Around 11 million people developed tuberculosis (TB) in 2021, and 1.6 million died from the disease. Current control strategies are insufficient, with global TB incidence falling by only 2% per year. One reason for the slow decline may be widespread reliance on passive case detection - requiring people with TB to present to healthcare services with symptoms. This means that people can be infectious for months or years before diagnosis, and an estimated 40% of incident TB was not diagnosed in 2021. Active case finding (ACF) - the systematic screening of high-risk groups or populations - is one way to find people with TB earlier, leading to reductions in transmission. The World Health Organization recommends ACF in areas with a high prevalence of TB. Recent National Strategic Plans from countries as diverse as South Africa, Uganda, and India contain plans to scale-up ACF in high risk populations. Despite the scaling up of ACF activities, considerable uncertainty remains as to their likely impact, and how it varies between approaches and settings. Three randomised control trials (RCTs) estimating the impact of ACF on transmission have been conducted. One trial achieved an impressive 50% (95% CI 22-68%) reduction in the prevalence of infection in children (a proxy for transmission), demonstrating that community ACF can be a highly effective in reducing transmission. The other trials used less intensive intervention approaches, and found no evidence for reductions in transmission. A fourth RCT found a reduction in TB prevalence, but did not estimate reductions in transmission. Mathematical modelling suggests that the differences between the trial results cannot be explained by differences in the tests used or numbers of cases detected. There is a need to understand factors that affect the reductions in TB incidence achieved through ACF, and to identify less intensive and expensive ACF approaches that can lead to reductions in transmission. Mathematical modelling can be used to predict the impact of ACF on TB incidence. However, assumptions typically made in models may not be correct, and models of ACF have rarely been validated using empirical data. In particular, we have identified three factors that may alter the impact of ACF on TB incidence: A) People who have been screened in previous rounds may be more or less likely to seek or accept screening. B) Coverage tends to be lower in men than in women, despite higher TB prevalences in men. C) The probability of participating in ACF may be higher for people who were closer to seeking care and receiving a diagnosis passively. The impact of these factors may vary by intervention design and setting.

The United Kingdom's (UK) population is ageing. As a result, common age-related diseases, such as stroke, fractures and dementia, are predicted to pose an increasing burden on the health system. The development of prevention strategies is therefore an imperative. Emerging evidence has suggested mechanistic links between these age-related diseases. For example, higher risks of hip fractures and dementia have been observed in people who have had a stroke, while a higher risk of hip fractures has also been observed in people who have dementia. These associations may be partly due to the first condition altering the risk of the second condition, but recent evidence suggests that the three conditions might share common risk factors including diet. Of the potentially modifiable risk factors, differences in the amount and quality of dietary protein intake have been suggested to be important. Specifically, low intakes of high quality protein have been associated with higher risks of haemorrhagic stroke (the more aggressive stroke type) and of hip fractures, possibly because protein is a key structural component for maintaining the strength and integrity of blood vessels and bones. The possible relevance of dietary protein intake in the risk for dementia development has been less studied, but low blood levels of insulin-like growth factor I (IGF-I), a peptide hormone that is known to be influenced by dietary protein intake, have been suggested to increase the risk of dementia as well as stroke and fractures. Research is needed to understand the effects of dietary protein adequacy and quality on common age-related diseases. This is particularly relevant in light of the global calls to limit animal source food consumption due to their high environmental impact, though these foods are generally considered higher quality proteins. Understanding the exact role of protein adequacy and quality will guide strategies to ensure optimal protein intakes, without compromising sustainability targets. This research will examine the role of dietary protein intake, focusing on quality as well as quantity, and protein-related biomarkers in the development of stroke subtypes, hip fractures, vascular dementia and Alzheimer's disease, and seek to clarify the links between the three sets of conditions, using data from large prospective cohorts in the UK and in other countries. The first work package will examine how differences in intakes of dietary protein, protein from different sources and protein rich foods affect the risk of each of the conditions of interest. I will also investigate the role of individual dietary amino acids, which make up dietary proteins, with the aim of investigating the association between protein quality and health. The second work package will explore how differences in protein intake influence the levels of protein-related biomarkers in the body, and how these biomarkers may be associated with disease risk, as a way of identifying potential disease mechanisms. This will include the examination of established clinical biomarkers (e.g. IGF-I), circulating amino acids and approximately 1500 novel circulating proteins (proteomics). It will also involve the use of genetic instruments to establish the causal relevance of the biomarkers of interest for disease risk. The third work package will investigate the mechanistic links between the three sets of diseases and the sequence of multimorbidity. I will identify the common dietary and non-dietary risk factors for the three outcomes, and evaluate whether the manifestation of the first condition has a direct effect on the development of multimorbidity, independent of the common risk factors. Overall, this programme of work will generate robust evidence on modifiable risk factors for common age-related diseases and the potential underlying mechanisms, and inform the optimal targets for strategies in disease prevention.

United States

Our experiences in early life can have life-long effects on our health and wellbeing. For example, in a rural population in The Gambia in West Africa we have observed that children born in the rainy season are 6 times more likely to die between the ages of 15 and 65 than those born in the dry season. In fact there is mounting evidence that detrimental influences on lifelong health can stretch right back to the early stages of embryonic development. This underlines the importance of research into the underlying mechanisms, so that the processes linking environmental exposures to negative outcomes can be understood, and hopefully corrected. One such possible mechanism involves a process known as methylation, which is one type of 'epigenetic' modification of the genome. Methylation requires a defined set of nutrients including folic acid and B-vitamins, both to provide the necessary chemical compounds, known as methyl groups, and to undertake the necessary metabolic conversions. Animal experiments have previously shown that supplementing the diets of female mice with these nutrients before they conceive has a profound effect on their offspring's appearance (e.g. changing their coat colour) and that these changes were associated with higher levels of methylation on their DNA. Until now it was unknown whether similar effects on offspring methylation occur in humans, but our group recently presented first-in-human evidence that they do. We have since followed up this work by looking at patterns of methylation across the genome. We found evidence of unusual or 'disrupted' methylation patterns associated with both maternal nutrient status and season of conception in certain types of genes, and notably in one gene (VTRNA2-1), where disrupted methylation has previously been linked with some forms of cancer and also with negative effects on the immune system. With this grant we hope to extend this work in a number of ways. Firstly, we want to characterise these patterns of disruption more precisely by looking at a larger number of infants; interrogating key regions of the epigenome at high resolution using more advanced technologies; and looking for methylation effects all the year round. We hope this will provide further clues about the mechanisms underlying epigenomic disruption. Secondly, we want to investigate the effects of disrupted methylation in VTRNA2-1. Our Gambian research centre is a particularly good place to do this as we are able to link an individual's epigenetic information with medical records and other demographic data, and we can also conduct detailed laboratory investigations on blood cells in individuals known to have abberant methylation. These functional studies are an important part of the chain linking epigenetic effects to real, adverse health outcomes in people. Finally, with the help of advanced computer modelling, we will identify the specific combination of MD-related nutrients that may be causing the observed patterns of disrupted methylation. We will then develop a nutritional supplement to correct the observed suboptimal nutrient profile, and we will test its effectiveness in a randomised controlled trial. If effective, in future work we would seek to assess the effect on offspring methylation of giving this supplement to mothers-to-be. The hope is that the patterns of disrupted methylation previously observed in infants conceived at certain times of the year would then be prevented. In the longer term, we hope that the work described here will inform strategies for pre-conceptional supplementation in mothers that will lead directly to improved outcomes for infant growth and development, with life-long benefits for health and wellbeing.

DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status. Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences. Prior research has been limited to populations of European ancestry, restricting understanding of DNAm variation to limited contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation. Evaluating DNAm variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group. Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments. Our first project aim is to map genetic and environmental determinants of human DNAm variation to understand mechanisms of DNAm variability. We will generate a catalog of genetic associations with DNAm across populations worldwide. This catalog will be used to assess which of the identified genetic associations with DNAm are also associated with human complex traits. This is important because the findings can inform the functional role of phenotype-associated genetic variation, and ultimately - our understanding of the mechanisms underlying human phenotype variation. The second aim of the project is to understand mechanisms of disease and disease discordance observed between population groups for childhood and cardiometabolic disease related phenotypes. This project focusses on childhood and cardiometabolic disease for which there is substantial disease discordance and health disparity across populations. For example, diabetes risk is substantially higher in individuals of South Asian origin even after accounting for known genetic and environmental risk factors. Identification of DNAm variation associated with type 2 diabetes that is context specific will contribute to explaining excess type 2 diabetes risk in the South Asian population group. In doing so, Identification of disease pathways restricted to specific genetic and/or environmental exposure profiles brings the opportunity to target treatment or intervention where it is effective. This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this proposal is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypes Identification of common and context specific mechanisms of health and disease mediated by DNAm is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.