NIHRDataInsights/HRCSData huggingface dataset:
Title: What is the value of adaptive designs? Estimating expected value of sample information for adaptive trial designs.
Funder: Medical Research Council

Abstract: Adaptive trials, as opposed to conventional trials, are those that change aspects of their design in response to interim analyses. Expected value of sample information (EVSI) estimates the economic value of trial designs to national health service decision makers. Our project aims to apply EVSI to the design and prioritisation of real-world adaptive trials exploring clinical and cost-effectiveness of competing interventions. The cost-effectiveness models underlying the EVSI will be decision trees and Markov models of varying complexity drawn from our own research. These include comparisons of implant combinations for total hip replacement, directly acting oral anticoagulants for prevention of stroke in atrial fibrillation, depression severity thresholds above which to prescribe antidepressants, and the Ross procedure with mechanical/biological aortic valve replacement. Adaptive designs will include trials with group sequential, multi-arm multi-stage, sample size re-estimation, adaptive randomisation, and population enrichment designs. EVSI will indicate the optimal design in terms of sample size, follow-up, number of interim analyses, number of treatment arms etc. Funding will be sought for the trials with the greatest EVSI compared with total trial cost. As EVSI estimation requires nested Monte Carlo simulation and repeated running of the cost-effectiveness model, estimating the EVSI for adaptive designs can carry a substantial computational burden. Efficient approaches to EVSI will therefore be explored and developed. We will use the recently published moment matching, importance sampling and Gaussian approximation techniques for EVSI estimation. We will also develop novel efficient estimation techniques for EVSI using quasi Monte Carlo, multilevel Monte Carlo, and multi-index Monte Carlo. The efficiency of all methods will be compared. These developments and comparisons will also be of benefit when estimating EVSI for conventional designs.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: GoodReports: An online tool helping authors find and use reporting checklists to improve completeness of reporting
Funder: Medical Research Council

Abstract: Many initiatives have been developed to prevent waste in biomedical research caused by poor methods and publishing practices. One such initiative led by the EQUATOR Network is promoting the use of reporting guidelines. Reporting guidelines exist for all main study designs, and there are hundreds more add-ons and extensions for different clinical specialities and report types. Reporting guidelines help researchers include all of the important information needed in an article to allow readers to judge the work's quality. There are two main barriers preventing authors from using reporting guidelines effectively: how to identify and access the most appropriate guidelines, and how to use them. Over the past two years the UK EQUATOR Centre has developed a prototype online tool called GoodReports to help researchers find and apply the appropriate reporting guidance to their work. Preliminary studies of its potential to improve reporting have been encouraging and led to it winning the Cochrane-REWARD prize for reducing waste in research in September 2018. We plan to use data from a pilot study of GoodReports with BMJ Open and website user surveys to inform enhancements and improvements to the tool's content and functionality. This will include adding more guidelines and facilitating the combination of items from more than one reporting guideline in a single checklist. After initial development, we will hold focus groups with local early-career researchers and online surveys of wider stakeholder groups to qualitatively assess the tool. These assessments and feedback from website users will be used to further refine and improve the tool, in an iterative cycle of feedback and development. Once finalised, we will test the tool in a randomised trial to test whether GoodReports (1) helps authors correctly identify the appropriate reporting guideline or combination of guidelines and (2) improves the completeness of reporting in health research articles.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: HCM: Using genetic associations to account for selection bias in epidemiology
Funder: Medical Research Council

Abstract: Selection bias occurs in epidemiological studies when the studied subjects are not representative of the source population, leading to biased associations between variables in the selected sample. Currently, methods of adjustment model the selection process in various ways, but cannot allow for unknown factors influencing selection. We have recently identified a new approach to selection bias using results of genome-wide association studies. We have initially developed an adjustment for index event bias, which occurs in studies of prognosis or survival among cases of disease. We obtain adjusted associations from the regression of total genetic effects on prognosis on the corresponding effects on incidence. Our approach has an analogy with Mendelian randomisation (MR), an increasingly prominent method that uses genetic associations to account for unmeasured confounding, and similarly to MR our approach entails untestable assumptions. Currently we require direct genetic effects on prognosis to be independent of corresponding effects on incidence, implying that different biological pathways are involved. In this project we will develop complementary methods based on the same insights but requiring different assumptions, to provide a suite of sensitivity analyses to assess the robustness of a given study to selection bias. We will develop methods for a related selection bias in studies of factors preceding the trait under selection. This will be particularly relevant to large cohort studies such as UK Biobank, in which participants are healthier than the general population. We will integrate our methods with MR to provide methods that are potentially robust to both confounding and selection bias. We will apply our methods to a study of genetic and traditional risk factors for subsequent events in ~250,000 coronary heart disease patients. We will further apply our methods to a genome-wide association study of survival with idiopathic pulmonary fibrosis.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: UKPRPICA: SPECTRUM: Shaping Public hEalth poliCies To Reduce IneqUalities and harM
Funder: Medical Research Council

Abstract: The main causes of NCDs include consumption of unhealthy commodities. These exposures are preventable, but the commodities involved are highly profitable. Their consumption and health and social impacts are also inequitable and driven by complex systems of production, distribution and promotion dominated by transnational companies -Unhealthy Commodity Producers (UCPs). UCPs' economic interests often conflict with health goals and their role in determining health has received insufficient attention. SPECTRUM aims to generate new evidence to inform the prevention of NCDs caused by unhealthy commodities and to transform policy and practice to encourage the adoption of healthy environments and behaviours. With a principal focus on tobacco and alcohol, our work will extend to foods high in salt, sugar and fat in key studies. Approaches we develop could in future be applied to other unhealthy commodities. We will conduct research in eight integrated Work Packages: 1.using systems science to understand and prevent behavioural drivers of disease and harm; 2.understanding and countering corporate conduct and influence; 3.using new data sources to inform action; 4.conducting economic analysis to inform policy and practice; 5.shaping the environment to change harmful behaviours; 6.evaluating the effectiveness of policies and natural experiments; 7.reducing mental health inequalities; and 8.building governance for health equity. Along with an inter-disciplinary research team, SPECTRUM's work will be co-created with research users from civil society organisations, companies and the main public health agencies in Great Britain. The public will be involved through engagement panels, citizen's juries and qualitative research. This partnership will ensure that research findings will benefit from an accelerated pathway to inform new policies and practices and will provide valuable data to assess the extent and effectiveness of approaches to addressing NCDs in the UK and beyond. This grant is funded by the UK Prevention Research Partnership (UKPRP) which is administered by the Medical Research Council on behalf of the UKPRP's 12 funding partners: British Heart Foundation; Cancer Research UK; Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Health and Social Care Research and Development Division, Welsh Government; Health and Social Care Public Health Agency, Northern Ireland; Medical Research Council; Natural Environment Research Council; National Institute for Health Research; The Health Foundation; The Wellcome Trust.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: PETRA: Prevention of Disease Using Trade Agreements
Funder: Medical Research Council

Abstract: 1. An initial literature search showed a lack of evidence on the links between trade and investment agreements and the prevention of NCDs, especially relating to unhealthy commodities. 2. PETRA will be an interdisciplinary community of interest on trade and health that develops a research agenda by building national and international links among: academia (trade, law, public health, economics, public policy, environmental sciences, sustainable development) the third sector Government Research funders. 3. Kingdon's policy windows theory will underpin PETRA. This uses the opportunities for change created by bringing policy actors and researchers together to take advantage of political circumstances. The model of change is shown in the figure below. 4. PETRA will involve the above academic disciplines, civil servants, and the third sector. The core network will stem from the UK Public Health Network that comprises UK state and third sector NCD prevention alliances. 5. Policy and practice will be influenced through scientific meetings, an ideas lab, further literature reviews (depending on funding), developing research collaborations, and a communications strategy to reach members and key audiences, including the public. 6. While new public health and trade advocacy groups focus on immediate political challenges of Brexit, PETRA's design makes it a unique and timely expert resource that will become a Centre of Excellence and Action for NCD prevention and trade R&D in the UK. 7. PETRA's added value will create sustainability by: tackling a major gap in prevention research timeliness in building capacity to negotiate trade agreements with health in mind. being a unique UK expert resource with a diverse range of disciplines and civil society users using existing links and developing new mechanisms of high level national engagement by state and civil society tackling a major determinant of NCDs at population scale. This grant is funded by the UK Prevention Research Partnership (UKPRP) which is administered by the Medical Research Council on behalf of the UKPRP's 12 funding partners: British Heart Foundation; Cancer Research UK; Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Health and Social Care Research and Development Division, Welsh Government; Health and Social Care Public Health Agency, Northern Ireland; Medical Research Council; Natural Environment Research Council; National Institute for Health Research; The Health Foundation; The Wellcome Trust.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Tackling Root Causes Upstream of Unhealthy Urban Development (TRUUD)
Funder: Medical Research Council

Abstract: There is a clear need to address the quality of urban environments and developments to prevent risk factors (air pollution, noise, lack of green space, physical inactivity, obesogenic food 'deserts) that cause Non-Communicable Diseases. Our vision is of urban development systems where health is a priority for those who make the key decisions, focusing in particular on control of land, finance and the development process. Our primary objectives are to: (WP1) map and understand urban systems; (WP2) develop and model the health impacts resulting from changes in decision-making; (WP3) co-produce the intervention and assess corporate governance models; (WP4) develop meaningful and effective ways of involving the lay public in upstream decision making; (WP5) conduct extensive knowledge exchange through workshops, conferences, films, and images and community practitioners; (WP6) develop a meta-research evaluation framework. Theory of change: By co-producing evidence and ways of integrating health at key tipping points in the planning process - we expect to change attitudes, decisions, and behaviours in the short-term and change policies, practice, adoption of project outputs (medium to long term). Lines of research and methods: Transdisciplinary research utilizing multiple methods from social science, law, management, systems engineering, and health economics. We will collect qualitative data; co-produce interventions; and undertake actor/network/socio-legal analysis, corporate characterization, and systems mapping and problem structuring. Plans for user engagement We will undertake multiple focus groups, four annual workshops and three industry workshops, and embed two full time researchers at our partner city and combined authority. Applications: The evidence and associated tools on valuing health will be applied in local development management; local and national cost-benefit analysis on infrastructure and other investment decision-making. This grant is funded by the UK Prevention Research Partnership (UKPRP) which is administered by the Medical Research Council on behalf of the UKPRP's 12 funding partners: British Heart Foundation; Cancer Research UK; Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Health and Social Care Research and Development Division, Welsh Government; Health and Social Care Public Health Agency, Northern Ireland; Medical Research Council; Natural Environment Research Council; National Institute for Health Research; The Health Foundation; The Wellcome Trust.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulated proteolysis of p62/SQSTM1, nutrient-sensing and human disease
Funder: Medical Research Council

Abstract: Nutrient sensing is fundamental to homeostasis, growth and proliferation. When nutrients are scarce, autophagy helps turnover existing material to restore nutrient supply. Autophagy is finely regulated by nutrient-sensing pathways, and in turn, autophagy feeds back to nutrient-sensing mechanisms. Therefore, deregulated nutrient-sensing or autophagy are linked to disease, including neurodegenerative diseases, bone or muscular diseases, colitis and types of cancer. Sequestosome 1 (SQSTM1), better known as p62, is a multifunctional ubiquitin-binding signalling scaffold involved in both autophagy and nutrient-sensing. However, the mechanisms underlying its dual role need to be better understood. Importantly, mutations in SQSTM1 are linked to frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Paget's disease of the bone (PDB) and distal myopathy with rimmed vacuoles (DMRV). Therefore, it is important to investigate the functions of p62/SQSTM1 and their disruption in disease. We discovered that the proteolysis of p62 by caspase-8 into p62TRM was essential for nutrient-sensing through the mechanistic target of rapamycin (mTOR)-kinase containing complex 1 (mTORC1). Two natural mutations (D329G linked to FTD and D329H) abolished p62 proteolysis and mTORC1 function, thereby indicating the detrimental nature of these mutations. In this proposal we will investigate factors that regulate p62TRM production and the crosstalk between nutrient-sensing and Toll-like receptor-signalling, both of which trigger p62 proteolysis. We will also determine whether other nonsynonymous mutations in SQSTM1 specifically impair autophagy and/or mTORC1. Our new synthetic p62TRM production system will help define the interplay of p62TRM and other disease-susceptibility genes, mutations in which can deregulate autophagy and/or nutrient-sensing. Overall, our goal is to define the fundamental roles of p62 and p62TRM and how they are compromised in human diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Deciphering the role of the MOF complex and H4K16ac in the regulation of neuronal enhancers
Funder: Medical Research Council

Abstract: Functional distal regulatory elements in a cell or tissue type (active enhancers) are predicted based on the presence of histone acetylations, although the significance of these acetylations in enhancer function is not known. The overall aim of the project is to develop an understanding of how histone acetyltransferase complex called MSL/MOF and acetylation of histone H4 lysine 16 (H4K16ac) contributes to enhancer function in neuronal cells and how their dysregulation leads to neurodevelopmental disorders. We will address these questions by A) Identifying active enhancers by genome-wide profiling of H4K16ac, H3K27ac and accessible chromatin in neuronal cells. B) Quantify the activity of identified putative active enhancer classes by performing a massively parallel reporter assay. C) Identifying the target genes of neuronal enhancers by studying the long-range interaction between enhancers and promoters in three-dimensional (3-D) space. D) Investigating whether binding of MSL3 and MOF to enhancers is sufficient to activate target genes. E) Investigating the impact of MSL3 and MOF depletion on chromatin structure and gene expression in neuronal cells. F) Determining the impact of MSL3 and MOF depletion on the neuronal phenotype. These insights will be invaluable in informing prioritization of disease-associated protein-coding and non-coding variants for thorough functional studies and to explore therapeutic opportunities. For example, the effect of some of the mutations leading to altered epigenetic status can be reversed by epigenetic drugs e.g. histone deacetylase inhibitors (HDACi), which are already in clinical trials for cancer therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding interactions between lifestyle and deprivation to support policy and intervention development.
Funder: Medical Research Council

Abstract: Aim: To improve our understanding of the risks of mortality and morbidity associated with combinations of lifestyle factors across the socioeconomic spectrum in order to inform future health policy and interventions. Objectives: 1) To examine the evidence for lifestyle factor combinations associated with adverse health outcomes and for interactions between these combinations and deprivation. 2) To assess associations between lifestyle factor combinations (including newer lifestyle factors) and health outcomes and describe whether the associations are modified by deprivation. 3) To determine which lifestyle factor combinations are associated with greatest risk for adverse health across socioeconomic groups. 4) To explore the views of key stakeholders of how the new evidence for the risks of both a wider range of lifestyle factors and high-risk combinations could be incorporated into efforts to reduce lifestyle harm, particularly in deprived areas. Methods: This is a mixed methods PhD involving: 1) a systematic review; 2) analyses of two large population cohorts to assess the relationships between lifestyle factor combinations and health outcomes, including the effect of deprivation on those relationships; and 3) qualitative work with stakeholders. Scientific/Medical Opportunities: Much is known about the adverse effects of unhealthy lifestyle factors such as smoking but little is known about the impact of unhealthy lifestyle combinations (including newer lifestyle factors) on health outcomes, especially for those living in deprived communities. Understanding these issues and stakeholder views on how such evidence should be translated into efforts to reduce lifestyle harm is essential to inform future health policy and workable interventions. This work will identify new targets for future complex interventions or natural experiments aimed at individual and population level.


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