Aims: To explore the effect of breathing disorders including asthma, atopy allergic rhinitis and sleep disordered breathing on face shape at age 15 years and to evaluate the effect of adenoidectomy and tonsillectomy on face shape.

Hypothesis: Breathing disorders, adenoidectomy and tonsillectomy have no effect on face shape in late adolescent.

Background: Respiratory activity may have an influence on craniofacial development and interact with genetic and environmental factors. It has been suggested that certain medical conditions such as asthma have an influence on face shape. Altered mechanics of breathing may influence the development of craniofacial structures and tends to result in significant changes in face shape particularly increased face height and retrusive mandible. However, removal of adenoids and tonsils has been reported to have a significant effect on obstructive breathing and if conducted early will normalize dentofacial morphology. ALSPAC provides the opportunity to explore a longitudinal data set with detailed facial morphology measures in late childhood on a large, representative sample.

Three-dimensional laser surface facial scans were obtained. Differences in the twenty-one reproducible facial landmarks (x, y, z co-ordinates) for the various groups will be evaluated as well as average facial shells will be created for asthmatic, atopic allergic rhinitis, sleep disordered breathing and healthy controls to explore surface differences.

Study design: observational longitudinal cohort study.

Confounding factors: height, weight, BMI, pubertal status.

Freeman K, Bonuck K 2012 Snoring, mouth-breathing, and apnea trajectories in a population-based cohort followed from infancy to 81 months: a cluster analysis. International Journal of Pediatric Otorhinolaryngology 76: 122-30

Jefferson Y 2010 Mouth breathing: adverse effects on facial growth, health, cademics and behavior. General Dentistry 58: 18-25

Wenzel A, Hojensgaard E, Henriksen J M 1985 Craniofacial morphology and head posture in children with asthma and perennial rhinitis. European Journal of Orthodontics 7: 83-92

Zettergren-Wijk L, Forsberg C M, Linder-Aronson S 2006 Changes in dentofacial morphology after adeno-/tonsillectomy in young children with obstructive sleep apnoea--a 5-year follow-up study. European Journal of Orthodontics 28: 319-26.

Aims:

To assess the theory of the Gateway Hypothesis, whereby the use of substances such as tobacco and alcohol ('Gateway Drugs') are a risk factor for the use of harder drugs such as cannabis, cocaine and opiods.

Hypotheses:

The hypotheses of this project can be subdivided into three phases:

1. Assessment of the relationship between patterns of smoking and patterns of alcohol consumption in adults. These hypotheses will be tested using the MR technique, where patterns of smoking can relate to either daily cigarettes smoked or short-term smoking cessation.

2. Assessment of the relationship between patterns of smoking and patterns of alcohol consumption in adolescents. This hypotheses will be tested used either standard epidemiological techniques or Mendelian randomisation.

3. Assessment of the relationship between cannabis and other illegal substances. These hypotheses will be tested using hair sample data taken from adolescents.

There is also scope for further analysis linking hypotheses 1 and 2 with that of 3; however this will be assessed at a later date when preliminary results have been obtained.

The following exerpt it taken from the proposal written in application of the PhD studentship for which this research is a part of and will explain all variables being used in the study:

Phase 1 - Relationship between smoking and alcohol in adults

SNP rs1051730 has been shown to be causally related to both heaviness of smoking and smoking cessation in adults. With this in mind, I propose to use the data collected from the mothers in the ALSPAC cohort in order to use MR to assess both the relationship between heaviness of smoking and alcohol consumption and smoking cessation and alcohol consumption. With regards to heaviness of smoking, the exposure variable used will cigarettes smoked per day in the sample of those who smoke, and for smoking cessation, smoking status before and during pregnancy. The outcome variable used for alcohol consumption will focus on heaviness of use.

Once observational epidemiology has been used to initially assess the relationship between tobacco and alcohol, the relationship between genotype and smoking status will be tested using a model with and without interaction terms between the two variables, using a likelihood ratio test. The relationship between genotype and alcohol consumption will also be tested in this manner in order to show whether the genotype is associated with alcohol consumption independently of smoking status. The effect of both heaviness of smoking and smoking cessation on alcohol consumption will be assessed using instrumental variable estimation by performing a two stage least squares under an additive model. This method will first fit the regression of the exposure (smoking) on the instrument (genotype) before the outcome (alcohol) is regressed on the predicted values of continuing smoking, where the estimate of the causal effect will be the coefficient produced. I will also test whether there is a direct effect of genotype on alcohol consumption in non-smokers.

Phase 2 - Relationship between smoking and alcohol in adolescents

To further the work undertaken in phase1 of this research, the relationship between heaviness of smoking and alcohol consumption and adolescents will be assessed using the ALSPAC child based questionnaires and interviews. As a current genetic signal for smoking in adolescence is not known, this work will explore the availability of a polygene risk score for use with MR, or use a standard epidemiological technique of this is unavailable. The exposure and outcome variables used for this section of analysis will be smoking initiation and heaviness of alcohol use.

The first stage of this analysis will be to gather cross sectional studies that have included the rs1051730 across a range of ages in order to assemble a longitudinal map of the effect of this variant, as has been previously done with the FTO gene.

If a genotypic signal is available for use in this analysis then statistical methods for the rest of the phase will be as for phase 1, however if a standard epidemiological method is applied then multinomial logistic regression will be used with smoking as the exposure and alcohol as the outcome with confounding from environmental factors taken into account.

Phase 3 - Relationship between cannabis and illicit drugs in adolescents

Finally, the relationship between cannabis use and the use of other substances as described in the Gateway Hypothesis will be assessed in ALSPAC adolescents using drug information obtained from hair samples. The hair samples can be used in one of two ways: (1) to validate the self report measures taken from the ALSPAC adolescents and (2) to use the information provided by the hair samples itself. With regards to the first option, this method will be used in assessment of cannabis, as hair samples are only able to provide information of regular or heavy use in relation to this drug. The hair sample analysis for other drugs is more sensitive than for cannabis, meaning that this data can both be used on its own and to validate the self report measures, therefore, for this section of the analysis we will use the biological marker as the outcome. As hair samples were not taken from all members of ALSPAC, this section of the study will have a smaller sample size than others; however, the loss of power from the biological marker will be made up for by increased precision and lack of bias. In order to link this with previous phases, cotinine levels of each of the ALSPAC adolescents will also be used to assess the relationship between tobacco and cannabis, ecstasy, cocaine, amphetamines and heroin.

Standard epidemiological statistical methods will be used here, with cannabis use from self reported questions (validated by hair sample data) as the exposure and the use of other illicit substances as shown by hair samples as the outcome.

Analysis:

All analysis will be undertaken by University of Bristol staff (Michelle Taylor) with Glyn Lewis, Matthew Hickman and Marcus Munafo acting as PhD supervisors.

Differences in cognitive ability determine developmental trajectories across the lifespan, affecting socioeconomic, psychological, and health outcomes. Children from disadvantaged socioeconomic status (SES) families show lower cognitive ability and reduced cognitive growth (i.e. ability gains over time) compared to their high SES peers. However, the mechanisms that underlie the SES-growth association are not fully understood. The proposed research investigates how and to what extent 3 aspects of children's lives - (1) dietary patterns, (2) preschool experiences, and (3) activity engagements - account for SES-related growth differences.

(1) Dietary Patterns. Diets directly impact cognitive function because they are the main source for micronutrients (e.g. vitamins and antioxidants) that enable enzymatic reactions and neurotransmitter synthesis in the brain. However, several diet characteristics have rarely been addressed in research, for example meal types (e.g. snack), times (e.g. breakfast), and preparation method (e.g. prefabricated). Likewise, no previous research has looked at the influence that children's drinking habits (e.g. milk, sugary drinks) may have for cognitive development.

(2) School Experiences. SES-related differences in primary school performance tend to increase or at least persist over time, with disadvantaged children continuing at lower quality secondary schools and obtaining fewer educational qualifications. Preschool attendance may reduce this achievement gap because it provides disadvantaged children with better learning environments than they receive otherwise. The benefits of preschool have not been studied in Britain, where several preschool types exist (e.g. nursery or childcare centre).

(3) Activity Engagement: The availability of activity engagement opportunities, for example music lessons or sport clubs, leads to better primary school achievement16 and is thought to benefit children's cognitive growth. High SES families encourage more frequent and diverse activity participation than do low SES families in the United States16 but these findings have yet to be replicated in Britain. Also, it is unclear if it is the quantity, quality or type of activity engagement that make the difference for children's cognitive development.

Methods: Data will be synchronized across 4 longitudinal, British cohort studies, including the British Cohort Study 1970 (BCS), the Growing Up in Scotland study (GUS), the Millennium Cohort Study (MCS), and the Avon Longitudinal Study of Parents and Children (ALSPAC). The cohorts comprise of large samples, representative of the British population, and span generations from 1970 to 2005 (Table 1). Thus, they allow for (1) exploring and (2) replicating effects of dietary patterns, preschool experiences and activity engagements (herein variable complexes) on cognitive growth, as well as for (3) analyzing possible generation-specific effects. In each cohort study, participants were assessed at least 3 times on cognitive ability, enabling (4) latent growth curve modelling of ability trajectories. They also completed several, mostly repeated measures for all variable complexes, permitting (5) in-depth investigations of their characteristics and continuity over time.

Introduction

Conducting an epidemiological study into acne using the ALSPAC study would give us a sound basis to identify further candidate exposures for development into further provocation/prevention studies. We will have strong patient and public involvement in this study to help us disseminate results and prioritise future research.

Aims

1. To study general descriptive epidemiology of acne in ALSPAC including prevalence and severity by age, sex and ethnicity using cross-sectional analyses.

2. To study the determinants of acne incidence (especially dietary factors) using longitudinal approaches

3. To study the natural history of acne e.g. the difference between those with acne early in adolescence compared to those in late adolescence using linked data from successive skin examination sweeps

4. To study the determinants of severe/persistent disease (especially dietary factors)

5. To study the consequences of having had acne such as rates of depression and time off school

Hypotheses for analytical aspects

There is an association between diet and obesity and acne onset.

The risk of severe and persistent acne is increased in those individuals with a high glycaemic index diet in late childhood and after acne has appeared.

Exposure variables

Questionnaire data via food frequency questionnaires on diet collected at 4 weeks, 6, 15, 24, 38, 54, 81, and 103 months and 13 years

Food diaries collected as part of children in focus as well as at the hands on clinics. (Three day diaries)

Food diaries collected at 4, 8, 18, 43 and 61 months and 7.5, 10.6 and 13.9 years.

We are seeking advice from a nutritional epidemiologist who is familiar with ALSPAC to develop appropriate compound variable and a suitable analysis strategy

Demographic data on those who took part in the study

Questionnaire data on other epidemiological data for example, stress and obesity

Outcome variables

Acne severity (from examined skin). Open comedones, closed comedones, red papules, pustules, nodules, fine, superficial/atrophic macular scars, deep ice pick scars, hypertrophic scars, keloid scars and any pigmentary changes were all graded on the face and chest into a few, moderate and many. The presence of acne on the back and shoulders and upper arms/buttocks and thighs was also noted but not graded. Overall, acne severity was graded as trivial, mild, moderate and severe.

Sebutape measurements if available (there may only be a few of these available in Leeds we are currently liaising with Dr. Anne Eedy who is assisting us in our search for them)

Variables that help to document the morbidity associated with having acne such as depression and time off school

Confounding variables

Age, sex, social class

Funding (not yet awarded)

1 NIHR (application closing date 16/1/13)

2 Wellcome (application closing date 08/02/13)

Our analysis of ALSPAC data, if granted, will allow us to test some hypotheses with two other cohort studies - the National Child Development Study and the 1970 British Cohort Study. Although the quality of acne data from these cohorts is limited (some examined acne data in the NCDS and only reported acne data in BCS70) they nevertheless allow some potential verification of findings generated from the rich ALSPAC study.

Background: An important question of public and policy concern is the extent to which mental health problems in young people has changed in prevalence over time. Diagnoses and treatment of problems such as autism, ADHD, and depression have shown substantial increases over recent decades, but changes may reflect changes in help seeking, clinical recognition and diagnostic practice. To address whether the population prevalence of child and adolescent mental health problems has changed comparison of unselected representative population cohorts is required (using comparable measures of mental health at each time).

Evidence of this kind shows that adolescent emotional and conduct problems have become increasingly common since the 1970s (Collishaw et 2004, 2010; Kosidou et al 2010; Sigfusdottir et al 2008; Sourander et al 2004; Sweeting et al 2009; Ticket et al 2008). These trends are important for service planning, as well as offering novel approaches to examining risk. Time changes in prevalence must be attributable to population-level changes in environmentally mediated risks. By contrast with findings in adolescence, there is a marked knowledge gap on trends in younger children's mental health. This is important as, knowing whether observed trends in adolecent mental health have their origins in childhood can help narrow down likely causal explanations. However, to date, findings on pre-adolescent children are limited and inconsistent (Achenbach et al 2003; McArdle et al 2003; Sourander et al 2008; Tick et al 2007).

Time trends research provides a method for identifying explanatory environmental risk at a population-level. Thus far, however, very few studies have attempted to go beyond documenting trends, and studies that have tested possible explanations have focused on adolescents (Collishaw et al 2007, 2011; Schepman et al 2011; Gore et al 2011; Sweeting et al 2010). It is important to examine whether population-level change in risk prevalence has contributed to change in child mental health problems.

It is also important to understand any consequences of changes in rates of child psychopathology. There is extensive evidence that mental health symptoms are associated with concurrent impairment and adverse later mental health and psychosocial outcomes (Green et al 2005; Costello et al 2011; Maughan & Kim-Cohen 2005; Scott et al 2001). To date, there has been very little attempt to investigate these associated features in studies of time trends, but it is important to do so, not least because it can provide further evidence of the validity of observed trends (Collishaw et al., 2004).

The project will capitalise on comparable assessments of the mental health (and related risk factors) in seven-year-olds across five UK population cohorts studied from 1965 to 2008 (NCDS, ALSPAC, BCAMHS99, BCAMHS04, MCS). Cross-cohort analyses of the type proposed here offer a unique opportunity to better understand changes in child mental health, and specifcally to address the following aims.

Aims

(1) To test trends in prevalence of child mental health problems over a 40-year period in the UK using comparable assessments of emotional, conduct, and ADHD problems.

(2) To test whether the prevalence and impact of pre-/peri-natal, neurodevelopmental and early psychosocial risks has changed and how such changes have contributed to child mental health trends.

(3) To test trends in the impact of child mental health problems on current functioning, and on later mental health and psychosocial adaptation (using the three longitudinal cohorts).

Hypotheses: Findings regarding trends in child mental health problems are inconsistent. However, it is hypothesised that any increases in symptom levels may be associated with rising rates of impairment and poorer later outcomes

Exposure variable(s)

(1) The primary 'exposure variable' with respect to aim 1 will be year of study.

(2) Exposure variables of interest with respect to aim 2 include

a) Pre- and peri-natal factors: gestational age, birth weight, prematurity, birth complications, maternal smoking in preganancy

b) Neurodevelopmental factors: neurological abnormalities, epilepsy, learning disabilities, language delay, chronic ill health

c) Early psychosocial factors: family composition, social disadvantage, early parental involvement

Outcome variable(s):

1) The primary outcome variable is the parent-rated Strength and Difficulties Questionnaire (SDQ) at age 7 years. This measure is available in three of the other cohorts. The predecessor of the SDQ (the Rutter A scale) will be used in NCDS with comparability ensured using calibration methods developed in our previous studies of time trends (Collishaw et al., 2004).

2) Additional outcomes of interest available in some (but not all) of the cohorts include the teacher SDQ at age 7, and later outcome data: SDQ at ages 11, 14 16 years; peer relations at age 11 and 16 years; school exam attainment/occupation at age 16 years.

Confounding variables: Predictors of non-response assessed at birth, child ethnic origin, child gender, child age (in months).

Underage drinking is pervasive in the U.S. For example, 39% of adolescents in grades 9 through 12 report to consume alcohol in the past month. Furthermore, problematic drinking behavior such as binge drinking (defined as consuming more than four drinks for women and five drinks for men in the past two weeks) and alcohol use disorders emerge in adolescence. Underage drinking brings long-term negative consequences such as permanent damage to brain development, later alcoholism and drug problems, and school drop-outs that affects later education and occupation. For adolescents, family environments such as family conflict and parental monitoring have been studied as risk factors for alcohol use and abuse. However, some people in those environments do not develop drinking problems while other do. Gene and environment interaction (GxE) studies could provide compelling explanations for this, demonstrating that an individual's genotypes strengthen or weaken their susceptibility to the environmental influences. Thus, this study will investigate the effect of interaction between one of a genotype (5-HTTLPR; serotonin transporter linked polymorphic region) and family environments (i.e., family conflict and parental monitoring) on adolescent alcohol use and related problems.

Using ALSPAC data, we will examine our hypothesis that individuals who have at least one short 5-HTTLPR allele and have experienced high levels of parental monitoring would be less likely to be involved in alcohol use than would individuals with only long 5-HTTLPR alleles in the same same environments. Also, we will examine whether individuals with at least one short 5-HTTLPR allele and have experienced high levels of family conflict would be more likely to be involved in alcohol use than would individuals with only long 5-HTTLPR alleles in the same environments. We will statistically control the effects of age, race, gender, puberty, the level of parents' education, and neighborhood context.

The implications of the potential findings are significant for prevention and intervention efforts to curtail prevalent alcohol use among adolescents. Results for the present study will provide information for specific family environments interacting with genetic risk to affect adolescent drinking problems. If family environments affect the relationship between 5-HTTLPR genetic risk and alcohol use in the way we have suggested, the findings will be useful in developing more effective prevention or intervention strategies designed to improve family environments for those individuals whose genotypes make them sensitive to those environments. Overall, the present study will contribute to our understanding of the etiology of adolescent alcohol use and the findings will be valuable for future research directions.

Aim: To estimate the frequency of KLK3 copy number variants in the general population.

KLK3 encodes PSA, the most widely used biomarker in the early detection of prostate cancer. Genetic variants in KLK3 may influence serum PSA levels. From a pilot of selected controls within the ProtecT biorepository, we have identified three subjects with very low serum PSA levels (less than 1 ng/micro-L) with evidence of heterozygous deletions that entirely encompassed KLK3 (Rodriguez et al., Clinical Chemistry, in press)

Hypothesis: That deletions in the KLK3 region can be identified from SNP raw data available from ALSPAC.

Background: SNP arrays were originally designed to genotype SNPs; however they have been adapted for structural variant discovery. Several tools to analyse data from SNP arrays have been developed recently, however they tend to be platform-specific (i.e. able to process either Affymetrix or Illumina array data).

Algorithms that handle data from Affymetrix arrays include programmes as Birdsuite (1), and ITALICS (2). Other algorithms were developed to analyse data from Illumina arrays, such as SCIMM (3) and TriTyper (4). Some software applications are "versatile"; capable of handling data from both platforms (e.g.) PennCNV (5) and QuantiSNP (6).

Approach: Access to the fluorescence SNP raw data for a genomic interval of ~18Mb on chromosome 19 is required; (Chromosome 19: [41,000,000 - 59,128,983] Human GRCh37 build). This interval includes the entire human kallikrein locus, comprised of 15 kallikrein genes -in tandem-, including KLK3 that encodes the prostate specific antigen (PSA). Indeed serum PSA of normal women is typically undetectable (around 1 pg/mL) (7), however, deletions in KLK3 could be transmitted from mothers to children. KLK3 deletions from the general population, and from prostate cancer cases are considered. ALSPAC mothers will fit in as a "control" group to data from the 1958 cohort and from the ProtecT cohort (males with prostate cancer and controls). Copy number variants with high confidence scores will be assembled from multiple scans using several algorithms, filtering out false positive/discrepant signals in the process. A list of copy number variants called from this study will be compared across other studies to estimate the frequency of deletion events in KLK3 among males vs. females, and male controls vs. prostate cancer cases. We will also request access to the SNP genotype data for the same genomic region for children. This will enable us to study deletion transmission patterns from mothers to children.

References:

Santiago Rodriguez, Osama A Al-Ghamdi, Kimberley Burrows, Philip A.I. Guthrie, J. Athene Lane, Michael Davis, Gemma Marsden, Khalid K Alharbi, Angela Cox, Freddie C Hamdy, David E Neal, Jenny L Donovan, and Ian N. M. Day (2012) Very low PSA levels and deletions of the KLK3 gene. Clin Chem, -in press-.

(1) Korn, J. M., F. G. Kuruvilla, S. A. McCarroll, A. Wysoker, J. Nemesh, S. Cawley, E. Hubbell, J. Veitch, P. J. Collins, K. Darvishi, C. Lee, M. M. Nizzari, S. B. Gabriel, S. Purcell, M. J. Daly & D. Altshuler (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet, 40, 1253-60.

(2) Rigaill, G., P. Hupe, A. Almeida, P. La Rosa, J. P. Meyniel, C. Decraene & E. Barillot (2008) ITALICS: an algorithm for normalization and DNA copy number calling for Affymetrix SNP arrays. Bioinformatics, 24, 768-74.

(3) Kelley, D. R. & S. L. Salzberg (2010) Clustering metagenomic sequences with interpolated Markov models. BMC Bioinformatics, 11, 544.

(4) Franke, L., C. G. de Kovel, Y. S. Aulchenko, G. Trynka, A. Zhernakova, K. A. Hunt, H. M. Blauw, L. H. van den Berg, R. Ophoff, P. Deloukas, D. A. van Heel & C. Wijmenga (2008) Detection, imputation, and association analysis of small deletions and null alleles on oligonucleotide arrays. Am J Hum Genet, 82, 1316-33.

(5) Wang, K., M. Li, D. Hadley, R. Liu, J. Glessner, S. F. Grant, H. Hakonarson & M. Bucan (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res, 17, 1665-74.

(6) Colella, S., C. Yau, J. M. Taylor, G. Mirza, H. Butler, P. Clouston, A. S. Bassett, A. Seller, C. C. Holmes & J. Ragoussis (2007) QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res, 35, 2013-25.

(7) Chang, Y. F., S. H. Hung, Y. J. Lee, R. C. Chen, L. C. Su, C. S. Lai & C. Chou (2011) Discrimination of breast cancer by measuring prostate-specific antigen levels in women's serum. Anal Chem, 83, 5324-8.

SPECIFIC AIMS

This research proposal aims to identify mechanisms explaining why early adversity, namely child maltreatment, is consistently associated with an elevated risk for mental disorder 1-7. While there has been much emphasis on the long-term effects of adversity, including how genes and adversity jointly shape risk 8, there is limited research on how timing of adversity shapes trajectories of development and risk for internalizing symptoms.

The overarching concept we seek to test is that there are "sensitive periods" in development 9-11, or windows of time in the lifespan when the developing brain is particularly vulnerable or sensitive to experience, including adversity. Sensitive periods are characterized by phases of high plasticity and rapid brain development in a given domain 12; 13. First articulated by Hubel and Wiesel 14, a robust literature in animals 15; 16 and now in humans has identified sensitive periods in visual 17 and auditory system processes, including language development 18-22. Several genes (e.g., GAD1, GAD2, GABA1 alpha subunit, and BDNF) and environmental exposures (e.g., exercise, psychotropic medications) have been shown in animal studies to manipulate sensitive periods, either triggering their opening or closing 23. Importantly, recent literature also suggests sensitive periods are not fixed or limited solely to the early years of life and brain development. Instead, sensitive periods can be reopened throughout the lifecourse, even in adulthood, as a result of genetically-mediated factors and environments that "remove the brakes on plasticity" 24; 25.

Currently, we lack an in-depth understanding of the time-dependent effects of adversity on the Research Domain Criteria (RDoC) functional domains 26-29. This is especially true for social system processes, including attachment, social cognition, and social communication, which are likely precursors of internalizing symptoms. Although understudied, extant research suggests there are sensitive periods in attachment 30 and social cognition 31. Child abuse and neglect are known to affect social system processing, including perception of emotional expression32. However, it is unclear whether these effects are the same for all maltreated children or whether there is individual variation, depending on the age when children are first exposed. To that end, early evidence from epidemiological studies now suggests the effects of child maltreatment on internalizing symptoms differ depending on age at first exposure, which is suggestive of a sensitive period 33-35.

Based on prior research and our preliminary studies, the main hypothesis we are testing is that disruptions in social system processes explain the elevated risk of internalizing symptoms among children exposed to maltreatment and that the magnitude of this relationship will depend on the developmental timing of exposure to adversity and what sets of genes are expressed at that point in time.

HYPOTHESES

This proposal will test the following aims/hypotheses:

Aim 1: Explore the time-dependent effect of maltreatment on social domains/internalizing symptoms

Hypothesis 1: Children exposed to maltreatment during a sensitive period (age 3-5) will have lower functioning in social system domains and higher internalizing symptoms when compared to both non-exposed children and children exposed outside of the sensitive period, even after adjusting for maltreatment features (e.g., duration).

Aim 2: Examine the association between age at first onset of exposure to child maltreatment, social function, and internalizing symptoms in adolescents

Hypothesis 2: Social functioning will partially mediate or explain the association between age at first onset of exposure to child maltreatment and internalizing symptoms.

Aim 3: Investigate whether developmental genes modify the association between age at first exposure to child maltreatment and both social domain functioning and internalizing symptoms

Hypothesis 3: Variants in genes shown in animal studies to regulate sensitive periods, and sets of genes shown in humans to be differentially expressed across the lifespan, will modify the effect of adversity timing on domains of social functioning and internalizing symptoms.

The expected outcome of this proposal will be the development of a more nuanced approach to defining sensitive periods and the time-dependent effects of adversity on domains relevant to RDoC. This knowledge will have major impacts on the field, including greater insights into the biology of and mechanisms explaining susceptibility to internalizing symptoms and lead to the development of novel preventions and treatments.

EXPOSURE VARIABLES

Caregiver Reported Childhood Adversities: At yearly intervals between ages 1 and 8, caregivers provided information about whether the child was exposed to the different adversities in the past 12 to 18 months, including being taken into some form of foster care; physically hurt by someone else; sexually abused; separated from mother; and separated from father. This was included in the section entitled "Upsetting Events."

Child Reported Childhood Adversity: At age 16 children were asked to report whether they had been exposed to 23 different types of stressors since age 12.

Documented Reports of Child Maltreatment: We are also seeking information from the 329 children who were invested by social services for suspected maltreatment prior to age 6; this includes 162 children who were placed on local child protection registries as having confirmed cases of maltreatment.

MEDIATOR VARIABLES

Diagnostic Assessment of Non-Verbal Accuracy (DANVA): We are requesting data from the DANVA, which provides information about the offspring's ability to accurately detect facial displays of emotion. This task was administered at age 8.

Emotion Triangles Task: The child's ability to attribute emotional states to other individuals, a component of theory of mind, was assessed at age 13, using the emotion triangle task.

Separation Anxiety, as measured by the Development and Wellbeing Assessment (DAWBA), was asssessed at ages 7, 10, 13, 15.

Social and Communication Disorders Checklist: We are requesting data from this measure, which taps domains of social cognition. It appears this measure was administered to children at ages 7 and 15 (and possibly 10 and 13).

OUTCOME VARIABLES

We are proposing to examine the following outcome variables: (1) Rutter parent scale for preschool children; (2) Strengths and difficulties questionnaire; (3) Development and Wellbeing Assessment; (4) Short Mood and Feelings Questionnaire. For all of these outcomes, we will examine symptoms of mood and anxiety disorders (as a continuous measure) as well as extremes in the symptom distribution or diagnoses (from DAWBA).

EFFECT MODIFIERS

We are proposing to examine sets of genes as effect modifiers of the association between maltreatment and both social system processing and mood and anxiety disorders. Please see Appendix 1B for further details on the genetic information we are requesting.

COVARIATES

We would also be interested in receiving basic demographic variables to use as covariates in our analysis. This includes information about: age, gender, race/ethnicity, socioeconomic status.

Aims: To determine whether sleeping position in the first 6 months is associated with long-term phenotypic changes.

Hypotheses:

1. That there is no adverse association of long-term physical health associated with sleeping on the back or side.

2. That a consequence of increased risk of chest infection associated with prone sleep position is a reduction in lung function in childhood.

3. That prone sleeping may be associated with improved motor ability and coordination.

4. That sleeping position has no long-term effect on cognitive abilities, behaviour or educational attainment.

Exposure variables:

Sleeping position, and other features of bedding and parenting up to 18 months

Outcome variables

All phenotypes on the database

Confounding variables

Gender; socio-economic features; housing; diet; parental education; child care; birthweight; gestation; etc.

Statistical approach will use a phenome scan, taking account of multiple testing. Regression analyses will be used to account for confounders as appropriate.