NIHRDataInsights/HRCSData huggingface dataset:
Title: The power of the environment: Environmental mediation of genetic liability
Funder: Medical Research Council

Abstract: Consequences of childhood obesity remains one of the greatest public health burdens. There is substantive evidence that obesity is highly heritable, but genetics cannot account for the recent rise of obesity in the population. Environmental factors have been proposed to be causal, but the mechanisms of gene-environment interplay are not clear. Specifically, the extent to which environmental factors can mediate the association between genetic risk and later disease. This fellowship will address these gaps in the literature by combining polygenic scores with mediation analysis. The main objectives are: (i) Estimating the mediating effects of parental feeding practices and child physical activity on the association polygenic score associated with BMI (PGS-BMI) and later childhood BMI. (ii) Comparing traditional structural equation modelling mediation methods with modern counterfactual methods, and the evaluating the differences of these methods when investigating the genetic-environmental aetiology of childhood obesity. (iii) Investigating the impact of non-transmitted maternal PGS-BMI on child BMI. (iv) Examining the interaction between child PGS-BMI and the build environment of the family home. Data will be from readily available longitudinal cohorts; Avon Longitudinal study of Parents and Children (ALSPAC, N~8650) and Millennium Cohort Study (MCS, N~10000). Exposures: PGS-BMI will be derived for both cohorts from GWAS summary statistics. Intermediate mediators: Parental reports of feeding behaviours (ALSPAC, N~5000), accelerometer data at 7 (MCS, N~6500) and 11 years (ALSPAC, N~4700), Geographical information systems data based on postcodes of families. Outcomes: Objectively measured BMI and body composition measures at 11 (MCS, N~100000), 12 (ALSPAC, N~7000) and 14 years (ALSPAC, N~6500, MCS, N~10000). Results advance our understanding of the underlying mechanisms of childhood obesity. The novel application of PGS in mediation analysis will be beneficial for oth


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of metabolism by inositol pyrophosphates
Funder: Medical Research Council

Abstract: Cell metabolism is at the very core of any physiological process in health or disease. Understanding metabolic control is, therefore, of fundamental importance. Our work on inositol pyrophosphates (PP-IPs) has positioned this class of cellular messengers at the interface between cell metabolism and cell signalling. The evidence that PP-IPs are involved in the pathogenesis of metabolic disorders such as obesity and diabetes has increased the interest in PP-IPs as regulators of metabolism. However, despite their clear relevance, many aspects of the PP-IPs modus operandi remain poorly understood. The proposed program intends to fill these lacunae by defining several aspects of PP-IPs biology, from regulation to mechanism of action, helping to pinpoint how these molecules regulate cell metabolism. Our comprehensive program aims to define the metabolic inositol fluxes leading to PP-IPs synthesis, as well as characterising the regulation of the PP-IPs synthesizing enzymes. These studies will be accompanied by analysing how PP-IPs regulate mammalian cellular phosphate homeostasis, since the nutrient phosphate is involved in virtually every biochemical reaction, and thus understanding its homeostatic control is fundamental to comprehending metabolism. To appreciate PP-IPs signalling and metabolic control we should understand the molecular mechanisms of action. Therefore, we aim to dissect the post-translational protein modifications directly and indirectly controlled by PP-IPs. Since transformative science can only be achieved by developing novel experimental approaches, we also aim to enable visualisation of inositol phosphates by Raman spectromicroscopy, and their detection by easy-to-perform LC-MS methods. These novel techniques will help us achieve our main objective of elucidating how PP-IPs control metabolism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE
Title: Contextual Awareness, Response and Evaluation: Diabetes in Ghana
Funder: Medical Research Council

Abstract: Ghana is a lower middle income country where type 2 diabetes (T2D) affects approximately 6% of adults and prevalence is increasing, resulting in poor mental and physical health, premature mortality, and increased costs for individuals, families and healthcare services. There is an urgent need for cost-effective T2D prevention programmes designed specifically for Ghanaian populations. Any such intervention must address the broad socio-cultural and economic determinants and consequences of T2D that include traditions and customs, gender norms, urbanisation, living conditions and housing arrangements, rural-urban migration cycles, health service provision and market forces and regulation. We will conduct truly interdisciplinary research to understand the history, epidemiology, narratives, socio-ecological drivers, consequences and responses to T2D. We will use this contextual understanding to identify specific strategies and recommendations for intervention. This will include community, health system, market and policy level solutions and will recognise the emergent potential of appropriate digital interventions such as mHealth education and behaviour change, electronic decision support, and enhanced peer-to-peer communication and consultation systems. Further, we will adapt and test a Participatory Learning and Action (PLA) community mobilisation intervention for T2D. The PLA intervention, proven to reduce T2D prevalence and risk in Bangladesh by over 60%, works by facilitating community discussion, mutual learning to raise critical consciousness and foster collective action to reducing disease risk in general populations. With appropriate contextual adaptation, we hypothesise that PLA community mobilisation has the potential for substantial impact on reducing the T2D burden in urban Ghana.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Effect of urban vs rural context on effectiveness of a community intervention to prevent diarrhoea and stunting in young children in Mali
Funder: Medical Research Council

Abstract: We will undertake a mixed-method evaluation of a low-intensity, culturally engendered, and scalable community intervention to promote food safety and hygiene and child nutrition (breastfeeding and CF content) practices. We aim to evaluate (qualitatively and quantitatively) the effect of intervention on diarrhoea and growth parameters, understand mediating factors contributing to the outcome along the causal pathway to health outcomes, and assess the role of context in the outcomes, with a particular focus on the influence of urban-poor and rural areas. Design: Mixed-methods - qualitative/ethnography and a parallel cluster randomised controlled trial Study duration: 36m Trial site: Mali: cities of Bamako, Kati and Ségou and rural villages in the same provinces Trial Management Centre: the University of Sciences, Techniques and Technologies (USTT), Bamako Intervention: 5 days of campaign community visits dispersed across 35 days (days 1,2,17,15,35) plus volunteer home visits and a 9-month reminder campaign day Control: 1 day campaign community activities on use of water in households and gardens Follow-up: 15-months Minimisation Randomisation after clusters have ratified participation and after baseline Outcomes: Primary: Observed and reported 24-hour diarrhoea, (primary outcome is observed photographed diarrhoea during 7-9 hours home observation from early morning till afternoon) Other outcomes include: 4 health, 3 microbiological, 4 behavioural, 1 environmental, and 3 social outcomes; all helping to explain any changes in the causal pathway to transmission of infection and growth parameters. Sample size: 120 clusters stratified by urban and rural, ethnicity and community size, with 27 mother-child pairs in each: 90% power to estimate a 25% reduction in diarrhoea and 25% relative difference between rural/urban with interaction and 3 measurement points. Dissemination and Capacity Building Plan will be established and monitored.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Systemic analysis of the molecular mechanisms of leukocyte entry into the pancreas
Funder: Medical Research Council

Abstract: Migration of leukocytes into the pancreas is a key pathogenic step in the development of diabetes. In order to extravasate into tissues, circulating leukocytes must first make rolling contacts with the vasculature before forming firm adhesions and subsequently transmigrating through the endothelium and basement membrane. These processes depend on the expression of integrins, which facilitate intercellular and cell-matrix interactions, and chemokines, which guide cell migration. Current studies are predominantly candidate-based and limited to broad neutralisation or gene deletion models, which prevents analysis of the intrinsic requirements of different cell types to infiltrate the diabetic milieu. Our approach will use genetic screening and natural genetic variants to unravel the specific molecular pathways that need to be targeted to prevent diabetogenic immune cell entry in pancreatic tissue. We will use two complementary systematic approaches to identify key pathways facilitating immune cell entry into pancreatic tissue: ProCode CrispR screening and Collaborative Cross natural variant screening. The ProcCode CrispR approach uses transfection of gRNA-lentiviruses, each with a unique protein barcode, to generate a mouse that has a mosaic population of leukocytes with representations of multiple different knockout lines. We can use this system to simultaneously screen for the functional role of all known integrins, adhesion molecules, chemokine receptors and matrix remodelling enzymes in each defined leukocyte population entering the tissues. Collaborative Cross studies compare >200 inbred mouse strains with defined parentage from eight diverse founder strains. By qualitatively and quantitatively assessing pancreatic infiltrate in these strains, we can use the predefined genetics to identify the molecular mediators down to the gene level.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Precision medicine in diabetes: Pharmacogenetic studies of large randomised controlled trials of diabetes therapies
Funder: Medical Research Council

Abstract: There are now many treatment options in type 2 diabetes, with an increasing trend to using newer agents earlier due to their added cardiovascular benefit. This will greatly increase treatment costs, yet we know that some drugs are ineffective or cause adverse effects in some patients. We have established that glycaemic response to metformin is moderately heritable and it is likely that other response traits to other diabetes drugs are also heritable. We now propose that understanding this genetic variation will provide insights into drug mechanisms and the potential to select patient groups who will benefit most to specific treatment options. To date, pharmacogenomics in diabetes has been limited to older drugs and to observational data. We have published the first metformin GWAS on just 1000 patients. In the present proposal we have assembled over 30,000 patients from randomised trials of the newer diabetes drugs (SGLT2i, GLP1RA and DPP4i) with completed genome-wide data. Both SGLT2i and GLP1RA have shown reduction in cardiovascular (CV) risk, yet the mechanism for this remains uncertain. We propose to use genomic data for SGLT2i, GLP-1RA and DPP4i to: 1) run GWAS of 9 response traits (endophenotypes), 5 safety outcomes and 5 CV outcomes. 2) To use partitioned polygenic scores of diabetes risk to investigate what genetically defined aetiological processes alter response to these drugs. 3) To investigate tissue site of action using PrediXcan and pathways associated with response traits from Aim 1. 4) To investigate shared genetic aetiology between response endophenotypes and CV outcomes within and between different drugs using bivariate GREML, and to investigate causal associations between endophenotypes and CV and renal outcome. The identification of genetic variants that predict response and outcomes with SGLT2i, DPP-4i and GLP-1RA drugs will provide a major advance in personalized treatments for diabetes.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Mobile Health Biometrics to Enhance Exercise and Physical Activity Adherence in Type 2 Diabetes
Funder: Medical Research Council

Abstract: T2D is one of the top 10 global causes of death. Worldwide cases are forecast to rise, and healthcare costs directed to the management and treatment are increasing faster than gross domestic product. Exercise and PA are central components of initial T2D management, and are recommended by international consensus. Yet, many people with T2D do not perform enough PA to elicit clinical benefit and help manage the disease, despite patients recognising that regular PA is important. Therefore, the development of scalable and cost effective interventions to support exercise and PA as part of T2D management is a major priority. Current strategies; (i) prescription of supervised exercise or (ii) PA counselling, are either clinically effective but unsuitable in routine practice (supervised exercise), or suitable in routine practice but clinically ineffective (counselling). Mobile health technologies, providing biometric data to patients and health professionals, may bridge the gap between intensive supervised and PA counselling, enabling patients to engage in long-term physically active lifestyles, which include regular exercise. We propose a dual country randomised controlled pilot study to test whether a translational solution of exercise and PA counselling using mHealth technology and biometric data can improve activity levels over and above standard advice. We will implement a theoretical model whereby mHealth technology is utilised to programme a personalised home-based exercise and PA plan, where exercise session intensity and daily PA, through heart rate and step count, respectively, are visible to patients and monitored remotely by health professionals to improve feedback and motivational support. This model will specifically inform the NHS RightCare Pathway in the UK and Diabetes 360 in Canada. Moreover, the intervention will assist in reaching remote communities, a recognised health inequality in Canada.


Research activity codes: 6.3 MEDICAL DEVICES;6.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE
Title: Long-term health after Severe Acute Malnutrition in children and adults: the role of the Pancreas - SAMPA
Funder: Medical Research Council

Abstract: In Africa and Asia acute malnutrition (MALN) remains common while the prevalence of non-communicable diseases such as diabetes is rising. Diabetes may be found at younger age and lower body mass index (BMI) in Africa and Asia than in Europe. We wish to investigate whether postnatal MALN is associated with later exocrine and endocrine pancreas function and structure. We will follow up our cohorts in Tanzania, Zambia, India and the Philippines whom we previously recruited for studies related to MALN. The cohorts experienced MALN in utero, as children or as adults and are now adolescents or adults. Never-malnourished people are available as controls for all cohorts. We will investigate several aspects of pancreas structure and function: size, gross structure and microarchitecture by MRI, calcification by X-ray, exocrine function by faecal elastase and plasma lipase, endocrine function by oral glucose tolerance tests (OGTT). We will do in-depth hormonal analyses in subsets of adult participants with repeated blood samples during OGTT and intravenous GTT to investigate the role of incretins, and the relative contribution to glucose dysregulation of decreased insulin production and increased insulin resistance. We will analyse proinsulin/insulin ratio in archived samples from one cohort to investigate the time course of abnormalities preceding overt diabetes. We will conduct univariable statistical analyses and multivariable models guided by a conceptual framework. We will investigate whether sex, age, BMI and dietary pattern are modifiers of the MALN-outcome links. Even if we find no important link between MALN and later glucose metabolism, the research will improve understanding of both the long-term consequences of MALN and the phenotype of glucose dysregulation in Africa and Asia. It will thus lead to improved health care for people with malnutrition and those with diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: CHild malnutrition & Adult NCD: Generating Evidence on mechanistic links to inform future policy/practice (CHANGE project)
Funder: Medical Research Council

Abstract: WP1: DATA SYNTHESIS/STANDARDIZATION Our project involves data from 7 distinct patient cohorts. We will first harmonise available datasets, highlighting common variables & agreeing on joint data strategies & definitions of exposure/outcomes WP2: UNDERSTANDING HOW POST-MALNUTRITION-WEIGHT-GAIN (PMWG) INFLUENCES RISK OF NCD (towards objective 1) Existing data from 3 prospective cohorts forms a natural experiment whereby: -Jamaica-LION involved inpatient treatment for malnutrition and overall had the fastest rates of PMWG -Ethiopia-ACAM was outpatient-only and had slowest PMWG -Malawi-ChroSAM was mixed in/outpatient and had intermediate PMWG Secondary analysis will explore inter-&intra-site PMWG and its association with NCD variables already captured in the datasets WP-3: DESCRIBING BIOCHEMICAL CHARACTERISTICS OF MALNUTRITION SURVIVORS (obj. 2a) Old blood samples from J-LION, M-ChroSAM, E-ACAM cohorts will be combined with new blood/urine samples collected from Malawi-2002-4 and Ethiopia-1980s famine cohorts. Metabolomic and lipidomic analysis will attempt to identify differences between: malnutrition survivors vs controls; survivors with/without NCD WP-4: DESCRIBING BIOCHEMICAL PROFILES OF DIFFERENT PATTERNS OF PMWG (obj. 2b) Blood/urine samples will be collected from two new cohorts: an observational birth cohort in Malawi; a cohort nested in an Ethiopian RCT. Metabolic/lipidomic profiles of different post-malnutrition growth patterns will be described WP-5: IDENTIFYING BIOCHEMICAL SIGNATURES LINKING PMWG & NCD RISK (obj. 2c) Data from WP3&4 will be compared. Biochemical markers common to early malnutrition/PMWG and later NCD can be used in future work as early markers of NCD risk WP-6: GRIPP (Getting Research into Policy/Practice) & Stakeholder engagement/research co-creation (towards overall AIM) Qualitative work will explore views of PMWG & malnutrition/NCD risk. A follow-on RCT will be co-created with key stakeholders to maximise impact


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Developing a policy to reduce the salt content of food consumed outside the home in Malaysia
Funder: Medical Research Council

Abstract: Salt intake in Malaysia is around 9g per day. According to Malaysia's National Health and Morbidity Survey, 35.3% of adults aged 18 years and over had hypertension in 2015 and cardiovascular disease is the main cause of death and disability in the country. In our previous project, we assessed knowledge, attitudes and behaviours of Malaysian adults, salt intake in a representative sample of the population and sources of salt in the diet. While 86.2% of respondents know salt is linked to negative health outcomes, 61.8% do not think they consume too much salt. A leading contributor to daily salt intake is food consumed outside the home. This impact grant will fund qualitative research with stakeholders to determine barriers to salt reduction in the out of home sector. We will interview 385 stakeholders from government and policy, catering operators, the food industry, street vendors and consumers via focus groups or semi-structured interviews to identify perceived barriers, analyse via thematic analysis and use these results to develop a strategy to reduce salt content in food sold in the out of home sector. We will also organise high level meetings with policy makers to gain commitment to the strategy and conduct capacity building activities, including training workshops and lectures, to help raise awareness of the need for salt reduction in chefs and caterers.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: METABOLIC AND ENDOCRINE
Title: Expanding the reach, impact and sustainability of ToyBox Study Malaysia: a kindergarten-based healthy behaviour intervention
Funder: Medical Research Council

Abstract: This project will increase the reach and sustainability of the ToyBox Study Malaysia kindergarten-based intervention. Impact will be extended by: (1) Translation of research outputs to improve teacher training and family engagement: a. Enhance the Train the trainers approach based on experience and feedback from ToyBox research: i. Increased understanding of behavioural and social factors contributing to health behaviours among preschool children ii. Empowered to act on this knowledge. b. Translate research intervention into pre-packaged programme materials (videos, animated stories). c. Develop, maintain and update programme materials on website. New online training and teaching materials will be developed to allow more flexibility in terms of time and environment and to reduce cost in training preschool teachers; online interactive teaching materials will make learning process more fun for teachers, children and their families. (2) Strengthen partnerships and knowledge exchange: a. Policy brief: Advice on programme sustainability and evaluation. b. Policy and legislation: Point of contact for expertise on the programme for policy makers and practitioners. c. Community benefits: Increased support in preventive strategies to promote healthier lifestyle for children and families. The experience of KEMAS and their kindergartens in implementing Toybox previously, their insights and understanding of the barriers for Toybox programme, will be invaluable in developing relevant and effective training and teaching resources for preschool teachers and children. We will also include additional stakeholders beyond KEMAS to bring Toybox to a wider community in Malaysia (e.g. Min. of Ed., Perpaduan). (3) Innovation: a. Develop interactive WebApp (videos, animation) and update programme materials as required (for new potential users, existing ToyBox users and researchers). b. Embed user surveys and monitor engagement using the Website/App feedback platform (Qualtrics).


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE