NIHRDataInsights/HRCSData huggingface dataset:
Title: HQLC Dementia Carers Instrument Development: DECIDE
Funder: Medical Research Council

Abstract: DECIDE has 3 objectives: 1. develop a quality of life measure for carers of people with dementia (Carer-QoL) 2. test key assumptions embedded in the current approach to measuring the benefits of healthcare interventions and 3. estimate preliminary values for the Carer-QoL. The project comprises 2 workstreams (psychometric and valuation) running in parallel. Workstream 1 psychometric (3 phases). Phase 1, item pool generation employing a needs-based approach through interviews of 42 purposively sampled carers. Phase 2, Item refinement following cognitive interviews with 24 carers. Phase 3, Psychometric evaluation employing Rasch methods to ensure the final item set is unidimensional and satisfies requirements necessary to enable transformation to interval scaling. Carers (n=400) will complete the item pool and the EQ-5D with a subset re-completing the item pool for test-retest reliability and sensitivity to change analyses. Workstream 2 valuation (3 studies). Study 1 compares health state values (EQ-5D derived) in carers and non-carers (n=1,000) using online surveying of self-reported health status using visual analogue scale rating and presenting descriptions of 8 "hypothetical" health states selected from the most frequently recorded EQ-5D health states. Study 2 will estimate the relationship between a draft Carer-QoL (Workstream 1 generated) and the utility-weighted index form of EQ-5D. Study 3 will quantify Carer-QoL values through direct valuation using an online Discrete Choice Experiment. Carer profiles will be generated from the draft carer-QoL items. Carers and non-carers (n=1,000) will select carer profile preference from a list of paired carer profiles. From this it will be possible to place a value on the Carer-QoL scores from both the carer and general population perspective. DECIDE outputs and data will be available for other researchers, clinical, social and voluntary service organisations, practitioners and government agencies.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: A general framework to adjust for missing confounders in observational studies
Funder: Medical Research Council

Abstract: We propose a general framework to deal with the confounding issue in epidemiological studies, integrating different sources of data. Administrative registries to study the relationship between an exposure X and an outcome Y ensure good population coverage and high statistical power to detect small effects or to analyse rare end points. However they do provide information on a limited set of confounders, thus suffering from residual confounding issues and leading to potentially biased results. Our strategy is to integrate registries with cohorts/surveys that contain a rich set of potentially confounding variables; however as these are based on population samples, information is only available for a subsample of the units in the registries, thus calling for imputation of the missing data. We will build a propensity score like index (PPS) to summarise the partial measured confounders from the cohorts/surveys so that only one variable needs to be imputed. The index is obtained regressing X against all the confounders and is then included in the regression model to link X and Y in a flexible way. Framed in a Bayesian perspective we will specify a joint model which incorporates the index construction, imputation and link with the health outcome, thus allowing for uncertainty to be propagated across all parts. At the same time we will investigate the impact of information from the outcome and from the exposure on the imputation of the missing PPS (called feedback in Bayesian literature). We will build the framework for individual level data and extend it to deal with small area aggregated data, commonly used in spatial epidemiology for the analysis of geographic patterns of diseases with respect to environmental, demographic, socioeconomic factors. We will apply our framework to two case studies and investigate how the epidemiological results are modified compared to the standard modelling approaches.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: HOD: Assessing risk of bias in non-randomized studies of interventions
Funder: Medical Research Council

Abstract: We propose a methodological programme of theoretical, applied and empirical research targeted at understanding strengths and weaknesses of non-randomized studies of the effects of interventions. The project will build on an initial version of A Cochrane Risk Of Bias Assessment Tool: Non-Randomized Studies of Interventions (ACROBAT-NRSI), which we made available in September 2014. First, we will consolidate the first version of ACROBAT-NRSI by considering its face validity. This will be achieved through formal reviews of literature relevant to its theoretical and empirical basis; and through investigation of the extent to which the tool identifies potential causes of discrepant results in specific instances where non-randomized studies and corresponding randomized trials have reached different conclusions. We will then develop ACROBAT-NRSI so that it addresses a wider variety of study designs, including time series studies, before-after studies and natural experiments, and analyses such as those based on instrumental variables and regression discontinuities. This will be done by setting up a series of working groups, culminating in a meeting of co-investigators and invited experts to decide on a revised tool version through consensus. We will then implement the revised tool in a large number of non-randomized studies within a meta-epidemiological study to examine empirically the relationship between assessments made using the tool and effect estimates. Finally, we will producing an interactive, easy-to-use online version of the revised tool in which structure, guidance and a suite of informative examples are seamlessly integrated.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding and targeting chromatin-surveillance mechanisms in human ageing
Funder: Medical Research Council

Abstract: A common cellular feature between progeroid laminopathies and physiological ageing is chromatin disorganization. Yet, the mechanistic understanding and therapeutic reversal of these chromatin perturbation's onset remain challenging. Having recently discovered the c-Abl-mediated KAT5 phosphorylation (KAT5-pY44) as a mechanism for chromatin surveillance; here, we hypothesized that this pathway operates in cell-models of ageing. Thus, we detected KAT5-pY44 in progeria and lamin-A/C-depleted cells, and found that drug-based inhibition of KAT5-pY44 reverses their chromatin disorganization and alleviates their overall cellular defects. Hence, our central hypothesis is that KAT5-pY44 senses initial chromatin perturbations in ageing cells, thereby contributes to the onset of further defects in chromatin organization resulting in overall cellular unfitness. This proposal seeks to mechanistically determine how KAT5-pY44 ensues upon lamin-A/C loss-of-function and to establish the molecular bases for the protective effect of inhibiting KAT5-pY44. We will use cell-based genetic complementation systems and pharmacological inhibitions in combination with quantitative cellular and molecular biology approaches to determine: -The direct contribution of inhibiting KAT5-Y44 phosphorylation to the cellular amelioration of lamin-A/C-depleted cells. -How KAT5-Y44 becomes phosphorylated in progeria and lamin-A/C-depleted cells. -The direct effects of KAT5-pY44 in progeria and lamin-A/C-depleted cells. -How inhibiting KAT5-pY44 mechanistically increases the fitness of lamin-A/C-defective cells. This study will provide new mechanistic insight into the causal contribution of chromatin disturbances to the overall defects in ageing cells, and will shed light on this challenging research area. Also, it will open potential therapeutic opportunity for laminopathies with possible impact on improving life-quality during normal ageing, which may in the longer term influence public health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural basis of meiotic chromosome organization by the synaptonemal complex.
Funder: Medical Research Council

Abstract: Sexually reproducing organisms rely on the process of meiosis for the generation of genetic diversity across generations. At the physical and functional centre of meiosis is the synaptonemal complex (SC), an evolutionarily conserved proteinaceous ultrastructure that mediates synapsis and genetic exchange, by holding homologous chromosomes in close and orderly juxtaposition during DNA recombination. Correct SC assembly is essential for proper recombination and segregation of homologous chromosomes and therefore ultimately for successful completion of meiosis, upon which human fertility depends. So far, our knowledge of SC function in meiosis has been based largely on genetic and cellular studies. However, lack of detailed knowledge about the molecular structure of the protein components of the SC and their mechanism of assembly restricts severely our current understanding of SC function in meiosis. In 2010, we initiated a research program aimed at providing a structural basis of SC function through the biochemical reconstitution and biophysical analysis of SC proteins (Davies et al, Open Biol, 2012; Syrjanen et al, eLife, 2014). The current proposal builds on our most recent work, to focus on the role played by SC proteins SYCP2 and SYCP3 in defining the 3D-architecture of the meiotic chromosome, which is essential for correct homologue pairing and crossover. To achieve our aim, we have designed a multi-disciplinary research plan that includes biochemical, structural, biophysical and cellular experiments, at bulk and single-particle level. Our work will advance our understanding of the molecular mechanisms underpinning genetic recombination in meiosis and ultimately human fertility. Furthermore, it will illustrate molecular principles of DNA organisation that will be relevant to our understanding of chromosome structure and dynamics and of pathologies resulting from aneuploidy and incorrect chromosome segregation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Elucidating novel pluripotency signalling networks
Funder: Medical Research Council

Abstract: Pluripotent Embryonic Stem Cells (ESCs) have the capacity to differentiate into all cell types in the adult body, and their application for the purposes of regenerative medicine and disease modelling has shown significant promise in recent years. However, it remains a challenge to harness the developmental capacity of ESCs, thereby capturing distinct pluripotent and differentiated states for use in regenerative therapeutics. A highly promising novel approach is to identify components of the phosphorylation machinery that control pluripotency and differentiation. Phosphorylation networks ultimately modulate the function of key regulatory targets such as transcriptional circuits to direct developmental potential. However, the kinases involved in these regulatory systems have not been extensively explored. Here, I propose to uncover fundamental molecular bases of pluripotency regulation and identify strategies to manipulate key signalling components using small molecules. The primary aim of this project is to identify novel kinases and mechanisms by which phosphorylation controls gene expression to modulate the developmental potential of ESCs. Preliminary data from my lab suggests that the ERK5 kinase signalling pathway is a key regulator of pluripotency, and I will explore the molecular mechanisms underpinning this regulation. I will also exploit an inter-disciplinary combination of cutting-edge chemical biology, gene editing technology and phenotype-based analysis to identify and specifically perturb novel kinases that modulate ESC pluripotency. My extensive preliminary data, including identification of the ERK5 pathway and validation of a high-throughput screen for kinase inhibitors that modulate pluripotent ESC states, demonstrates the feasibility of the proposal. This research will generate new opportunities for chemical manipulation of ESC phosphorylation networks, allowing distinct developmental fates to be synthetically programmed in the laboratory.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: PHOSPHOINOSITIDES IN CILIA FUNCTION AND CILIOPATHIES
Funder: Medical Research Council

Abstract: To determine phosphoinositide (hereafter PIP) content in ciliary and periciliary membranes, we will express PIP sensors in living zebrafish embryos. These sensors consist of PIP binding pleckstrin homology (PH) domains fused to a fluorescent tag, such as GFP. We chose PH domains because they are small and their binding specificities are well defined. Although such sensors have been used in tissue culture, their uses in intact organisms have limited history. By imaging the embryo, we will determine PIP content in physiologically relevant conditions at several stages of embryogenesis in a broad range of tissues. In parallel, we will test the function of several PIPs by either down- or up-regulating their ciliary content. To do that, we will take advantage of the ability to efficiently and specifically target exogenous proteins to cilia. Using this approach, we will target to cilia PIP kinases and phosphatases of well-characterized specificities. These enzymes will either decrease or increase the concentration of specific PIPs in the cilium. Because cilia are small, imaging PIPs in cilia requires particularly sensitive tools. To improve sensitivity of PIP detection in cilia, we designed a sensor that is initially actively targeted to cilia via small molecule-mediated dimerization with a ciliary protein. Once the dimerising agent is removed, sensor retention rate in cilia is indicative of PIP content. Numerous human ciliopathy genes are likely to affect ciliary PIP content. We will use PIP sensors to determine PIP content alterations in zebrafish mutants that model human ciliopathies. Moreover, we will manipulate ciliary PIP content to alleviate pathologies in such mutants. This project will enhance our understanding of ciliary function in normal development and physiology and reveal pathological processes that contribute to human disease. We will also generate tools broadly applicable to study cell biology of many cilia-related processes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Looking for a Home? - Stem Cell Migration
Funder: Medical Research Council

Abstract: Aim: To investigate the therapeutic efficacy of pharmacological methods of mobilising mesenchymal stem cells (MSCs) into the blood; their ability to home to the fracture, and their potential role in fracture healing; and whether these mechanisms can be genetically exploited to enhance regeneration further. Objectives: 1) To determine the most effective protocol to mobilise MSCs in the rat. 2) To determine if mobilised MSCs differ from bone marrow (BM) isolated MSCs. 3) To determine if mobilised MSCs can be used therapeutically and contribute to bone healing, both by innate homing and after extraction and processing. 3) To determine if intentionally increasing the expression of homing signals can further increase fracture localisation and healing. Methodology: In a rat model, the CXCR4-SDF1 axis, which modulates stem cell migration and homing, will be exploited. AMD3100, a selective antagonist of CXCR4, will be used to mobilise MSCs into the blood. MSCs will be assayed through FACS, plastic adhesion, CFU-F and tri-differentiation and compared with BM isolated MSCs. An established osteotomy model will be used and comparison of local MSC administration to systemic administration will be made. Processed cells will be traced with cytoplasmic highly fluorescent quantum dot (QDot) tracker nanocrystals. We will further exploit MSC homing to damaged tissues where SDF-1 has been shown to be upregulated, by CXCR4 adenoviral transfection of MSCs. Functional healing will be mechanically tested, and tissue regeneration will be assessed through histology, radiography and pQCT. Opportunities: This represents a significant change in methodology for implementing stem cell/regenerative medicine therapies. It could have significant cost and patient morbidity savings. As a methodology, mobilising stem cells within the body to augment healing may have clinical benefit beyond the fracture healing model outlined here, to many other diseases.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Genomic prediction of anthropomorphic traits using hundreds of thousands of individuals
Funder: Medical Research Council

Abstract: Genome-wide association studies have identified a large number of genetic variants associated with complex traits. Despite the importance of these discoveries, it is clear that translation into medically useful tools that could help tailoring disease management to the genetic make-up of the individual has lagged behind. We will use genotypes to predict nine quantitative traits measured in the UK Biobank, which comprises around 500,000 individuals. We have shown by simulation that, for a range of heritabilities and genetic architectures, this sample size should allow us to achieve prediction accuracies that are clinically relevant. We now propose to test this using real data. Both, the large sample size of the UK Biobank and the software that we have developed will allow us to develop accurate genetic predictors of these complex phenotypes. We will use mixed linear models to model additive and non-additive sources of genetic variation, and will develop computationally efficient approaches that could be used to combine information of multiple datasets when it is not possible to share individual level data across multiple cohorts. Our predictions will be validated using internal and external cross-validation. This is a proof of principle proposal: if genomic prediction worked for exemplar quantitative traits, then it would likely work for other disease or quantitative traits provided that large training datasets were available for analysis and would take us one step closer to personalised medicine.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: The EPIC-Norfolk prospective population study: biological and behavioural determinants of health and disease in an ageing population
Funder: Medical Research Council

Abstract: The aim of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) is to help us understand what we can do to improve health and prevent disease and disability in later life. There is a particular focus on patterns of diet and physical activity. EPIC-Norfolk is a study of 30,000 men and women living in Norfolk who first agreed to take part in the study in 1993 when aged 40-79 years of whom 25,623 attended a detailed health examination in 1993-1997 and who have been followed up to the present for health. This is a very well characterised population with extensive baseline data available on behavioural factors, health including medical and family history, and anthropometry, assessment of heart disease risk factors including blood cholesterol and blood pressure, and provided blood and urine samples for analysis and for establishment of a biological sample bank. Participants have continued to take part in repeated health assessments 1997-2000 and 2006-2011 with further Participants have continued to take part in repeated health assessments with further measures to assess bone health, eye health and visual function, and physical and mental performance, the most recent being between 2006-2011, and answered further questionnaires about their health including psychosocial factors such as stress and anxiety, sleep patterns and quality of life. All participants have been followed up to the present for health outcome including total mortality by cause and disease incidence through routine record linkage with health records. We are proposing to continue maintenance and follow up the cohort, including testing of new hypotheses relating to health and disease, and to resurvey the cohort to characterise longitudinal trajectories of objective physical and cognitive functional performance.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Ensuring test evaluation research is applicable in practice: investigating the effects of routine data on the validity of test accuracy meta-analyses
Funder: Medical Research Council

Abstract: Aims Diagnostic test accuracy (DTA) research is not always informative in practice. Primary DTA studies and meta-analyses may produce results that do not transfer to practice. Recently we developed methods that evaluate the validity of DTA meta-analyses and incorporate routine data to generate a tailored meta-analysis (TMA) estimate that is specific to the practice. Both of these need further development and evaluation. Objectives 1. To synthesise a database for use in other work streams and review constrained models 2. To develop models which incorporate constrained data 3. To investigate methods which determine the validity of DTA review's results 4. To explore integrating the TMA model into UK General Practice Methodology There will be 4 overlapping work streams (WS) WS 1 We will construct a database of different cases of DTA meta-analyses with associated routine practice data collected on the test to provide input data to WS 2-4. We will also review methods that explore modelling constrained data WS 2 This will develop other models that include all studies but weight the less probable studies accordingly. We will investigate both a constrained maximum likelihood and a Bayesian approach. In addition, we will use covariate modelling in meta-regression analyses to explore causes of heterogeneity WS3 The validity of meta-analysis results may be determined by combining a cross validation procedure with an appropriate method for comparing primary and secondary study estimates. We have developed one method which predicts where a new study is likely to lie, but other approaches are possible and these will be investigated WS 4 The TMA model for test evaluations will be integrated into general practice so GPs may apply it to their patients. Templates will be designed within the electronic records system (ERS) to collect routine data. The TMA model will be developed as a web-application to access from the ERS and will be tested in 6 practices


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE