The negative health risks of exposure to cigarette smoke are well known; including personal, second-hand and foetal exposure during pregnancy. In spite of this, rates of smoking (even during pregnancy) remain high, typically above 10% in most countries. This rate is even higher among certain subgroups of the population, and appears to be increasing in low and middle-income countries.
Smoking status is therefore of great importance in most epidemiological studies. Although questionnaires are the simplest and least invasive way to interrogate smoking status, the result is often unreliable and may be biased, particularly if based on self-report during pregnancy. Furthermore, questions about the number of cigarettes smoked may not capture exposure differences resulting from personal variation related to cigarette brands, smoking patterns such as depth of inhalation, metabolism rates and exposure to second-hand smoke.
Serum cotinine, a metabolite of cigarette smoke, can be measured but is limited by its short biological half-life of 17 hours for the average person. This half-life is even shorter (8 hours) for pregnant women, due to markedly accelerated metabolic clearance of cotinine during pregnancy. Cotinine measurements taken after even a single day of smoking cessation could result in false negatives. It certainly could not be used to estimate smoking intensity or pack-years.
DNA methylation, by contrast, appears to provide reliable and long-term biomarkers of tobacco smoke exposure. In fact, it is possible to use linear combinations of methylation levels at smoking-associated CpG sites to not only differentiate among current, former and never smokers but to also detect smoking intensity and number of smoking years.
We will use ARIES DNA methylation data to develop predictors of smoking behaviour which we will then test by comparing against self-reported smoking behaviour from questionnaires and ALSPAC cotinine data. This should allow us to assess the degree of smoking behaviour misreporting across defined groups of individuals (see aims and objectives).

Several studies have investigated the relationship between traits of personality and smoking behaviours. An essential feature of a healthy personality is to be able to self-regulate behaviour and, in so doing, to feel in control. Addiction is accompanied by a lack of this feeling. The extent to which an individual attributes the effects of events to him/herself or to the environment is called locus of control. However, to our knowledge, no investigation of locus of control and smoking phenotypes has been conducted. This study will assess the association between locus of control, assessed in 8 year old children and 16 year old teenagers, with smoking behaviour at the age of 20.

The numbers of Children in Need particularly those who become Looked After in the Public Care system are increasing in the UK. Risk factors for childhood vulnerability are understood in a general sense but the magnitude of risk attributable to particular factors alongside their possible value as risk predictors is less well understood. Similarly whilst there is evidence (for example from evidence provided by local authority Children's Services that Looked After Children have adverse health and social outcomes evidence on the magnitude of increased risk of these from contemporary population based samples is limited. Also limited is evidence how this risk may be ameliorated by other factors, including health and social care interventions. This lack of evidence mainly reflects the difficulty of studying these questions in population based studies. ALSPAC represents an opportunity to overcome these difficulties. From a population based sample of nearly 14,000 children recruited before birth Children in Need up to age 6 were identified from study data and from linkage to Child Health Records. Children who subsequently became Looked After are identified in the National Pupil Database to which ALSPAC participants are linked. As well as including information on category of vulnerability (such as neglect, physical abuse, sexual abuse, emotional abuse) the NPD also contains information on different types of Public Care provision (such as Local Authority Foster Care, Special Guardianship Orders, Kinship Care, Private Foster Care). ALSPAC are also linked to primary and secondary medical care records, education records including results of national assessments at Key Stages 1-5 and Criminal Records held in the Police National Computer. ALSPAC thus represents a valuable resource to answer questions around why some children enter Public Care, what happens to them subsequently and what difference do alternative models of care, and other factors, make to these outcomes

Chronic fatigue syndrome (CFS, also known as 'ME') is a debilitating disease which has a major impact on the lives of children and adults. Previous ALSPAC research studies have estimated how common CFS is (the 'prevalence' of CFS) among ALSPAC children at ages 13, 16 and 18 years. These studies also identified several important risk factors for CFS in children and young people, including family adversity and maternal mental health. ALSPAC data have not yet been used to investigate the prevalence of CFS in adults. ALSPAC mothers were asked about their medical history, including whether they had ever had CFS or ME, in questionnaires which were completed when ALSPAC children were age 8 and 11 years. Mothers' responses to these questions can be used to estimate the population prevalence of CFS in women in the UK. The relationship of CFS in ALSPAC children with CFS in ALSPAC mothers can also be investigated, and we can see whether risk factors for CFS in mothers are the same as the known risk factors for CFS in children.

Background
Eczema is a major contributor to years lost due to disability worldwide and globally the burden of eczema continues to increase, currently affecting 20% of children in developed countries. Eczema is complex, with varied clinical presentations and different responses to treatment. Traditionally eczema is divided into subtypes with and without allergy; however this approach is suboptimal. The recent discovery of the importance of genes regulating the skin barrier in eczema have led to a major change in understanding why eczema occurs and how it is characterized. Individuals with mutations in filaggrin, a protein essential for skin barrier function, are more likely to have earlier onset, more persistent therapy-resistant disease. The recent trials of dupilumab biological therapy for severe eczema highlighted that despite improvement in eczema with active treatment, only 40% of individuals had clear/almost clear skin at 12 weeks, and responses were not predictable based on allergy or filaggrin status, suggesting that a deeper understanding of disease subtypes is now critical. Failure to identify eczema subtypes limits the development of prevention strategies, as it hinders our understanding of why eczema develops. It also contributes to our current suboptimal treatment strategies for eczema, which rely on intensive topical therapy and broad immunosuppressive therapies for severe disease. If we had better understanding of the different eczema subtypes, (as now exists for asthma), we could determine if different risk factors and treatments are relevant for both the onset and the treatment of these different eczema subtypes. Subtyping eczema is timely given the novel drugs targeting specific pathways currently being developed for eczema treatment
There has been a paradigm shift in how eczema is perceived, from being considered a transient disorder of childhood to an understanding that eczema is a systemic inflammatory disorder. Systemic inflammatory disorders may be associated with adverse health and social outcomes, including cardiovascular disorders and impairment of their educational and occupational attainment. There are emerging signals that eczema may be associated with adverse medical outcomes, including strokes and heart attacks. However current studies are limited by the use of cross-sectional designs or by important differences between people that have eczema and people without eczema that may be associated with adverse outcomes, for example adiposity or treatment effects. Different subtypes of eczema may have differing associations with adverse health and social outcomes and may respond differently to treatments as different biological pathways may mediate disease. This research will determine if adverse effects are associated with eczema overall or restricted to certain disease subtypes. Given the high prevalence of eczema, detecting if people with eczema (or specific subtypes of eczema) are at increased risk of adverse outcomes is critically important as it could rapidly inform prevention and/or screening strategies.
Aims
1. To create a new phenotypic classification of eczema in birth cohort data that may be associated with medical and social outcomes and responses to treatment
2. To determine if people with eczema overall and eczema subtypes specifically have an increased risk of cardiac events and poorer educational attainment, and, if increased risks are detected, to establish the predictors of increased risk
Design and methods
1. I will use available social, family and medical data from a subgroup of participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective birth cohort study (N =250 eczema cases; N = 50 controls) to creating a new phenotypic classification of eczema (subtypes) in birth cohort data.
2. I will also use cohort study designs to determine if individuals with eczema and specific subtypes have an increased risk of cardiovascular events. I will do this by looking at the relationship between eczema and cardiometabolic risk factors in ALSPAC
3. I will use data from ALSPAC to determine if individuals with eczema and specific eczema subtypes are at increased risk of poorer educational and occupational attainment and if this is mediated by treatment.

Asthma is the commonest long-term disease affecting children. It develops because of allergies to substances like dust and animal dander, associated with repeated colds, caused by viruses and bacteria during early life. These result in lifelong effects including a permanent reduction in lung function. Although the cells lining the airways (airway epithelial cells) have a central role in determining the response of a baby's immune system to inhaled allergens and infections, how the airway epithelium develops in health and disease is unknown. We know that the bacteria that normally keep our lungs healthy (called microbiota) are changed in asthma. We will study how airway cells from the nose and lungs work from birth and during early life, and how these cells interact with the immune system, the microbiota and genes. We will compare actions of cells from children who do and do not develop wheezing and look at these following exposure to infection with viruses and bad bacteria and allergens. We want to understand what triggers asthma and find out ways of predicting which babies will develop the disease; so we know which ones to treat and ultimately improve lifelong lung health.

Childhood obesity is a world wide public health issue with both immediate and long-term health effects (1). The etiology of obesity is multifactorial and studies indicate it is caused by the interaction between genes and environmental factors leading to the increase in body weight (2,3).

Researchers looking into gene-diet interactions have demonstrated that the obesity susceptibility gene (FTO) was associated with ‘increased and preferential consumption’ of fatty food and abnormal eating behavior described as ‘loss-of-control eating episodes’ when consuming high fat foods. Animal studies show carriers of the genes over-eat high fat foods but have normal eating behavior when fed with a low fat diet (3).

Human breast milk has numerous documented benefits. Studies looking at the effects of breastfeeding on obesity in adolescents and adults demonstrated a 15% to 30% reduction in obesity rates for those who any breastfeeding occurred compared to those who were not breast fed at all (4). Additionally, research on the duration of breastfeeding revealed that for each month of breastfeeding there is a 4% reduction in risk of being over weight (5). Research on the physiology of breastfeeding indicate the presence of hormones; leptin, ghrelin, obestatin, resistin and IGF-1 in human milk. Leptin acts in specific areas of the brain (hypothalamus) resulting in the increase of energy expenditure and reduction of food cravings (6).

Our research project seeks to investigate the effect of both exclusive breastfeeding and complementary feeding on growth trajectories and dietary choices of children carrying the obesity susceptibility genes.

References

1. Faith MS, Stettler N, Pietrobelli A. Engaging Primary Care Clinicians in Early Obesity Prevention Research. JAMA. 2015;314(8):823-824. doi:10.1001/jama.2015.6262.
2. Chesi A, Grant S. The Genetics of Pediatric Obesity. Trends in Endocrinology and Metabolism. 2015;26(12):711-721.
3. Garver, W. S., Newman, S. B., Gonzales-Pacheco, D. M., Castillo, J. J., Jelinek, D., Heidenreich, R. A., & Orlando, R. A. (2013). The genetics of childhood obesity and interaction with dietary macronutrients. Genes & Nutrition, 8(3), 271–287. http://doi.org/10.1007/s12263-013-0339-5
4. Policy Statement: Breastfeeding and the Use of Human Milk. Retrieved from http://pediatrics.aappublications.org/content/early/2012/02/22/peds.2011...
5. Ip S, Chung M, Raman G, Trikalinos TA, Lau J. A summary of the Agency for Healthcare Research and Quality’s evidence report on breastfeeding in developed countries. Breastfeed Med. 2009;4(suppl 1):S17-S30
6. Savino, F., Liguori, S. A., Fissore, M. F., & Oggero, R. (2009). Breast Milk Hormones and Their Protective Effect on Obesity. International Journal of Pediatric Endocrinology, 2009, 327505. http://doi.org/10.1155/2009/327505

The aim of this work is to validate novel genetic associations discovered by collaborators based at the University of Exeter. The discovery analysis was conducted in an independent epidemiological cohort study called InCHIANTI. In this work a range of circulating metabolites were measured and a genome-wide association study conducted to find genetic variants associated with those metabolites. The unique aspect of this discovery analysis was the kind of genetic data that was used. Researchers made use of a brand new resource which provides a more detailed genetic profile than has previously been available in large cohort studies - that is, genetic data imputed using the Haplotype Reference Consortium (HRC). By combining together multiple cohorts, the reference panels produced by the HRC project increase the accuracy of the genotype imputation, especially at low-frequency variants, and the number of imputable variants, thus increasing the power of association studies. Ultimately, this means researchers can probe areas of the genome which have up until now been inaccessible. Through this approach, researchers at the University of Exeter have identified what they believe to be novel genetic associations and are now seeking to validate those associations. The ALSPAC resource represents one of only a small number of studies that has both the phenotype and genotype data required to do these validations.

Maternal smoking during pregnancy is associated with a number of psychological problems in offspring including depression but it is not clear whether this is due to intrauterine exposure to tobacco smoke or due to other lifestyle (confounding) factors. This project will compare associations of maternal smoking during pregnancy to those of paternal smoking during pregnancy with offspring depression measured at 18 years. Maternal and paternal smoking during pregnancy should be similarly associated with lifestyle and demographic factors. However, paternal smoking during pregnancy will expose the foetus to much lower levels of tobacco exposure than active smoking by the mother. Therefore if there is an intrauterine effect on depression, we would expect to see much stronger associations with maternal smoking than with paternal smoking.