NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of methods for the analysis of complex survival and joint longitudinal-survival data with application to linked electronic health records
Funder: Medical Research Council

Abstract: The first project will develop parametric multi-state models, combining various families of standard parametric models, with more flexible approaches using splines, estimated jointly, allowing a general framework where each state can be modelled using different or the same family of models, greatly extending existing approaches. There will be a concerted effort to provide easily interpretable predictions and summaries of the impact of risk factors on outcomes, such as differences and ratios of transition probabilities or length of stay, across changing covariate patterns. Multi-state profiles occur commonly in areas such as cardiovascular disease, cancer and infection, and therefore this project has the potential to impact widely across the health domain. The framework will be extended to a semi-Markov setting, to account for the likely association between previous and future events, an assumption which is often ignored. The second area will be to extend joint longitudinal-survival models. Firstly, we will incorporate sampling weights into the joint likelihood, in a case-cohort approach, both at the observation and patient-level, which will enable their use in large epidemiological datasets. Secondly, they will be extended to allow a general level model, using adaptive Gauss-Hermite quadrature to calculate the M-level likelihood, and also derive analytic derivatives for extensive computational benefits. Such data occurs widely, such as biomarkers nested within patients, nested within GP practice. This project is centred on addressing substantial limitations in key methodological areas, within the field of survival analysis, to provide accessible models which can be used in a diverse range of clinical research. Each development will be directly utilised to answer important clinical questions in heart disease and cancer research. Finally, user-friendly software will be provided, complimented by training courses to provide platforms for their use in medical research.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding disease through environment-wide association studies
Funder: Medical Research Council

Abstract: Susceptibility to disease is influenced by the genotype, the environment and their interactions. Genome-wide association studies (GWAS) have become widespread and serve as a highly successful hypothesis free approach to identify genetic variants associated with disease. Hypothesis free quantification of risk factors, including, for instance, external environmental exposures and behavioral lifestyle choices, on the other hand has received comparatively little attention. In this project we will develop and apply methodology to perform Environment-wide Association Studies (EnvWAS) whilst adjusting for large numbers of genetic markers in samples of unprecedented size. We will showcase the methodology using myocardial infarction and stroke as exemplars. Power of EnvWAS could potentially be increased by using generalized linear mixed models (GLMM) that will allow us to adjust for the genetic make-up of participants, similar to adjusting for a polygenic effect when testing individual variants within a GWAS. Utilizing distributed computation on computer clusters we will implement algorithms that will allow for fitting of the necessary GLMMs with dense covariance structure on sample sizes of hundreds of thousands of individuals. Using incident cases and the rest of ~460,000 White-British individuals in the UK Biobank as controls we will test for association of ~1200 potential risk factors with myocardial infarction and stroke. Estimates of effects for significantly associated risk factors will be obtained by fitting them in a joint model. Finally, the shared environmental and genetic burden between the two diseases will be investigated.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Going beyond health related quality of life - towards a broader QALY measure for use across sectors
Funder: Medical Research Council

Abstract: The aim of this project is to develop a measure of quality of life that is valued on the zero to one scale necessary to calculate Quality Adjusted Life Years (QALYs) for use in economic evaluation, which gives due recognition to the impact of clinical, public health and social care interventions on physical and mental health and broader emotional health and wellbeing on service users and their families/carers. To achieve this aim we will develop a classification system that reflects the impact of clinical, public health and social care interventions on physical and mental health and broader emotional health and wellbeing on service users and their families/carers using a full range of evidence with full public involvement in all stages. This will be based on a mixed methods study. Qualitative review of the literature and interviews will be used to generate core themes which will be combined with quantitative psychometric analysis of a large data set. Items will be generated for the core themes and face validity tested through interviews (n=50) with patients, social service users and their carers, and psychometric testing on data from a large general population and service user survey (n=2000) in order to select the final items for a classification system. The classification system will be valued in two general population samples using time trade off (n=600) and a deliberative approach (n=20). Values from the two approaches will be compared. The weights for the new measure will be used to re-weight the EQ-5D in order to examine the impact the new measure is likely to have on decision making priorities.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Sustainable day-care for 1-4 year olds in disadvantaged urban communities in Dhaka, Bangladesh
Funder: Medical Research Council

Abstract: Low-income countries are experiencing rapid and uncontrolled urbanisation [1;4]. With a population of 16 million, a quarter of whom are slum-dwellers, Dhaka, Bangladesh exemplifies this transition. The poor infrastructure and conditions of slums limit child health and development [2; 3; 9]. Increasing numbers of urban poor women are working outside the home [9], often leaving children with limited supervision. The 1-4 year age group are particularly vulnerable to injuries, poor nutrition and infections, yet intervention at this age can positively impact physical and cognitive development [2;5]. A 2011 systematic review showed day-care improved early childhood development (ECD), but also identified no robust studies of urban day-care in Asia or Africa, and insufficient quality evidence to assess health outcomes. Our partners, CIPRB, have shown that community day-care for 1-4 year olds in rural Bangladesh is effective in reducing all-cause mortality by 44% (95% CI: 20% to 61%), drowning by 82% (95% CI: 42% to 94%) and injuries by 88% (95% CI: 61% to 96%) compared to children not in day-care [9]. We wish to adapt this model so that it can be appropriately, feasibly and sustainably delivered to benefit urban disadvantaged communities. This early phase study will: (1) use a survey and qualitative interviews to understand the extent and nature of demand for day-care amongst slum and non-slum households. (2) Co-produce, with communities, government and NGOs, a proto-type self-sustaining, child day-care model focusing on ECD, nutrition and hygiene improvement. (3) Use participatory action research to test and refine the model in one of Dhaka's largest slums. (4) Assess the feasibility and then refine methods for recruitment, assessment and follow-up among day-care users and a potential comparator group. The outcomes of this research will inform the design and pilot testing of a future evaluation to assess the cost-effectiveness of the day-care model.


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: Pathways governing the competitive behaviour of pluripotent cells
Funder: Medical Research Council

Abstract: Ensuring that mutations are not propagated within stem cell populations is key to proper development and homeostasis. This is especially relevant when it comes to pluripotent cells, that not only can give rise to all lineages, including the germ line, but that are also of great importance to regenerative medicine. We have found that cell competition is a novel mechanism that ensures the fitness of the mammalian pluripotent stem cell pool. We found that during the onset of differentiation, cell competition measures the relative fitness of pluripotent cells and eliminates those cells that are less-fit than their neighbours. This implies that cell fitness is not only a cell-intrinsic property, but is also measured relative to a cells' neighbours. We do not know how cells perform this relative fitness sensing and this will be the thrust of this proposal. In preliminary work to this proposal we have identified that specifically when wild-type and defective pluripotent cells are confronted with each other at the onset of differentiation, the defective cells decrease mTOR signalling and this decrease is sufficient to explain their elimination. Furthermore, we have shown that restoring mTOR signalling in loser cells is sufficient to rescue their elimination. These results indicate that the mTOR pathway is key read-out of the competitive behaviour of cells. Here we will do four things. First, we will study the pathways regulated by mTOR during differentiation to understand how mTOR mediates defective cell elimination. We will also study the signals upstream of mTOR to gain insight into the mechanisms by which cells communicate their relative fitness levels. Third, we will screen for novel pathways that regulate cell competition. Finally, we will study what happens when cell competition fails to gain insight into the fate of cells not eliminated by this mechanism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The structure and function of the beta-barrel assembly machinery: an Achilles heel of Gram-negative pathogens
Funder: Medical Research Council

Abstract: The goal of this 5-year progamme grant is to deliver a step change in our understanding of how the proteins that comprise the outer membrane of E. coli are folded and inserted into the crowded outer membrane (OM): a feat achieved the beta-barrel assembly machinery (BAM). This integral membrane protein complex is comprised of five polypeptide chains in E. coli and is essential in all Gram-negative bacteria, including major human pathogens. Despite an explosion of structural information about BAM in the last 6 months, including our own 4.9 Å resolution cryo-EM structure, how BAM recognizes its substrate OMPs and catalyzes their folding into the OM remain unknown. Here we will combine state-of-the-art cryo-EM, with ensemble and single molecule FRET, and functional assays of BAM in liposomes, nanodiscs, SMALPs and in E.coli, to reveal how this fascinating molecular machine functions. Using cross-linking and freeze trapping we will attempt to trap BAM caught in the act of OMP folding. We will also use cryo-ET to visualize BAM in 'OMP islands' in vivo and in a proposed supercomplex that spans the OM. The experiments build on a plethora of preliminary data that demonstrate the feasibility of the challenging experiments proposed. Specifically, we will address the following questions: - How does the conformation of BAM change during its functional cycle? - How does the native lipid environment affect BAM structure and function? - How does BAM fold and assemble OMPs into the OM? - How does BAM interact with the OMP-delivering chaperone SurA? - What is the structure of BAM in situ in the bacterial OM? Answering these questions will reveal fascinating new insights about this important molecular machine that is conserved from bacteria to man. Crucially, it will also provide opportunities for structure-based design of reagents able to inhibit BAM function, and thus to kill pathogenic microbes or render them susceptible to existing antimicrobial agents.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the role of retromer-like in endolysosomal cargo sorting in health and disease.
Funder: Medical Research Council

Abstract: The endolysosomal network sorts thousands of integral membrane proteins (termed cargos), and is essential for organelle biogenesis, maintenance, and quality control. Our research seeks to achieve a thorough mechanistic understanding of endolysosomal cargo sorting, specifically how cargo are retrieval from the lysosomal degradative fate and export and recycling to various organelles. Retromer is a heterotrimer of VPS35, VPS29 and VPS26, that has emerged as a key regulator of cargo sorting that is de-regulated in Parkinson and Alzheimer disease. In the current programme we build on our discovery of 'retromer-like' (RETL), an evolutionary conserved heterotrimer of C16orf62, DSCR3 and VPS29 that orchestrates retromer-independent endolysosomal sorting of cargos that include integrins and low-density lipoprotein receptors. Using an array of cutting-edge techniques, from protein biochemistry, quantitative proteomics and in vitro analysis in cell culture through to disease-associated studies and in vivo analysis in Drosophila, we will address two inter-related aims (in conceptual order). First, the fundamental question of how RETL functions to regulate endolysosomal cargo sorting. Here we will define the underly principles behind assembly of the RETL heterotrimer, establish the cargo proteins sorted via the RETL complex, and how RETL assembles accessory proteins to form a function sorting coat. Secondly, we apply acquired knowledge to establish how RETL-mediated cargo sorting contributes to cell, tissue and organism-level physiology in health and disease. Here we focus on RETL-mediated integrin sorting in cell migration, including the in vivo analysis of Drosophila hemocyte migration, and the role of RETL in neuronal function and viability using in vitro iPS cells and Drosophila photoreceptor as model systems. For the latter, we explore the potential plasticity between retromer-dependent and RETL-dependent endolysosomal cargo sorting.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the roles of distinct fibroblast subpopulations in skin homeostasis and disease
Funder: Medical Research Council

Abstract: Our goal is to understand how fibroblast heterogeneity contributes to pathological dermal changes. To do this we will characterise fibroblast lineages in adult mouse skin (aim 1); and discover how they contribute to injury-induced skin fibrosis (aim 2), to acute and chronic skin inflammation, and skin tumour development (aim 3). In aim 4 we will translate the findings from mouse models to human skin by identifying human fibroblast subpopulations and assaying their functions in vitro and in vivo. The underpinning methodology for aims 1-3 is using Tamoxifen-inducible Cre recombinase to express fluorescent reporters of different fibroblast subsets. The location and properties of the fibroblasts will be evaluated by confocal microscopy of histological sections, whole mounts and flat mounts and by flow cytometry of isolated cells. The model of injury-induced fibrosis (aim 2) is application of Bleomycin via an osmotic mini-pump. To study inflammation and development of benign and malignant skin tumours we will use 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) skin carcinogenesis (aim 3). In aim 4 we will filter gene expression profiles of human fibroblasts from different dermal layers against mouse datasets to identify candidate human subpopulations and validate them by antibody labelling of healthy and pathological human skin. Using flow cytometry to isolate human fibroblast subpopulations, we will examine their properties in culture, including immunomodulation, proliferation, alphaSMA expression and ECM production. We will also model human fibroblast dynamics in vivo during skin reconstitution and in grafts of fibrotic skin on NOD/scid/IL-2Rgamma-/- mice. In Aims 2-4 we will attempt to alter connective tissue by selective killing or expansion of fibroblasts of interest. The research has the potential to identify new therapeutic strategies to treat fibrosis and prevent tumour spread.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of TPD52-like proteins in cell migration and disease
Funder: Medical Research Council

Abstract: Cells modulate the levels of proteins on their surface. They do this to control how they respond to external cues and to change how they adhere to, and migrate on, surfaces. One way that cells modulate the density of their cell surface proteins is to change the relative rates of internalization and reinsertion of proteins at the plasma membrane. While much is known about the endocytic machinery, less is known about the proteins involved in recycling receptors back to the plasma membrane. The tumour protein D52 (TPD52)-like proteins TPD52 and TPD54 are known to be involved in intracellular membrane trafficking, but their precise role is unclear. They are found on various types of intracellular vesicles and our preliminary work shows that these vesicles are positive for Rab4, Rab11a and Rab25 (recycling vesicles) but not other Rabs such as Rab5, Rab7 and Rab9. Cell migration and invasion is dependent on the recycling of integrins, and Rab4, Rab11a and Rab25 are known to be involved in these pathways. There are three aims of this project. First, we will define the function of TPD52 and TPD54 on the endocytic recycling pathway. Second, we will uncover the role of TPD52 and TPD54 in cell migration and invasion. Third, we will understand the activity of TPD52 and TPD54 in integrin recycling. The project will therefore investigate membrane trafficking in the physiological process of cell migration which is important in health and in diseases such as cancer and heart disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding how the NuRD complex assembles and functions in mouse embryonic stem cells (mESC's)
Funder: Medical Research Council

Abstract: We have developed a novel chromosome conformation capture (Hi-C) method to determine genome structure in single mouse ES cells. We find that highly NuRD-regulated genes form clusters (which we confirmed using super-resolution microscopy) that associate with active enhancers/promoters, which bind key transcription factors such as KLF4. These results suggest that NuRD may regulate the binding of key transcription factors. We now want to understand how NuRD assembles and how it affects the binding of e.g. KLF4 to regulate gene expression. To study NuRD assembly we have purified a core NuRD complex, with deacetylase but not chromatin remodelling activity, and have carried out preliminary cryo-EM and cross-linking mass spectrometry (CL-MS). We have also purified larger NuRD complexes with the chromatin remodeller CHD4, as well as complexes of CHD4 and mono-/di-nucleosomes. To understand how the various components contribute to NuRD activity, we will use a deacetylation assay and a single-molecule Förster Resonance Energy Transfer (FRET) assay for nucleosome remodelling. We will also use these assays to study small molecules that have been found by our collaborators to bind to NuRD, or to regulate Human stem cell self-renewal, and utilise them in the single-molecule imaging approaches described below. Finally, we will determine structures of NuRD/nucleosome complexes by cryo-EM/CL-MS, and later by X-ray crystallography after generating smaller constructs from limited proteolysis and CL-MS analysis. In parallel, we have developed approaches for single-molecule tracking of proteins in live ES cells and we have developed a novel single-molecule FRET approach for the tracking of protein complexes. These studies have suggested cell-cycle dependent assembly of NuRD. We would now like to use these approaches to study how NuRD assembles at specific genomic loci and how it affects the binding of proteins like KLF4.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Harnessing electronic health records to monitor the progression of chronic diseases
Funder: Medical Research Council

Abstract: EHR data Dementia: D-CRIS contains data on N~7,000 with at least 3 MMSE observations, current medication use will be used as a proxy for co-morbidities. Chronic Obstructive Pulmonary Disorder (COPD): CPRD contains data on N ~ 117k COPD patients with at least two FEV1 observations, plus co-morbid diagnoses. Chronic Kidney Disease (CKD): SIR (primary and secondary) contains creatinine and co-morbidity data on over 23k patients with CKD. Objectives: 1. Model disease progression and the effect of co-morbidities using standard approaches stratified by disease stage or type 2. Investigate the utility of alignment approaches for characterizing the effect of co-morbidities on disease progression 3. Examine whether latent classes can be used to identify clinically meaningful subgroups with different progression characteristics 4. Use findings to extend existing disease specific models and develop personalised medicine approaches Methods Objective 1: Mixed effect models of patients with same disease stage or type at first visit. Joint longitudinal and survival models will be used to assess impact of missing data due to death. Objective 2: Villemagne alignment will be tested in a simulation study, before being applied to study patients who have the relevant diagnosis by last visit. Regression will be used to relate model residuals to co-morbidities. Objective 3: The existence of subgroups will be assessed by looking for multimodality in distributions from objectives 1 & 2. If evidence for subgroups exist, latent class extensions to alignment or mixed effect models will be used. Objective 4: Models from objectives 1 - 3 will be used to extend established disease progression models, which will then be used for decision support tools. Potential additional objectives: Study individual-level treatment effect in EHR embedded trials or in observational EHR treatment studies. Additional use cases, e.g. visual acuity in macular degeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE