NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving statistical methods to address confounding in the economic evaluation of health interventions
Funder: Medical Research Council

Abstract: Motivation: Confounding is a major methodological challenge in health economic evaluations that use non-randomised studies (NRS). Currently recommended methods are not directly applicable for complex settings, such as when cost-effectiveness of a continuous or dynamic treatment regime is of interest, and when treatment is administered at the area level, without an appropriate control group. The causal inference literature proposes methods to address confounding in these settings, however to deal with the specific challenges of economic evaluation, these methods need to be critically assessed, and extended. Methodology: First, I will compare the generalised propensity score method with regression approaches, to model dose-response relationships in economic evaluation. Second, I will compare novel causal inference methods for adjusting for time-varying confounding when evaluating dynamic treatment regimes, such as the targeted maximum likelihood estimation and parametric g-computation, when estimating parameters for decision analytical models. Third, in the evaluation of health policies without an appropriate control group, I will consider the synthetic control method that makes weaker assumptions about unobserved confounding than traditionally used difference-in-differences estimation, and extend it to handle health care data at the patient and provider level. I will then develop a new framework for assessing the robustness of cost-effectiveness estimates under alternative assumptions around unobserved confounders. Throughout, I will use case studies and simulation studies to compare new statistical methods to traditional approaches in typical settings for economic evaluation. Research output: This project will provide insights about the relative merits of alternative methods for addressing confounding across complex settings in health economic evaluation. Methods will be widely disseminated so that future studies can provide a sound basis for policy making.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: Improved methodology for understanding the genetics of complex traits, with particular application to epilepsy.
Funder: Medical Research Council

Abstract: Heritability analysis supposes a random effects model where the correlation structure of the random effect is specified by a kinship matrix K. When K corresponds to allelic correlations, it is convenient to view the underlying model in terms of an equivalent linear regression model, where each individual's phenotype is determined by a linear combination of its SNP genotypes (plus an environmental noise term), and each SNP's effect size is assumed normally distributed with constant variance. To realise the full potential of heritability analysis, it is necessary to appreciate that there are many varieties of this underlying model, meaning many different K can be computed. For example, I intend to improve BLUP by incorporating more than one kinship matrix, such that each corresponds to a separate variance term. For example, if allowing K1 and K2, the revised BLUP would benefit when K1 tends to correspond to stronger effect SNPs and K2 to weaker ones. The standard kinship matrix corresponds to assigning each SNP an independent effect size. When rare variants are included, the (effective) degrees of freedom becomes prohibitively large to allow useful estimation of h^2. However, the degrees of freedom can be reduced by placing restrictions on variant effect sizes, such as hierarchical priors. Two of my proposed methods concern enhancements of the REML algorithm. Although a classical technique, this can be viewed from a Bayesian angle. For example, estimation of h^2 equates to computing the posterior mode of h^2. This task is optimised through use of an eigen decomposition. When using this trick, including a prior on h^2 requires only a slight amendment (the need to differentiate this prior), so computation time will be barely affected. To estimate the distribution of h^2 for use in heritability meta analysis, requires sampling from its posterior distribution. But again, as the bottle-neck of REML is the decomposition, this will result in only a modest delay.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Southampton Imaging: 3D imaging at millimetre to nanometre scales for regenerative medicine using multiple complimentary modalities
Funder: Medical Research Council

Abstract: Increased aging populations pose new challenges and emphasize the need for approaches to augment and repair tissue lost through aging, trauma or disease. Regenerative medicine promises to deliver specifiable replacement tissues. As living tissue is inherently 3D, comprehensive quantitation of cell interaction, differentiation and tissue architecture necessitates the use of 3D analytical platforms with appropriate resolution, structural differentiation and volumetric analysis capabilities, along with time resolved, ex vivo and in vivo capabilities. Southampton Imaging offers an open access resource to imaging these tissue constructs pre- and post-implantation, vital to understand and validate the tissue structure and function. To deliver appropriate tissue resolution we request a Gatan 3View system to produce nanometer scale 3D image stacks by electron microscopy, able to visualise cell organelles and local cell-scaffold interactions. This will be complemented by a LaVision light sheet microscope, capable of imaging blocks of up to 1 cm cube substantially extending the depth and volume that can be imaged. This would for example include representative vascular networks that can be specifically labelled by immuno fluorescence or affinity methods. The platform allows non-destructive imaging of smaller live samples and critically reduces the light flux permitting long-term imaging of live tissues and cell migration in 3D tissues. Together with an Xradia ultra-high resolution microCT with phase contrast imaging, we will be able to image large volumes of tissue constructs including bio-compatible matrices of all types as well as hard and soft tissue elements. The requested equipment will integrate with extensive imaging infrastructure (including 12 dedicated supported staff), computational and image processing capacity (including UK's most powerful supercomputer) providing a unique Image resource for the Regenerative Medicine community.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Automation of Cell Banking & Characterisation Pathways at the UKSCB: Underpinning Delivery of a Core Component of the UK Infrastructure for Regen Med
Funder: Medical Research Council

Abstract: The equipment included in the bid falls into two areas: 1. Equipment for automating aspects of cell banking; 2. Equipment intended to streamline or enhance the quality control and underpinning research in the area of stem cell characterisation and safety testing. Details of the equipment requested are given in the Case for Support. 1. In considering the requirements of the Bank for automation we have considered the role that the UKSCB will play in the development of regenerative medicine in the UK and the transit of NIBSC into the MHRA. In response to potential CoIs, the Bank has moved away from the provision of large clinical trials stocks, toward the provision of seed stocks for clinical application. Scale-up, to produce large banks of cells through fully-automated systems are not warranted for the size of banks the UKSCB intends to produce in the future. The need is for flexibility, in terms of size and number of cell lines produced at any given time and the ability to respond rapidly to the provision of cell banks for hESC and hiPSC research collaborations of the kind already undertaken by the Bank. 2. Automation, to enhance our ability to increase the throughput of samples for QC testing and research, is another facet of this bid. There is a need to provide robust and enhanced assays for genomic and global transcriptomic profiling of cell banks. Microarray technology provides a first-line analysis method that allows for cost-effective acquisition of comprehensive cell genotype and gene expression data. Further analysis and validation of array data can then be performed by sequencing and real time PCR using current facilities at NIBSC. These technologies, in conjunction with a microarray platform, would allow for a seamless workflow from global profiling to targeted confirmation. Acquired genomic and transcriptomic data will be complied to form a reference database for the UKSCB user community for the UKSCB cell lines.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Pluripotent Stem Cell Platform -Capital Investment
Funder: Medical Research Council

Abstract: The Pluripotent Stem Cell Platform (PSCP) will build upon and integrate emerging PSC technologies with advanced cell manufacturing technology to establish optimised processes for consistent, scalable, production of PSC and their derivatives that meet the requirements of clinicians, regulatory authorities and industry for cell therapy applications. In this way PSCP will establish a leading position in the field of stem cell product development for clinical trials and its potential for industrialisation. PSCP will concentrate in-house activities on PSC and derivative tissue stem cell intermediates. However, the field in general will also benefit from tackling key knowledge gaps including: (i) establishment of standardised systems for generation of robust genetically stable human PSC populations suitable for therapeutic translation, (ii) development of genetic modification tools that bypass the risk of insertional mutagenesis and are subject to science based risk assessment, (iii) development of effective, reliable and reproducible differentiation protocols yielding functional, clinically compliant tissue-specific donor cells, (iv) quality control systems suitable for consistent manufacturing of stem cells and differentiated progeny suitable for use in human applications. The PSCP programme will address these issues through the following workpackages: i) Methods for iPSC production for clinical applications; ii) Development of a GMP-ready PSC expansion platform; iii) Assessment of the genomic and epigenomic integrity; iv) Development of protocols for production of neural progenitors; v) Development of protocols for production of endoderm lineages; vi) Product and process evaluation - integration of biology with process engineering and manufacture; vii) Safety qualification of PSC for clinical application.; viii) Process development for viable and cost-effective GMP of exemplars,notably dopaminergic and otic neurons; ix) Reproducibility and comparability.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Open-access biomaterials microfabrication and non-invasive imaging facilities for Regenerative Medicine.
Funder: Medical Research Council

Abstract: Biomaterials fabrication: The biomaterials fabrication suite will house a femtosecond laser-based microstructuring facility, able to structure macroscopic 3D tissue engineering scaffolds on a high speed and with sub-micrometer resolution. This set-up will be complemented with a fused-deposition modelling set-up to produce scaffolds from thermoplastic polymers and composite materials and for precise protein patterning and cell printing. Additionally, a commercial electrospinning rig will be used to allow for reproducible manufacture of electrospun scaffolds for clinical applications. Non-invasive imaging: Light Sheet Fluorescence Microscopy provides enhanced sectioning capabilities by exploiting thin laser light sheet for imaging samples perpendicularly to the direction of observation. The advantage of this equipment is its application to living samples as it causes less photo-damage and stress, as only the observed section is illuminated, leading to higher contrast imaging. A Raman Spectrometer including 455, 532, 633, 780 nm excitation lasers and a FTIR spectrometer equipped with a microscope, Attenuated Total Reflectance (ATR), Diffuse Internal Reflectance (DRIFT) and Photo-Acoustic Sampling (PAS). Both experiments will provide micro-spectroscopic information of a wide range of natural tissues and scaffold materials. The FTIR set-up will also enable time- and phase resolved spectroscopy. In addition, these set-ups will allow monitoring of single cell, cell interactions with the scaffolds and cell proliferation. Advanced clinical biophotonic imaging based on a clinical OCT and multi-photon imaging facility: (i) an in-vivo multi-beam OCT will enable monitoring in-vivo tissue regeneration and angiogenesis. (ii) a commercial in-vivo second harmonic and multi-photon platform will be used to study In-vivo collagen formation. This system also provides label-free imaging of lipids, to study barrier layer formation and damage mechanisms in-vivo.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: State of the Art Biomaterials Development and Characterization of the Cell-Biomaterial Interface
Funder: Medical Research Council

Abstract: The vision for this equipment bid is to complete the formation of a UK centre of excellence in the fabrication and analysis of acellular technologies. The instruments in our request include a confocal Raman system along with a high-end FTIR, which will be incredibly informative to the cell-material interface and will build upon prior work elucidating and informing phenomena occurring on and between materials and cells. A 3D printer will allow the formation of materials with precise control over morphologies that mimic tissues and other internal structures. A Biocell will elucidate activities occurring on material surfaces under ambient conditions, whist an Electrospinning Rig will produce well-controlled fibrous materials and will become an incredible asset for the production of porous 3D hierarchical scaffolds. These new materials can be treated with plasma to create modified and sterile materials that are otherwise unattainable using standard synthetic procedures. The remaining instruments on our request, which include an Observer microscope system, MicroCT, Plunge Freezer, LCMS, SEC and Electroforce Series II Force instrument will increase the capacity of our facilities to finely characterise our materials or cells on these substrates for applications within Regenerative Medicine. As well as directly benefiting all current and future members of the UK RMP Hub "Acellular Approaches for Therapeutic Delivery", we will also provide some of the equipment as a National facility with core support funded from UoN.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: In vivo imaging technologies to assess the efficacy and safety of regenerative medicine therapies
Funder: Medical Research Council

Abstract: The novel SPECT system that will form the nuclear imaging component of System A (9.4T MRI/SPECT platform, see case for support, CfS) will be specified by the University of Liverpool and will consist of cadmium zinc telluride sensors with an application specific integrated circuit (ASIC) read out and electronics system incorporating a field programmable gate array (FPGA). The design will specify dimensions and materials suitable for use in the 9.4T magnetic field. This MRI/SPECT system will be used to evaluate the short to medium term biodstribution and fate of cells labelled with superparamagnetic ion oxide nanoparticles (SPIONs), and monitor their effect on host tissues. We expect that this system will be capable of dynamic imaging, allowing kinetic modelling of the initial dynamic phase of a bolus injection. System B at UoL, comprising micro-SPECT/CT, fluorescence and bioluminescence imaging (FL/BLI), will primarily be used to evaluate the biodstribution and behaviour of cells expressing nuclear/FL/BLI reporters over the short to long term. System C at UoM, comprising low-field MRI and micro-PET, will primarily be used to evaluate the short to long term biodistribution and behaviour of cells expressing nuclear reporters, but as the benchtop scanner will operate at the field strength of clinical scanners (typically 1.5T or 3T), it will also provide valuable information for translation of MR protocols to the clinic. The enhanced MSOT system at UoL (see CfS), will have additional detectors that will increase spatial resolution. The MSOT has multispectral photoacoustic capability, permitting imaging and consolidation of data from multiple wavelengths; the instrument is thus capable of visualising administered cells (labelled with gold nanorods or expressing a photoacoustic reporter), monitoring their behaviour (e.g. Annexin V-based probes for apoptosis), and evaluating effects on host tissues and organs (e.g. through visualising the vasculature).


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Pre-clinical In-vivo Functional Imaging for Translational Regenerative Medicine
Funder: Medical Research Council

Abstract: Basic science knowledge in regenerative medicine is still mostly histology-based with poor longitudinal in-vivo imaging. Hence, its clinical relevance remains poor. Our objectives and overall strategy is to invest in four modern in-vivo functional imaging technologies for our pre-clinical experimental models with strategic alignment to the imaging already available for our research patients. This will boost translation by transforming the available histology-based knowledge into the functional, longitudinal imaging-based knowledge that drives modern clinical practice. To this end we request: a multi-photon microscope for zebrafish, a micro-CT and a micro-PET for mice, and a 3T-MRI scanner for large animal (pig, sheep). The latter item is in synergy with our other project of establishing a unique in the UK large Translational Biomedical Centre (TBC) for large animal also including two GLP surgical theatres (one hybrid with a biplane angiography imaging suite), a GLP lab, two sponsor rooms for academic partnerships with biomedical industry and research office space. The plan is to house the TBC on our Veterinary Science School campus in Langford. Our TBC project is in line with the outcome of the recent MRC-BHF Cardiovascular Working Group Meeting. At academic and regulatory level, one of the pressing needs to facilitate translation in regenerative medicine is to obtain clinically relevant longitudinal in-vivo imaging monitoring and tracking of cells to ensure effective delivery, quantify cell engraftment/homing, and retention; thereby informing patient safety. In addition, the long-term functional impact of cell delivery, measured in-vivo with clinically relevant technology, is as critical as demonstrating engraftment and residency to inform efficacy, hence translation.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Computational and Chemical Biology of the Stem Cell Niche
Funder: Medical Research Council

Abstract: UKRMP Centre for The Computational and Chemical Biology of the Niche (CCBN) The resource requested is the use of MRC funds to i) immediately fit out of existing "shelled" space to create a dry-lab Computational and Chemical Biology Centre for stem cell niche analysis within the Systems Medicine building at the Institute of Genetics and Molecular Medicine (IGMM) and ii) purchase the equipment required to upgrade our existing facilities for next-generation Chemistry, together with the construction using matched University funds of iii) a dedicated wet-lab facility for niche Chemistry as an extension of the SCRM building that houses the MRC-CRM and the newly created UKRMP Hub for engineering and exploiting the stem cell niche. These facilities will function as a "research hotel" for the UK stem cell and regenerative medicine community. Visiting researchers will occupy dry-computational and/or wet lab space for a period of time, with minimal barriers, to develop their particular cell/niche activity, thereby maximising the national strategic value of the investment and accelerating the translation of regenerative medicines.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Function and Regulation of the Pituitary Stem Cell Compartment in Mammals
Funder: Medical Research Council

Abstract: Pituitary progenitor/stem cells (PSCs) have been identified using in vitro and in vivo techniques and have been show to contribute to all hormone-producing cell types of the gland. These cells are mostly quiescent and are not solely responsible for the essential turn-over that takes place in the anterior pituitary throughout life. My preliminary research has identified that PSCs are a source of WNT ligands capable of activating surrounding cells. I have found that rapidly dividing progenitors which do turn-over the anterior pituitary, can activate the WNT/beta-catenin signalling pathway and express the pathway target Axin2. We will investigate the role of WNT signalling in pituitary homeostasis in vivo, by genetic deletion of the pathway in different uncommitted cell populations. The contribution of PSCs or progenitors will reveal the typical adaptive capacity of the gland to respond to specific physiological demand. Using novel mouse models, we will characterise the identity of WNT-responsive and WNT-secreting cells and reveal the source of signals through mapping Wnt expression using ultra-sensitive mutliplex in situ hybridisation. Through gene expression profiling by RNA-Seq, we aim to identify novel pathways involved in the control of PSC and progenitor cell compartments, opening up new avenues to understand regulation of homeostasis. To do this we will utilise genetic tools enabling cell purification of PSCs based on expression of known genes that mark populations containing PSCs. Our hypothesis is that WNT ligands control self-renewal and differentiation and we will test this through cutting-edge ex vivo imaging of the whole pituitary. Using a series of mouse models identifying the different populations, we will reveal the consequences of altering levels of signalling on cell fates and divisions. Overall, this proposal will reveal important insights into the biology and regulation of PSCs, information that can be invaluable to tackle treatment of human disease


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE