Epidemiological and clinical studies interested in circulating glucose as a risk factor or outcome typically measure levels in the blood at a single or widely spaced time points (e.g. every few years). While these are important health indicators, there has been an increasing appreciation that glucose levels and variability in free-living conditions during both the day and night, may also provide important health measures in clinical (e.g. diabetic or obese) and ‘healthy’ populations.

Continuous glucose monitoring (CGM) systems measure interstitial glucose levels ‘continuously’ by implanting a sensor subcutaneously. This produces a sequence of measurements for each participant (e.g. the average glucose level every 5 minutes over several days), that can be used to assess how a person’s glucose levels vary over both the day and night. We have recently published a novel software package called GLU, for deriving a consistent set of summary variables from CGM data. The derived summary variables can be used in analyses to assess how different characteristics of glucose levels and variability relate to health exposures and outcomes.

Previous research has indicated that individuals with ADHD have an increased likelihood of developing mental health problems such as depression, anxiety and antisocial behavior. Despite mental health problems being increased in individuals with ADHD, not all children go on to develop poor mental health outcomes. Research has indicated that resilience is a dynamic process that arises from normal adaptive mechanisms and can be influenced by many factors. However, why some individuals with ADHD show higher levels of resilience and better outcomes compared to others is not yet well understood. One way of defining resilience is better-than-expected long-term mental health outcome than predicted by initial severity of childhood ADHD. Therefore, the current research project will focus on first identifying risk mechanisms which increase the likelihood of individuals with childhood ADHD developing adult mental health problems, and then will aim to identify potentially modifiable protective factors that could be the focus of prevention and intervention programs.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) have difficulties with sustaining attention, being overactive and being impulsive. It is one of the most common childhood disorders and causes difficulties in school, and with family relationships and friendships, whilst those with ADHD are also at higher risk of other difficulties such as anxiety and depression both in childhood and later life. Not all individuals with ADHD have the same problems though, so it is important to understand who is at greatest risk of them. Difficulties with attention or hyperactivity are present across many people whilst only some have sufficient problems to be diagnosed with ADHD. International guidelines indicate where the dividing line between having a diagnosis or not is set, but we know that individuals who do not meet this diagnostic threshold can still have difficulties due to their ADHD symptoms whilst even in those with a diagnosis, the specific constellation of problem behaviours differs between individuals. This project aims to examine how differences in the symptom presentation and impairments in children are linked to other difficulties they have in childhood and as they grow into adulthood. It will also look at how genetic risks for ADHD and other disorders are related to these different presentations. This will be examined in both the general population (the ALSPAC cohort) and a clinical sample of children with ADHD, with additional replication in other international cohorts.

Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Identification of the genetic variants and pathways associated with PCOS susceptibility may provide insights into the pathogenesis of the condition and potential targeted treatments.

We propose to study phenotypes in children that may be associated with PCOS, including obesity, dyslipidemia, and premature adrenarche. Premature adrenarche is a pediatric condition characterized by early production of adrenal androgens such as DHEAS and androstenedione and has been proposed to be a precursor to PCOS in girls. We will calculate a polygenic risk score for PCOS in prepubertal children and test for associations with premature adrenarche and associated cardiometabolic and hyperandrogenic outcomes and biochemical and anthropometric traits. In addition, we will examine these outcomes during the pre-pubertal period in girls who later develop a diagnosis of PCOS in adolescence and young adulthood.

The extension of PCOS genetics to prepubertal children provides the unique opportunity to 1) classify the PCOS pathways into ovarian-dependent factors and nonovarian-dependent factors and 2) characterize the pediatric phenotypes associated with PCOS genetic risk factors, and 3) understand the pre-pubertal manifestations of a future PCOS diagnosis. Overall, investigations in prepubertal children have the potential to provide valuable insights into the mechanisms of pathogenesis and targets for treatment for PCOS.

Cleft of the lip and/or palate is a common birth defect worldwide and occurs at a rate of one in 650 live births in the UK. Being born with cleft places a significant burden on children, their families and the health system as they require surgery (multiple times depending on cleft type), and other interventions to improve appearance, speech, hearing, dentition and other adverse outcomes. They are also at increased risk of psychological, psychiatric and cognitive problems [1]. There are several possible mechanisms underlying these associations that may be operating alone or together. First, they may reflect the psychological, developmental and social impacts of clefting and its treatment. Second, they may reflect genetic factors either as pleiotropic outcomes of genetic susceptibility to clefting or as independently inherited genetic risk.
The aetiology of both cleft and of psychiatric disorders is complex, with common risk alleles [3] [4] of individually small effects as well as rare genetic mutations of large effect and environmental factors playing roles. One group of rare mutations of large effect are Copy Number Variants (CNVs), referring to deletion or duplication of a part of the genome leading to differences between individuals in the number of copies of genes within the affected region. CNVs are known to increase risk of neurodevelopmental disorders (ND-CNVs), such as ADHD and autism, as well as mental health disorders but the presence and the impact of CNVs have not been studied in cleft [5].

The PhD project will provide the first detailed description of neurodevelopmental and mental health outcomes in children with cleft and examine the contributions of genetic and environmental factors. For this we will use two unique genetically informative clinical cohorts of children; the Bristol University Cleft Collective and the Cardiff University longitudinal ExperiencCes of people witH cOpy number variants (ECHO) study. Control samples will consist of the Avon Longitudinal Study of Parents and Children (ALPSAC) and the Millennium cohort which are deeply-phenotyped cohorts of typically developing children.

Socioeconomic disadvantage and stress are associated with adverse pregnancy and child health outcomes. There is some evidence to suggest that these associations may be mediated by changes in placental development and function. However, studies of the placenta are often small or limited to pathologic samples, which may not be representative. ALSPAC routinely collected placentas of participants, including term deliveries, and ALSPAC has rich parental sociodemographic information and longitudinal follow-up on child health and development. This presents a unique opportunity to estimate associations between socioeconomic disadvantage and child development and to examine the mediating role of placental pathology in a well-characterized, representative sample.

Pain which lasts for more than 3 months is termed "Chronic Pain". It often occurs in the absence of obvious injury. It can be very difficult to treat.
We believe that the body may produce antibodies (part of the natural defence against infections) that can activate "pain" nerves. This may contribute to Chronic Pain.
Antibodies, produced by the body are known to sometimes interfere with the nerves in diseases such as Myaesthenia Gravis.
If we can demonstrate that these antibodies can cause chronic pain, we will be able to treat patient with chronic pain much more effectively.

Attachment theory explains social, relationship and personality development across the lifespan (Bowlby 1969) and has been shown to provide a psychological framework for understanding mental ill health (Mikulincer & Shaver, 2007). The basic postulation is that very early childhood social interactions with primary caregivers are internalised to create and maintain conscious and unconscious mental representations of the self and others. These form the basis of ‘attachment styles’, which have an impact on close relationships and ability to regulate emotions. There is extensive evidence that attachment style is a predictor of coping strategies, adjustment in response to stressors and therefore a vulnerability to mental health problems (see Mikulincer & Shaver 2012 for a review). Research has widely demonstrated an association between secure attachment style and well-being and positive mental health, whilst both insecure attachment styles (anxious and avoidant) have been associated with poor relationship quality, psychological vulnerability and maladjustment, and mental health difficulties (e.g. Sroufe et al., 1999; Hankin et al., 2005; Mikulincer & Shaver 2007; Groh 2016; Spruit 2019). However, the direction of causality is less well established as most studies rely on cross-sectional design and measure attachment style as a discrete variable at a single point in adulthood.

By using a large prospective birth cohort, we will be able to (a) investigate the prospective relationship and (b) use latent variable modelling of repeated measures of attachment to create a more robust and detailed measure of attachment style. This will aid more nuanced explanations of how and when insecure attachment style may lead to mental ill health, such that the association can be interrogated to identify possible intervention targets.

This proposal has implications for healthcare provision and public health policies around childhood and parental interventions to support research to address the growing number of mental health difficulties in later adolescence.

Risk towards poor mental health is impacted by a number of biological, psychological, and social factors that work together throughout the lifespan and across generations. A large body of research supports the influence of the prenatal environment on children’s developmental and mental health outcomes. For example, prenatal depression has been linked to later risk of depression in children, and prenatal depression, prenatal anxiety, and stressful life events during pregnancy have all been associated with risk of anxiety disorders in children. There is also growing interest in understanding the potential biological causes that may drive these relationships. In particular, inflammation has been suggested as a potential factor that may influence these associations, due to its role in the onset of depression and other mental and physical health disorders. However, few studies to date have examined the role of inflammation in relationships between prenatal maternal stress and child and adolescent mental health outcomes, calling for continued research in this area.

In addition, although the relationships between prenatal stress and child and adolescent mental health outcomes are well-established, children continue to be exposed to a number of influences, both positive and negative, after birth. For example, research suggests that the relationships between prenatal stress and child outcomes may differ depending on how mothers are able to cope with the stress they experience, including their degree of partner and social support, and availability of psychological resources including higher self-esteem and self-efficacy. Furthermore, a growing number of studies suggest that parenting behaviours may play an important role in these associations. For example, children exposed to parental warmth and positive relationships with their mothers and fathers may be buffered to the impacts of early adversity; conversely, children exposed to maltreatment or harsh parenting may exhibit increased vulnerability. Considering how both maternal coping resources and parenting further increase or reduce the risk towards chronic inflammation and later mental health outcomes in children exposed to prenatal stress, however, is an area that requires further investigation. In addition, the influence of many coping resources and parenting behaviours on later inflammation is an understudied area.