NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional analysis of constitutive heterochromatin and its relationship with oncogenic pathways
Funder: Medical Research Council

Abstract: Constitutive heterochromatin is characterised by high compaction, enrichment for repetitive elements, and low transcriptional activity, and it has both regulatory and structural roles. Its loss activates repetitive elements, disrupts chromosome organisation, and alters gene expression, and dysfunction is associated with human disease, including cancer. Despite its importance, our understanding of how constitutive heterochromatin forms and functions is extremely limited, especially in animals. We recently characterised a C. elegans heterochromatin network that collaborates with small RNA pathways to ensure transposon repression, DNA repair, fertility, and growth, and found that the tumour suppressor p53 mediates some of the mutant defects, linking heterochromatin with tumourigenesis pathways. We will capitalise on these results and the experimental strengths of C. elegans to dissect mechanisms of heterochromatin formation, identify new components, and investigate links with disease pathways through three distinct but interrelated aims: (1) decipher mechanisms of heterochromatin formation and the molecular interrelationships between known and new components using super-resolution dSTORM microscopy, high-throughput profiling, and molecular tethering approaches. (2) define a functional network of heterochromatin components, regulators, and mediators of dysfunction using large-scale genetic interaction RNAi screening. Novel conserved components identified in the screens will be prioritised for study and human orthologues pursued with collaborators. (3) determine mechanisms of interactions between heterochromatin and tumourigenic pathways and investigate the hypothesis that chromatin plasticity may contribute to this connection. Advancing knowledge of mechanisms of heterochromatin formation and how dysfunction causes pathologies has potential for identifying new therapeutic targets and is essential for understanding genome regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structure and function of chromatin remodelling ATPase's and their dysfunction in in human disease.
Funder: Medical Research Council

Abstract: Recent high resolution structures of chromatin remodelling enzymes bound to nucleosomes provide a snapshot of these enzymes in action. In order to gain insight into domain motions during the course of ATP-hydrolysis, we will determine structures in different nucleotide bound states and apply advanced image analysis to identify likely domain motions. Single molecule FRET and pulsed electron paramagnetic resonance will be used to measure these changes directly. Structural and biochemical studies provide a context in which to understand how these enzymes function and malfunction in disease states. Therefore, we will also characterise the defects to enzyme action that arise as a result of mutations that are found repeatedly across many ATPases in tumour tissues. The effects of several shared mutations will be assessed across a panel of purified ATPases. To determine whether the downstream consequences of different ATPases mutations are related, we will characterise how and where chromatin is altered when different ATPase mutations are introduced into mouse ES cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding prevalence and impact of frailty in chronic illness and implications for clinical management
Funder: Medical Research Council

Abstract: Aim To assess the prevalence and importance of frailty using three exemplar non-communicable diseases (NCDs) (type 2 diabetes, rheumatoid arthritis and chronic obstructive pulmonary disease), and to explore implications of frailty for management. Objectives -Assess the prevalence of frailty, by age and sex, in each exemplar NCD, comparing general population estimates to participants in randomised controlled trials -Examine the association between frailty and clinical outcomes -Explore if the efficacy of drug treatments differs by frailty status -Assess how self-management should be supported in frail people Methods Data will be drawn from large population cohorts as well as individual patient data from phase 3/4 randomised controlled trials. Frailty will be quantified using a frailty index (in trials and population cohorts) and frailty phenotype (cohorts only). The prevalence and degree of frailty in trial populations will be compared to population estimates accounting for age, sex, and clustering inherent in the data. The relationship between frailty and clinical outcomes will be assessed. Where frailty is present in clinical trials, the impact on adverse event rates and relative treatment effectiveness will be analysed using interaction terms. A systematic review of self-management interventions for type 2 diabetes will explore if interventions account for frailty or functional status, and to what extent this affects outcomes. Scientific/medical opportunities Frailty has not previously been studied in clinical trial settings for these conditions. The proposed work will help us better understand prevalence and implications of frailty and also assess the extent to which existing evidence takes account of frailty in target populations. Where frailty is identified, this work will inform the application of clinical evidence to this population. This will allow more accurate estimation of potential risks and benefits and tailoring of interventions.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE
Title: Beyond resource allocation formulae: analysing the role of local health authorities and providers in achieving equity in service delivery
Funder: Medical Research Council

Abstract: The aim of the fellowship is to acquire the kills to develop and apply an extended framework for the analysis of resource allocation that accounts for how local organizations determine the equitable and efficient use of resources. This proposed research has four specific objectives: 1) To develop a framework to analyse prospectively the distributional consequences of policy scenarios, involving changes in allocation and/or local organizations' policies and characteristics; 2) To assess the extent to which the distribution of health care and expenditure across individuals matches the distribution of need and therefore the equity and efficiency criteria underpinning resource allocation formulae; 3) To determine which factors, including local organizations' policies and characteristics, determine the extent of this match; 4) To simulate the effect of a changes in local organizations' policies and characteristics on the distribution of health care and cost (expenditure) across individuals with different needs. I will use the definition of need used in the resource allocation formulae in England (cost and use of care predicted assuming no variation in supply). I will make explicit the structural model underlying the reduced form equation used to need and derive the framework for the subsequent analysis. The structural model will build on the work of Fleurbaey and Schokkaert (2009) on the analysis of unfair health inequalities. I will apply techniques, including benefit incidence analysis, multilevel regression analyses and microsimulations based on structural equations, to individual level linked administrative data covering five years. In the simulation I will allow local budget allocations and organizations' characteristics amenable to change (how providers are paid, regulated, owned and organised) to vary. Only at the end I will consider the general equilibrium implications of relaxing the assumptions of fixed budget, individual and area level characteristics.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: A prospective multicenter birth cohort study of iron adaptive homeostasis, growth and development in three Peruvian regions
Funder: Medical Research Council

Abstract: Background. Despite economic growth and improvement of development indicators, Peru has a high prevalence of iron deficiency (ID) and iron deficiency anaemia (IDA), for reasons that are unclear. A complexity of eco-bio-social-political factors underlies anaemia and it will be posing increased pressure on the most marginalised people, if not addressed adequately, from an integrative sustainable perspective. Most government interventions are aimed at treatment and not prevention. Aim: To understand the complexity of environmental, social, and nutritional factors altering mechanisms of adaptive iron homeostasis in infants during the Anthropocene. Methods: This is a multicentre prospective cohort study with an eco-bio-social-political approach in 3 cities of Peru located in the Coast, Andes and Amazon. Study period: April 2019 to March 2022 (36 months) Study population: healthy newborns at > 34 weeks of gestation, born in 2020. Follow-up: Prenatal (mothers), then at birth and at months 4, 6, 8 and 12 (mother-infant pairs). Exposure: nutritional or environmental factors that modify iron homeostasis. Outcomes: Primary Outcome: Iron Deficiency; Secondary outcomes: IDA, delay in infant growth. Measurements: Ecological/Environmental: Water samples, GIS-mapping. Biological: Mother and infant: Blood, stool samples; anthropometric assessment according to standard procedures. Social: nutritional household survey; 24 hours of nutritional observation, in-depth interviews and focus groups with participating mothers. Political/Economic: Policy and capacity analysis, focus groups with stakeholders. Official Development Assistance This research will contribute to the social and economic development of Peru by addressing the complexity of factors determining iron deficiency anaemia in distinct parts of Peru. Ethics An Institutional Research Ethics Committee will review the study protocol at the Instituto Nacional de Salud del Niño (Peru) and at QMUL (London, UK).


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE
Title: Intercultural models to improve nutrition and health of indigenous populations through gender-sensitive agroforestry practices in Peru
Funder: Medical Research Council

Abstract: For indigenous groups in the Peruvian Amazon, agroforestry is widely practised and contributes to livelihoods, natural resource management, nutrition and health. This interdisciplinary project will use participatory approaches and intercultural models to co-develop gender-sensitive agroforestry options with the potential to sustainably address high levels of chronic undernutrition and anaemia in indigenous populations. The study will be conducted along a transect of coffee and cocoa-based agroforestry systems which support the livelihoods of indigenous groups in the Peruvian Amazon. Research activities will be conducted in the Amazonas Region on the Cenepa River Basin (4 native Awajun indigenous communities) and on the La Jalca district (4 migrant indigenous communities or 'colonos'). An initial census will identify households that practice agroforestry and contain a child <=5 years of age. Random sampling will be used to enrol 200 Awajun and 200 colonos households. Research activities will involve five steps, starting with (1) a participatory appraisal of socio-ecological contexts; and (2) a survey of agroforestry practices and local biodiversity contributing to food security across seasons. These two steps will inform (3) an observational study to evaluate the influence of specific agroforestry practices, use of local biodiversity, and gender, socioeconomic and cultural factors on maternal and child dietary adequacy (i.e. individual nutrients & mean probability of adequacy over a range of nutrients), anthropometric outcomes (i.e. height-for-age & weight-for-height in children, BMI in women) and anaemia status. Findings from steps 1-3 will contribute to (4) determining the pathways through which agroforestry impacts diets and the nutrition and health status. This model will guide (5) the development of culturally-appropriate and gender-sensitive agroforestry options and food-based recommendations to address identified nutrition and health challenges.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Nutrition, Lifestyle, Genes and Metabolome - A Biosocial Cohort Study of Obesity in Young Adults from Urban Peru
Funder: Medical Research Council

Abstract: Young Lives (YLS), a longitudinal study of childhood poverty that has tracked the lives of 2,000 children in Peru over 15 years, has shown that prevalence of childhood and adolescent obesity is increasing in all sections of the population, especially in urban areas and among the better off. To date, there has been no study investigating the role of biosocial factors on obesity in Peru. Lifestyle, nutrition, genetics and metabolome have been implicated in creating an obesogenic environment and hence, SONGS (Study of Obesity, Nutrition, Genes and Social factors) will use a biosocial approach to examine the impact of dietary patterns, lifestyle, genetic factors, physical places of residence, sensory perception of foods and the metabolome on obesity-related outcomes in 1,000 urban YLS participants aged 19 from 10 clusters of the previous rounds of YLS. The role of diet, physical activity, residential neighbourhood, sensory perception and food preference phenotypes in shaping participants' life course trajectories, dietary intake and health status will be assessed. Genetic risk score, generated from a previously identified genome-wide association study which discovered BMI-related genetic variants, will be tested for its association with obesity and interaction with lifestyle and social factors. The metabolic signature of blood will also be characterised to assess the impact of these factors on health outcomes. Finally, the impact of obesity trajectories on the risk of developing non-communicable diseases will be examined. This biosocial cohort study in Peru will provide a platform from which to identify novel biosocial markers that can be used as early predictors of adult obesity and cardiovascular risk. Through the understanding gained in this study, we aim to influence government policies that will have a positive impact on the diet of the poorest population, aiming to attenuate an obesity epidemic resulting from urbanisation.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Foodborne diseases and public health governance: comparing food safety, consumer preferences and governance in the supply of meat to urban markets
Funder: Medical Research Council

Abstract: Foodborne diseases are a major cause of morbidity, mortality and undernutrition including micronutrient deficiencies, with animal-derived food posing the highest risk for consumers in low and middle-income countries such as Peru. Traditional food markets are still the dominant distribution channel for locally produced food in developing countries and the main food source for most poor urban households. The research will explore the safety of meat supplied through traditional food markets that serve poor urban consumers. Our proposal is framed around three main questions: 1.What are the food safety risks of local smallholder-supplied meat compared with industrially processed meat on offer in food markets? 2.How are food safety risks experienced, perceived and addressed by farmers, traders, processors, food vendors and poor urban consumers? How do consumers perceive the link to their/their children's nutritional health? 3.What food hygiene measures can improve the safety of meat sourced from different supply chains? 4.What are public policies that facilitate the emergence of food safety governance models that address public health and food safety while facilitating local food production? We will adopt an interdisciplinary approach combining value chain analysis, policy analysis, qualitative nutrition studies and probabilistic modelling of the fate of foodborne pathogens along the supply chains. Based on an assessment of the microbiological safety of meat products from a heterogeneous purposively selected sample of market outlets, and the identification of critical control points along six supply chains, we identify entrance points for national policies and local governance arrangements that support the safety of meat supplied by local small-scale producers in urban food markets. By combining quantitative modelling of pathogens with value chain and policy analysis, we intend to propose strategies that incorporate the perspectives of actors along the food chains.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Multimorbidity clusters, trajectories and genetic risk, in British south Asians
Funder: Medical Research Council

Abstract: Our proposal seeks to deliver new knowledge on multimorbidity, focusing on clustering, trajectories and its potential genetic risk in British South Asians, who are under-represented in research despite disproportionately high morbidity and mortality. In an unselected, multiethnic, socioeconomically-deprived east London population of 1.05million, we will identify multimorbidity clusters, using exploratory factor analysis in electronic health record (EHR) data. We will investigate how clusters vary between British south Asians (and subgroups) and Whites. Trajectories of multimorbidity will be studied using a longitudinal data using multi-state modelling and survival analyses. We characterise the contribution from known risk factors to these trajectories as well as their ethnic variation. East London Genes and Health (ELGH) is a community health and genomics study of British-Bangladeshis and -Pakistanis, with target (funded) recruitment of 100,000. Multi-source linked EHR data, exome-sequencing and genotype chip data will be used to study the association between multimorbidity and genetic risk. The possible genome-wide effects of autozygosity (from parental relatedness) on multimorbidity clusters and trajectories will be studied, hypothesising that they may increase the burden of rare homozygous damaging gene variants, and/or increasing additive variance and polygenic disease susceptibility. We will also investigate whether polygenic risk scores (PRSs) for individual traits can be combined to optimise prediction of multimorbid disease, and whether these PRSs for specific diseases and multimorbidity perform as well in south Asian as in White populations. Causal inference studies (e.g. Mendelian randomisation) will be applied where indicated. Our proposal will deliver impact through the generation of new knowledge readily translatable to clinical care and societal benefit, and focusing on understudied populations.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Bringing Innovative Research Methods to Clustering Analysis of Multimorbidity (BIRM-CAM)
Funder: Medical Research Council

Abstract: In this programme, to increase our understanding of multimorbidity (MM), we develop and implement state-of-the-art statistical methods for the analysis of electronic health records data. We will focus on identifying MM clusters and then investigating their consequences and causes. We will hold a stakeholder workshop to seek consensus on methods for investigating MM clusters. As well as critically reviewing existing literature, we will construct new outcome-guided probabilistic clustering techniques to identify cross-sectional and longitudinal patterns of MM associated with clinically relevant outcomes. For the latter, we will produce new time-sequence kernel approaches for grouping sequences of acquired conditions and multi-state models that will additionally model time-to-condition (new comorbidity, hospitalisation or mortality) data. Landmarking approaches will be used to include trajectories of continuous biomarker data within these models to improve their prognostic utility. These methods will serve as the basis of novel clinical prediction tools that can be used to guide decision making. All our methods will be documented and made freely available via a "methodological commons" that will provide reproducible code notebooks and visualisation of findings in ways that aid clinical interpretation. The utility of our methods will be demonstrated and validated using two large national primary care databases (THIN and CPRD) and we will conduct a detailed exploration of longitudinal implications of clusters for polypharmacy, prognosis and frailty. We will examine the aetiological mechanisms of MM clusters by referencing data within the UK Biobank and ELSA using sociodemographic, environmental, behavioural and biomarker variables. By identifying the characteristics of patients within these clusters, we will identify candidates for development and evaluation of interventions to improve outcomes for multimorbid patients by better tailoring care to their MM profile.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Application of machine learning to discover new multimorbidity phenotypes associated with poorer outcomes
Funder: Medical Research Council

Abstract: We will exploit the most deeply phenotyped population e-cohort in the UK, created by HDRUK investment, containing detailed multi-sourced data on a 2.5M population with GP records in Wales from 2000-2020, augmented with demographic, multiple disease registry, hospital inpatient, outpatient data and laboratory results from 2007. No other part of the UK has this depth of records in a stable population with low levels of migration and loss to follow up. Useful algorithms will be adopted by the NHS with tracking of intervention and subsequent impact. Objectives A. complete the most deeply phenotyped population e-cohort in the UK using existing data from the Secure Anonymised Information Linkage (SAIL) system augmented with Census data B. apply innovative machine learning approaches to validate and refine clusters of conditions detected across the adult life course C. use cohort data to identify mechanistic pathways underlying disease combinations D. report on prevalence, social patterning and health inequalities using small area, census, taxation, and household composition data E. identify potential biomarkers predicting individual and multiple morbidities through longitudinal trajectories of values in routinely collected laboratory data F. undertake a comprehensive analysis of variables used in established morbidity/comorbidity indices with multiple correspondence analysis and factor analysis of mixed data to identify clusters G. provide new variables for linkage to the 20,000 Welsh participants in UK Biobank, 7,000 in Airwave and 15,000+ in Healthwise Wales and use algorithms for 40+ cohorts in DPUK for further studies into the genetics of shared mechanistic pathways H. contribute data on incidence, prevalence and burden to the Global Burden of Diseases I. contribute validated algorithms into NHS systems to allow for early NHS adoption, supporting precision medicine and impact measurement


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE