Observing that an exposure (e.g. higher meat intake) is associated with an outcome (e.g. higher BMI) does not necessarily mean that the exposure caused the outcome. Other factors may "confound" the association by causing both the exposure and the outcome. Such confounding can be difficult to detect if the factors responsible have not been measured. A recent study proposed a method to detect confounding by unmeasured variables if they cause discontinuous variation in the exposure. We intend to develop this method further and apply it to the question of whether eating meat affects a person's BMI. The method should tell us whether simple observation of people's meat intake and BMI reveals the causal effect or is confounded.

A recent large scale evidence review has demonstrated the importance of exclusive breastfeeding to 6 months with partial breastfeeding continued though the first year of life, but few studies have considered whether starting solids earlier than 5-6 months, but with continued breastfeeding, increases the risk to health or causes earlier cessation of breastfeeding.
The review also found new evidence from the developing world that giving extra iron in children who are not short of iron may cause increased infections and slower growth. Formula milks which have higher iron content than either breast milk or doorstep milk are currently recommended from 6 months to 12 months where an infant is not breastfeeding to prevent iron deficiency anaemia and iron fortified follow on formulas are widely advertised. However the potential risks of iron supplemented formula milks have never been examined.

More than 20% of children will experience a traumatic event before they are 16 years old. Of those who experienced a trauma, a sizable minority will develop Posttraumatic Stress Disorder (PTSD), and other deleterious developmental, health, and psychiatric consequences (herein called Child Traumatic Stress). To diminish the considerable burden of traumatic stress on children and their families, the capacity to predict a child’s risk and to intervene to diminish this risk is extremely important. The literature on prediction of child traumatic stress from risk factors has yielded only modest results and - of those risk factors found to be predictive – it is difficult to determine which represent processes would lead to a diminution of risk, if effective intervention were applied. Almost certainly, traumatic stress results from a complex set of interacting bio-behavioral and social environmental processes, unfolding in specific ways over the course of development, and related to specific aspects of the traumatic exposure. Our project aims to apply state-of-the-art Machine Learning predictive modeling methods with a wide array of risk variables from the ALSPAC data set to generate reliable and accurate predictive models of PTSD and other child traumatic stress outcomes. We also aim to apply advanced non-experimental causal discovery algorithms to discover potentially remediable processes leading to traumatic stress outcomes that may reveal new opportunities for preventative intervention.

The proposal is to continue the collaborative work we have been doing with this Swiss group over the past few years. Ben Spycher was a Marie Curie Fellow who worked with ALSPAC data previously. Prof Kuehni leads eth Leicester Asthma Cohorts and has established the Swiss Paediatric Airway Cohort (SPAC). OUr joint objective is to discover influences that determine the onset and progression of asthma in children, how asthma varies between individuals in type and severity and whether we can predict the outcome of asthma using individuals' information. The data in eth Leicester adn Swiss cohorts is complementary to data held in ALSPAC and we have had joint publications where ALSPAC is able to replicate findings in the other cohorts run by the Swiss group.

Asthma affects the lives of 5.4 million people across the UK. COVID-19 attacks the lungs and can trigger asthma symptoms like wheezing, chest tightness and difficulty breathing, which is very distressing for patients and can cause feelings of anxiety. We want to know if participants with asthma at 23-24 years were more likely to report respiratory symptoms, mental health issues, shielding during the COVID-19 lock-down.

We'll also be interested to explore differences between people with asthma and COVID-19 related symptoms and people with asthma and non-related COVID-19 symptoms, e.g. economical status, asthma severity....

A single mutation within the genome (called rs71564871 near a gene called BEND6) has been previously linked to fat distribution in the body, specifically the proportion of fat stored across the waist compared to the hips, in women of the ORCADES study and UK Biobank. Within this study, we want to assess whether this single mutation is similarly related to the same pattern of fat deposition in the Avon Longitudinal Study of Parents and Children.

Human evolution has been associated with drastic changes in environment and lifestyle over time, with each of these changes resulting in selective pressures (Voight et al., 2006). Natural selection is the differential reproductive success of genetically distinct individuals or genotypes within a population. Strongly deleterious mutations will rapidly be eliminated from populations, whereas strongly positive mutations will quickly rise to fixation leading to changes in allele frequency over time. This process leaves signatures on the genome which can then be detected (Sabeti et al., 2006).

Epigenetics refers to heritable changes outside of the DNA sequence itself and provides a potential mechanism by which environmental and lifestyle exposures can impact gene expression over the course of a lifetime. Epigenetic mechanisms can include DNA methylation and histone modifications. DNA methylation is the most widely studied epigenetic change and involves the addition of methyl groups to nucleotide bases (Vocht et al., 2018).

Natural selection is a long term, multigenerational response to environmental factors that can influence the role of genes in human traits (Bamshed and Wooding, 2003) whereas epigenetic inheritance allows stable changes in DNA methylation to be passed from one generation to the next (Feil and Fraga, 2012). Both selection and methylation act in response to environmental exposures but over different timescales. This project will aim to unravel the interplay between selection and methylation to assess whether DNA methylation offers a mechanism to respond to exposures in the short term which may eventually lead to changes in allele frequency.

References
1. Bamshad, M. & Wooding, S.P. Signatures of natural selection in the human genome. Nature Reviews Genetics 4, 99-111A (2003).
2. de Vocht, F. et al. DNA methylation from birth to late adolescence and development of multiple-risk behaviours. Journal of Affective Disorders227, 588-594 (2018).
3. Feil, R. & Fraga, M.F. Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics 13, 97-109 (2012).
4. Sabeti, P.C. et al. Positive natural selection in the human lineage. Science 312, 1614-1620 (2006).
5. Stearns, S.C., Byars, S.G., Govindaraju, D.R. & Ewbank, D. Measuring selection in contemporary human populations (vol 11, pg 611, 2010). Nature Reviews Genetics 12, 1 (2011).
6. Voight, B.F., Kudaravalli, S., Wen, X.Q. & Pritchard, J.K. A map of recent positive selection in the human genome (vol 4, pg 154, 2006). Plos Biology 4, 659-659 (2006).

It has been suggested that night eating is related to increased fat storage and therefore increased body weight. There is also no clear definition of what is meant by night eating. The potential effects of night eating on obesity have primarily been examined in adults to date and any studies in childhood have been cross-sectional, with none in the UK. Based on information collected in diet diaries at the age of 7, this project will aim to examine different definitions of night eating and examine the effects on childhood weight status and it's change over time. This will be carried in two different cohort studies - one based in the UK and one based in China.

Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonises on the gastric epithelium, and there is clear evidence for its role in causing gastrointestinal diseases. Studies in the United Kingdom have demonstrated the prevalence of H. pylori infection status ranging from 26-66% of the population. There is increasing evidence of the role H. pylori in the development of other diseases, including cardiovascular disease and cancer. Given the relatively high prevalence of infection, this is potentially an important disease risk factor that merits causal investigation. Studies have suggested that infection with H. pylori may affect lipid metabolism, especially with the cardiovascular risk factors: HDL-cholesterol, triglyceride and apolipoproteins. By this mechanism, this could increase the risk of developing atherosclerosis and coronary artery disease. Additionally, studies have postulated that H. pylori could be involved in the development of atherosclerosis by causing vascular inflammation and endothelial dysfunction. H. pylori has also been shown to be involved in gastric carcinogenesis. Through the disruption of epithelial cell functions by H. pylori cytotoxin-associated antigen A (CagA), this oncogenic factor activates oncogenic pathways in these cells and induces epigenetic modifications which play a significant role in initiating carcinogenesis.