Albumin is a protein present in blood and excreted in urine. Slight increases of levels of albumin excretion in urine (so called microalbuminuria) are related to an increased risk for renal and cardiovascular disease, even in otherwise healthy individuals. Nevertheless, the exact cause and the underlying mechanism of microalbuminuria are still unknown. Moreover, data on microalbuminuria in young individuals are scarce.
With this project we intend to learn more about the prevalence of microalbuminuria in school-aged children and young adults. We also want to test the hypothesis that some individuals have higher urinary albumin levels already early in life, that these findings persist in time and that such individuals carry a higher risk for renal, cardiovascular and, possibly, metabolic disease.
Moreover, we intend to explore possible causes of microalbuminuria, evaluating genetic background and associations between albuminuria and antenatal and postnatal determinants.
We plan to integrate the extensive data from the ALSPAC cohort with data from the Dutch GECKO birth-cohort (Groningen, The Netherlands), where urine samples have been collected at a younger age and thorough information about obesity risk factors are available. By investigating these two cohorts, we aim to gather data describing the spectrum of albuminuria from early childhood into young adulthood.

In this study we will explore the feasibility of using smartwatches to capture detailed information about individuals alcohol drinking behaviours. We will be using an approach called Ecological Momentary Assessment (EMA) to gather data about people's alcohol consumption as they go about their normal lives. Specifically, we will be using a new version of EMA called microEMA, which is designed to minimise the level of interuption and burden to people, whilst allowing us to capture detailed data about their drinking behaviours. We have developed a microEMA application to run on a normal, commercially available smartwatch, and will use this, alongside a more traditional questionnaire, to capture information about the type and quantity of alcoholic drinks consumed during each day, and if these drinks are consumed at home or outside the home, and in the company of others or alone. We will do this over a period of 3 months. Because we will ask people about their drinking behaviours throughout the day, we hope to capture more accurate and detailed information about their drinking behaviour with our smartwatch microEMA application than with traditional questionnaires, which people complete days afterwards, and which are known to suffer from problems related to remembering what was consumed, and other reporting biases. We can then use these data to explore differences in drinking behaviours between different groups. We will explore differences in drinking behaviour between high and low social economic position groups. This will allow us to understand, not just the differences in drinking behaviours between the two groups, but if there are differences in the way the two groups use and experience the new smartwatch-based microEMA approach, if this if different to the way they use and experience more traditional questionnaire approaches, and if new approaches like micro EMA might introduce other unexpected biases that could affect the data they collect.

It is commonly believed that continence problems affect only young children and the elderly, but these problems can affect people of all ages. Despite their high prevalence and adverse effects, research into the causes, prevention and treatment of continence problems is scarce. Clinicians recognise that psychological factors are strongly associated with continence problems but research is needed to examine whether these factors actually cause continence problems.
The proposed research will use cutting edge statistical methods to examine whether there are causal effects of psychological factors on continence problems in childhood, adolescence and adulthood. The psychological factors we will examine include depression, anxiety, emotional and behaviour problems, stressful life events, maternal mental health, parenting, and childhood adversity. We will investigate whether characteristics relating to the child (e.g. toilet anxiety), parents and wider influences (e.g. peers, school) may help to explain the association between psychological factors and continence problems. We will also examine the role of inflammation as a biological process that might underlie the link between psychological factors and continence problems.
If we find evidence that psychological factors cause continence problems, this could help clinicians to develop more effective interventions and treatments. Ultimately, our research could improve the lives of people affected by continence problems and help the NHS make better use of its resources.

Genetic studies often need to compare diseased participants with healthy participants. In this project, a study of Head and Neck Cancer patients (HN5000) has no healthy participants to compare to. Therefore, participants in ALSPAC are going to be utilised as healthy genetic controls. To do this successfully some ALSPAC participants, who've already had their genetic data measured, will have it remeasured alongside the HN5000 participants. By doing this any errors that may occur in the laboratory process can be identified rather than potentially contributing to false findings. Once this cross-check is complete all ALSPAC participants (unless already diagnosed with HNC) can be used as healthy controls which will greatly increase the utility of the HN5000 study.

In order for the public to have faith in the conclusions of scientists it is important that the methods they employ are robust and transparent. This is especially important for controversial topics with major implications for mental health. The public should rightly demand that such findings are not contingent on the beliefs of the scientists, their particular methods, computational quirks or simple accident. This is of particular relevance when total transparency is not possible because the data is sensitive.

This study addresses the question of robustness by taking a controversial question, “Is there an association between screen time and depression and anxiety?”, recruiting teams of independent data analysts and looking at how they answer the question using the same data, effectively ‘crowd-sourcing’ the data analysis.

The study will use the answers teams provide to this controversial question to answer further questions such as: “Do the methods used to answer the question influence the result and if so by how much?” and, “Do the beliefs and particular expertise of the analysts influence their results?”. To do this, we will use a statistical technique called a ‘multiverse analysis’, whereby reasonable alternatives to choices made by the teams, during the data analysis, are explored and recorded to see how sensitive the results were to the choices made.

To ensure the study is transparent we will investigate the use of anonymised data. Using anonymised data is controversial as the anonymisation process may erase important features of the data. This study will ask “Does the anonymisation process affect the results and if so by how much?”.

The answer to all these questions will help us understand how scientists arrive at answers to controversial questions and whether crowd sourced analysis and data anonymisation techniques can ensure findings are robust and transparent.

Finally, our study will challenge the teams to come up with interesting ways to visualise the answers to these questions in exchange for a prize. Visualising the teams’ answers, along with how robust they are, in a clear, accessible way will be important to help communicate complex results both for this study and in the future.

Fetal alcohol spectrum disorders (FASDs) are lifelong disabilities caused by prenatal alcohol exposure. FASD is thought to be the leading preventable cause of developmental disability in the world and is associated with mental health problems, antisocial behaviour and substance misuse. Understanding which individuals are most at risk to develop FASD is key as it has been shown that an early diagnosis or risk identification could help with primary and secondary prevention, as well as amelioration and treatment efforts. Early identification of individuals most at risk for FASD via the identification of robust maternal and infant biomarkers will offer an early window for intervention, will focus specialist diagnostic efforts in a resource-limited healthcare system, and will contribute towards mitigating FASD-related disabilities in later life. It may also prevent or reduce foetal exposure to alcohol in subsequent pregnancies.

This project will focus on early identification of FASD by DNA methylation levels, which are known to be altered by alcohol use. Indeed, a DNA methylation alcohol (DNAm-Alc) score, comprising 144 CpG sites, was recently developed by Liu et al. that can robustly distinguish between current heavy drinkers and non-drinkers in a general population. In addition, strong evidence from animal models indicates that alcohol use during pregnancy is capable of altering offspring DNAm.

McQuire et al. have developed an algorithm to identify individuals at high risk of FASD regardless of them having received a formal (and rare!) diagnosis. We propose to compare this algorithmic identification with DNAm-based markers to find out whether prenatal risk assessment would be possible.

References
Liu, C. et al. A DNA methylation biomarker of alcohol consumption. Mol. Psychiatry 23(2):422-433 (2018)

McQuire C, Mukherjee R, Hurt L, Higgins A, Greene G, Farewell D et al. Screening prevalence of fetal alcohol spectrum disorders in a region of the United Kingdom: A population-based birth-cohort study. Prev Med (Baltim) 2019; 118: 344–351.

Infections during pregnancy1 and early childhood2 have been linked to increased risk of schizophrenia in observational studies. Inflammation, as measured by interleukin-6 (IL-6) and C-reactive protein (CRP), contribute to host defence against infections3,4. Observational epidemiologic studies suggest that inflammatory biomarkers have a positive association with schizophrenia. Interestingly, we have recently shown that individuals who are genetically predisposed to lower activity of the inflammatory response (i.e. CRP levels and blockade of IL-6 cell signalling) have higher risk of schizophrenia5. This, seemingly contradictive, finding may be explained by a genetically determined decreased inflammatory response resulting in an increased susceptibility to early life infection4. In this project, the link between inflammation, psychosis and early life infection will be explored using publicly available genome-wide association study (GWAS) data and newly measured antibody titres available in the ALSPAC cohort6.

1. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med. 2013;43(02):239-257.
2. Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB. Childhood infection and adult schizophrenia: A meta-analysis of population-based studies. Schizophr Res. 2012;139(1-3):161-168.
3. Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727.
4. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805-1812.
5. Hartwig FP, Borges MC, Lessa Horta B, Bowden J, Smith GD. Association between genetically elevated levels of inflammatory biomarkers and risk of schizophrenia: a two-sample Mendelian randomisation study. 2017.
6. Mitchell RE, Jones HJ, Yolken RH, et al. Longitudinal serological measures of common infection in the Avon Longitudinal Study of Parents and Children cohort. Wellcome Open Res. 2018;3:49.

Pregnancy and infancy are critical periods for nutritional programming of metabolic health. Epigenetic changes seem to have a crucial role in pathways leading from early-life nutrition to metabolic health across the life course. The NUTRIprogram consortium (University of Bristol, Erasmus University Rotterdam, IS-Global Barcelona, University of British Columbia and LMU) has been set up to facilitate research in this area. We will study key maternal and infant nutrition-related exposures in relation to DNA methylation in mothers and offspring at different ages, and metabolic health across the life course.