The World Health Organisation describes adverse childhood experiences (ACEs) including abuse, neglect, violence and other household dysfunction, as the commonest and most intense childhood stressors. About half of us experience at least one and those exposed to several are likely to experience more health problems later in life, including chronic pain. There is a strong relationship between exposure to multiple ACEs and social deprivation, and additional associations with having a young mother or being male. Although there is increasing evidence that ACEs contribute to health inequalities, there is no widespread screening to identify interventions. Reasons for this include the limited range of ACEs in existing methods of assessment and little consideration of other factors that may contribute to vulnerability.

CAPE will develop a thorough questionnaire for assessing ACEs to enrich large population cohort data. This information will be linked to prescribing, social care records, neuroimaging, genetics and tissue samples, enabling identification of biopsychosocial factors that create vulnerability to chronic pain and adverse responses to treatment.

Certain behavioural (e.g. diet, smoking, physical activity) and physiological (e.g. obesity, cholesterol, glycaemic control, blood pressure) risk factors have long been known to increase risk of atherosclerotic CVD in later life. Although clinical events rarely occur prior to middle-age, our group have previously shown that early signs of damage to the vasculature can be detectable from as early as childhood (Charakida et al 2012 JACC; Dangardt et al 2019 Lancet Child and Adolescent Health; Chiesa et al JACC Imaging 2019), and that cumulative exposure to this damage across the lifespan likely represents one of the biggest causes of later-life events.

Intriguingly, recent research strongly suggests that these modifiable health behaviours and risk factors may also contribute to another of the world's most pressing global health crises – dementia. A wealth of recent research supports the concept that the development and progression of cognitive decline and eventual dementia can be slowed or perhaps even prevented by addressing various risk factors more commonly linked to CVD (Livingstone et al 2020 Lancet). The implementation of early-life prevention strategies to improve heart health may therefore also provide dual benefits for long-term brain health.

Our group and others have recently contributed to accumulating evidence suggesting that it is exposure to these CV risk factors earlier in the lifespan which appear to relate most strongly to risk of cerebral (i.e. brain) disease risk in later life. These findings suggest that although dementia diagnoses are almost exclusively made in older age, they may in fact represent the end result of cumulative damage to brain tissues which have been sustained over decades previously. However, how early this damage starts and what factors are responsible for its appearance is currently unknown, as very few populations are available in which detailed brain scans have been carried out on a young population with wide-ranging CVD risk factors.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic condition of childhood, but remains a relatively rare condition. Whilst there is growing knowledge about JIA disease management, we have very limited knowledge about the wider impacts of the condition, particularly in adolescence and adult life. For example observational data suggests that JIA patients have adverse educational attainment levels and employment outcomes. There is also growing concern about wider health implications of JIA such as cardiovascular disease risk, similar to that seen for adult rheumatoid arthritis patients, although long term follow-up data of JIA patients into adulthood is very limited. Within this PhD a range of different techniques are being used to explore causes and effects of JIA across the life course using observational and ‘omic data. Our earlier work has shown associations between JIA and a number of other health outcomes, however outcome datasets have all derived from older adult populations. Building on earlier work, this project aims to examine the association between the level of the genetic risk of JIA (using polygenic risk scoring) and a range of clinical (e.g. cardiovascular risk factors), biological (e.g. circulating CRP levels), metabolic (eg circulating lipids) and molecular (e.g. changes to DNA methylation) outcomes during childhood and early adulthood. This will allow us to identify potential JIA associated comorbidity earlier in disease to a) allow earlier risk stratification of patients and b) allow underlying mechanisms of comorbidity to be explored.

Children with precocious puberty are defined as girls with breast development before age 8 years and boys with testicular enlargement before age 9 years (which corresponds to minus 2 standard deviations (SD) compared to the average age of these changes in both sexes). Earlier age at pubertal start has been associated with earlier age at first vaginal bleeding (menarche) in girls and earlier age at voice change in boys, and with long-term consequences, including shorter adult height and psychosocial adverse effects. Although more frequent in certain ethnicities, the prevalence of precocious puberty in girls is constantly increasing worldwide, following the increase in cases of pediatric obesity. Most children with precocious puberty do not present any endocrine, metabolic, neurologic or neurosurgical condition explaining their earlier pubertal start (these cases are defined as “idiopathic” precocious puberty), but extensive work up (including specific hormone measurements and radiological exams) is routinely performed to eliminate such conditions. An important portion of children with precocious puberty will be considered for treatment with puberty-blocking pharmacological agents, without clear evidence that these treatments will increase their adult height.
Late puberty is defined as an absence of breast development by age 13 in girls (or absence of menarche by age 15), and an absence of testicular enlargement before age 14 in boys. This phenomenon is more frequent in boys, in most of which no pathological cause is detected, and these children will end up developing a spontaneous puberty and achieve a normal adult height. Nonetheless, these children are often referred for endocrine evaluation and investigated to eliminate an underlying medical condition.
Given that age at pubertal start in the population follows a Gaussian distribution, 2.3% of normal healthy children will start their puberty at and age below 2 SD below the mean for each sex, and another 2.3% will start their puberty above 2SD above this mean. Defining which children with precocious or late puberty correspond to these 2.3% of the general population is important, since this would avoid unnecessary investigations and treatment in these patients.
Pubertal traits (age at breast development and menarche in girls, testicular enlargement and voice change in boys, age at pubertal growth spurt in both sexes), have a polygenic nature, and an overlapping genetic architecture in boys and girls. It has been estimated that about 50% of variation in age at menarche can be attributed to genetics. Polygenic risk scores (PRS) have been demonstrated to have an improving ability to identify individuals at significantly high/low predisposition towards complex diseases. Therefore, it has become possible to identify individuals who will lie at the extreme distribution of a trait, such as age at menarche in girls or age at voice change in boys.
Therefore, we posit that PRS for age at menarche in girls or age at voice change in boys, in combination with clinical risk factors (such as increased body mass index) may be able to effectively predict children diagnosed as having idiopathic precocious puberty and in which no further investigation or treatment would be required to achieve a normal adult height (within their parental target height). Also, the same scores could identify children in the opposite extreme of the normal distribution, ie children with late puberty.

Cancer outcomes are improved when it is detected early. There is therefore a need for assays for identifying individuals with high cancer risk that can be applied to peripheral tissues such as blood or saliva. There is strong evidence that DNA methylation levels in these tisues encodes biomarkers for cancer risk factors such as cigarette smoke exposure, BMI, diabetes and biological aging. We plan to create DNA methyhlation models of cancer risk factors that can be combined to identify individuals with high cancer risk using peripheral blood samples.

DDepression affects up to 300 million people worldwide and is one of the greatest causes of disability in the world. While many aspects of depression trajectories from adolescence to adulthood are well understood, depression is still among the most unreliable diagnoses of all categorical mental disorders. Additionally, changes in symptom levels across adolescence and young adulthood are as yet poorly understood. This may result from nosological conceptualizations of mental disorders that do not vary for children as compared to adolescents or adults. Only the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders describes irritability rather than depressed mood as an additional core symptom for children and adolescents. In this vein, researchers and practitioners often apply sum score models that reflect these considerations. However, these models rely on strong assumptions and we therefore aim to use Avon Longitudinal Study of Parents and Children data to investigate depressive symptoms in more depth.

While previous research has consistently shown a relationship between adverse childhood experiences (ACEs) and developmental and behavioral outcomes later in life, understanding of mechanisms that explain the relationship is still insufficient. In particular, the role of genetics remains unknown. In this project, we propose to study how genetic factors and ACEs jointly and interactively affect individuals' developmental and behavioral outcomes, such as delinquent behavior and substance use. Specifically, we propose to examine whether and to what extent the influence of ACEs on the developmental and behavioral outcomes depends on children’s genetic susceptibility. Moreover, to what extent effects of parental genetic risk on child’s developmental and behavioral outcomes operate via ACEs.

Metabolic health is emerging as an important risk and prognostic factor for metabolic diseases, including cardiovascular disease (CVD), diabetes and cancer. (1-12) Metabolic health has been defined according to the presence or absence of a minimum number of cardiometabolic risk factors defined according to clinical cut-points (i.e. elevated waist circumference, triglycerides, blood pressure, and fasting glucose, low HDL-cholesterol, insulin resistance (HOMA-IR) and inflammatory biomarkers (hsCRP), or pharmacological treatment for these parameters). Obesity is associated with poor metabolic health, but metabolically unhealthy individuals may be at high risk of metabolic diseases, independent of BMI (metabolically unhealthy normal-weight phenotype, MUHNW) and obese individuals that are metabolically healthy may have similar disease risk to their lean counterparts (metabolically healthy obese phenotype, MHO). (1) Analysis of data from the US National Health and Nutrition Examination Survey showed that a substantial proportion of overweight or obese individuals are metabolically healthy and over 30% of normal weight individuals are cardiometabolically unhealthy. (13) The etiologies of the associations between these phenotypes and cardiometabolic disease risk are unclear. Recent studies have demonstrated the utility of using a metabolomics approach to explore the concepts of MUHNW and MHO in relation to cardiometabolic disease endpoints. For example, an 'obese metabolome' (metabolites related to insulin resistance, branched chain and aromatic amino acids, nucleotide metabolites, and several lipid classes) associated with a 2 to 5-fold increased risk of cardiovascular events, independent of BMI, in the TwinsUK cohort. (14) Matched for BMI, MUHNW individuals had higher visceral adiposity, higher blood pressure and were also more likely to become obese over time compared with their metabolically healthy lean counterparts. Such findings point towards the potential of metabolomics for disease risk stratification, where BMI alone can fail to identify a significant proportion of individuals that may be at risk for cardiometabolic disease. We propose to leverage the unique resources of COMETS to determine metabolites associated with metabolic health, how this profile associates with obesity-relevant diseases (i.e. obesity-related cancers and cardiovascular disease), and the extent to which metabolites mediate the association of body mass index with these outcomes.