally-occurring genetic variation of mtDNA influences the function of mitochondria in humans -possibly by influencing the assembly of OXPHOS protein complexes. It is therefore of great interest that different haplotypes of mtDNA have been associated with type 2 diabetes, hypertension, obesity and the metabolic syndrome, survival following infection, and several neurodegenerative diseases. Many of these studies were small, and the findings have not been replicated. Therefore, the role of common variants of mtDNA in many of these disorders remains unclear.
Commercially-available arrays used for nuclear genome-wide association studies also include a number of mtDNA variants. The precise number varies from platform to platform, but the variants were all chosen based on their frequency in the European population. We have recently developed a method of interpreting this data by imputing the relationship with tightly-associated functional variants through the study of over 1500 complete mitochondrial genomes from population control subjects. We have used this approach to successfully replicate original low-resolution studies associating mtDNA with Parkinson's disease, and by exploiting a large GWAS dataset, we have increased the resolution of the genetic association, deriving the likely mechanism of the association. The data and the tools are therefore in place to study mtDNA genetic variation in the ALSPAC cohort, and to study the relationship with common phenotypes within the cohort.
There are a priori reasons to study the following phenotypes, as examples:
Height
Measures of obesity
Hypertension
Metabolic syndrome
Neurodevelopmental disorders including autism spectrum disorders
Hearing
Vision
It is important to note that, being common genetic variants, in the vast majority of instances, the SNPs will be homoplasmic (ie all the mtDNA in any one individual sample will be identical). In addition, being exclusively maternally inherited, the mtDNA in the child will be identical to the mother. This will allow genotype data from one individual to be reliably used in a phenotypic analysis of another immediate maternal relative.
We would take the following approach:
- Comparison of allele frequencies in the ALSPAC cohort with other UK datasets including WTCCC3 and the North Cumbria Community Genetics project (data already in our hands). Our prior hypothesis is that the allele frequency will not be significantly different for alleles present at greater than 5% frequency.
- Principal components analysis, to determine related haplotype groupings, and compare to ethnicity determined by reliable nuclear genetic markers. This would be an essential quality-control (QC) step, because mtDNA is particularly susceptible to the effects of population stratification.
- Study the relationship between the phenotypes listed above and all variants reaching greater than 95% call rate after appropriate QC. Several statistical approaches could be used. We favour the Tmax function within PLINK because this allows the incorporation of structural relationships within the actual data set, and avoids the need for a harsh Bonferroni-type correction for multiple significances, which is inappropriate for mtDNA alleles. A similar approach will be taken for quantitative trait data.
- Study the plausibility of interactions existing between nuclear and mitochondrial variation within the ALSPAC sample. We are as yet uninformed as to the existence of such relationships, however the availability of these data will allow for the examination of the possible relationships between these sources of genetic variation and their impact on measured phenotypes.
Based on discussion with the ALSPAC team, we are not requesting any data to be sent out of Bristol. Rather, Dr Gavin Hudson will apply for honorary status with Bristol University, and travel down to Bristol to assist with the analysis, working directly with the Bristol team. In Bristol, Professor Davey Smith, Dr Timpson and PhD student John Kemp will be involved in the analysis of these data and will facilitate this work.
B1114 - An investigation into the determinants of scoliosis induction/progression and the impact of scoliosis on young adults - 08/02/2011
Scoliosis is defined as a lateral curvature of the spine greater than 10 degrees[1]. It most commonly starts between aged 10 years and skeletal maturity[2] (adolescent idiopathic socliosis, AIS), and has an incidence ranging between 1-3% depending on populations studied[3, 4], although this incidence does appear to be increasing[5]. There is an equal gender prevalence for minor scoliotic curves (10 degrees), but far more girls have curves greater than 30 degrees compared with boys[6]. For unknown reasons, 80-90 percent of thoracic and thoracolumbar curves are to the right[7] suggested to be linked with handedness[8], but 70% of single lumbar curves are to the left[7]. Again, for reasons that are not clearly understood, some scoliotic curves progress: estimates vary from 3.5%[9] to 15%[10], while others remain static.
Scoliosis is not always a benign structural abnormality, although the mortality rate for individuals with AIS is comparable to that of the general population[11]. There is a direct correlation between the magnitude of the thoracic scoliotic curve and pulmonary function[12]; back pain is a complaint in 80% of scoliotic patients in long-term follow-up studies[13]; and the psychological and social effects of scoliosis are real but variable and hard to quantify. Nevertheless, studies that have looked into this area consistently find mild social dysfunction such as an unwillingness to wear snug clothing or bathing suits[12], but also high rates of work disability[14,15] and reduced rate of marriage[15], although no studies that we could find assess the psychological and social effects in children and young adults.
Current knowledge about the causes of the initiation or induction of the scoliotic curve is scarce. Some work has been carried out on the determinants of the initiation or induction of the scoliotic curve, but very little using a longitudinal prospective study design. Some work has also been done on the determinants of curve progression, but contradictory results have been found for the association with bone density, anthropometry, and hypermobility, probably because of small sample sizes. No coherent picture on the genetic determinants of either induction or curve progression has been found, probably because scoliosis is due to a complex interplay between environmental and genetic influences. This also suggests that scoliosis may be a heterogeneous group: more accurate phenotyping according not only to curve structure, but associated clinical features, may therefore allow more accurate classification into subgroups with different prognosis and different genetic determinants.
Therefore the aims of this project are
1. to quantify the incidence of scoliosis in the UK population from aged 7 to 17 years, and to describe the percentage progression and regression (i.e. natural history), using a large population based birth cohort.
2. to assess the association between the standard Adams forward bending test with Cobb angle measured by DXA analysis in children
3. to assess the impact of scoliosis induction and progression in children (in terms of time off school, pain, sleep, physical activity, fractures)
4. to accurately phenotype and therefore classify into relevant subgroups, children with scoliosis in terms of curve structure and associated clinical features such as hypermobility, bone density, muscle function, family history
5. to prospectively investigate the risk factors for scoliotic curve induction or initiation, focussing on early life events, bone and muscle quality and growth
6. to prospectively investigate the risk factors for scoliotic curve progression or regression, focussing on growth, anthropometry, puberty, bone density and hypermobility
7. to investigate the genetic determinants of scoliosis using a large population based birth cohort to carry out genome wide association studies, with replication and further study to be carried out in a secondary care disease cohort
Methods
The Adams forward bending test was performed at research clinics when the offspring were aged 7, 9, 10, 11 and 13 by trained research assistants. We are requesting funding for this measure to be repeated at aged 17. The results of the Adams forward bending test will be used as the main outcome of interest, with children being categorised into having or not having scoliosis on the basis of an ATI greater or less than 7 degrees. Analyses will be repeated using the ATI as a continuous outcome to assess trends. In addition, total body DXA scans have been performed with full spinal DXA results. Cobb angles (traditional method of assessing scoliosis on plain X-rays) will be measured on these scans.
Exposures of interest
(1) demographics and early life events, (2) growth, (3) bone and muscle parameters, (4) genetics
Concept: Specific measure: Person: Source: Time point:
demographics gender child Q birth
ethnicity child Q birth
SES mother Q preg, birth, aged 4
early life event gestational age child Q birth
birth weight and length child assessment birth
growth anthropometry child assessment 7, 9,10,11,13,15,17
puberty child Q 9, 11, 13, 15
R/L handedness child Q
arachnodactyly child assessment 12
bone and muscle parameters total body DXA child assessment 9,12,15
grip strength child assessment 13
hypermobility child assessment 13,17
genetics GWAS data child biological
Impact of scoliosis
(1) chronic pain, (2) sleep, (3) physical activity, (4) time off school, (5) psychological, (6) lung function (7) fractures
Concept: Specific measure: Person: Source: Time point:
chronic pain chronic pain child Q 17
sleep disrupted/poor sleep child Q 13,14,16
physical activity reported child Q 9
accelerometer child assessment 12, 17
time off school time off school child Q 14,16
psychological DAWBA child Q 7,9,10,11,13,15
CIS-R child Q 7,9,10,11,13,15
lung function methacholine challenge child assessment 8
spirometry child assessment 9
NO, salbutamol challenge child assessment 15
fractures fractures child Q 12, 15
[1] Kane W (1997) Clin Orthop 126:43-46
[2] Dobbs MB et al (1999) Orthop Clin N Am 30:331-341
[3] Wang Y et al (1996) Chinese J Epi 17:160-162
[4] Grivas et al (2002) Studies Health Tech Info 91:76-80
[5] Wong HK et al (2005) Spine 30:1188-1196
[6] Roach JW (1999) Orthop Clin N Am 30:353-365
[7] Rinsky LA et al (1988) West J Med 148:182-191
[8] Burwell RG (2003) Develop Neurorehab 6:137-170
[9] Robitaille YVON et al (1984) Int J Epi 13:319-323
[10] Dickson RA et al (1980) BMJ 281:165-167
[11] Weinstein SL et al (1983) J Bone Joint Surg Am 65:447
[12] Aaro S et al (1984) Spine 9:220
[13] Weinstein SL et al (1981) J Bone Joint Surg Am 63:702
[14] Fowles JV et al (1978) Clin Orthop 134:212-217
[15] Nachemson A (1968) Acta orthop Scand 39:466-476.
B1115 - Differential Susceptibility to Environmental Influences - 07/02/2011
The current proposal is for three scientific papers investigating (1) a potential genetic moderation of prenatal environmental conditions on maternal self-reported prenatal stress, (2) a potential genetic moderation of prenatal maternal stress on infant temperament, and (3) a potential interaction between the effects of prenatal and postnatal environmental conditions on socioemotional and behavioural outcomes in childhood.
BACKGROUND: Effects of prenatal stress have been found to predict various negative psychological outcomes across childhood (Glover, 2011). This observation has been interpreted in terms of the fetal programming hypothesis which stipulates that the fetus adjusts its phenotype in utero as a means of adapting to anticipated conditions of the postnatal environment (Barker, 1998). We recently raised the notion that in some cases prenatal stress seems to promote developmental plasticity in the postnatal period rather than foster psychopathology (Pluess & Belsky, 2011). This is based on the observation that infant difficult temperament and cortisol reactivity--both consistently associated with the presence of prenatal stress--moderate the effects of the early care environment for better and for worse. More precisely, children with these characteristics will be more negatively affected by early adversity but also benefit more from a supportive environment, consistent with the differential susceptibility hypothesis which claims that individuals fundamentally differ in their susceptibility to both negative and positive environmental influences as a function of behavioural, physiological or genetic factors (Belsky & Pluess, 2009). Recently, we were able to show that a genetic susceptibility factor--the serotonin transporter polymorphism--moderates the effects of prenatal maternal stress on infant temperament (Pluess et al., in press) using data from the Generation R study, a large Dutch birth cohort study (Jaddoe et al., 2008).
The current proposal aims at further testing the theorised complex relationships between genetic susceptibility of both the mother and fetus to prenatal environmental conditions in the prediction of behavioural susceptibility factors and the consequent moderation of postnatal environmental influences by prenatally programmed susceptibility.
PAPER 1
The first paper we propose seeks to test a gene-environment interaction (GXE) between prenatal environmental conditions and maternal susceptibility genes in the prediction of maternal subjective stress during pregnancy.
RATIONALE: Most studies on the effects of prenatal maternal stress on child development are based on subjective measures of maternal anxiety, depression and perceived stress (Pluess, Bolten, Pirke, & Hellhammer, 2010). The differential susceptibility hypothesis proposes that mothers differ in their susceptibility to environmental effects as a function of genetic differences amongst others. In a recent study mothers carrying susceptibility alleles (COMT val/val, DRD4 7-repeat) were more affected by daily hassles regarding their parenting sensitivity than mothers with different alleles (van IJzendoorn, Bakermans-Kranenburg, & Mesman, 2008). This is consistent with Caspi et al.'s (2003) ground breaking findings that effects of stressful life events on depression are moderated by the serotonin transporter polymorphism. In other words, some individuals will be more affected by environmental conditions than others as a function of genetic differences (Belsky & Pluess, 2009). We want to investigate whether such a GXE also characterises maternal response during pregnancy (i.e. subjective measures of prenatal stress) to objective prenatal stressors.
PRINCIPAL AIMS: We want to overcome limitations of previous studies which ignore individual differences in mothers' susceptibility to prenatal environmental conditions in order to better understand the relationship between objective and subjective measures of prenatal maternal stress as they relate to child outcomes.
PAPER 2
The second paper seeks to replicate and extend recent findings within the Generation R study of a GXE between prenatal stress and genetic susceptibility of the child in the prediciton of infant difficult temperament (Pluess et al., in press).
RATIONAL:Using data from the Generation R study we recently reported that the effects of prenatal stress on infant temperament vary across fetuses due to their genetic make-up (Pluess et al., in press).Infants carrying the short allele of the serotonin transporter polymorphism (5-HTTLPR) were rated as more negatively emotional when mothers reported anxiety during pregnancy while there was no difference between genotypes on negative emotionality when maternal anxiety was low. The association between maternal anxiety during pregnancy and negative emotionality in early infancy was significant in infants carrying one or more copies of the short allele, but not in those homozygous for the long allele. We want to replicate this finding within the ALSPAC data.
Recently, the approach to combine several genes into a cumulative genetic score when investigating GXE has yielded promising results. Belsky and Beaver (in press) found that the more susceptibility genes (of 5 different polymorphisms) adolescents carried the more affected they were regarding their self-regulation by the parenting quality they experienced.We want to investigate whether the effects of prenatal environmental influences on infant temperament are moderated by a composite genetic score based on 4 different genetic polymorphisms (5-HTTLPR, COMT, MAOA, BDNF).
PRINCIPAL AIMS: The proposed paper aims at replicating and extending, within ALSPAC, the GXE that recently emerged in the Generation R data. We want to investigate whether the effects of prenatal environmental influences on infant early temperament are moderated by (1) the 5-HTTLPR, and (2) a composite genetic score based on 4 different genetic polymorphisms (5-HTTLPR, COMT, MAOA, BDNF).
PAPER 3
In the third paper we want to investigate whether postnatal environmental conditions moderate effects of prenatal environmental conditions on socioemotional and behavioural outcomes across childhood.
RATIONAL: Recent empirical evidence suggests that the effects of prenatal stress on child development are dependent on the quality of the postnatal environment. For example, the association between prenatal stress and observed child fearfulness at 17 months postpartum proved to be moderated by attachment security (Bergman, Sarkar, Glover, & O'Connor, 2008). The effect of prenatal stress on child fearfulness was strongest in children with an insecure/resistant attachment. In another study maternal anxiety during pregnancy moderated effects of maternal sensitivity on child mental development with children whose mothers were suffering from anxiety during pregnancy being more susceptible to maternal sensitivity (Grant, McMahon, Reilly, & Austin, 2010). Intriguingly, children of prenatally anxious mothers had the best outcomes when sensitivity was high and the worst when sensitivity was low suggesting that prenatal maternal anxiety increases postnatal susceptibility consistent with the differential susceptibility hypothesis outlined above.
PRINCIPAL AIMS: We want to test, within ALSPAC, whether prenatal stress moderates the effects of postnatal environmental conditions on behaviour problems and social skills across childhood.
CONCLUDING REMARKS: We seek to break new ground in the study of GXE and prenatal programming using the ALSPAC data. Not only will we evaluate whether differential susceptibility characterises the manner in which select polymorphisms moderate environmental influences during the prenatal period on later development, but whether this proves so when one employs cumulative measures of (a) environmental risk/support and (b) genetic plasticity. Indeed, we predict that the more putative plasticity alleles an individual carries, the more cumulative contextual risk/support will predict infant temperament-and in a differential-susceptibility manner. Thus, more genetically malleable or plastic individuals will benefit more than others from environmental support but, at the same time, be more adversely affected by negative environmental conditions.
REFERENCES
Barker, D. J. (1998). In utero programming of chronic disease. Clinical Science, 95(2), 115-128.
Belsky, J., & Beaver, K. M. (in press). Cumulative-genetic plasticity, parenting and adolescent self-control/regulation. Journal of Child Psychology and Psychiatry.
Belsky, J., & Pluess, M. (2009). Beyond Diathesis-Stress: Differential Susceptibility to Environmental Influences. Psychological Bulletin, 135(6), 885-908.
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2008). Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness. Journal of Child Psychology and Psychiatry and Allied Disciplines, 49(10), 1089-1098.
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301(5631), 386-389.
Glover, V. (2011). Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. Journal of Child Psychology and Psychiatry and Allied Disciplines.
Grant, K. A., McMahon, C., Reilly, N., & Austin, M. P. (2010). Maternal sensitivity moderates the impact of prenatal anxiety disorder on infant mental development. Early Human Development, 86(9), 551-556.
Jaddoe, V. W., van Duijn, C. M., van der Heijden, A. J., Mackenbach, J. P., Moll, H. A., Steegers, E. A., et al. (2008). The Generation R Study: design and cohort update until the age of 4 years. European Journal of Epidemiology, 23(12), 801-811.
Pluess, M., & Belsky, J. (2011). Prenatal Programming of Postnatal Plasticity? Development and Psychopathology, 23(1), 29-38.
Pluess, M., Bolten, M., Pirke, K. M., & Hellhammer, D. (2010). Maternal trait anxiety, emotional distress, and salivary cortisol in pregnancy. Biological Psychology, 83(3), 169-175.
Pluess, M., Velders, F. P., Belsky, J., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Jaddoe, V. W., et al. (in press). Serotonin Transporter Polymorphism Moderates Effects of Prenatal Maternal Anxiety on Infant Negative Emotionality. Biological Psychiatry.van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., & Mesman, J. (2008). Dopamine system genes associated with parenting in the context of daily hassles. Genes, Brain, and Behavior, 7(4), 403-410.
B1113 - Using MR to investigate the role of DNA methylation in mediating smoking-related outcomes in children - 02/02/2011
Prenatal exposure to smoking has been linked to various adverse outcomes that can affect a child at birth and/or in later life. Given that this exposure is modifiable, it represents a pivotal area in which to alleviate major social, economic and health burdens. There is immense interest in epigenetic processes and the role that they might play in mediating complex disease risk through gene-environment interactions. This project adopts a genetic epidemiology approach, Mendelian randomisation, and aims to further our understanding of the contribution made by in utero exposures on child outcomes via epigenetic mechanisms. We will use SNP and DNA methylation data currently available from the ALSPAC cohort-both gene-specific and genome-wide - and supplement with 27K methylation array data as funding becomes available.
We will explore whether maternal smoking is related to infant outcomes via intrauterine influences and if so, whether this is mediated by epigenetic changes, (i.e. DNA methylation.) Studies of exposure to maternal smoking are challenged by significant confounding of exposure measures. Due to social stigma, self-report of smoking during pregnancy may be particularly prone to bias. As well, differences in smoking topography limit the correlation of reported smoking quantity with dose of inhaled tobacco products. Most importantly, there is a well-known association of maternal smoking with measures of social class. The Mendelian randomisation approach can be used to overcome these design issues. It allows for the use of a specific maternal genetic variant as a proxy for a given exposure. There are a growing number of such variants. For example, findings from several genome-wide association studies indicate that genetic variation in the region of the CHRNA5- CHRNA3- CHRNAB4 gene (chromosome 15q25) is closely linked to smoking quantity. Given that the randomisation of gene variants occurs at meiosis and precedes the development of phenotype, variation at this site can be used as a relatively unconfounded proxy of smoking quantity in smokers. The CHRN variants will be used together with other potentially informative smoking related SNPs both as individual instruments and as multiple instruments.
For smoking-related outcomes, we will select child phenotypes having strong evidence of gene-environment interactions based on animal and human data, specifically birth parameters, respiratory health and neurodevelopment phenotypes at various and multiple points throughout the lifecourse. We will investigate these outcomes as well as relevant covariates such as gestational age, related family history of outcome phenotypes, maternal obstetric health, maternal grandparent smoking history and family social status. To determine intrauterine effect, history of paternal smoking will be used as a control.
Using data already generated by the ALSPAC cohort, we will explore potential relations between maternal smoke exposure, (determined via genetic proxy and self-report,) and offspring DNA methylation patterns. Currently, global and gene-specific DNA methylation data for 192 children is being generated. This analysis will serve as proof of principle to support future funding requests to obtain further DNA methylation data. To date, there is limited data comprehensively linking fetal exposure to maternal smoking, gene-specific epigenetic modifications, changes in gene expression and finally disease phenotype. However, studies connecting two or more nodes in this pathway offer several potential candidate genes. We will maximize our capacity to detect smoking-related epigenetic changes in candidate genes by comparing "typical" and "atypical" cases and controls. "Typical" refers to mother-infant pairs that demonstrate the expected relation between maternal smoking and adverse infant outcomes, (e.g. maternal smoking and lower birth weight.) Conversely, "atypical" refers to pairs that demonstrate the opposite relation. Thus, atypical pairs reveal mechanisms that are unlikely related to the exposure and can help target candidate genes.
If evidence of a smoking-related intrauterine effect on DNA methylation is found, a secondary objective will be to interrogate the interaction between prenatal smoke exposure and methylation of genes associated with the outcomes, (e.g. birthweight and BDNF gene.) Such analyses may shed light on potential biological pathways linking smoke exposure to pathophysiologic processes in utero. Our findings can gain further support through cross referencing with 46K Illumina expression chip data when it becomes available.
Proving causality poses unique statistical issues when performing correlations between multiple genetic proxies and phenotype. We will use specific data analysis techniques that address directionality and the use of multiple genetic mediators to strengthen causal inferences.
The study will make a significant contribution to the emerging field of epigenetic epidemiology and will serve as proof of concept for further studies linking smoke exposure, epigenetic modifications and child outcomes.
B1121 - APPRaisal of the health of new ENTrants Into the workplaCE - the APPRENTICE study - 31/01/2011
Aims and objectives
The objectives of the proposed study are (i) to investigate the factors associated with occupational choice (e.g. influence of past behavioural patterns and psychosocial factors, pre-existing conditions, attainment at school, socioeconomic status, and risk factors for developing certain conditions); (ii) to assess the impact of work on health (incident asthma, skin symptoms/dermatitis, accidents, newly recorded or recurrent mental ill health by occupation following starting work); (iii) to describe absenteeism and presenteeism as a result of work-related conditions; (iv) to determine the effect of pre-existing conditions (particularly respiratory- and mental-related, and histories of injuries) on the incidence of conditions and accidents following starting work; (v) to formulate appropriate recommendations specific to those new entrants to the workplace and in whom work-related ill health occurs and for their employers; and in the long run, (vi) to explore the approaches to assessing the economic costs of these impacts.
We propose to explore the following questions:
1. What factors are associated with the decision to continue in further education or to enter the workplace within the ALSPAC subjects?
2. What is the spread of occupations and what are the factors associated with occupational choice?
3. What is the incidence of respiratory conditions (new asthma and new wheezing), skin symptoms/dermatitis, and newly recorded or recurrent mental ill-health by occupational group following starting work?
4. What is the incidence of accidents at work by occupational group?
5. What is the effect of pre-existing conditions (respiratory and mental, and history of injuries) on the incidence of conditions and accidents following starting work?
B1112 - Psychosocial resilience in children of mothers with depression - 31/01/2011
Aim 1: Identification of high-risk group
A core concern is to ensure that resilience is defined by reference to a clearly defined risk, and that variation in child outcomes does not merely reflect variation in severity of exposure to the risk factor of interest. Parent depression symptom data from pregnancy up to child age 12 will be analysed using group-based trajectory models to identify parents with chronic high levels of depressive symptoms. Additional information on severity of comorbid psychopathology, and functional impairment will be used to further characterise variation in severity of risk.
Aim 2: Definition of offspring mental health resilience
Most previous studies have focused on specific outcomes or on adaptation on a single occasion, limiting conclusions about the extent and stability of positive adaption in children defined as resilient. The second aim will be to define resilience by assessing adaptive youth outcomes over multiple mental health and related psychosocial domains (i.e. absence of depression, anxiety, disruptive behaviour disorders, substance use, self harm, suicidality, lack of functional impairment as rated on SDQ and DAWBA) and over multiple time points spanning adolescence. Sensitivity analyses will address how far results generalise across varying definitions of resilience.The project will also attempt to go beyond simple categorical indicators of resilience using latent growth mixture modelling in order to distinguish adaptive from maladaptive developmental pathways.
Aim 3: Identifying predictors of resilience in children of depressed parents
The third aim will be to evaluate the extent to which the different parent, family, child and peer factors outlined above predict resilience. Analyses will assess longitudinal associations using multivariate models to highlight the most important independent predictors of resilience in this high risk group.
Aim 4: Testing causal mechanism underlying resilient adaptation
Having identified the most important predictors of resilience, the study will use structural equation modelling to further exploit the longitudinal nature of the two studies and test causal mechanisms underlying well-being. For example, meditational models will assess whether resilience arises when key risk pathways are interrupted, and moderational models will test which factors act as buffers to enhance children's resilience. Cross-lagged models of change will assess direction of effects, and analyses will consider potential confounding variables.
Aim 5: Identification of predictors of resilience of particular relevance to children of depressed parents
The ALSPAC data offers the opportunity to distinguish between general predictors of positive mental health and specific predictors of resilience in children of depressed mothers. In particular, we will test interactions between resilience factors and maternal depression risk status.
B1111 - Genomewide association study and meta analysis for allergy and sensitisation - 27/01/2011
Having discussed initially informally and then through email follow-up, we have determined that there are at least 7 cohorts within the bounds of the EAGLE consortium containing phenotypic measurements for allergy. This follows closely to the asthma and atopy analysis efforts that are currently already in motion, however forms a discrete analysis effort which will attempt to identify genetic variation associated with allergic reaction as measures objectively through "skin prick" testing.
The initial cohorts recognized with respect to the carriage of skin-prick measurement are:
ALSPAC - UK
B58C_T1DGC - UK
B58C_WTCCC - UK
LISA - Germany
NFBC 66 - Finland
PIAMA - The Netherlands
RAINE - Australia
Please find attached our proposal for an analysis plan. Our suggestion is a primary analysis combining all cohorts with specific IgE in blood and SPT in order to get sufficient numbers and simply include individuals positive to any of the allergens tested for in the respective cohort.
Since IgE in blood is a more sensitive measure than SPT, we would suggest the initial analysis to be specific IgEgreater than =0.35IU/mL and/or SPT greater than =2mm (I have checked with the SPT cohorts that they will all be able to define various weal sizes). This will result in 25%-50% cases in the cohorts.
As a sensitivity analysis we would suggest also asking for IgEgreater than = 3.5 IU/mL and/or SPTgreater than =3mm. This will reduce the numbers of positive samples with app 20-40% with highest effect in the childhood cohorts.
We propose asking the cohorts for analyses of these 2 cut offs now (both separate and combined analyses.Cohorts with only one of blood IgE or SPT (50%) only have to run 2 analyses).
On the basis of this we can then perform meta-analyses on:
*Low cut off combined
*Higher cut off combined
*Blood IgE and SPT separately
*Adult and child cohorts separately
We propose doing this as a first step. Depending on results we can then consider a second round looking at:
*Multiple sensitizations
*Very high levels of IgE
*High level combined specific IgE/weal against the most common inhalant allergens
We are aware of other, competitive, efforts in this field. Principally, the GABRIEL consortium is currently preparing a large body of work on asthma explicitly, though not allergy. As such, we will attempt to contact this body by way of follow-up, however will restrict primary analyses to those cohorts within the EAGLE consortium.
B1110 - Effects of type and amount of daycare on child school-entry social and cognitive functioning - 26/01/2011
BACKGROUND/ RATIONALE: Findings on the long-term effects of the number of hours that a child spends in daycare (as well as the time that the child begins attending daycare) on maladjustment are mixed. For example, in 2010, Vandel et al found no significant association between the amount of time spent in center-care and a long-term effect of that daycare on a child's cognition. A limitation of this study, however, is that it has not explored the age of onset that a child begins daycare, but rather, the amount of daycare per day or week. Additionally, there was no recorded entry-level assessment, when beginning formal education (Vandell, Burchinal, Vandergrift, Belsky & Steinberg, 2010). However, studies have revealed that children attending daycares also exhibit greater amounts of childhood problematic behavior, thus suggesting that there may factors that influence the impact of daycare on a child's behavior (Vandell, Burchinal, Vandergrift, Belsky & Steinberg, 2010; Belsky, 2001; Lamb & Ahnert, 2006; Loeb et al., 2007). While the study of Vandel et al is impressive, it has been conducted on a sample within the United States of America, not among a British cohort (thus the appeal of analyzing data gathered from the ALSPAC sample). Accordingly, no cross-cultural comparisons have been made, nor have any similar studies been conducted with a cohort from a different origin than the United States. This study plans to use trajectory analysis with hours of usage of non-familial daycare as the repeatedly measured outcome at ages 2, 3, 4 and 5, as well as the age at which the child first attended daycare. Secondary analysis will assess the contributions of family risk (e.g. poverty, maternal warmth, parenting styles) and quality of daycare (e.g. the staff-child ratio).
PRINCIPAL AIMS: The aim of this study is to use trajectory analysis to determine how the onset of when a child begins daycare and how the number of hours spent in daycare later contributes to the level of socio-emotional maladjustment and poor academic standing at formal school entry. We will explore this query by means of group-based trajectory analysis anticipating finding a trajectory of children who start daycare early, and spend a relatively high amount of hours per week in daycares (i.e. those on the high trajectory path) will exhibit an increased maladjustment. We will be using the computer software programs Mplus v.6.1 and STATA v.10 to conduct our trajectory analysis.
B1105 - Role of rare CNVs in learning difficulties - 24/01/2011
It has previously been shown in many clinical collections of patients with moderate to severe learning disabilities that rare CNVs can explain a proportion of these patients, typically 10-15%, depending on the phenotypic severity, presence of additional clinical features and resolution of the CNV discovery technology applied.
It remains an open question to what degree rare CNVs contribute to more mild learning difficulties. Learning difficulties can be variously defined, depending on the context (educational, clinical, social), but can include many problems affecting schoolwork, which may include specific learning difficulties such as dyslexia, dyscalculia or dyspraxia as well as more severe cognitive impairments.
Rare CNVs can be mined from primary intensity data from SNP GWAS chips. We propose to call rare CNVs from the existing ALSPAC genotype data held at the Sanger Institute, using a combination of algorithms to improve specificity.
We will then investigate the association of rare CNVs, both in terms of the presence/absence of large rare CNVs, and the overall genome-wide rare CNV burden, on various measures of cognitive performance reflecting learning difficulties.
It would be useful to know from the ALSPAC team if there are important covariates to account for when investigating these phenotypes.
B1104 - Role of CNVs in muscle phenotypes - 24/01/2011
We have previously identified two CNVs that are highly differentiated in allele frequency between European and West African populations (Conrad et al 2010). These two CNVs are an intronic deletion in the PDLIM3 gene and an intronic VNTR in the ACTN2 gene. These two genes physically interact in the sarcomere. Consequently we hypothesised that these two CNVs might influence muscle phenotypes and thus underpin part of the known differentiation in muscle phenotype between European and West African populations.
In this project we propose to test for association between these two CNVs and grip strength. We propose to extract the CNV data on these two loci from the CNV data previously generated on a CNV genotyping chip designed at Sanger and run at Oxford Gene Technology, funded by Sanger in collaboration with ALSPAC. These data were subsequently normalised and genotypes called, where possible, at Sanger. These CNV data were generated on a selected set of ~1,000 densely phenotyped child samples from within the ALSPAC collection.
Association of the same phenotype against other CNVs typed on the same chip will be performed to test for any inflation of test statistics.
B1103 - Investigating changes in female puberty 1960 to present in the UK - 24/01/2011
Between 1830 and 1960 there is a documented secular trend for a reduction in menarcheal age of about four months per decade declining from age 17 to around 12.8 years1. While recent literature argues that this decline has stabilised2, analyses of longitudinal data in Europe and America highlight a trend towards earlier female pubertal onset, and especially earlier breast development (thelarche) in girls3,4,5. Additionally, these studies find that girls in the highest weight categories are more likely to enter puberty asynchronously via thelarche, as opposed to the synchronous (simultaneous) development of breasts and pubic hair, or the asynchronous development via pubarche (pubic hair growth). So, it is suggested that an earlier pubertal onset is therefore lengthening the period between pubertal onset and menarche, and that heavier girls are most at risk of this phenomenon.
In the UK, a study using ALSPAC data5 found that heavier girls are more likely to enter puberty via thelarche. Further to these findings, this current study aims to understand long-term changes in puberty in girls in the UK, by using a number of longitudinal datasets. The goals are to understand: 1) whether age at pubertal onset has reduced from the period of 1960 to the present; 2) whether there is a continued secular trend for earlier age at menarche over the same period; 3) whether, there is a lengthening of the period from pubertal onset to menarche; 4) whether the heaviest girls enter puberty first, and 5) whether there is an increasing trend over that period for asynchronous pubertal development via thelarche, particularly for girls in the highest weight categories, and 6) whether UK trends are similar to girls in the USA and continental Europe.
ALSPAC is particularly useful in this context since the data contain extremely detailed pubertal and mid-childhood growth data on a number of children. Moreover, the data are relatively recent, and provide one of the most comprehensive, up-to-date databases for the analysis of current female pubertal development and its relationship with the changes seen in female puberty over the last 50 years.
Analyses of changes in female pubertal development will compare ALSPAC data with similar pubertal measures from the Harpenden growth study and the British Cohort Study. Additionally, trends in female pubertal development in the UK will be compared with hunter-gatherer and agriculturalist girls living in vastly different ecologies to the UK, where the impact of obesity and the modern environment is almost zero. This will indicate how the progression to different pubertal milestones (e.g. pubertal onset to menarche) differs across different ecologies.
1 Tanner, J.M. (1962) Growth at Adolescence. Oxford. Blackwell
2 Bau AM, Ernert A, Schenk L, Wiegand S, Martus P, Gruters A and Krude H. (2009) Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche. Eur J Endocrinol. 160(1):107-13
3 Biro FM, Lucky AW, Simbartl LA, Barton BA, Daniels SR, Striegel-Moore R, Kronsberg SS and Morrison JA. (2003)Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty. J Pediatr. 142(6):643-6
4 AU - Biro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, Teitelbaum S, Windham GC, Kushi LH and Wolff MS. (2010) Pubertal Assessment Method and Baseline Characteristics in a Mixed Longitudinal Study of Girls. Pediatrics. 126(3):E583-E590
5 Christensen KY, Maisonet M, Rubin C, Flanders WD, Drews-Botsch C, Dominguez C, McGeehin MA, Marcus M, (2010) Characterization of the correlation between ages at entry into breast and pubic hair development. Ann Epidemiol. 20 (5): 405-8.
B1109 - Antecedents of text comprehension skills of children from diverse home backgrounds - 23/01/2011
There are two primary objectives of the proposed study. Firstly, we aim to examine the longitudinal predictors of children's comprehension of written and spoken text (i.e. reading and listening comprehension). More specifically, the study seeks to examine the predictive relationships between cognitive-linguistic skills and children's listening and reading comprehension development across different developmental periods. As the simple view of reading posits (Gough, Hoover, & Peterson, 1996; Hoover & Gough, 1990), spoken text comprehension and decoding are two central subcomponents of reading comprehension. There is an abundance of research evidence showing that once word reading proficiency increases and therefore, ceases to constrain comprehension processes, listening comprehension becomes the most powerful of reading comprehension skills (Adolf, Catts, & Little, 2006; Babayi?it & Stainthorp, in press; Gough & Tunmer, 1986; Kendeou, Savage, & Broek, 2009). Currently, the longitudinal research into children's comprehension of both spoken and written text is highly limited (Oakhill & Cain, 2007). The findings from the proposed study will have implications for furthering our understanding of the causal antecedents of text comprehension skills as well as highlighting early markers of text comprehension difficulties. Furthermore, the findings will help to elucidate the evolving relationships of different oral language and cognitive skills with text comprehension skills. It is widely acknowledged that different subprocessing skills may play different roles along the trajectory of children's literacy development (Tilstra, McMaster, Van den Broek, Kendeou, & Rapp, 2009), hence the importance of longitudinal research that spans wider developmental periods.
Our second aim with this study is to examine the role of socio-economic background in children's text comprehension. More children from disadvantaged backgrounds have been found to underachieve on the measures of reading where the focus is on reading comprehension of complex text rather than accurate decoding of words, such as the reading SATs at Key Stage 2 (SFR, 2009). Similar findings have also been reported by studies that used standardised measures of reading comprehension (e.g., Kieffer, 2008). There is a consensus in the literature that broader oral language skills such as vocabulary and syntactic skills play a central role in children's reading comprehension levels (e.g., Catts, Adlof, & Weismer, 2006; de Jong & van der Leij, 2002; Dickinson, McCabe, Anastasopoulos, Peisner-Feinberg, & Poe, 2003; Kendou, Van den Broek, White, & Lynch, 2009). The observed text comprehension difficulties of some children from disadvantaged backgrounds have primarily been associated with weaknesses in oral language skills (e.g., Chall, Jacobs, & Baldwin, 1991; Snow, Barnes, Chandler, Goodman, & Hemphill, 1991). However, it is also widely acknowledged that any study examining home background factors also need to take into account educational aspirations as well (see Sinclair, McKendrick, & Scott, 2010). The proposed study will address these issues and examine in more detail the developmental trajectories of children's oral language, cognition, and text comprehension skills from diverse home backgrounds. Hence, the findings from this investigation will clearly have important far reaching implications for the development of preventative educational practices in order to address the reported educational achievement gap of children from disadvantaged backgrounds.
For this purpose, the proposed study seeks to examine the developmental relationships between oral language, cognition, literacy, and text comprehension skills from five years to fourteen years of age (KS3). Powerful statistical tool such Structural Equation Modeling and Multilevel Modeling will be used to examine the outlined complex developmental relationships. For instance, SEM involves the use of latent variables and enables to address the issues of measurement error as well as reciprocal relationships between the predictor variables. Hence, the use of a large dataset from the ALSPAC will enable us to use statistical tools like SEM and thereby, undertake more complex data analysis.
In conclusion, with this study it will be possible to address several important research questions as regards to the development of children's text comprehension skills, which in turn is expected to produce several outputs and thereby make a significant contribution to this area of research and educational practices of text comprehension.
References
Adolf, S. M., Catts, H. W., & Little, T. D. (2006). Should the simple view of reading include a fluency component? Reading and Writing: An Interdisciplinary Journal, 19, 933-958.
Babayi?it, S., & Stainthorp, R. (in press). Modeling the relationships between cognitive-linguistic skills and literacy skills: New insights from a transparent orthography. Journal of Educational Psychology.
Catts, H. W., Adlof, S. M., & Weismer, S. E. (2006). Language deficits in poor comprehenders: A case for the simple view of reading. Journal of Speech, Language & Hearing Research, 49, 278-293.
Chall, J. S., Jacobs, V. A., & Baldwin, L. E. (1991). The reading crisis: Why poor children fall behind. Cambridge, MA: Harvard University Press.
de Jong, P. F., & van der Leij, A. (2002). Effects of phonological abilities and linguistic comprehension on the development of reading. Scientific Studies of Reading, 6, 51-77.
Dickinson, D. K., McCabe, A., Anastasopoulos, L., Peisner-Feinberg, E. S., & Poe, M. D. (2003). The comprehensive language approach to early literacy: The interrelationships among vocabulary, phonological sensitivity, and print knowledge among preschool-aged children. Journal of Educational Psychology, 95, 465-481.
Gough, P. B., Hoover, W. A., & Peterson, C. L. (1996). Some observations on a simple view of reading. In J. Oakhill & C. Cornoldi (Eds.), Reading comprehension difficulties: Processes and interventions (pp. 1-13). Mahwah, NJ: Erlbaum.
Gough, P. B., & Tunmer, W. E. (1986). Decoding, reading and reading disability. Remedial and Special Education, 7, 6-10.
Hoover, W. A., & Gough, P. B. (1990). The simple view of reading. Reading and Writing: An Interdisciplinary Journal, 2, 127-160.
Kendeou, P., Savage, R., & Broek, P. v. d. (2009). Revisiting the simple view of reading. British Journal of Educational Psychology, 79, 353-370.
Kendou, P., Van den Broek, P., White, M. J., & Lynch, J. (2009). Predicting reading comprehension in early elementary school: The independent contributions of oral language and decoding skills. Journal of Educational Psychology, 101, 765-778.
Kieffer, M. J. (2008). Catching up or falling behind? Initial English proficiency, concentrated poverty, and the reading growth of language minority learners in the united states. Journal of Educational Psychology, 100, 851-868.
Oakhill, J., & Cain, K. (2007). Issues of causality in children's reading comprehension In D. S. McNamara (Ed.), Reading comprehension strategies: Theories, interventions, and technologies (pp. 47-72). Mahwah, NJ: Erlbaum.
Sinclair, S., McKendrick, J. H., & Scott, G. (2010). Failing young people? Education and aspirations in a deprived community. Education, Citizenship and Social Justice, 5, 5-20.
SFR (2009). Statistical First Release. Key Stage 2 attainment by pupil characteristics, in England 2008/09 (SFR 31/2009). from http://www.dcsf.gov.uk/rsgateway/DB/SFR/s000889/SFR312009KS2Attainmentby... Characteristics.pdf.
Snow, C. E., Barnes, W. S., Chandler, J., Goodman, I. F., & Hemphill, L. (1991). Unfulfilled expectations: Home and school influences on literacy Cambridge, Mass: Harvard University Press.
Tilstra, J., McMaster, K., Van den Broek, P., Kendeou, P., & Rapp, D. (2009). Simple but complex: Components of the simple view of reading across grade levels. Journal of Research in Reading, 32, 383-401.
B1108 - Investigation into the relationship of dietary vitamin D to serum 25OHD and bone quality - 21/01/2011
Aims and research questions:
1. What is the dietary intake of vitamin D at 6-7 years or 8-9 years old and how does this relate to serum concentration of 25OHD at 7, 9 or 11 years old?
Question 1. Method: These relationships will be investigated using multivariable regression analyses, with dietary intake of vitamin D as the exposure variable and serum concentration of 25OHD2 and 25OHD3 as outcome variables.
From initial analyses of serum 25(OH)D2 we know that this has a non-normal distribution with a large proportion of participants below the lower limit of detection of the assay and therefore for 25(OH)D2 we will generate a categorical variable consisting of those below the lower limit of detection and thirds of the remainder of the distribution and use ordinal linear regression to examine associations with this outcome. 25(OH)D3 has an approximate normal distribution and linear regression will be used here.
To examine possible effect modification by season we will define season as 'vitamin D winter' (October to March) and 'vitamin D summer' (April to September) as defined by Webb et al (1988) for Edmonton (52 degrees North; Bristol is 51.5 degrees North) and examine associations within each seasonal subgroup. We will formally test for differences between subgroups with a likelihood ratio test.
Potential confounding by age, sex, socioeconomic position, puberty, body composition, physical activity, time outdoors, and other dietary characteristics will be taken into account in the multivariable analyses.
2. What is the relationship between dietary intake of vitamin D at 8-9 and 12-13 years old and DXA, PQCT and fracture variables as outcomes?
Question 2. Method: Multivariate linear regression will be used to explore the relationship between dietary intake of vitamin D with bone quality (DXA and PQCT variables) and fractures as outcome variables.
Potential confounding by age, sex, socioeconomic position, puberty, anthropometry, body composition, physical activity, time outdoors and other dietary characteristics will be taken into account in the multivariable analyses.
1. SACN position statement, 2007
2. Gregory et al (2000) National Diet and Nutrition Survey: Young People Aged 4 to 18 years. London: The Stationary Office.
3. Webb et al (1988) Journal of Clinical Endocrinology & Metabolism, 67: 373-378
4. Ashwell et al (2010), British Journal of Nutrition, 104: 603-611
5. Davies et al (1999) European Journal of Clinical Nutrition, 53: 195-198
6. Bates et al (2003) Osteoporosis International, 14: 152-159
7. Hill et all (2008) British Journal of Nutrition, 99, 1061-1067
8. Cashman (2007), Post Graduate Medical Journal, 83: 230-235
9. Holick (2007) New England Journal of Medicine, 357:266-281
10. Ginty et al (2004) European Journal of Clinical Nutrition, 58, 1257-1265
11. Lehtonen-Veromaa et al (2002) American Journal of Clinical Nutrition, 76: 1446-1453
Cranney et al (2007) Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No.158. Rockville, MD: Agency for Healthcare Research and Quality (http://www.ahrq.gov/downloads/pub/evidence/pdf/vitamind/vitad.pdf).
B1098 - The role of pet ownership in enhancing childhood self esteem and mental wellbeing - 20/01/2011
Aims and hypotheses
The aim of this study is to examine the association between self esteem at age 8 and pet ownership, in a large, well characterised both cohort.
Consideration of the literature indicates the complexity of this subject and leads to a set of interlinked hypotheses. Hypotheses to be tested are:
- Children that live with pets at age 8 will have increased self esteem outcome of global self worth.
- Children that have lived with pets all of their life will have increased self esteem compared to those that obtained pets at a later life-stage.
- Children that live with dogs and cats will have increased self esteem compared to those that live with other pets such as fish.
- The association between self esteem and pet ownership will differ between male and female children.
- The association between self esteem and pet ownership will be stronger for children that are a single child or the youngest in the family, than those with older siblings, for which other support relationships are available.
Methods
We will use a large existing dataset, the "Avon Longitudinal Study of Parents and Children" (ALSPAC) study. This a prospective study which recruited 14,000 pregnant women with delivery dates between April 1991 and December 1992.
Self-esteem was measured in approximately 7000 children visiting the Children In Focus clinic at age 8years. A 12-item shortened form of Harter's Self Perception Profile for Children (28) was used, comprising the global self-worth and scholastic competence subscales. The measures used valid and reliable procedures explicitly designed to elicit data from children. The children were guaranteed confidentiality.
At a number of time points, the carer of the child (usually the mother) was asked 'do you have any pets' and 'how many of the following pets do you have'. Pet types included cats, dogs, rabbits, rodents (mice, hamster, gerbil etc), birds (budgerigar, parrot etc) and 'other' pets. However, from 2 years onwards a further two categories were added; fish, and turtles/tortoises/terrapins. Pet questions were asked during gestation, and at approximate child age 8 months, 21, 33, 47, 85, 97 and 122 months (up to 10 years old). The pet ownership variables have since been converted into binary responses (yes/no for that pet type) (29). The assumption will be made that the child also lives with the pets reported by the main carer.
The main predictor variables to be used in this study will be pet ownership reported at 8 years by the mother, and pet ownership history recorded throughout childhood, as previously described by the applicant (29). Univariable and multivariable regression analysis will be used to examine for an association between the outcomes of global self worth, or scholastic competence at age 8, with both pet ownership as a whole, and ownership of each pet type. Analysis will account for potential confounding variables available in the dataset which may be associated with self esteem (such as anxiety, depression and social competence), and variables related to pet ownership (as identified in our previous research, for example measures of socioeconomic status (29)). Stratification of samples by gender will be used to compare the association between pet ownership and self esteem in each sample. Stratification by sibling status will allow examination of differences between those children with siblings and those without, and any effect of being the youngest or an only child.
B1107 - Maternal and offspring iron genes early infections and growth disentangling causality - 19/01/2011
1. Assess whether there is a causal relationship between maternal iron status and offspring infection in infancy and childhood using maternal genetic variants (adjusted for offspring variants); and estimate its magnitude.
2. Assess whether there is a causal relationships between maternal iron status and offspring growth trajectories using maternal genetic variants (adjusted for offspring variants) that are robustly associated with iron status; and estimate its magnitude.
3. Unpick the direction of association between post-natal iron status (using haemoglobin measured at 8, 12 and 18 months) with childhood infections (measured at 6 and 18 months) and growth trajectories (0-5 years); and use genetic variants that are robustly associated with iron status to test for causality.
B1106 - Maternal and paternal physical activity in pregnancy and CVD risk factors in offspring - 19/01/2011
Until several decades ago, physical activity during pregnancy was a cause for concern because of the perceived associated risk of maternal injury and of physiological changes physical activity induces in blood flow, body temperature, and fetal oxygen delivery that could potentially have both short term and lasting detrimental effects on the fetus.(American College of Sports Medicine 2006) More recently, several observational studies have reported beneficial effects of greater levels of physical activity during pregnancy for the pregnant woman, such as a decreased risk of gestational diabetes (Tobias et al. 2011) and preeclampsia.(Magnus et al. 2008;Rudra et al. 2008) Thus guidelines recommend that pregnant women maintain the same level of moderate physical activity as non-pregnant women.(Artal and O'Toole 2003)
However, current evidence is inconsistent on whether exercise during pregnancy is beneficial, harmful, or neutral for the health of the developing fetus.(Kramer and McDonald 2006) These mixed findings are likely to reflect different methods of exposure and outcome assessment, different timing during the pregnancy for exposure and outcome assessments, differences in pre-pregnancy exercise habits between the study populations, and differences in the studies' abilities to control for potential confounding factors. By far the largest observational study to date, including over 90,000 participants in the Danish National Birth Cohort, found a strong and linear association between increasing levels of physical activity in early pregnancy and miscarriage before 18 weeks gestation.(Madsen et al. 2007) As with other behaviours in pregnancy, RCTs in this area are difficult. However, a Cochrane systematic review of randomized controlled trials to promote aerobic exercise during pregnancy concluded that regular aerobic exercise during pregnancy (mostly swimming, static cycling, floor exercises) appears to improve women's physical fitness, but that current evidence was insufficient to draw firm conclusions about its likely overall risks or benefits for the woman or baby.(Kramer & McDonald 2006) The reviewers concluded that larger, better quality trials are needed before confident recommendations could be made about the benefits and risk of exercise during pregnancy.
The long-term effect of physical activity in pregnancy on offspring future health is even less well studied. Two small prospective studies assessed outcomes in offspring of women who exercised regularly throughout pregnancy compared with offspring of active women who did not exercise at 1 and 5 years of age. In the first study,(Clapp, III et al. 1998) which included 104 mother-offspring pairs, weight, length and abdominal and head circumferences at mean age 1 year were similar in offspring of women who did or did not continue regular physical activity throughout pregnancy. In another study by the same group,(Clapp, III 1996) which included just 40 mother-offspring pairs, at mean age 4 years offspring of women who engaged in vigorous physical activity during pregnancy were lighter and had less subcutaneous fat but were of similar height as offspring of women who voluntarily stopped exercising in pregnancy. They also scored higher for oral language skills and general IQ (assessed by the Wechsler Preschool and Primary Scale Intelligence). Motor, integrative and academic readiness skills were similar between groups. In both studies women were matched for pre and post-natal characteristics known to influence outcomes.(Clapp, III 1996;Clapp, III, Simonian, Lopez, Appleby-Wineberg, & Harcar-Sevcik 1998)
Thus, it is unclear whether variation in levels of physical activity during pregnancy is causally (either beneficially or detrimentally) related to long term health outcomes in offspring. Here we propose to study the association of maternal physical activity during pregnancy with CVD risk factors (including BMI, waist circumference, fat mass, blood pressure, lipids, fasting insulin and glucose) in childhood (age 9 and 15), anti-Mullerian hormone (AMH, a measure of ovarian and testicular function, age 15), cognitive function (age 8) and educational attainment (at age 16 years). We will compare the association of maternal physical activity during pregnancy with the association of paternal physical during pregnancy with the same outcomes. If the association of maternal physical activity with offspring outcomes is greater than the paternal one and remains even when controlling for paternal physical activity, this would suggest a causal, intra utero effect. However, if the associations are of similar magnitude and are abolished with mutual adjustment, this would suggest that familial characteristics such as socioeconomic position or genetic variation are more likely explanations. As a further means of examining whether any associations may be due to intrauterine mechanisms we will examine the extent to which any associations are mediated by offspring levels of physical activity. If the associations are largely or completely explained by offspring activity this would suggest that mechanisms are related to postnatal parental effects on the child's participation in physical activity rather than an effect of physical activity in pregnancy on e.g. risk of preeclampsia and placentation and other pregnancy specific factors that affect fetal development and their later cognitive and cardiovascular health. We will also compare the associations of maternal and paternal physical activity in pregnancy with outcomes measured at different ages, in order to assess whether associations are lasting or perhaps diminish with age.
Our request to include AMH as an outcome here is based on its association with metabolic abnormalities (for example: Park 2003) and we wish to extend a previous application (Prof. Lawlor as the main applicant) to examine smoking, gestational weight gain, blood pressure changes, and diabetes/glycosuria as determinants of offspring AMH.
B1101 - Analysis of Longitudinal Food RElated Data ALFRED - 17/01/2011
The major health problems of obesity, diabetes, CVD and cancer have all been related to diet (e.g. WHO, 1990; Block et al, 1992; Department of Health, 1998; Hooper et al 2001). In response to this, key public health campaigns have encouraged people to increase their daily consumption of fruit and vegetables, reduce their intake of salt and saturated fats, and eat more complex carbohydrates, amongst other aspects of diet. In light of these health messages, research based on cross-sectional and longitudinal research data sources suggest, for example, that there have been population level increases in consumption of fruits and vegetables, dietary fibre and poultry, and a decline in consumption of whole milk, butter and red meat (Prynne, Wagemakers, Stephen and Wadsworth, 2009; The Information Centre for Health and Social Care, 2009; Prynne, Paul, Mishra, Greenberg and Wadsworth, 2005) and eating less saturated fat, less trans fatty acids and less added sugar (Bates, Lennox and Swan, 2010).
The Department of Health has tasked NatCen to undertake scoping analysis project (including descriptive data analysis) to identify the type of food related data available from longitudinal sources in order to guide future research and policy priorities. The focus of this project is on longitudinal data in order to explore changes overtime and the factors associated with a change in diet. This will include analysis of the data by key break variables (to include sex, age, whether a family with children aged under 16, socio-economic classification, education/ highest qualification of mother (for datasets including children) and ethnic group (where data includes sufficient numbers)) and key health variables.
In addition, NatCen will be reporting to the Department of Health on the types of food related data currently being collected and suggesting where new data sources need to be developed including advice about questions/modules for inclusion on future surveys going forward.
Main research objectives
What can longitudinal surveys tell us about changes in eating and cooking practices?
The project will use different variables relating to eating and cooking practices to identify healthy and unhealthy practices, and explore how these vary by key sociodemographic variables and change over time. The primary sources for such data are ALSPAC and Whitehall II. These variables will include the types of fats used with vegetables and bread, and for frying and baking, the use of salt in cooking and at the table, frequency of eating takeaways, microwave and convenience meals and whether family meals are shared.
What can longitudinal surveys tell us about changes in choice and access to food?
Here key data relates to the ability to afford quality and variety of food. Primarily using data from the Family and Children's Survey (FACS) we will analyse a number of variables relating to choice and access, including whether the family is able to afford a cooked meal everyday, good quality/brand name food, fresh fruit and fresh vegetables daily and whether child maintenance goes on food. We will then be able to examine the circumstances of those of those with good choice and access to those with worse choice and access.
What can longitudinal surveys tell us about intake of key nutrients and foods?
The Department of Health has identified key nutrients and foods of policy interest for this project. Exact methods of analysis will vary depending on the data collection method used in the datasets accessed. Where possible, we will use will use the UK Dietary Reference Values as our benchmark and focus on recommended intakes for non-starch polysaccharide and percentage of energy from fat, saturated fat and non-milk extrinsic sugars. We may also include intake of Vitamin C, calcium and iron. For foods we will focus on intake of fruit and vegetables and, where age appropriate, relate this to the 5-a-day recommendation. For those surveys that primarily use food frequency questionnaires (such as Whitehall II) it may also be possible to develop a total fat score (classifying respondents as high, medium and low, an approach used in the Health Survey for England 2007).
References
Bates,Lennoxand Swan (2010). National Diet and Nutrition Survey: headline results from year 1 (2008/2009). Food Standards Agency and the Department of Health.
Block, Patterson & Subar (1992). Fruit, vegetables and cancer prevention: a review of epidemiological evidence. Nutr Cancer, 18: 1-20.
Department of Health (1994) Nutritional Aspects of Cardiovascular Disease.London: HMSO
Department of Health (1998) Nutritional Aspects of the Development of Cancer.London: The Stationery Office.
Hooper, Summerbell, Higgins et al (2001). Dietary fat intake and the prevention of cardiovascular disease: a systematic review. BMJ, 322: 757-763.
Prynne, Wagemakers, Stephen andWadsworth(2009). Meat consumption after disaggregation of meat dishes in a cohort of British adults in 1989 and 1999 in relation to diet quality. Euro Journ of Clin Nutr, 63: 660-666.
The Information Centre for Health and Social Care (2008). Health Survey for England 2007- Healthy lifestyles: knowledge, attitudes and behaviours.
The Information Centre for Health and Social Care (2009). Health Survey for England- 2008 trend tables http://www.ic.nhs.uk/statistics-and-data-collections/health-and-lifestyl...
World Health Organisation (1990).Diet, nutrition, and the prevention of chronic diseases. Report of a WHO Study Group.Geneva: World Health Organisation
Other data sets to be included in this project-
Freely available datasets
? English Longitudinal Study of Aging (ELSA) (http://www.esds.ac.uk/longitudinal/access/elsa/l5050.asp )
? Families and Children Study (FACS) (http://www.esds.ac.uk/findingData/snDescription.asp?sn=4427)
? British Household Panel Survey (BHPS) http://www.esds.ac.uk/longitudinal/access/bhps/L33196.asp - Youth Cohort
Datasets subject to access application
? Whitehall II
http://www.ucl.ac.uk/whitehallII/
? MRC National Study of Health and Development
B1100 - The effect of maternal iron status and intake during pregnancy on cardiovascular disease risk in the offspring - 17/01/2011
Objectives:
To examine the association of maternal dietary iron intake (including supplements) and haemoglobin levels during pregnancy with offspring brachial artery endothelial function measured by FMD, arterial stiffness by carotid-radial PWV and brachial distensibility (DC) at age 10 years.
To explore whether the association of maternal dietary iron intake with the offspring vascular phenotype in objective 1 is likely to be due to a causal intrauterine mechanism, by comparing maternal dietary iron - offspring vascular phenotype associations to partner dietary iron intake (assessed ~4.5 years after birth of index child) - offspring vascular phenotype.
To examine the association of cord ferritin with offspring brachial artery endothelial function measured by FMD, arterial stiffness by carotid to radial PWV and brachial distensibility (DC) at age 10 years.
To examine whether the association of maternal dietary iron intake and haemoglobin levels with offspring vascular phenotypes (as in objective 1) are mediated by cord ferritin levels.
To examine whether any of the associations of maternal dietary iron intake, haemoglobin levels or cord ferritin with offspring vascular phenotypes are mediated by offspring birth weight, gestational age, BMI and dietary iron intake.
B1099 - Oxytocin pathways and social development outcomes - 17/01/2011
Specific aims:
Oxytocin plays an essential role in maternal behavior, social bonding, prosocial behaviors, establishment of trust, anxiety reduction, and the modulation of stress. This research is significant in determining the impact of exposures and experiences on oxytocin pathways. Our approach is twofold in seeking to determine the impact of oxytocin on social development trajectory and outcomes. We will examine both exogenous oxytocin administered at birth and effects of exposure and experiences on exogenous oxytocin. Thus there are three factors that are to be studied in oxytocin pathways: exogenous administration, genetic polymorphisms, and epigenetic effects. Finally, our research is significant in examining interactive effects of maternal behavior on the child and the child's behavior on the mother.
1. To determine prosocial and atypical social developmental trajectories and outcomes from infancy through adolescence in the ALSPAC birth cohort and to correlate these findings with indices of OT pathways. We hypothesize that these outcomes will be moderated by (a) exogenous administration of synthetic oxytocin (syntocinon) at birth and dose response, (b) polymorphisms in genes for OT and the OT receptor, genetic and epigenetic regulation of OT receptor expression during development, related perinatal variables, and (c) epigenetic modification of genes in this pathway during development.
2. To empirically derive developmental trajectories from infancy to childhood and adolescence and correlate these trajectories to OT pathways related to:
a. prosocial behavior
b. autistic traits
c. social anxiety
d. social communication deficits
e. anti-social and disruptive behaviors
3. To determine the impact of the following perinatal experiences on social developmental trajectory and outcomes:
a. dosage of synthetic OT (syntocinon/pitocin)
b. caesarian section
c. maternal illness (diabetes, eclampsia) and alcohol and substance use/abuse
d. type of anesthesia or analgesia (e.g. opiates, and "caine" drugs) or other medications administered during the birth process
e. physiologic stress on the mother (e.g. hypertension) and emotional stress (anxiety, depression) in the parents
f. physiologic stress in the newborn e.g. fetal monitoring measures and Apgar score
g. breast feeding (incidence and duration)
h. maternal diet (omega fatty acids)
i. demographic variables ( e.g. parental age, family history of disorder, SES.)
j. post natal experiences (family adversity index, abuse, etc)
4. To examine polymorphisms and unique genetic variants in genes in the OT/vasopressin pathways (peptides, receptors and other factors regulating the release or functions of these peptides) on differences in social behaviors and developmental trajectories listed in Specific Aim 2. Because polymorphisms in the OT receptor are associated with social behaviors we hypothesize that those polymorphisms may modulate human behavior to have a direct effect on developmental trajectories in the ALSPAC cohort.
5. To examine the effects of exogenously administered synthetic OT and its dose response, along with the perinatal variables listed in Specific Aim 3, on the epigenetic expression of genes in the OT pathway on developmental trajectories in Specific Aim 2. We hypothesize that the regulation of the OT receptor (e.g. methylations in the CpG island) may affect social developmental trajectories and that early exposure to synthetic OT will have dose-dependent and long-lasting consequences for gene expression for the OT receptor.