NIHRDataInsights/HRCSData huggingface dataset:
Title: Improved targeting of stroke prevention by enhanced phenotyping of trends, risk factors, symptomatology, aetiology, and outcome: Oxford Vascular Study
Funder: Wellcome Trust

Abstract: Having founded the new Centre for Prevention of Stroke and Dementia (CPSD) to allow junior/intermediate colleagues to develop their programmes, my own research will continue to focus on better phenotyping of TIA and stroke and of known risk factors in order to substantially improve the targeting of preventive treatments. My work involves four core themes: • Understanding the distinct temporal trends in incidence of different stroke subtypes to monitor the effectiveness of prevention and to develop new strategies; • Obtaining reliable data on prognosis of different TIA/stroke subtypes to better target preventive treatments; • Having proved the impact of better prediction and prevention of early recurrent stroke, I aim to substantially improve prevention of later recurrent stroke, focussing particularly on the utility of more detailed phenotyping (e.g. identification of occult atrial fibrillation, intracranial stenosis, and PFO, and remote monitoring of home-BP); • By more detailed assessment of BP I will inform the treatment of hypertension in primary prevention of stroke (by studying long-term pre-morbid BP) and in secondary prevention (home telemetric BP-monitoring); Taken together the results of this work will impact on the treatment of almost all patients with TIA or stroke (2 million prevalent cases in the UK alone).

Lay abstract: Background: Life expectancy in the UK has increased dramatically, but there has been less success in prevention of age-related morbidity. The number of older people suffering from stroke, dementia and other chronic disabling vascular conditions has therefore risen steeply. Yet researchers have neglected the practical research necessary to determine how best to prevent these common diseases in everyday practice. Approach: I founded the Stroke Prevention Research Unit in 2000 to improve prevention of stroke in older people. I now have 40 research/support staff and have set-up several cohort studies in collaboration with 100 local GPs. In 2019, I established a new purpose-built Centre for Prevention of Stroke and Dementia that will focus on better understanding of known risk factors and more effective use of existing treatments. Impact: I have a strong track record of identifying/evolving new cost-effective preventive strategies that impact quickly on the effectiveness of prevention in routine practice.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: STROKE;CARDIOVASCULAR
Title: Asymptomatic Carotid Surgery Trial-2 (ACST-2): an international randomised trial to compare carotid endarterectomy with carotid artery stenting to prevent stroke
Funder: Department of Health (England)

Abstract: About one million adults in Europe alone have atherosclerotic narrowing of one or both of their carotid arteries. They are therefore at a substantially increased risk of stroke over the next 5 or 10 years even with long-term medical treatment that reduces this risk (e.g. antiplatelet antihypertensive and lipid-lowering drugs). Our previous international randomised trial in 3000 such patients (ACST) showed that CEA (with 3% risk of peri-operative stroke or death) greatly reduces the subsequent stroke risk. CAS is an increasingly popular alternative to CEA that may produce lower peri-operative risks with long-term benefits comparable to CEA. Our proposed new international trial (ACST-2) will randomise more than 5000 such patients equally between CEA and CAS. The primary aim of this trial is to compare the immediate operative risks (up to 1 month post-procedure) and the long-term (5-year) risks between the two treatment interventions. Secondary to this comparisons of health-related quality of life will be assessed as part of the health economic evaluation. ACST-2 is the only proposed trial that could be large enough to address this important question reliably. The findings which emerge from ACST-2 will affect thousands of patients with carotid artery stenosis who are at risk of stroke.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: STROKE;CARDIOVASCULAR
Title: Enhanced invitation methods to increase uptake of NHS Health Checks. A randomised controlled trial
Funder: Department of Health (England)

Abstract: Study design: Three-arm randomised controlled trial. Interventions: A QBE questionnaire followed by standard invitation one month later; B QBE questionnaire + financial incentive (retail voucher) to return the questionnaire followed by standard invitation one month later. An arm with financial incentive is included to assess the impact of this on the response rate; C No questionnaire standard invitation only. QBE questionnaires will be sent with a stamped addressed envelope one month before the standard invitation letter for health checks is posted. Participants: Participants will be patients registered with general practices in three South London boroughs aged 40-75 and scheduled for invitation to the NHS Health Checks programme. Allocation: Randomisation of individual participants will be in blocks stratified by general practice. Outcomes: Primary: proportion of partcipants attending for NHS Health Checks within 6 months. Secondary outcomes: proportion attending at 3 months (prior to reminder letter); cost per additional participant attending for NHS Health Checks. Sample size: To detect a minimal important difference in uptake of Health Checks between any treatment arm of 5% 2128 participants are needed per arm at 80% power and 5% significance with Bonferroni correction. Analysis: Intention-to-treat analyses by logistic regression accounting for age sex and stratification comparing outcomes between arms A vs C B vs C A vs B. Secondary analyses will compare outcomes by deprivation quintile.Timetable (months): 0-6: set-up ethics establishing trial steering committee research networks; 6-18: recruitment (600/month); 12-24: 6 months follow-up; 25-30: data analysis write up dissemination.Ethics: Research ethics and NHS R&D approvals will be obtained. Initial consent will be from participating general practices.Study team: includes skills in epidemiology (Gulliford) statistics (Cornelius Nicholas) health psychology (Burgess Wright) health economics (Bokhari) and public health (Dodhia).


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: STROKE;CARDIOVASCULAR
Title: Integrated functional characterisation in acute vascular syndromes: multimodal MRI / PET-CT imaging combined with leukocyte expression profiling
Funder: Medical Research Council

Abstract: Hypotheses: (i) atherosclerotic plaques with an increased 18FDG-PET signal reflect macrophages deep within the plaque core that display a "hypoxic" gene profile; (ii) superficial macrophages in the shoulder regions of plaque (responsible for cap disruption and acute events) express an "inflammatory" gene profile and are not associated with 18FDG-PET signal; (iii) peripheral blood monocytes' gene expression profile will reflect the activation status of these superficial cells and may be useful as a systemic biomarker. Primary objective: To define the gene expression characteristics (signature) of macrophages and /or macrophage-derived foam cells from explanted human carotid plaque following acute stroke and endarterectomy, and to relate this molecular "signature" to plaque characteristic using MRI/PET-CT. Secondary objective: To study the differential contribution of hypoxia versus inflammation in overall plaque vulnerability in patients with recent stroke, and to help further define the functional significance of 18FDG signal used in vascular inflammation PET imaging. Tertiary objective: To evaluate potential blood soluble/cellular biomarkers of plaque instability. Methodology: A case-control observational study of patients undergoing carotid endarterectomy. Up to 25 patients with recent TIA/stroke and with >60% ipsilateral carotid stenosis on screening ultrasound will undergo study imaging protocol (3T MRI & PET-CT). Control will be asymptomatic individuals scheduled to undergo carotid endarterectomy, matched to similar severity of carotid disease. Following endarterectomy, a small part of each plaque will be processed for conventional light microscopy for micro-structure, and the larger part will be subjected to immunohistochemistry and laser capture micro-dissection (LCM) to extract location-specific plaque macrophages/foam cells. Following LCM, mRNA will be extracted from isolated cells and under go linear RNA amplification before microarray gene analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: STROKE;CARDIOVASCULAR
Title: Enhancing cardiovascular disease risk prediction through using longitudinal measures of risk factors in clustered data
Funder: Medical Research Council

Abstract: CURRENT CARDIOVASCULAR DISEASE (CVD) RISK MODELS Most CVD risk models in clinical use have been constructed from Proportional Hazards models regressed on single measures of selected risk factors. Thus, clinical CVD risk assessments do not take into account repeated measures of risk factors if available. MODELS FOR LONGITUDINAL MEASURES AND TIME-TO-EVENT DATA There has been active statistical methodology research into constructing joint models for longitudinal measures and time-to-event data. Most joint models use a set of random effects to induce association between the longitudinal measures and time-to-events, but then require computational intensive approaches for estimation. Consequently, such models are not commonly applied to real problems despite their qualities and abilities to answer key questions. Whilst the relevance of using joint models to assess aetiological associations between longitudinal measures and disease risk is clear, it is less certain how risk predictions from such models can be applied for clinical CVD risk assessment. WHAT IS THE PROPOSED RESEARCH? The added value of using longitudinal risk factors for CVD risk prediction in observational and clinical data has not been thoroughly evaluated. We propose to determine statistical methods for developing, assessing and validating CVD risk prediction models using longitudinal measures of risk factors. We will: 1. determine an appropriate CVD risk prediction model that incorporates longitudinal measures of risk factors from multiple studies/centres. 2. determine how to extract and translate CVD risk assessments from a risk prediction model that incorporates longitudinal measures. 3. determine a suitable choice of prognostic measures and graphical and/or tabular presentations for assessing the added value of using longitudinal markers in risk prediction models. 4. quantify the added value of using longitudinal measures of risk factors for CVD risk prediction.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: STROKE;CARDIOVASCULAR
Title: The Second European Carotid Surgery Trial (ECST-2): Pilot study
Funder: Department of Health (England)

Abstract: Background Randomized trials run over the last 20 years are considered to have established the benefit of endarterectomy for symptomatic and asymptomatic carotid stenosis in preventing stroke, above medical treatment. However, risk modelling studies have shown that many patients in the trials did not benefit because their risk of stroke on medical treatment alone did not exceed the risk of surgery. Over the last 2 decades the risk of surgery has changed little, but there have been major advances in medical treatment. Thus, with optimised modern medical therapy (e.g. targeted blood pressure control, lipid lowering, and combined antiplatelet therapy) endarterectomy may now be unnecessary or harmful in patients whose risk profile was not associated with clear benefit from surgery in previous trials. Aims We aim to use our existing network of centres collaborating in a randomised trial of carotid stenosis treatment, to set up a pilot study for the second European Carotid Surgery Trial (ECST-2), with the long-term aim of determining the best regime for treating carotid stenosis in patients at low and intermediate risk of stroke. We hypothesize that the patients who in the previous trials had a 5-year risk of stroke treated medically of Plan of Investigation ECST-2 is a multicentre, randomised, controlled, prospective clinical trial. Patients with asymptomatic or symptomatic carotid stenosis whose 5-year stroke risk is Potential Impact Atherosclerotic carotid stenosis causes about 15% of all strokes. About 5000 carotid endarterectomies are done annually in the UK at a direct NHS cost of about £12 million. The patients with a 5-year risk of stroke of < 20%, which we will include in ECST-2, accounted for over half of those randomized in the previous trials. These patients still undergo endarterectomy in most centres. If ECST-2 shows that the use of OMMT with our risk modeling approach allows these patients to avoid surgery, the number and costs of endarterectomies could be reduced by more than half, potentially saving the NHS around £8.5 million annually, as well as reducing the number of strokes and improving quality of life in these patients. It is likely that OMMT will also reduce coronary and other vascular events.


Research activity codes: 6.4 SURGERY;6.1 PHARMACEUTICALS
Health categories: STROKE;CARDIOVASCULAR
Title: Estimating and comparing the cost effectiveness of primary prevention policies affecting diet and physical activity in England.
Funder: Wellcome Trust

Abstract: In England, there are many government policies aimed at preventing heart disease and stroke. These range from national campaigns such as 5 A DAY which promotes increasing fruit and vegetable consumption, to individuals receiving prescriptions to visit the gym. In an increasingly resource constrained health service, informing policy makers of how the costs and benefits of different health policies compare is key to making better decisions. This research project will compare the impact on he art disease and stroke in England, and the associated implementation and healthcare costs and savings, of policies that affect diet and physical activity. To do this, a computer model will be developed. The results will estimate the health impact for each gender, for different age groups, and for different income groups. These outcomes will be investigated over time meaning that it will be possible to estimate the impact of the policy five, ten, or 20 years following its implementation. The mode l will be designed so that in the future it can be further developed to assess a wider range of policies and disease outcomes, as well as be used directly by decision makers.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: STROKE;CARDIOVASCULAR
Title: Uncovering novel risk factors and molecular markers to improve the prevention and treatment of cancer
Funder: Wellcome Trust

Abstract: Cancer is one of the major causes of illness and death in the world1. Its burden is expected to increase due to population ageing and growth, and because people are leading increasingly unhealthy lifestyles by smoking, drinking alcohol, gaining excess weight, eating unhealthy diets and being physically inactive2. Although evidence regarding the aetiology of cancer is growing and several causes of cancer have already been identified, evidence for some risk factors is still weak and the underlying biological mechanisms driving many of the observed associations remain unclear2,3. I will explore associations between several lifestyle/biological risk factors and cancer, as well as potential metabolic pathways mediating these associations using novel causal inference methods, such as Mendelian randomization. A better understanding of the causes of cancer and the mechanisms involved in cancer development could contribute to the targeted prevention and treatment of the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Developing a Methodological Framework to Evaluate the Impact of Health Intervention Sequences
Funder: Wellcome Trust

Abstract: The goal of my research is to uncover how the sequence of health interventions influences their effects. As an example, should a cancer patient be treated first with the newest and costly drug upon diagnosis, or should such drug be reserved as the last resort, after all other drugs have failed? Typically, it is unclear whether there are any other effective treatments when a new drug fails. Quitting smoking is another example of where the sequence can matter. We know that e-cigarettes are more effective in helping smokers to quit compared to nicotine replacement therapy (NRT). However, this has been shown mostly in people who have tried NRT and failed before trying e-cigarettes. Therefore, it is unknown whether smokers would have been more successful in quitting if they had used e-cigarettes first. Or would e-cigarettes only work after failed quitting attempts with other methods? In summary, changing the order of healthcare interventions can result in either positive or negative outcomes. To better understand this phenomenon, I plan to apply novel statistical approaches to existing medical records, surveys and trial data to explore the optimal sequence of interventions and to model the relative cost-effectiveness of different sequences.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: STROKE;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Impact of Visual Impairment after Stroke (IVIS)
Funder: Department of Health (England)

Abstract: This research programme has four objectives: 1) identify different questionnaires available for people to tell us about their visual problems and identify different treatments available for eye movement problems, 2) determine how frequently visual problems occur and what happens over time, 3) identify issues faced by stroke survivors relating to visual problems, and 4) plan a trial of treatments for eye movement problems following stroke. This new study will help us find out what problems people experience with their sight after a stroke, how we can get better at testing for these problems and what we should do to help.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: STROKE;EYE
Title: The Kadoorie Biobank Study
Funder: Wellcome Trust

Abstract: The Kadoorie Biobank Study is one of the world's largest blood-based prospective studies of the environmental and genetic determinants of chronic diseases. During 2004-8, 515,000 adults aged 35-74 from 10 regions across China were enrolled, with extensive data collection by questionnaire and physical measurement, and with storage of blood (including DNA) for future research. Funding is requested over the next 5 years to cover a re-survey of 25,000 participants; maintenance, management and analys is of data; secure storage of blood samples; and follow-up of cause-specific morbidity and mortality. During the next 5 years, there will be ~125,000 hospital admissions and ~25,000 deaths among the participants, which should yield reliable information about the effects of smoking, BMI, blood pressure, lung function, and many other non-blood-related factors on diseases in this population. Moreover, since stroke is relatively common in China and routinely investigated by CT/MR imaging, a nested c ase-control study of blood-related factors (including lipid fractions, inflammatory markers and genes) could be conducted during that period among ~7,500 well characterised strokes and ~15,000 matched controls. Much of what is discovered in the Kadoorie Biobank Study will be of general relevance to disease mechanisms in other developing and developed populations.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;GENERIC HEALTH RELEVANCE
Title: Systematic reviews and meta-analysis
Funder: Medical Research Council

Abstract: The Meta-analysis Group of the MRC Clinical Trials Unit (CTU) aims to rigorously evaluate the effectiveness of interventions for cancer and other diseases/conditions using systematic reviews and meta-analysis, to inform both clinical practice and research. We also aim to improve the quality and reliability of systematic reviews and meta-analyses through associated methodological research.|Moderate improvements in outcome are often the best that can be expected of new interventions, but these can be clinically worthwhile and important in terms of public health. Where randomised trials recruit too few patients to detect such modest differences reliably, they may have inconclusive results, or by chance, have results in favour of a particular intervention. Collating and appraising such trials in a systematic review, provides an objective summary of all the available evidence. Combining the results of these trials in a meta-analysis, can give sufficient statistical power to obtain a reliable and precise estimate of effect.|The Group predominantly conducts systematic reviews and meta-analyses based on individual patient data (IPD MA). These involve the collection, checking and re-analysis of the original IPD from all the relevant trials worldwide, necessitating extensive collaboration. Compared to standard systematic reviews based on trial-level data extracted from publications or obtained from trial investigators, the collection of IPD can improve the quality of data and breadth of analysis, and so it is considered the gold standard approach. As IPD MAs are resource-intensive and take time to complete, we also use standard systematic reviews to identify questions that require the IPD approach, when a more timely answer is needed, or when resource is limited. We are one of few groups worldwide with expertise in IPD MAs and have an international reputation in their conduct.|The Group has completed IPD MAs and other systematic reviews of therapies for ovarian, lung, oesophageal, bladder, brain and cervical cancer, and soft tissue sarcoma, as well as human prion disease, pre-eclampsia and venous leg ulcers. We have ongoing projects in lung and colorectal cancer, and in stroke. We are piloting consumer involvement in our IPD projects. Methodological projects have included investigations of publication and patient exclusion bias, and the development of methods for analysing published time-to-event data. Ongoing projects include comparing meta-analyses based on summary data with those based on IPD, evaluating the methods for assessing treatment by patient covariate interactions and methods for analysing IPD.|We act as the main CTU link to the Cochrane Collaboration, with members of the Group active in a number of Cochrane Review Groups and Methods Groups. We also co-convene the IPD Meta-analysis Methods Group.


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