Proposal summaries
B770 - Pubertal timing and depressive symptoms in adolescent girls The roles of family and peer relationships - 23/01/2009
(No outline provided).
B768 - Genomewide association study meta-analysis for birthweight gestational age and related phenotypes - 21/01/2009
ALSPAC is one of few studies (currently less than 5) available which has access to extensive phenotypic data measuring birthweight and gestationsal age, related maternal and neonate variables and genomewide genetic data. As an important player in the newly formed Early Growth Genetics (E.G.G.) consortium, ALSPAC is well placed to contribute to a developing line of analyses concerned with the heritability of growth and development related traits. It is for this reason that we seek to enter summary results from available ALSPAC genomewide tests of association with birth weight, gestational age and related traits into the growing meta-analysis for these measurements. As stand alone studies, analysis of these traits in ALSPAC and the National Finnish birth cohort have not revealed sufficiently strong associations to yield statistically robust findings. Consequently efforts to examine the genetics architecture of these traits will require extensive meta-analysis, a process we wish to involve ALSPAC in.
B769 - Levels determinants and consequences of variation in ovarian and testicular function using Anti-Mllerian hormone - 16/01/2009
We request permission to use available funds to complete assays of Anti-Mullerian hormone (AMH) on the serum residuals that are currently held in Glasgow from samples taken at the 15+ clinic. An NIH funded grant (PI: DA Lawlor) provided funds for fasting glucose, insulin and lipids to be completed on a predicted 7000 samples at the 15+ clinic. Blood samples from this clinic were only available on ~3500 samples and relevant assays are now near complete on these. Because a smaller number of samples were assayed funds are available to complete AMH assays on these 3500; and sufficient serum for these assays is currently available in Professor Sattar's laboratory in Glasgow. AMH assays would be relevant to the NIH grant application since we will use these to examine developmental origins of ovarian and testicular function which are in turn related to vascular and metabolic health outcomes.
We would like to address the following objectives in relation to AMH:
a. Describe the distribution of AMH in contemporary males and females at mean age 15
b. Determine the association of parental smoking in pregnancy; maternal weight gain in pregnancy; blood pressure change in pregnancy; gestational diabetes/glycosuria in pregnancy and parental smoking whilst breast feeding (in those offspring who were breastfed) with offspring AMH levels at mean age 15
c. Determine the prospective associations of offspring smoking, fat mass and change in fat mass, growth trajectories from birth to age 15, age at menarche (females) with AMH levels at mean age 15
d. With available data (current 3000 or larger if grants funded) complete a genome-wide association study with AMH (In collaboration with David Evans & Nic Timpson) of AMH levels
e. Examine the cross-sectional associations of AMH with glucose, insulin and lipids at age 15.
Background
AMH and ovarian and testicular function
Anti-Mullerian hormone (AMH, Mullerian-inhibiting substance) is a member of the transforming-growth factor-beta family. AMH has the primary role of regression of the Mullerian duct in the male fetus during early testis differentiation. However, expression of AMH persists after completion of the reproductive duct system in males, and furthermore commences expression in females at this time, in whom it is produced by ovarian granulosa cells from early fetal life[1]. Although AMH is initially observed in granulosa cells of primary follicles, maximal expression occurs in preantral and small antral follicles[2, 3]. AMH expression declines as antral follicles increase in size, with nominal expression restricted to the granulosa cells of the cumulus[3]. This loss of AMH expression during the follicle stimulating hormone (FSH)-dependent final stages of follicular growth, and the lack of expression by atretic follicles[4], suggests that basal levels of AMH may more accurately reflect the total developing follicular cohort and consequently potential ovarian response to FSH. The clinical utility of this, and a demonstration of the likely causal signficance of AMH as a measure of ovarian function, is that AMH is strongly associated with oocyte yield, clinical pregnancy and live birth in IVF cycles[4-7]. It is also a sensitive measure of the gonadotoxic effect of differential chemotherapy regimens and falls rapidly after toxic stimuli[8-12]. It is elevated in polycystic ovarian syndrome, a condition associated with increased preantral follicles[13-18]. Lastly, it can indicate the timing of the menopause transition approximately 5 years prior to the sentinel event as determined by amenorrhoea and circulating follicle stimulating hormone levels[19, 20]. Importantly, AMH has also been shown to be relatively consistent across the menstrual cycle[21-23], consistent with its role reflecting the continuous, non-cyclic growth of small follicles in the ovary. AMH has therefore overtaken other markers and is now recognised as the optimal measure of follicular reserve in females[7, 24, 25].
AMH is also produced in males, and the ontogeny of AMH is similar across species[26, 27], in that circulating AMH produced by Sertoli cells remains high until the onset of puberty, when they progressively decrease, correlating with the stage of pubertal development. This decline in AMH is principally due to the inhibitory effect of intratesticular testosterone and meiotic cells on Sertoli cell AMH expression[28], and male AMH values decrease to female levels[29]. Male AMH therefore provides a unique handle on Sertoli cell number and function - the principal determinant of testicular germ cell number. Consistent with this subfertile men have a significantly lower AMH than controls[30], and that even the relatively mild insult of a varicocele is associated with a lower AMH in prepubertal, pubertal and adult males[30, 31].
Prenatal/developmental determinants of ovarian and testicular function
Gestational cigarette smoking is plausibly a strong determinant of ovariant and testicular function and likely to be related to AMH via intrauterine and lactation exposure. In female fetuses, smoking may have a direct toxic effect on the primordial follicle, leading to premature exhaustion of the follicular germ pool[32, 33]. In animal models impairment of fertility in the offspring following prenatal exposure to polycyclic aromatic hydrocarbons (in cigarette smoke) via the mother during pregnancy has been demonstrated. Histological analysis of ovarian tissue from the exposed offspring mice demonstrate a markedly reduced number of primordial follicles[34, 35], suggesting that a detrimental impact on ovarian reserve and follicular dynamics underlies this phenomenon. Notably, in mice models, the combination of pre-pregnancy and lactational exposure to polycyclic hydrocarbons was associated with a 70% reduction in primordial follicle number[36]. This loss of primordial follicles and primary follicles if applicable to humans has profound biological consequences, as it is generally accepted that mammals are born with a finite number of primordial follicles that are incapable of proliferating and replenishing, and it is this dogma which underlies the chronological decline in the fecundity of both natural[37-39] and stimulated ovarian cycles[40, 41] and the relatively static onset of the menopause.
Human studies examining the impact of maternal smoking on the ovarian reserve of the offspring have been limited[42, 43]. A small epidemiological study of 230 women with offspring recall of maternal smoking status during the index pregnancy demonstrated a reduced cumulative conception rate[42]. This association was robust to adjustment with frequency of intercourse, the offspring's age and own smoking status and childhood exposure. Prenatal exposure to maternal smoking and reduced fecundability in the offspring was also observed in a recall study of 663 women from Minnesota[43]. Analysis of time to pregnancy in 1653 female twins also demonstrated a reduced fecundability in the exposed female offspring[44]. In contrast for offspring exposed during childhood to parental smoking an increased fecundability in the offspring was observed in both of these studies[43]. Importantly this apparently conflicting data regarding the timing of exposure is dependent on offspring recall of parental smoking status and has not examined differential smoking status across gestation, lactation and childhood and has no information regarding dose-dependent effects. With the prospective data in ALSPAC we will be able to examine the association of smoking in pregnancy, during infancy (and lactation where relevant) and childhood on AMH levels an index of ovarian reserve (see above) and we will be able to compare associations with paternal smoking to establish whether maternal associations are likely to be acting through intrauterine mechanisms.
With respect to males maternal cigarette smoking during gestation has been increasingly associated with rising incidences of cryptorchidism and hypospadias and reductions in testis size, sperm counts/quality, and fertility[45-47]. Thus, we hypothesise that maternal smoking during pregnancy and lactation will also be related to reduced AMH levels in males as well as females.
In both males and females there is epidemiological evidence of an association between obesity, metabolic parameters and fertility and other reproductive outcomes. These characteristics also cluster within families, with intergenerational associations. Whilst AMH levels have been assessed in prepubertal offspring of mothers with PCOS (and shown to be elevated in comparison to similar aged offspring of women without PCOS[14], to our knowledge no one has previously examined the association of maternal obesity, weight gain and metabolic/ vascular characteristics during pregnany with offspring AMH levels
Genetic determinants of AMH
Many reproductive characteristics and diseases have high levels of heritability including age at menarche (50-70%; [48]), age at menopause (~ 50%;[49, 50]) and PCOS (~60% [51]). Analysis of 359 women with PCOS, demonstrated an association between circulating AMH levels and three SNPs of the ACVR1 gene which encodes the common ALK2 component of the heteromeric AMH receptor complex in an allele dose manner[52]. In contrast AMH was not associated with SNPs in either the AMH gene or the specific AMH type II receptor part of the heteromer, despite biological effects when expressed in cell lines[53]. We hypothesise that in a general population a number of common variants will have modest associations with AMH levels. In particular given that AMH and follicular function are linked to metabolic derangements, we will examine common variants of genes, regulating metabolic function and adiposity.
Associations of AMH with vascular and metabolic traits
The relationship reproductive health with vascular and metabolic traits, and specifically the association of PCOS with insulin resistance and reduced insulin secretion would predict associations of AMH with glucose, insulin and lipid levels.
Methods
AMH will be assayed on existing ALSPAC samples from 15+ at Professor Naveed Sattar's laboratory. The AMH assay used will be the commercial ELISA kit provided by DSL (Webster, Texas, USA). This kit is in routine use in our laboratories[5, 7]. Current inter and intra-assay CVs in our laboratory are 3.0% and 2.6% respectively. The Glasgow laboratory adheres to UK external quality control for all parameters and is Clinical Pathology Accreditation (CPA) accredited.
For objectives a-c and e relevant datasets will be compiled by DA Lawlor and standard linear / logistic regression models used in analyses. Sensitivity tests of possible non-paternity will be used when comparing maternal and paternal exposures with offspring AMH levels.
For objective d, data management and analyses will be undertaken by Dave Evans & Nic Timpson from MRC CAiTE, University of Bristol.
References
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26. Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP, et al. Anti-mullerian hormone and anti-mullerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology. 1995 Nov;136(11):4951-62.
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29. Lee MM, Donahoe PK, Hasegawa T, Silverman B, Crist GB, Best S, et al. Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab. 1996 February 1, 1996;81(2):571-6.
30. Goulis DG, Iliadou PK, Tsametis C, Gerou S, Tarlatzis BC, Bontis IN, et al. Serum anti-MA1/4llerian hormone levels differentiate control from subfertile men but not men with different causes of subfertility. Gynecological Endocrinology. 2008;24(3):158 - 60.
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45. Storgaard L, Bonde JP, Ernst E, Spano M, Andersen CY, Frydenberg M, et al. Does smoking during pregnancy affect sons' sperm counts? Epidemiology. 2003 May;14(3):278-86.
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47. Jensen MS, Toft G, Thulstrup AM, Bonde JP, Olsen J. Cryptorchidism according to maternal gestational smoking. Epidemiology. 2007 Mar;18(2):220-5.
48. Bradford Towne SACEWDJBAFRRMS. Heritability of age at menarche in girls from the Fels Longitudinal Study. American Journal of Physical Anthropology. 2005;128(1):210-9.
49. Murabito JM, Yang Q, Fox C, Wilson PWF, Cupples LA. Heritability of Age at Natural Menopause in the Framingham Heart Study. J Clin Endocrinol Metab. 2005 June 1, 2005;90(6):3427-30.
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51. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of Polycystic Ovary Syndrome in a Dutch Twin-Family Study. J Clin Endocrinol Metab. 2006 June 1, 2006;91(6):2100-4.
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B764 - Investigating the role of the HNF4A T130I variant in fetal growth - 13/01/2009
We wish to use ALSPAC as a replication study to investigate the role of the HNF4A T130I variant (rs1800961) in fetal growth and intermediate traits related to type 2 diabetes (T2D).
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study is a multi-centre study of 25,000 mothers and their babies, which demonstrated a continuous relationship between maternal glucose and measures of birth size and fetal adiposity (1). A genetic association study of 1536 SNPs in ~80 candidate loci previously implicated in insulin secretion/sensitivity, has been carried out in a subset of HAPO samples to investigate associations with maternal glycemia at ~28 weeks gestation and offspring size at birth. Included in the study were 3828 mothers of European (Belfast and Manchester, UK, and Brisbane and Newcastle, Australia) and 1813 mothers of Asian (Bangkok, Thailand) ancestry and their offspring.
Among the top signals from the analysis was rs1800961, which encodes a Thrgreater than Ile amino acid change in exon 4 of HNF4A. This was strongly associated with increased fetal head circumference (0.5cm [95%CI: 0.3-0.7] per maternal risk (A) allele; P=1.2x10-7) in those of European descent. The maternal risk allele was also more weakly associated with 1-hour glucose from OGTT (4.3mg/dL [95%CI: 0.5-7.9]; P=0.03), birth length (0.7cm [95%CI: 0.2-1.1]; P=0.003), birth weight (52.6g [95%CI: -8.0-113.3]; P=0.09), and sum of skinfolds (0.3cm [95%CI: -0.1-0.6]; P=0.13). This same risk allele in the fetal genome was weakly associated with cord C-peptide (0.1ug/dL [95%CI: 0.01-0.22]; P=0.03), and head circumference (0.2cm [95%CI: -0.1-0.4]; P=0.08). The same trends were observed among the Thai (Pgreater than 0.05).
We are interested to seek replication of these results in ALSPAC for the following three reasons:
1. Statistical evidence: the maternal genotype-head circumference association survives Bonferroni correction for multiple testing, while multiple other traits show associations at Pless than 0.1 in a consistent direction
2. The SNP is has been recently associated with HDL-cholesterol levels with evidence that exceeds the generally accepted criteria for "genome-wide significance" (Pless than 5x10-8) (2). This evidence that the SNP is marking a real biological function increases the prior odds that it will be associated with fetal growth. The minor A allele, associated with increased fetal head circumference in the HAPO study, predisposes to lower HDL levels in the general population.
3. Carriers of rare diabetes-causing mutations in HNF4A experience greatly increased fetal growth (3). The associations in HAPO of the fetal allele with raised C-peptide and head circumference are consistent with this. Also, in line with the genome-wide lipid data, HDL levels are lower in individuals with HNF4A mutations (4).
Power
The SNP is relatively rare (MAF=4% in Europeans and 2% in Thai). Assuming 7000 ALSPAC mothers in the analysis, we estimate that we will have greater than 99% power to detect a change in head circumference of the magnitude seen in HAPO at Pless than 0.05. To detect a change in birth weight of 50g per allele, we will have 64% power. Even if the associations observed in HAPO represent true underlying effects on fetal growth, it is likely that the "Winner's Curse" has led to an overestimation of effect sizes. Therefore, it will be important to meta-analyse data from the individual HAPO study sites, along with ALSPAC. We will also genotype the SNP in samples from the Exeter family study (950 population based parent-newborn trios), and we will potentially be able to add further samples from the HAPO study (~1500 further Caucasian mother-offspring pairs; 1250 African-Caribbean; 800 Hispanic). We hypothesize that real genetic associations will be consistent across all of these studies - i.e. even if individually studies show only nominal significance, or even P values greater than 0.05, a meta-analysis of all studies will provide highly significant results.
We therefore propose to analyse the polymorphism in ALSPAC to test the following hypotheses:
1. Fetal genotype and maternal genotype are associated with measures of fetal growth, including head circumference, weight and length at birth.
2. Offspring genotype is associated with diabetes-related traits in childhood including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.
To do this we would like to genotype (at Kbiosciences) all ~20,000 ALSPAC samples. We will need the following phenotypes to test our hypotheses (a detailed list is in the next section):
1. Birth weight, length and head circumference
2. Covariates of birth weight to check if genotype is acting through them: gestational age, maternal age, maternal BMI, smoking , parity, twin status to exclude non-singletons, ethnicity as genotype frequency may alter with ethnic origin and confound analyses.
4. Type 2 diabetes-related intermediate traits including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.
REFERENCES
1. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA: Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:1991-2002, 2008
2. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA: Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41:56-65, 2009
3. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT: Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4:e118, 2007
4. Murphy R, Ellard S, Hattersley AT: Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 4:200-213, 2008.
B758 - Intrauterine origins of autism risk placental analysis of infection and hypoxia - 09/01/2009
Hypothesis 1. Autism risk is associated with exposure to intrauterine cytokines and/or hypoxia.
Autism and other neuropsychiatric risks have been linked to intrauterine exposures to cytokines and/or hypoxia. These studies are limited in that they have been forced to rely upon retrospective cohorts, maternal serum samples, maternal medical history, etc., each of which is problematic in terms of bias (true peer "control" sample), ascertainment (retrospective assessment of maternal gestational illness), or true measure of fetal exposure (maternal serum cytokines do not necessarily imply fetal cytokinemia).
The ALSPAC cohort will allow us to avoid most of those pitfalls, in a nested case-control study that will use both standard histopathologists' definitions and image analysis, to determine the presence and severity of
* acute inflammation (most commonly a marker of intraamniotic infection),
* chronic placental inflammation (with a differential diagnosis generally considered to be congenital viral infection or maternal attack against the semi-allogeneic fetoplacental unit), and
* the villous effects of uteroplacental malperfusion (villous fibrosis, excess syncytial basophilia and knotting, infarcts, abruption, generally reflecting reduced fetal oxygenation secondary to the abnormal maternal perfusion of the placenta and/or damage to the placenta).
Hematoxylin and eosin stained slides (and special stains as indicated) will be scored by a team of 3 trained and expert pathologists, and the digitized slides will be evaluated using sets of segmentation and quantification algorithms developed to measure inflammation and hypoxia.These semiquantitative (pathologist') and continuous (image analysis) variables will be correlated with case-control status, with adjustment for gender, gestational age and birth weight at delivery using structual equation models in which the placental histology features are considered to be indicators of underlying latent variables (e.g., maternal acute inflammatory responses, fetal acute inflammatory responses, maternal malperfusion). The model including all
All cases of autism identified in ALSPAC (n=56) will be included in this nested case-control study. We will select four controls for each case to maximize statistical power of the comparisons. The gain in statistical power with the use of additional control subjects is negligible. The large size of the ALSPAC cohort allows us to match on a few key variables that may be differentially distributed among the cases. We propose to match on infant sex and gestational age (=/- 1 week ideally, 2 weeks if necessary). Prematurity is not a major risk factor for autism so we expect matching on gestational age to be feasible.
2. Placental vascular branching is a biomarker for Autism.
Autism is a disorder of abnormal neuronal connectivity and, by extension, abnormal neuronal dendritic branching. The placenta is an organ that is architecturally little more than a thin tissue sheath covering a vascular tree. It is uniquely dependent on coordinated and accurate paternal gene expression, and its growth is regulated by gene families that regulate events that may be key to the connectivity issues described in autism. We hypothesize that the vascular architecture of the placenta is a proxy for aspects of neuronal differentiation, elongation and navigation that are germane to the genesis of autism risk. Thus autism risk will have parallel placental findings of altered villous and vascular branching.
Neurons and the Vasculature: Shared Pathways for Outgrowth, Proliferation and Branching Diversity. Placental blood vessels provide oxygen and nutrients to and remove metabolic products from the embryo/fetus. It has been recognized that the signals and guiding principles to differentiate, elongate and navigate blood vessels towards their destinations are analogous to those in neuronal development. Vascular endothelial growth factor (VEGF) promotes vascularization of the placenta as well as neuronal differentiation. Similarly, a number of factors promote endothelial proliferation and angiogenesis; moreover, their cross-talk-and in particular their defective cross talk-may be at the root of a wide range of both vascular/ neurological and placental diseases .
Antiangiogenesis and Autism: Thalidomide and Valproate. Thalidomide and valproate exposures in early pregnancy are recognized risk factors for autism. Animal models exposed in utero to valproate demonstrate neuroanatomical changes in the brainstem and cerebellum that are comparable to those in brains from children with autism. Both of these drugs are antiangiogenic as well as teratogenic. Mechanisms of such damage involve disruption to vascular growth factors, i.e., VEGF and placental growth factor (PlGF) and their associated signal transduction pathways. Note, VEGF and PlGF are produced and released by the placenta.
Hypothesis: Placental Vascular Branching is an Indicator of Normal Fetal Neuronal Connectivity. Autism is a disorder of abnormal neuronal connectivity and, by extension, abnormal neuronal dendritic branching. The placenta is an organ that is architecturally little more than a thin tissue sheath covering a vascular tree. It is uniquely dependent on coordinated and accurate paternal gene expression, and its growth is regulated by gene families that regulate events that may be key to the connectivity issues described in autism. We hypothesize that the vascular architecture of the placenta is a proxy for aspects of neuronal differentiation, elongation and navigation that are germane to the genesis of autism risk. Thus autism risk will have parallel placental findings of altered villous and vascular branching.
Measuring Placental Vascular Abnormality. The placenta is accessible (delivered with each baby born), and can be measured reliably. In a series of papers, we have developed novel methods for the study of the placental vascular arborization. We have introduced a dynamic model of the placental vascular growth based on a well-studied fractal random growth process (DLA). The model has allowed us to associate an abnormal morphology of the placenta with the abnormal vascular branching and connectivity. The standard marker of the branching density of a fractal tree is a version of a fractal dimension. While mathematically elegant, it is difficult to quantify in a practical study. We proposed a new idea, relating the placental vascular branching structure with a metabolic scaling exponent. This quantity is easy to measure as a ratio of logarithms of the fetal birth weight and the placental weight, and is a biologically relevant version of the fractal dimension of the vasculature. Our studies have demonstrated an association of the scaling exponent with the known factors affecting the normal vascular development.
Preliminary Findings on a Female-Specific Risk Factor for Autism: Advanced Paternal Age. Autism and Autism Spectrum Disorders have a strong genetic component, and a predilection for males. Recently, a risk factor for autism, advanced paternal age, was demonstrated to have an effect confined to female offspring, who inherit their second X-chromosome from their fathers [18]. The operative hypothesis is that the X-chromosome, which contains many genes associated with cognition and intelligence, may acquire either mutations or epigenetic alterations over the father's lifespan that then alter those gene's expression in his daughters. We have recently identified a female-specific negative effect of advanced paternal age on birth weight in the National Collaborative Perinatal Project, a well studied national cohort with over 24,000 cases with placental data. The placentas were thinner in this case, indicating a less arborized vascular tree.
Methods of the Proposed Research.
a. Placental Processing: Placentas will be processed according to protocols that have been reviewed and agreed to by the Pathology Department University of Bristol Hospital. Specific features include:
1. Digital photography of the chorionic surface and of slices of the placental disk.
2. Tissue sampling to include:
2 cross sections of the umbilical cord
1 membrane roll
4 samples of grossly normal placenta obtained from each placental quadrant
2 "functional units" (2.5 cm square full thickness regions with a terminal chorionic surface vessel)
Digital photographs will be uploaded to the Placental Analytics FTP site for analysis. Tissue samples will be processed to wax blocks. The blocks will be shipped to Placental Analytics, LLC for slide preparation.
Data extracted from the digital photographs and copies of the files of all digitized histology slides prepared from the placental tissue samples will be returned to ALSPAC as they are generated throughout the course of the study.
Tissue blocks will be retained by Placental Analytics, LLC until completion of the study at which point they will be returned to ALSPAC.
Placental Vascular Analyses: A key to our analysis of the placental vascular branching structure is the connection between the arborization of the vascular tree and the metabolic scaling exponent (a biologically relevant fractal dimension), as well as the morphological factors, such as the shape and the size of the placenta. Using the DLA model of placental angiogenesis, we can connect the variability in the placental shape with a perturbation in the placental vascular architecture. Fourier analysis of the two-dimensional images of the chorionic plate can be used to reliably identify such perturbations which appear early in gestation, and are hypothesized to be connected to Autism risk. An early reduction of the placental angiogenesis is also related to a larger value of the metabolic scaling exponent - a quantity which is particularly easy to measure at the time of delivery, with implications for an early diagnostic of the related Autism risk factors.
We have begun the analysis of 3-dimensional placental shapes, beginning with the study of the thickness and variability of slices perpendicular to the chorionic plate. The thickness of the slices, in particular, is associated with the vascular density. Our preliminary findings show that for female babies, the average thickness is adversely affected by the advanced paternal age, which is a known Autism risk factor. The variability of thickness is also associated with the suppressed angiogenesis in the DLA model [16]. We have also initiated the study of the skeletonized structure of the placental vasculature both for DLA models (with the skeletons of vascular trees traced automatically) and for digital photographs of the chorionic surfaces (with manually traced skeletons). We have developed measures of average density of the large and medium blood vessels in the placental surface, which complement the techniques described above, with similar results. We plan to further this approach by developing automated digital recognition of the large-scale branching structure in the chorionic plate surfaces.
B759 - Behavioural and psychiatric side effects of medication use in childhood - 08/01/2009
The issue of chronic medication use during childhood is sometimes controversial, particularly in regard to psychotropic medication (Lancet, 2008). Little is known about the long-term effects of psychotropic drug use in children and evidence for efficacy can be scant. One of the commonest chronic medications prescribed for children are inhaled corticosteroids which are the mainstay of preventive treatment for asthma. It is estimated that between 4- 9% of children under 12 in the UK are prescribed medication for asthma (Turner et al, 2009). Many children remain on inappropriately high doses of steroids for longer than is necessary (Turner et al, 2009). Although there is awareness of adverse effects of steroids such as growth retardation, adrenal insufficiency and ocular and skin effects (Lipworth , 1999; Covar et al, 2000) there appears to be little awareness of the potential adverse effects of these medications on children's mental health.
Clinically, from our work in liaison psychiatry, it is evident that steroid treatment commonly results in psychotic-type symptoms in the general hospital setting. Case studies on adult patients have demonstrated a wide range of behavioural and psychiatric side effects resulting from corticosteroid treatment, including disturbances of mood, cognition, aggression, hyperactivity and psychosis (Warrington and Bostwick, 2006). However, there is little data available for paediatric populations. One randomised controlled trial on the efficacy of high dose corticosteroids in the treatment of acute lymphoblastic leukaemia in children has reported on psychiatric side effects. These included severe depression, violence towards self and others, mood swings and lability, and psychosis (Mitchell et al., 2005). In fact, "behavioural toxicity" was the most significant side effect recorded in the study. It is not known whether psychotropic effects would be seen with low-dose corticosteroids (such as the normal doses for inhaled steroids). To our knowledge, no research to date has been conducted to formally assess psychiatric symptomatology among children using corticosteroid medication. As a result, the true side effect profile of this medication is unknown.
Our application to ALSPAC is prompted by an intriguing (unpublished) finding from analysis of our Challenging Times study data (Lynch et al., 2004; Kelleher et al., 2008) which showed a significant association between a diagnosis of asthma and psychotic-type symptoms in children aged 12-15 years of age. Fourteen percent (n=29) of the adolescents interviewed had a history of asthma. 58.6% of these participants had been treated with corticosteroid medication in the course of their illness. Further analyses revealed that the adolescents who had received corticosteroid therapy for their asthma were significantly more likely to have experienced psychotic symptoms than the adolescents who had a history of asthma but no corticosteroid use. The numbers in our study are small, however, and the ALSPAC data would allow more careful analysis of this important research question. We would like to examine other psychiatric symptoms also as potential adverse effects of steroids.
We are also interested in adverse side effects of stimulant medication use in children, in particular the possible association between stimulant use and psychotic-type symptoms. Stimulant medication has been commonly used for treatment of Attention Deficit Hyperactivity Disorder (ADHD) although concerns are increasingly being expressed about its use as a first line treatment (Kendall et al, 2008) There are few studies that have examined the behavioural and psychiatric side effects of stimulant medication use in children (Barkley et al., 1990). The few data available on methylphenidate have shown side effects including depression, irritability, violent behaviour and mania (Schachar et al., 1997). Psychotic reactions have also been documented in the literature (Cherland and Fitzpatrick, 1999), but this has been noted as a result of obvious psychotic disturbance and not a result of systematic investigation of psychotic symptoms. It, thus, likely represents an underestimation of the true side effect profile of stimulant medication.
In order to address our research questions, the following psychological variables would be needed for all time points available:
Exposure information:
- Medication use in childhood and adolescence
- Medical and psychiatric illness diagnosed in childhood and adolescence
Principal outcome measure:
- Psychotic symptoms: PLIKS age 12 (interview) , PLIKS (questionnaires) ages 13, 14, 15, 16
Secondary outcome measures:
- Other Psychopathology: DAWBA (ages 7,10,13, 15); SDQ (age 4, 6,8,9,11,13); MFQ (ages 9,10,11,12,13); Antisocial behaviour (ages 8,10, 12), borderline personality interview (age 12).
- Measures of cognitive function and educational attainment:
IQ test scores (4,8,15); Attention measures (age 8,11); Exam scores SATS ages 7,11,14, GCSEs age 16
Possible Confounders:
- SES; gender, family history of psychiatric disorder
Analysis:
Analysis will be performed in STATA (v9). We will study repeated measures of psychopathology in relation to commencement (and discontinuation) of medication. Our main outcome of interest is psychotic-type symptoms but we will also measure the changes in other psychopathology and cognitive ability in relation to medication use. We will take account of possible confounders such as social class, gender and family history of psychiatric illness.
References:
Barkley RA, McMurray MB, Edelbrock CS, Robbins K (1990) Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics, 86 (2): 184 - 192
Cherland E and Fitzpatrick R (1999) Psychotic side effects of psychostimulants: a 5-year review. Canadian Journal of Psychiatry, 44 (8): 811 - 813
Covar RA, Leung DY, McCormack D et al (2000) Risk factors associated with glucocorticosteroid induced adverse effects in children with severe asthma. J Allergy clin Immunol, 106: 651-9
Kelleher I, Harley M, Lynch F, Arseneault L, Fitzpatrick C and Cannon M (2008) Associations between childhood trauma, bullying and psychotic symptoms among a school-based adolescent sample. British Journal of Psychiatry, 193: 378 - 382
Kendall T, Taylor E, Perez A, Taylor C. (2008) Diagnosis and management of ADHD: summary of NICE guidance. 337: a1239
Lancet editorial (2008) Chidren and psychiatric drugs: disillusion and opportunity. 372:1194
Lipworth BJ. (1999) Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 159:941-4.
Lynch F, Mills M, Daly I, Fitzpatrick C (2004) Challenging Times: a study to detect Irish adolescents at risk of psychiatric disorders and suicidal ideation. J Adolesc, 27: 441 - 451
Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TOB (2005) Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 controlled trial. British Journal fo Haematology, 129: 734 - 745.
Panico L, Bartely M, Marmot M, Nazroo JY, Sacker A, Kelly YJ. (2007) Ethinic variation in childhood asthma: findings from the Millenium cohort. Int J Epid 36:1093-1102.
Schachar RJ, Tannock R,Cunningham C, Corkum PV (1997) Behavioural, situational and temporal effects of treatment of ADHD with methylphenidate. Journal of the American Academy of Child and Adolescent Psychiatry, 36 (6): 754-763
Turner S, Thomas M, von Ziegenweidt J, Price D (2009) Prescribing trends in asthma: a longitudinal study, Arch Dis Child; 94:16-22
Warrington TP and Bostwick JM (2006) Psychiatric adverse effects of corticosteroids. Mayo Clin Proc, 81 (10): 1361 - 1367.
B757 - Genome Wide Association Study in ALSPAC mothers - 08/01/2009
Pregnancy has been conceptualised as a metabolic challenge, since the normal physiological/hormonal response to pregnancy - high oestrogens and cortisol levels - results in a temporary metabolic like syndrome.(1) These changes are likely to be hormonally driven through acquisition of fat in early pregnancy and its rapid mobilisation later, and it has been hypothesised that women with greater weight gain during pregnancy are likely to be at greater risk of extreme metabolic and vascular changes during pregnancy and increased risk of the later development of diabetes and CVD.(1;2) There is also increasing evidence that greater weight gain in pregnancy is associated with offspring obesity risk in childhood and early adulthood,(3-10) and from a recent study conducted by the PI of this application that this association results in greater blood pressure in offspring.(3) At the extreme, the metabolic and vascular changes of pregnancy are manifest as clinically diagnosed gestational diabetes and hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) both of which are associated with a wide range of other adverse (for mother or general populations in non-pregnant states) vascular, metabolic and inflammatory changes during pregnancy and with future glucose intolerance, diabetes, dyslipidaemia, hypertension and cardiovascular disease risk in the mother,(1;2;11-15) and her offspring in later life.(2;3;16-18)
The mechanisms that link pregnancy related characteristics to later cardiovascular and metabolic phenotypes in women are unclear. Our proposal will contribute to understanding the extent to which two hypothesised mechanisms for this association might be responsible.(19) These two hypotheses are (i) that an existing predisposition (in part a genetic predisposition) for adverse vascular and metabolic outcomes is unmasked by the stress test of pregnancy(1;20) and (ii) that adverse vascular and metabolic changes are caused by pregnancy in some women and these changes remain permanent and therefore increase the risk of future disease in later life. In the latter fetal genotype might drive the maternal changes in order to increase their nutrition during intrauterine development, particularly in the situation of placental underperfusion.(19;21) If the first hypothesis has a substantial role in explaining the association of pregnancy with later life maternal phenotypes then we would anticipate similar genetic variation to be associated with both pregnancy and non-pregnancy (later life) phenotypes. If the second has a substantial role then we would anticipate some maternal genetic variation to be associated only with non-pregnant phenotypes and we might expect some fetal (offspring) genetic variation to be associated with maternal pregnancy phenotypes. We will be able to test these possibilities in this proposal.
We will also be able to explore the extent to which intrauterine (developmental origin) mechanisms or shared genetic heritability contribute to the link between maternal pregnancy characteristics and offspring metabolic and vascular phenotypes. If intrauterine factors are important then we would anticipate that maternal genetic variation that is associated robustly with her phenotypes (e.g. weight change in pregnancy) to be associated with offspring phenotypes even after controlling for the offspring's own genotype. Whereas if genetic inheritance explains the intergenerational association we would anticipate the association of mother's genotype with offspring phenotype to be attenuated to the null upon adjustment for offspring genotype.
B760 - Interactions between maternal stress and MTHFR polymorphisms in the development of childhood asthma - 05/01/2009
The asssociation between maternal psychological variables, particularly maternal antenatal anxiety, has been linked with clinical [1,2] and biochemical [3] outcomes in the offspring of their pregnancies. These observations support possibility of prenatal programming mediated through the developing hypothalamo-pituitary-adrernal (HPA) axis of the fetus. There have been two reports of an association between maternal stress in early childhood and the development of wheeze [4] and asthma [5] in children. We have also reported in ALSPAC an association between prenatal maternal anxiety and asthma in the offspring at age seven years [6]. Although it has been speculated that this association may also be mediated through the HPA axis and thus affect the developing immune system, we found no strong evidence to support a stronger effect in atopic compared with non-atopic asthmatic children.
We have developed a collaboration with a group in Western Canada that has published on maternal stress and asthma [5] and has recently identified evidence of an interaction between chronic maternal stress and a functional polymorphism of the MTHFR gene in association with childhood asthma. We found no association of maternal or child genotype for the C677T polymorphism of MTHFR and asthma [7], in contrast to a study of Danish adults [8] but we have not invesitgated the possibility of an interaction between this genotype and maternal psychological variables. Therefore, we wish to test the hypothesis that maternal stress (anxiety and depression) in the prenatal and postnatal periods (particularly chronic stress) interacts with the C677T allele of MTHFR in association with asthma at age 7 years in the ALSPAC cohort.
1. O'Connor TG, Heron J, Golding J, Glover V. Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis. J Child Psychol Psychiatry. 2003 Oct;44(7):1025-36.
2. Glover V, O'Connor TG, Heron J, Golding J. Antenatal maternal anxiety is linked with atypical handedness in the child. Early Hum Dev. 2004 Sep;79(2):107-18.
3. O'Connor TG, Ben-Shlomo Y, Heron J, Golding J, Adams D, Glover V. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry. 2005 Aug 1;58(3):211-7.
4. Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study. Am J Respir Crit Care Med. 2002 Feb 1;165(3):358-65.
5. Kozyrskyj AL, Mai XM, McGrath P, Hayglass KT, Becker AB, Macneil B. Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma. Am J Respir Crit Care Med. 2008 Jan 15;177(2):142-7.
6. Cookson H, Granell R, Joinson C, Ben-Shlomo Y, Henderson J. Mothers' anxiety during pregnancy is associated with asthma in their children. J Allergy Clin Imunol (submitted)
7. Granell R, Heron J, Lewis S, Davey Smith G, Sterne JAC, Henderson J. The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort. Clin Exp Allergy. 2008 Feb;38(2):320-8.
8. Husemoen LL, Toft U, Fenger M, Jorgensen T, Johansen N, Linneberg A. The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy? Int J Epidemiol. 2006 Aug;35(4):954-61.
B847 - Eating disorders phenotypes across adolescence in two longitudinal general population cohorts GUTS ALSPAC - 01/01/2009
(No outline received).
B746 - Vitamins C and B12 and protection from chronic disease Using Mendelian Randomisation to access causality - 23/12/2008
There is substantial debate about the role of vitamin C, a powerful antioxidant, in preventing chronic disease [1]. Whilst there is evidence from observational studies that lower vitamin C plasma levels are associated with higher risks of cancer, cardiovascular disease and death, randomised controlled trials (RCTs) of vitamin supplementation have not provided evidence for the protective effects of vitamin C against these diseases [2].
The associations seen in observational studies are likely to be confounded since plasma vitamin C levels have been shown to be associated with a number of socioeconomic and behavioural factors throughout the lifecourse [2] which are also strongly related to disease outcomes eg social class, smoking, diet. While information on these confounding factors is often collected, it is difficult to ever fully capture lifestyle differences between subjects.
B-vitamin status has also been linked to cardiovascular disease and cancer [5]. B-vitamins (folate, B12 and B6) play a key role in homocysteine metabolism and studies have shown that higher levels of plasma homocysteine are associated with increased risk of cardiovascular disease [6]. Evidence from a Mendelian randomisation study supports a causal relationship between homocysteine plasma levels and stroke [5]. However, there is conflicting evidence from RCTs about the effects of B-vitamin supplementation on risk of cardiovascular disease [6;7].
Mendelian randomisation methods can be used to investigate causal effects free from confounding or reverse causality [9] by using genetic variation associated with risk factors of interest as proxies for exposures. Since genes are randomly assigned to individuals due to random assortment of alleles at meiosis, potential confounders should be distributed evenly amongst genotypes.
Recently, common variants of genes associated with Vitamin C [9] and Vitamin B12 [10] plasma levels have been identified. SLC23A1 and SLC23A2 encode sodium-dependent vitamin C transporters, which are necessary for the major pathway of vitamin C absorption in humans[10]. Pilot data from four studies has shown that single nucleotide polymorphisms (SNPs) in the SLC23A1 gene are associated with plasma vitamin C levels (see plot below).
Appendix Figure 1.
Meta-analysis of SLC23 A1 variation effect on circulating vitamin C taken from the 10 Towns Study, the British Women's Heart and Health Study, MIDSPAN and the EPIC cohort. Meta-analysis explicitly marks the effect of rs33972313 on square root transformed vitamin C, r^2=~0.002 (BWHHS & 10 Towns) p_meta=6.5x10-12, I^2=0%.
Strong associations have been found between variants of the FUT2 gene and plasma vitamin B12 levels [10]. The mechanism by which this gene may influence B12 levels is not yet fully understood but the authors hypothesise that differences in susceptibility to infection by H.pylori conferred by variants of this gene may lead to differences in B12 absorption, since H.pylori infection leads to reduced secretion of the glycoprotein intrinsic factor, which must bind to B12 before it can be absorbed.
This project aims to use these newly discovered genetic variants to investigate whether the observed relationships between plasma concentrations of vitamins C and B12 and metabolic and cardiovascular outcomes are causal. Our aim here is to relate this to early and later lifecourse indicators of chronic disease. These findings should provide important information regarding the appropriateness of vitamin supplementation as a preventive measure for chronic diseases.
During the initial phase of the proposed study, genotyping of the relevant SNPs in all ALSPAC children and mothers for whom genetic data is available (N~7-9000 for each group) will be carried out by KBioscience.
We have selected the following genetic variants for assessment:
Vitamin C
Gene: SLC23A1 SNP number: rs33972313
Vitamin B12
Gene: FUT2 SNP number: rs492602 [11]
Statistical analyses will be conducted in STATA 10. We will test to see if genotype frequencies are in Hardy-Weinberg equilibrium. The relationship between genotypes and potential confounding factors (sex, age, social class, education, exercise, diet, smoking and alcohol consumption (in the mothers)) will be investigated using linear regression methods to assess if genotype is independent of confounders. Using linear regression we will then investigate the relationship of genotypes with outcome measures: BMI, blood lipids, glucose, insulin, blood pressure.
We also propose to undertake a scheme of genotype based selection of samples for serum vitamin C measurement within the ALSPAC cohort. This will be undertaken in efforts to provide an optimal subset of the ALSPAC cohort to provide replication data for the primary association of concern (i.e. SLC23A1 variation and circulating vitamin C). The measurement of circulating vitamin C will be undertaken by Naveed Sattar (University of Glasgow) and will be in a subset chosen to provide a balanced sample of the variant rs33972313. This variant has been chosen owing to its consistent relationship with circulating vitamin C (Figure 1), and as a consequence of the low MAF of this variant (~0.03). To capture the vitamin C effect expected from previous work, power calculations based on figures from the British Women's Heart and Health Study predict that if a MAF of 0.3 can be simulated by genotype based sample selection, then as few as ~700 individuals would be required to detect the effect of rs33972313 (80% power,). These parameters are summarised in Apendix Figure 2.
This stage of data collection and analyses will allow us to confirm associaitons between circulating vitamin C and variation at the SLC23A1 variant within a select sample suitably powered to detect the expected magnitude in vitamin change.
Findings will be written up for publication in a peer reviewed journal.
References
1. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr 2003; 22:18-35.
2. Lawlor DA, Davey SG, Kundu D, Bruckdorfer KR, Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 2004; 363:1724-7.
3. Haggarty P. B-vitamins, genotype and disease causality. Proc Nutr Soc 2007; 66:539-47.
4. Homocysteine SC. Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis. JAMA 2002; 288:2015-22.
5. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. The Lancet 2005; 365:224-32.
6. Ishihara J, Iso H, Inoue M, Iwasaki M, Okada K, Kita Y, Kokubo Y, Okayama A, Tsugane S, for the JPHC Study Group. Intake of Folate, Vitamin B6 and Vitamin B12 and the Risk of CHD: The Japan Public Health Center-Based Prospective Study Cohort I. J Am Coll Nutr 2008; 27:127-36.
7. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease: A Randomized Trial. JAMA 2008; 299:2027-36.
8. Davey Smith G, Ebrahim S. What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 2005; 330:1076-9.
9. Eck P, Erichsen HC, Taylor JG, Yeager M, Hughes AL, Levine M, Chanock S. Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2. Hum Genet 2004; 115:285-94.
10. Hazra A, Kraft P, Selhub J, Giovannucci EL, Thomas G, Hoover RN, Chanock SJ, Hunter DJ. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet 2008; 40:1160-2.
11. Erichsen HC, Engel SA, Eck PK, Welch R, Yeager M, Levine M, Siega-Riz AM, Olshan AF, Chanock SJ. Genetic variation in the sodium-dependent vitamin C transporters, SLC23A1, and SLC23A2 and risk for preterm delivery. Am J Epidemiol 2006; 163:245-54.
Appendix Figure1.
Meta-analysis of SLC23A1 gene variant effect on circulating levels of vitamin C. Gene variant rs33972313 is assessed in these analyses and data is shown as square root vitamin C levels.
Appendix Figure 2.
Summary of power calculation statistics. Three-way plot of number of samples required to achieve 80% power to detect effect sizes of varying strength at differing minor allele frequencies. As stated above, a minor allele frequency of 0.3 in a sample of ~700 ALSPAC children would yield 80% power to detect a main effect equivalent to that seen between rs33972313 and circulating vitamin C in other cohorts.
B755 - HabEat FP7 Critical periods in food habit formation in early childhood - 18/12/2008
Background
As interventions studies have shown it is difficult to change food habits once firmly established, identifying how they develop is crucial if public health recommendations or early interventions in at risk individuals are to be developed (Te Velde, 2008; Moreno, 2008). Few studies have investigated early factors influencing the development of food habits (Northstone, 2001; Coultard 2009). Early life is a period of fast and coordinated changes to establish physiological and social functions. Critical periods in child's growth that control later body composition have already been found (Botton, 2008; Monteiro, 2005, Ekelund 2007) and probably correspond to specific needs in energy and nutrients. In parallel cognitive and motor development follows well described steps. The development of the child eating behaviour is characterised by critical periods for food habits.
These are influenced by characteristics of the child including appetite, satiety, food preferences, food neophobia, fussiness, and by the food environment and the social and emotional context of meals. Parental attitudes are also important in determining what children eat.
Subjects
Avon Longitudinal Study of Parents and Children (ALSPAC) study is an ideal enviroment in which to investigate these critical periods and relate them to later outcomes such as eating behaviours, growth and development.
Data has been collect on 14000 children whose mothers were recruited between 1991 and 1992 early in pregnancy. The completed child follow-up comprises questionnaires at 6 months (n=11490), 15 months (11 077), 24 months (10 432), 3 year (10 145), 4 year (9722), 5 year (9013), 7 years (8515) and 9 years (7965). The early questionnaires covered milk feeding, weaning, age of introduction of each type of food and feeding problems. Parental attitudes to food and feeding their child have been covered in a series of questionnaires to parents about themselves. The study has collected detailed records of foods and drinks taken by the children over 3 days (up to 1000 children at 4, 8 & 18 months, 3.5 and 5 years and over 6000 children at 7, 10 & 13 years). These can be used to determine the amount and types of key foods, such as fruit and vegetables, eaten in relation to early feeding practice. The children have been weighed and measured at all these time points so these feeding practices can be related to growth and obesity development.
Methods
Secondary analysis of data already collected will be undertaken to build on the work of Emmett and Northstone which has investigated the relationship between late introduction of chewy foods and later feeding difficulties up to age 7 years. This will be extended to look at outcomes up to 13 years including body compostion and types of foods eaten (assessed by diet records). Further analysis will look at the age of introduction of various types of solid foods, such as meat, fruits, vegetables, processed foods and the relationship with eating patterns, foods and nutrients up to 13 years. Parental behaviours and attitudes to feeding the child will be investigated to determine benificial and detrimental practices.
Staff
Kate Northstone (5% for 2 years) will be a co-applicant and will provide statistical support to a team in COBM.
This will comprise 1-day per week from a statistical assissant, 3-days per week from a nutritionist (Louise Jones) and 2 days a month from Pauline Emmett as PI. This work will be for 24 months from Jan-01. The second 2 years of the project we will provide an advisory role only fullfilled by Pauline at 1.5 days a month.
The work will be part of an FP7 funded EU project lead by Dr. Sylvie Issanchou, Institut National de la Recherche Agronomique (INRA), France.
B753 - Investigating the role of language in childrens educational and social outcomes - 18/12/2008
Background
The role that children's language plays in promoting their educational and social success is increasingly recognised. This is the case for children who have particular difficulties in acquiring speech, language and communication and in a more general sense for the entire population. The longer term impact of speech, language and communication impairments on a child's literacy, education, behaviour, employability and social inclusion has been reported in a number of clinical studies (Baker & Cantwell 1987; Catts, 1993; Clegg, Mawhood, Howlin & Rutter 2005; Cohen, Vallance, Barwick, et al. 2000; Johnson, Beitchman, Young et al. 1999; Rutter, Mawhood, & Howlin 1992; Stothard, Snowling, Bishop et al. 1998). Findings that show high proportions of young offenders with poor speech and language have also increased awareness of the links between language skills and educational and social success. (Bryan, 2004; Bryan et al, 2007). Concern has been expressed that children are entering school 'without the extended vocabulary and communication abilities they need for learning and for making friends' (Children's Minister Beverley Hughes, 2008) and head teachers surveyed by the Basic Skills Agency were of the view that children's language skills have declined over the previous five years (Basic Skills Agency, 2002). 'Every Child a Talker' has been set up to address these concerns and enhance children's language during the Early Years.
Despite growing reports of the negative outcomes associated with limited language skills, our knowledge about which particular contexts and factors give rise to impairments and limited language in the individual is still largely speculative. Children who present as late talkers show varying rates of resolution by school age, depending on the clinical samples recruited; awide range of risk and predictive factors have been identified including speech and language features, characteristics of play, gesture and social skills, the presence of otitis media, family history as well as socio-economic factors and parenting style(Olswang, Rodrigues, and Timler, 1998). However, how such factors play out in the individual is still unclear. In particular, the role of children's social environment is controversial. So for example, Wells (1985) studied naturalistic language samples of preschool children in Bristol and concluded that there was no evidence to support an association between parental social status and the language environment of the child. Conversely, Hart & Risley (1997) compared the naturalistic vocabulary environment of children up to the age of 3 years old, in US families of differing social status and showed a threefold difference between families from professional backgrounds with those on welfare; these differences were still apparent when the children were aged 9 and 10 years old. Furthermore, it is not clear if there are factors which act as moderators that facilitate language acquisition in spite of adverse environmental conditions and in what conditions these might operate or indeed if language itself is a moderator of social adversity. In a study of educational resilience, Schoon et al (2004) noted that protective factors seemed to operate more with socially advantaged families. They concluded that protective factors are context specific.
Luthar et al (2000) note a number of difficulties with the investigation of resilience, in particular, definitional problems, the heterogeneity in how risk and resilience play out in the individual and the instability of resilience. Within the field of language, there have certainly been definitional issues: language impairment itself is a variable construct with the interface with normal distribution being controversial. Further, Schoon et al (2004) criticize the use of single indicators such as parental employment to identify levels of social risk. The Avon Longitudinal Study of Parents and Children (ALSPAC) provides a unique opportunity to investigate the role that language plays in the education and social success of individual children. The cohort has a wealth of data about the individual children's psychological and linguistic development, their family and social context as well as their educational outcomes both in terms of specific measurements of literacy as well as Standard Assessment Test scores (SATs) and GCSE results.
Research Questions:
The overall aim of this study will be to identify the role of language as a protective factor in children's educational progress.
Particular questions include:
* How closely related are a child's social and communication environments?
* How do components of a child's social and communication environments impact upon their language and literacy skills?
* How do social and child-based factors interact with a child's language and literacy to impact upon their social and educational outcomes?
* Are there protective factors that facilitate positive educational outcomes for the children.
Analytical strategy
We will undertake a preliminary descriptive stage to identify and provide means, ranges and standard deviations for all the key variables. This will include children's social and educational outcomes such as their SATs, GCSE results, friendships and social activity.
Following that, the first analytical stage is to build a number of composite variables that will also include a time element: a) a social composite (following Schoon et al, 2004) to represent the social resources available to the child and family including parent's education and employment, housing situation and other economic indicators; b) a communication environment composite comprising activities and resources available that indicate levels of interaction with the child such as book reading, television watching, parent-child interaction measures; c) a number of 'protective factors' - some of these will comprise a single measure such as the child's temperament, intellectual development, and others will be constructed to provide further composite measures such as attendance at child care and nursery facilities.
The second stage will be to model the child's developing language and literacy from early prelinguistic phases including babbling and attention to sound through to comprehension of paragraphs and vocabulary at the age of 8 years and scores on the Children's Communication Checklist at 9 years. Using latent class analyses and a series of regression analyses we will develop language and literacy trajectories.
Thirdly, we will undertake a series of multiple linear/logistic regression analyses to investigate interaction between the various composite variables. Structural equation modeling will be used to investigate possible mechanisms and the influence of factors over time. In particular the aim is to identify protective factors which result in positive educational outcomes for the children.
B750 - PPAR-gamma-2 gene polymorphism Pro12Ala breastfeeding and early growth - 10/12/2008
The aim of the study is to examine the effect of PPAR-gamma-2 gene polymorphism Pro12Ala and early postnatal growth and to see whether the effect is modified by breastfeeding. For this purpose we will require birth weight and postnatal growth data, and PPAR-gamma-2 genotype.
First, we will look at cross-sectional differences of growth characteristics at various ages in both cohorts. Then, will we examine longitudinally differences in growth rate (defined as grams/months) from birth to 5 years (3 years in Generation R) between the genotypes. Finally, we will explore whether there is an interaction effect between breastfeeding duration and genotype on growth characteristics.
B751 - Anxiety and Depression During Pregnancy Measurement Course and Consequences - 09/12/2008
Mental disorders during the perinatal period have serious consequences for women and their offspring. The majority of research on perinatal mental health has focused on the postnatal period and particularly on postnatal depression. Depression and anxiety during pregnancy have been largely neglected despite evidence suggesting symptoms of these disorders are higher during pregnancy than the postnatal period (Evans et al., 2001; Heron et al., 2004; Lee et al., 2007; Ross, Evans, Sellers, & Romach, 2003). Furthermore, research in this area indicates that antenatal depression and anxiety increase the likelihood of postnatal mental health problems (Heron et al., 2004), and are associated with negative offspring outcomes in childhood (Deave, Heron, Evans, & Edmond, 2008; O'Connor, Heron, Glover, & the ALSPAC Study Team, 2002; O'Connor, Heron, Golding, Beveridge, & Glover, 2002; O'Connor, Heron, Golding, Gover, & the ALPAC Study Team, 2003). While existing research highlights the need for increased attention to anxiety and depression experienced during pregnancy, important questions remain. The current proposal seeks to use data from a longitudinal, community-based study, the Avon Longitudinal Study of Parents and Children (ALSPAC; Golding, Pembrey, Jones, & the ALSPAC Study Team, 2001), to investigate the following aims:
Aim 1. To examine the presentation of anxiety during the perinatal period.Analyses will be conducted to examine perinatal anxiety symptoms as measured by a commonly used perinatal depression rating scale, the Edinburgh Postnatal Depression Sale (EPDS), in comparison to the Crown Crisp Experiential Index (CCEI). The proportion of women with clinically significant anxiety symptoms at 18 and 32 weeks gestation and 8 weeks and 8 months postnatally, the contribution of the anxiety subscale to the total EPDS score, and the extent to which antenatal anxiety and depression are comorbid will be investigated. It is hypothesized that the EPDS will reveal patterns of perinatal anxiety that are similar to those previously seen with the CCEI and will be a valid measure of perinatal anxiety.
Aim 2. To assess the impact of antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression on alcohol use during pregnancy and postpartum.Analyses drawing upon ALSPAC gestation data will be conducted to determine if women with antenatal anxiety, women with antenatal depression, and women with comorbid antenatal anxiety and depression have increased alcohol use during pregnancy and the postnatal period compared to women with no antenatal anxiety or depression. Antenatal mental health problems are hypothesized to predict increased use of alcohol both during and after pregnancy.
Aim 3. To examine the effects of antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression on age 10 child behavioral and emotional problems. Reports from multiple informants (i.e., mothers and teachers) on the Development and Well-Being Assessment (DAWBA) and the Strengths and Difficulties Questionnaire (SDQ) will be included in analyses examining the association between antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression and child behavioral and emotional problems at age 10. Antenatal mental health problems are hypothesized to increase risk for behavioral and emotional problems in offspring.
Deave, T., Heron, J., Evans, J., Edmond, A. (2008). The impact of maternal depression in
pregnancy on early child development. British Journal of Obstetrics and Gynaecology, 115, 1043-1051.
Evans, J., Heron, J., Francomb, H., Oke, S., & Golding, J. (2001). Cohort study of depressed
mood during pregnancy and after childbirth. British Medical Journal, 323, 257-260.
Golding, J., Pembrey, M., Jones, R., & the ALSPAC Study Team. (2001). ALSPAC - The Avon
Longitudinal Study of Parents and Children I. Study methodology. Paediatric and Perinatal Epidemiology, 15, 74-87.
Heron, J., O'Connor, T. G., Evans, J., Golding, J., Glover, V., & the ALSPAC Study Team.
(2004). The course of anxiety and depression through pregnancy and the postpartum in a community sample. Journal of Affective Disorders, 80, 65-73.
Lee, A. M., Lam, S. K., Sze Mun Lau, S. M., Chong, C. S., Chui, H. W., & Fong, D. Y. (2007).
Prevalence, course, and risk factors for antenatal anxiety and depression. Obstetrics & Gynecology, 110, 1102-1112.
O'Connor, T. G., Heron, J., Glover, V., & the ALSPAC Study Team. (2002). Antenatal anxiety
predicts child behavioral/emotional problems independently of postnatal depression. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1470-1477.
O'Connor, T. G., Heron, J., Golding, J., Glover, V., & the ALSPAC Study Team. (2003).
Maternal antenatal anxiety and behavioural/emotional problems in children: A test of a programming hypothesis. Journal of Child Psychology and Psychiatry, 44, 1025-1036.
O'Connor, T. G., Heron, J., Golding, J., Beveridge, M., & Glover, V. (2002). Maternal antenatal
anxiety and children's behavioural/emotional problems at 4 years. British Journal of Psychiatry, 180, 502-508.
Ross, L. E., Gilbert Evans, S. E., Sellers, E. M., & Romach, M. K. (2003). Measurement issues
in postpartum depression part 1: Anxiety as a feature of postpartum depression. Archives of Women's Mental Health, 6, 51-57.
B745 - Is a Meditteranean diet in pregnancy associated with childhood atopy and asthma - 04/12/2008
It has been shown in a Menorca birth cohort that scoring higher on the Mediterranean Diet Score [MDS] (1) during pregnancy is protective for persistent and atopic wheeze and atopy at age 6.5 years (2).
In the ALSPAC cohort, dietary patterns in pregnancy using PCA have been obtained (3). We found no association between these patterns and childhood asthma or atopy after adjustment for a wide variety of potential confounding factors (4). However, we have not examined any specific a priori scores.
Given the cultural differences in diet between these two cohorts it will be of interest to see how the two methods of examining dietary patterns compare within the cohorts (PCA and a prior MDS score).
Following discussion it was agreed between MT and KN that PCA would be performed on the Menorca dietary data, while MDS would be applied to the ALSPAC data to further examine the associations with atopy/asthma.
We will therefore calculate a MDS for the ALSPAC mother's during pregnancy and relate these scores to childhood atopy and asthma, as presented in our submitted paper (4). We will treat the MDS as both continuous and categorical (using a low and high score as presented by Chatzi etal (2)).
1. Trichopoulou A, Costacou T, Bamia C et al. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348; 2599-2608.
2. Chatzi L, Torrent M, Romieu I et al. Mediterranean diet in pregnancy is protective for wheeze and atopy in childhood. Thorax 2008; 63: 507-513.
3. Northstone K, Emmett P, Rogers I. Dietary patterns in pregnancy and associations with socio-demographic and lifestyle factors. Eur J Clin Nutr 2008; 62: 471-479.
4. Shaheen S, Northstone K, Newson R, et al. Dietary patterns in pregnancy and respiratory and atopic outcomes in childhood. Submitted.
B743 - The Dynamics of Domestic Violence - 04/12/2008
AIMS
In this project we will seek to map out the dynamic relationships between employment, health and domestic violence using all available relevant information in the ALSPAC data. The data will be analyzed using both generic statistical methods and specialised structural dynamic models. The purpose will be to understand not only the incidence of domestic violence, but also its timing and the causal linkages between violence, health, partnership status, and economic outcomes.
A second aim of the project is to consider the impact of domestic violence on child outcomes. There is evidence that living with violence has health, psychological, behavioural and emotional effects on children (see e.g. Mullender, 2001). However, a challenge in this literature is to separate out the effect of domestic violence from other unobserved family characteristics. For this purpose the ALSPAC data, which is rich in information both with respect to family background and with respect to child outcomes, can provide further insights into the true causal impact of living in a family characterised by abuse. The specific requirements for the project involve information from existing questionnaires. Measures of domestic violence will be based on the repeated question on occurrence of physical (and emotional cruelty) by the partner. However, we will also be making use of available information on health status, partnership status, economic activity. Hence will be making use of information from the questionnaires completed by the mothers (and partners) at all points in time. For the analysis of child outcomes we will be needing information from the child-based questionnaires, the child-completed questionnaires and the schools questionaires.
B744 - Investigating the relationship between symptoms of infection in early life and demographic factors - 30/11/2008
1 Background
Increasing levels of allergic disease amongst children in Westernised countries has lead to proposal of the 'Hygiene Hypothesis' [1, 2]. This suggests that a lack of exposure to common infection in early life leads to an increased risk of atopic sensitisation and allergic disease development. Investigation of the relationship between demographic factors (such as number of siblings, breastfeeding, hygiene levels, day care attendance) and infectious symptoms will lead to greater understanding of the factors that affect the level and type of infectious symptoms experienced in childhood.
Information on the incidence of overall common infection in infants is sparse, most data are collected relating to serious infections resulting in hospitalisation and serious morbidity or mortality. Others concentrate on one very specific, clinically diagnosed infectious disease, for example measles. Data from medical records will underestimate incidence of infections, as they do not include those that don't require a visit to the doctor. The ALSPAC study has collected data on the parental-reported information on various common medical conditions and occurrences that may lead to a visit to the GP including symptoms of infectious disease, accident, fits or wheezing [3]. Questionnaires were sent to parents when the child was 6, 18, 30, 42 and 57 months old with questions on 14 items. Previous research using the ALSPAC data-set has shown that levels of one symptom, cough, did not vary by maternal education but the percentage of those children taken to the GP or given medication decreased with increasing maternal education. The same paper also found children with a larger number of older siblings were more likely to have been reported to have a cough in the first 6 months of life [4]. Further description of the relationship between common infectious symptoms will help to investigate which children are most likely to have such symptoms and their relationship with attendance at the doctor.
2 Study aim and hypotheses
The aim of this research will be to use data collected within the Avon Longitudinal Study of Parents and Children to investigate relationships between reported levels of common infection requiring and not requiring a visit to the GP and demographic, social and environmental factors that may influence infection levels including day care attendance, hygiene practices, siblings and population mixing.
The hypothesis to be studied will be:
Do the number and type of infections reported in early life vary due to demographic factors such as number of siblings, day-care attendance and population mixing?
Within the United Kingdom there are few data available on the prevalence of common infectious symptoms experienced within early life in the general population and therefore little is known as to how well other factors relate them. The work carried out within this project will allow quantitative assessment of the most common infectious symptoms in young children and their relationship with proxy measures of infection used in epidemiology such as day care attendance. It will also allow an investigation into underlying classifications of infectious disease and symptom presentation.
3 Study design
3.1 Data
The work carried out will be using data already collected and available within the ALSPAC cohort. The ALSPAC study has collected data at 6 and 18 months on several symptoms and consultations in children including:
* Diarrhoea
* Vomiting
* Cough
* High temperature
* Snuffles/cold
* Ear ache
* Ear discharge
* Colic
* Rash
Parents then ticked one of the following choices for each symptom: 'yes and saw a doctor', 'yes but did not see a doctor' or 'no did not have'. Those listed above represent symptoms which could be linked to infections.
Information was also collected on the age and sex of other children living in the house when the child was aged 6 months and 18 months. At 15 months a questionnaire was administered including a section on childcare asking who regularly looks after the infant apart from the person completing the questionnaire. The choices were: partner, baby's grandparent, other relative, friend/neighbour, paid person outside the home, paid person in the baby's home, day nursery, other. Also collected were hours per week this occurred and age of the baby in months when it started. Also for each months of the child's life (up to 15 months) a chart is completed giving the number of hours of outside childcare, the person carrying this out and at what place. Residential postcode will be used to link to the 2001 census area in which the child resides and from this information about the area can be collected including population density, deprivation level and population mixing. Other general variables as used in other analyses (maternal age, time of questionnaire delivery, sex of the child etc.) will also be required.
3.2 Statistical analysis
Statistical analysis will be carried out including latent class analysis to investigate whether specific patterns of infectious symptoms are associated with any of the demographic variables recorded. The methods will allow the identification of the relationships between specific symptoms being present in early life and their relationship to different demographic factors e.g. Some demographic factors may be related to having a large number of mild heterogeneous symptoms whereas another may be related to having fewer, more severe infections with a specific symptom present such as a fever. The relationship between demographic factors and the likelihood of a parent taking a child to the doctors or giving the child medication can also be investigated. Previous analyses of symptom check-lists have been carried out using similar methods [5] and such analyses allow the identification of groups of individuals with similar behaviour or patterns of disease [6, 7] - in this case it will be those with similar infections and their relationship to demographic factors.
4 Experience of the research team
We are internationally recognised in the field of childhood cancer epidemiology and specifically current research into population mixing and other infectious measures and their association with childhood leukaemia (PMK/GL). The team have a large amount of experience in statistical analysis of epidemiological data including complex mobile phone record data in case-control studies of adult cancer (SH). Computer systems are already in place to allow the secure storage of data including a secure storage area on the Faculty of Medicine and Health server for keeping electronic data.
Within the Centre for Epidemiology and Biostatistics there are several internationally recognised statisticians specialising in structural equation modelling and the development of latent class analysis methods (Professor Mark Gilthorpe, Dr Yu-Kang Tu, Dr Robert West) and their expertise will be available for consultation on the best methods and use of statistical software.
5 References
1. Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J (2006) Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clinical and Experimental Allergy. 36: 402-25.
2. Strachan DP (2000) Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax. 55 Suppl 1: S2-10.
3. Hay AD, Heron J, Ness A (2005) The prevalence of symptoms and consultations in pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC): a prospective cohort study. Family Practice. 22: 367-74.
4. Dewey CR, Hawkins NS (1998) The relationship between the treatment of cough during early infancy and maternal education level, age and number of other children in the household. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Child Care Health Dev. 24: 217-27.
5. Sacker A, Wiggins RD, Clarke P, Bartley M (2003) Making sense of symptom checklists: a latent class approach to the first 9 years of the British Household Panel Survey. Journal of Public Health Medicine. 25: 215-22.
6. Steffen AD, Glanz K, Wilkens LR (2007) Identifying latent classes of adults at risk for skin cancer based on constitutional risk and sun protection behavior. Cancer Epidemiology, Biomarkers and Prevention. 16: 1422-7.
7. Spycher BD, Silverman M, Brooke AM, Minder CE, Kuehni CE (2008) Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. European Respiratory Journal. 31: 974-81.
B741 - Does the ingestion of contraceptive progestins in breast milk have any harmful consequences for infants and children - 24/11/2008
The Human Reproduction Programme of the World Health Organisation (HRP) produces a series of guidelines relating to sexual and reproductive health including two aiming to improve the quality of care in contraceptive provision; The Medical Eligibility for Contraceptive use (which gives guidance on who can use specific contraceptive methods) and the Selected Practice Recommendations for Contraceptive Use (how to use the available methods safely and effectively). Both are available on the HRP website [1] and both have been updated in 2008.
The Guideline Development Group has struggled with giving guidance on use of hormonal contraceptives by women who are breastfeeding. Since there is good evidence that exogenous estrogens reduce the quantity of breast milk the guideline recommends that all combined hormonal contraceptives (the pill, patch, ring and combined injectable) should not be used at all during the first 6 weeks postpartum and can only be used if no other method is acceptable or available from 6 weeks to 6 months after childbirth. While there is no evidence that progestogen-only methods impair lactation, some group members have suggested that the ingestion of progestins in breast milk may interfere with the development of the brain and liver of neonates and infants. For this reason the guideline also recommends that progestin-only methods are avoided during the first 6 weeks post partum.
Many members of the group responsible for updating the guidelines are uncomfortable with limiting the use of progestin only contraceptives (POC) because the evidence for any harm is extremely limited and of poor quality. There is also very limited research evidence for their being no harm. However hundreds of thousands (perhaps millions) of women in both developed and developing countries have used POC in the early post partum period - in some countries high dose depot injections (Depo Provera(registered trademark) and Norethisterone-enanthate) have been routinely given on the day of delivery and there is no evidence for any serious consequences for neonatal health. An expert group was convened in late October 2008 to consider whether there is any compelling evidence for an effect of progestins in breast milk on development of the brain or liver of neonates and infants. The experts included, among others, a paediatrician and two basic scientists who have done a lot of research on the effect of estrogen and progestogen on the brain - but in rats! While the conclusion of the meeting was that there was no compelling evidence of harm, the experts pointed out that they could not exclude a subtle effect of contraceptive progestogens on behaviour (such as ADHD for example), cognition or even sexuality in later years. So we are stuck with not recommending POC for women during the first 6 weeks postpartum (and logic would ask why, if there could be a harmful effect, is it acceptable to use these methods after 6 weeks when the baby's brain is still developing rapidly).
Of course the chance of a breastfeeding woman conceiving before 6 weeks after delivery is remote. However in many developing countries it is difficult for women to negotiate condom use with their partners, intrauterine devices are rarely available and diaphragms are not used so this leaves not much else for effectively preventing pregnancy and short inter-birth intervals. The long-acting methods of POC give 3-5 years protection from pregnancy (or longer) but the only opportunity to start these methods, since they require a skilled health professional, is missed if the newly delivered mother leaves the place where she had her baby and does not have access to a skilled provider thereafter.
We are aware that the ALSPAC cohort of mothers and infants has collected data on a wide range of outcomes and wonder whether it may be possible to use your data to investigate the effects of contraceptive progestogens ingested in breast milk on infants and children. Breastfeeding women in the UK commonly start using the progestogen-only pill at 28 days after delivery and some who use Depo Provera(registered trademark) may start even earlier.
We are unsure as to whether ALSPAC has collected data on postpartum contraceptive use which is of sufficient detail to cast light on the possible effects on breastfeeding babies and infants (i.e. contraceptive method used and start (and stop) dates. If not there is no point in pursuing this further. If data are sufficiently detailed we would be interested in linking contraceptive use during breastfeeding with any subsequent pathology in the offspring.
1. http://www.who.int/reproductive-health/publications/family_planning.html)
B740 - Adjustment outcomes as a function of receptive nonverbal ability and locus of control orientation - 22/11/2008
The purpose of the propsed study is to use children's receptive nonverbal skill and locus of control orientation at 8 years of age to predict their personal and social adjustment when they are older. It is predicted (1) that children who are deficient in reading emotion in facial expression and tones of voice will develop problems in personal and social adjustment at 10, 13/14 and 15/16 and (2) that the type of problem children develop will depend on their locus of control orientation. If they are poor at reading emotion in faces and voices and internally controlled they will develop internalizing types of problems like anxiety, depression, and low self esteem; if they are externally controlled then they will develop externalizing difficulties such as acting out behaviors, conduct disorders and antisocial problems.
To evaluate these possiblities we would require the following data from the ALSPAC data set.
CONCEPT SPECIFIC MEASURE PERSON SOURCE TIME POINTS
Nonverbal information DANVA (faces/voices) CF CF 8 years
Locus of control PPNSIE CF Ques. 8 years
Separation anxiety DAWBA K Ques. 10 to 15/16
Phobias K Ques. 10 to 15/16
PTSD K Ques. 10 to 15/16
Obsessions/Compul. K Ques. 10 to 15/16
General anxiety K Ques. 10 to 15/16
Depression K Ques. 10 to 15/16
Atten/Activ K Ques. 10 to 15/16
Oppositional beh. K Ques. 10 to 15/16
Conduct problems K Ques. 10 to 15/16
Hyperactivity SDQ K&S Ques 10 to 15/16
Emotional Symptoms SDQ K &S Ques. 10 to 15/16
Conduct problems SDQ K &S Ques. 10 to 15/16
Prosocial behaviours SDQ K & S Ques 10 to 15/16
Antisocial behaviour Antisocial behaviour CF Ques. 10 to 12
Friendships CHAMP CF Ques. 10 to 14
Bullying Wolke et al(2000) CF Ques. 10 to 15/16
Romatic relations SexualActivity Index CF Ques. 10 to 15/16
Self esteem SPPC (Harter) CF Ques. 8 years
Self Image Self Image Profile CF Ques. 14
The above proposed study is based on research that has shown that the inability to read emotion in facial expressions and tones of voice has been found to be related to a wide variety of social difficulties such as lower popularity, lower teacher rated social competence, attention deficit disorder, nonverbal and verbal learning disabilities, externalizing problems and conduct disorder, emotional problems, depression, social anxiety, speech and language impairment, and aggression.The purpose of the present project is to see if children's locus of control orientation will help identify which children develop internalizing and which develop externalizing adjustment difficulties.
Locus of control was chosen because it plays a significant role in children's behavior. Locus of control refers to the connection individuals perceive between their behavior and what happens to them (Rotter, 1966). When they perceive a connection between their efforts and what happens to them, they are called internally controlled. When individuals do not see a connection between what they do and what happens to them, but rather they view what happens to them as the result of luck, fate, chance, or powerful others, they are seen as externally controlled. Whether events are perceived from more internal or external perspectives has been found in literally thousands of studies to be related to an extensive number of important personal, social and academic outcomes (Kalechstein & Nowicki, 1998; Rotter, 1990).
In the present study, we assume that children who are experiencing relationship failures with peers (and perhaps with adults, especially teachers) because of an inability to read emotional cues in facial expressions and tones of voice can view their failures one of two ways through the prism of locus of control. If children are internally controlled (so they believe that what happens to them is due to their efforts and how they behave), then they would be more likely to attribute their interpersonal failures to some aspect of themselves or their own behavior. And if children blame themselves for their interpersonal failures they would be more likely to develop feelings of depression and anxiety and low self-esteem; characteristics usually used to describe internalizing problems.
In contrast, children who are externally controlled (and believe that luck, fate or chance or powerful others determines what happens to them), would be more likely to blame others and not themselves for their interpersonal failures. Consistent with this kind of attribution, externally controlled children would be more likely to become angry and "act out" at those whom they believe are preventing them from attaining social success; characteristics of what have been used to describe externalizing problems.
Thus we are proposing that locus of control will act as a moderator between receptive nonverbal ability and personal and social outcomes gathered by ASLPAC after 8 years of age when nonverbal and locus of control measures were obtained.
We will examine boys and girls separately. Because there is some evidence especially from the preschool period that mothers talk more about sadness and with girls and anger with boys, it is predicted that girls will be better at identifying sadness and boys at identifying anger at age 8 (Adams, Kuebli, Boyle, & Fivush, 1991; Fivush 1991) and may lead girls to develop internalizing and boys externalizing problems.
B742 - Genome-wide association analysis in the Avon Longitudinal Study of Parents and their Offspring - 21/11/2008
The project will involve the genome-wide SNP typing of 6000 ALSPAC children at the CNG Paris on either the Illumina 370K or Illumina 610K SNP chip (depending on costing). If successful, it will mean that the entire cohort of ALSPAC children (for whom DNA is available) will have genome-wide data. The resulting genotypes will be linked with ALSPAC phenotype data and genome-wide association analysis will be performed. Loci showing genome-wide evidence of association (e.g. p less than 5.0 x 10-7) will be followed up in the Raine, Generation R and North Finland birth cohorts depending on the availability of similar phenotype measures. Bristol PIs who are experts in the relevant phenotypic measures will be offered involvement in the analysis, write up, and replication of the findings (e.g. Jon Tobias with the bone mineral density phenotypes).
LOGISTICS:
-Genotyping will be performed by CNG in Paris.
-I will require DNA for genotyping on the Illumina 370K/Illumina 610K platform (which platform is chosen will depend upon cost).
-I will require access to all children's phenotypes contained with the ALSPAC cohort.