NIHRDataInsights/HRCSData huggingface dataset:
Title: Human Cell Atlas - development atlas extension
Funder: Wellcome Trust

Abstract: We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week. We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo. This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling. Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Factors of biological ageing: does it all go together when it goes?
Funder: Wellcome Trust

Abstract: Ageing-related cognitive decline carries a huge personal, societal, and financial cost. Understanding its underlying mechanisms with a view to ameliorating age-related cognitive decline is a huge challenge. It is essential to identify biomarkers of cognitive ageing and their potential determinants. Brain structural imaging markers in older age, their correspondence with proteomic and other biomarkers, and their potential determinants, are poorly characterised. Our understanding is informed by cross-sectional studies (which cannot fully reflect the dynamic within-person processes of ageing) and mainly univariate longitudinal data (i.e. describing how brain regions individually decline over time): most aspects of brain structure decline, on average. However, these approaches do not tell us whether there are important patterns of coordinated change, nor are they well-aligned with other levels of biological explanation. Such information could potentially aid stratification of risk and identification of important clusters of determinants of brain and cognitive ageing. I will apply cutting-edge factor-analytic methods to large longitudinal datasets to detect and validate patterns of correlated biological changes (brain structure, serum proteomic and DNA transcriptomic). I will test how these dimensions of ageing are associated with each other and with cognitive ageing, and use several techniques to ascertain their lifestyle, genetic and epigenetic predictors.

Lay abstract: As older people form an increasingly large proportion of human populations globally, greater resources will be needed for their management and care. Cognitive ageing, the process by which some cognitive abilities decline in older age, is of particular concern because it can lead to reduced quality of life, problems with daily tasks, a loss of independence, and increased risk of dementia. Yet, much of our understanding of dynamic biological changes that accompany cognitive ageing is not based on tracking the same people over time, or describes one aspect of change at-a-time. Using multiple large datasets that track people's brain structure, blood markers and aspects of their genes, I will identify patterns of coordinated changes within each domain. I will test how they correspond to each other, and to cognitive ageing, and identify lifestyle and genetic features that may help identify those at greatest risk of these dimensions of ageing.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: From Collection to Cultivation: Historical Perspectives on Crop Diversity and Food Security
Funder: Wellcome Trust

Abstract: Many experts agree that crop genetic diversity is essential to agricultural productivity, present and future, and therefore an important determinant of human health and well-being. Yet the routes through which this diversity is made valuable in agriculture, for example in breeding more disease-resistant or nutritious crops, remain underexplored. The dominant narrative credits plant breeders alone with generating value from crop diversity and has enabled breeders and seed companies to claim ownership over plant varieties. This in turn has encouraged a dramatic consolidation of the seed industry that many consider a threat to global food security. The narrative of breeder-generated value must be assessed and challenged. Through four historical case studies and a synthetic account, this project argues for a more encompassing view of how diverse materials give rise to the crops eaten around the world. It documents the contributions of researchers engaged in plant exploration, introduction, conservation, and utilisation. It charts efforts to locate disease-resistant varieties, prevent the spread of crop pathogens, ensure access to dietary diversity, and locate the genes that give rise to nutrient-rich varieties. By following neglected actors and methods, the project changes our understanding of how and by whom modern agricultural crops have been made.

Lay abstract: Many experts agree that the genetic diversity of agricultural crop plants is essential to food security, present and future. But how this diversity makes its way into agricultural production—for example as more disease-resistant or nutritious crops—is not well understood. This poses problems for scientific and political decision making. In this project, we are charting the histories of the different types of knowledge, labour, techniques and tools needed to transform plants gathered around the world into novel crop varieties destined for farms and eventually markets. By studying key historical examples, we will provide detailed accounts of how different kinds of agricultural scientists have used and managed crop diversity to increase agricultural productivity since the early twentieth century. Ultimately, we will show that genetic diversity has been made valuable not just by plant breeders, but by a wide range of researchers involved in plant exploration, introduction, conservation, and utilisation.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Next-generation digital histology infrastructure to probe and exploit the biology of tissue microenvironments
Funder: Wellcome Trust

Abstract: This bid will support molecular histology infrastructure at UoB, addressing major technical challenges and limited capacity in this expanding area to create a nationally leading molecular histology facility. Building on existing infrastructure and expertise, it leverages a wide user-base, featuring an expanding portfolio of fundamental and clinically-facing biomedical science. It will stimulate three strategically important and overlapping UoB scientific themes: Immune Regulation, Metabolism, and, aligning with our WT-CRF, Immunotherapy Development, catalysing our understanding of the role of specific cell types and processes within highly defined tissue microenvironments. The synergistic platforms requested collectively represent a step-change in digital histology capability. A new multispectral immunofluorescence platform (the Vectra-Polaris), builds on our ‘Key Opinion Leader’ status for this approach. Secondly, two Leica platforms will increase capacity in multiplex staining and IHC scanning. Finally, we request a Nanostring-GeoMx ‘digital spatial profiler’ and associated nCounter, a potentially game-changing platform allowing highly multiplexed, spatially resolved analyses of RNA/protein markers in tissues. Funding will support UoB’s place on Nanostring's early access scheme for this technology, one of only 25 sites globally. A successful bid will establish a cutting-edge Birmingham Molecular Histology Facility catalysing fundamental scientific and clinical advances, yielding novel hypotheses, publications, stratification approaches, and clinical trials.

Lay abstract: Understanding immune and metabolic processes that occur in body tissues is a critical step towards devising new therapies and defining patient groups best placed to benefit from existing therapies. This grant will fund cutting-edge equipment allowing scientists to probe the microenvironment of our body’s tissues in unprecedented detail. This will enable them to simultaneously assess the levels, location, interactions, and function of crucial cell types, metabolic processes, and key receptors. In turn, these new technologies will help us unlock how such features influence diseases including chronic inflammation and cancer, transforming our understanding of the biology of critical tissue microenvironments. The nationally-leading facility this grant will help establish will catalyse a step-change in our understanding of disease progression, response to treatment, and emerging therapeutic targets, and stimulate new clinical trials. Ultimately this will help target the right therapy, to the right patient, and maximise opportunities for development of game-changing new treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: A multiuser radioanalytical facility for molecular imaging and radionuclide therapy research
Funder: Wellcome Trust

Abstract: This core facility at King’s College London (KCL) will form the hub of a multi-institution consortium of leading UK molecular imaging researchers and their clinical and biomedical collaborators. It will provide radiochemists and radiobiologists with a unique, comprehensive range of radioanalytical equipment for development and characterisation of the next generation of radiopharmaceuticals for whole-body molecular imaging, cell tracking and targeted radionuclide therapy. The objectives are to: 1. enable chemical synthesis and analysis, and biological evaluation, of new radiochemical platforms and radiopharmaceuticals, and develop radiosynthetic protocols for their clinical translation; 2. develop a new generation of radiotracers, building on recent innovations to help develop and support the clinical use of new advanced therapies: novel molecular, cell-based, nano and radio therapies; 3. use radionuclide molecular imaging to understand disease environment, pathology and resistance to treatment. The facility will enable a consortium of chemists, biologists, pharmacists and clinicians to pursue these objectives across cancer, immunology, neurology, cardiovascular disease, infection, regenerative medicine and transplant therapies, through collaboration with the applicants and through direct access. The requested equipment will complement existing KCL research facilities including whole-body preclinical imaging PET/CT and SPECT/CT scanners funded by a previous Wellcome Multi-User Equipment Grant (2008 – 2013).

Lay abstract: Scientists have recently discovered how cells such as stem cells and immune cells can cure disease, leading to new therapies based on cells rather than drugs. For this knowledge to benefit patients, it is important to understand how these cells behave in the body: Where do they go? Do they survive? Scientists have also discovered that particular disease cell "markers" can be used to predict whether or not a disease will respond to therapy. Detecting these markers by imaging the whole body with radiotracers will enable better disease monitoring and treatment. We propose to establish a research facility that will house equipment to enable doctors, chemists and biologists to develop new radiotracers which can bind to therapeutic cells or disease "markers" to map their location in living subjects across the whole body, enabling doctors to use new cell-based therapies and cell marker diagnostics safely and efficaciously.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: North and South: Regional Health Inequalities in England
Funder: Wellcome Trust

Abstract: North and South: Regional Health Inequalities in England The ‘north-south health divide’ in England is longstanding and persistent, documented both before and after the epidemiological transition. In the mid-19th century, life expectancies in northern cities were four years lower than in southern cities, and today, there is still a two-year difference in average life expectancy between the northern and southern regions. However, there has been no thorough academic study of regional health inequalities, so we know little about the temporality, aetiology, experience, representation or perception of the ‘north-south health divide’. This oversight is becoming even more pressing given emerging evidence that health inequalities are increasing and that the north is falling further behind. Using a novel, mixed-method, intensive, multi-disciplinary approach, the North and South project will fill this gap by providing the definitive account of the ‘north-south health divide’ and regional inequalities in health in England – contextualised within the wider European experience. By drawing on concepts, data and methods from geography, epidemiology, sociology, history, social policy and literary studies, the project will enhance our understanding of the ‘north-south health divide’; provide insights into how to close it; and advance the international health inequalities field empirically, methodologically, and conceptually.

Lay abstract: North and South: Regional Health Inequalities in England There are deep-rooted and long-term regional health inequalities across England, with a two-year gap between the north and the south in how long people are expected to live. However, despite the size of the ‘north-south health divide’, we know little about how regional health inequalities have developed over time, what causes them, and how people experience, represent and perceive them. This is becoming an increasingly important issue which needs to be examined now - as health inequalities are worsening and the north is falling further behind. Combining data and ideas from different academic disciplines, I will provide a detailed investigation of the ‘north-south health divide’ and regional health inequalities in England – now and in the past. I will also compare England to other European countries. My project will increase our understanding of health inequalities and how to reduce them.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Suicide Cultures: Reimagining Suicide Research
Funder: Wellcome Trust

Abstract: Suicide Cultures: Reimagining Suicide Research (SC) will undertake a transformational, qualitative mixed-methods study of the social contexts and cultural meanings of suicide in diverse communities across Scotland. The project aims to shift understandings of what suicide research can be and do, contributing to innovation in how societies might best respond to suicide as a social and cultural phenomenon. SC consists of five inter-related workpackages. WP1: a qualitative sociological autopsy study of up to 390 cases of suicide across 3 areas of Scotland. Data will include formal reviews of suicide deaths (300), and interviews with family/friends bereaved by suicide (90 cases). WP2: qualitative, in-depth interviews with 60 people, recruited from the same 3 areas, who have self-harmed– those who may have died, but who did not. WP3: will explore understandings of suicide among different community groups, using collaborative arts-based methods. WP4: entails close, ethnographic study of up to 6 localities, identified iteratively during fieldwork, and studied in-depth to develop social and cultural explanations for particular features (e.g. clustering, demographic peculiarities) of suicide in particular places. WP5: an embedded PhD studentship will analyse how race/ethnicity shape understanding and meanings of suicides, ensuring this sorely neglected area is addressed.

Lay abstract: Most research about suicide takes a psychological or psychiatric perspective, on the understanding that it is primarily a ‘mental health issue’. However, it is increasingly accepted that suicide is also related to social and cultural factors – to socioeconomic inequalities, gender relations, and social identities. To prevent suicide, we need to conduct research that helps us better understand how these complex factors contribute to suicides. This project will revitalise existing understandings of suicide by examining the dynamic relationships between suicide and social and cultural factors. We will study suicide in three areas of Scotland, by interviewing people bereaved by suicide, and people who have self-harmed, alongside analysis of formal reviews of suicides. We will also carry out participatory arts-workshops with diverse communities, and embed researchers in these communities, so they can develop deep, contextual understandings of how society and culture shape suicides among different people, in different places.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhancement, dissemination and application of the PhyreRisk/Phyre resource for modelling protein structures and the effects of genetic variants
Funder: Wellcome Trust

Abstract: We are applying to support the enhancement, dissemination and application of the PhyreRisk/Phyre resource. PhyreRisk ( http://phyrerisk.bc.ic.ac.uk ) caters for researchers studying human genetic variation. Through PhyreRisk, a user can map DNA variants, from either genomic or proteomic coordinates, onto experimental and Phyre-predicted protein structures. The Phyre web-server (www.sbg.bio.ic.ac.uk/phyre2 ) is a widely-used (>90,000 distinct users in 2018) ELIXIR-UK resource to predict protein structure from sequence. Additionally, our program Missense3D (http://www.sbg.bio.ic.ac.uk/~missense3d/ ) provides structure-based evidence for the effect of a missense variant. Funding will be used to develop the following new predictive features within Phyre for subsequent inclusion in PhyreRisk:(i) prediction of ligand/protein interactions,(ii) template-free tertiary structure prediction using contacts(iii) domain/domain packing. PhyreRisk will be markedly extended by:(i) increased structural coverage from Phyre and predicted complexes from our collaborator in Kansas(ii) enhancing Missense3D to include functional residues, protein/protein interactions and membrane-bound proteins to yield quantitative predictions(iii) the inclusion and subsequent analysis using Missense3D of genetic variants reported in major databases (e.g. gnomAD, ClinVar, COSMIC, Genomics England and UK-BioBank). (iv) linking PhyreRisk, particularly the structural data, to other resources including gnomAD. We will disseminate the resource via workshops, conference presentations and publications.

Lay abstract: With many human genome sequencing projects underway, there is a pressing need to elucidate the functional effects of genetic variants and thus assist in confirming their disease association. Knowledge of protein three-dimensional structure greatly assists in this interpretation. Moreover many biomedical research areas are transformed by knowledge of protein structure. However experimental structures only cover 17% of the human proteome but prediction extends this to over 50%.We propose to further develop our PhyreRisk database (http://phyrerisk.bc.ic.ac.uk) to guide DNA variant interpretation based on both experimental and predicted structures. We will obtain the structural data within PhyreRisk from our Phyre prediction resource (www.sbg.bio.ic.ac.uk/phyre2) whose functionality will also be enhanced.In 2018, Phyre had 90,000 distinct users and enhancements will directly benefit numerous researchers. PhyreRisk is an accessible resource for the genomics community to interpret genetic variation with its major implication for enhanced screening, prevention and treatment of many diseases.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhanced Statistical Rigour in Health Data Research
Funder: Wellcome Trust

Abstract: In medical research, a lack of reproducibility of research results has caused alarm, raising concerns about the reliability of scientific findings and the wasted resources, both human and financial. Key contributing factors include the explosion in the amount of data available to researchers, who often have inadequate statistical training, and a lack of statistical methods and software to produce robust evidence-based results. My Fellowship will develop methodology to enable non-specialist data analysts to simultaneously assess the sensitivity of their results to four key sources of bias in health research: non-random selection into the study, unmeasured confounding, measurement error, and non-ignorable missing data. Whilst some data analysts provide a qualitative discussion of the effect of such biases on their results, few provide a quantitative assessment; thereby, leading to over-confidence in their scientific findings. Along with the developed methodology, I will provide guidelines for non-specialist data analysts (disseminated via tutorial style papers and training courses) and in collaboration with the UK Reproducibility Network I will engage with stakeholders to ensure that sensitivity analyses become a routine part of study conduct and reporting. My proposed research will make a major contribution to addressing the reproducibility problem, leading to improved public confidence in health-science.

Lay abstract: Lack of reproducibility of research results (i.e., the inability to obtain the same results on repeating the same study) has caused alarm, raising concerns about the reliability of scientific findings and the wasted resources, both human and financial. Key contributing factors include the explosion in the amount of data available to researchers, inadequate statistical training, and a lack of statistical methods and software to produce reliable results. My Fellowship will develop user-friendly methods and software, with accompanying guidelines, such that non-specialist data analysts can assess the sensitivity of their results to four key sources of bias in health research. Whilst some data analysts provide a qualitative discussion of the effect of such biases on their results, few provide a quantitative assessment; thereby, leading to over-confidence in their scientific findings. My proposed research will make a major contribution to addressing this reproducibility problem, leading to improved public confidence in health-science.

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