NIHRDataInsights/HRCSData huggingface dataset:
Title: Fetal programming of health and disease; follow-up of children whose mothers took part in a pre-conceptional nutrition trial in Mumbai, India
Funder: Medical Research Council

Abstract: As described above, the Mumbai Maternal Nutrition Project was a randomised controlled trial in Mumbai, India, which aimed to test whether improving the micronutrient quality of a women's diet before conception and throughout pregnancy increases birth weight and improves the long-term health of the child. The intervention reduced the incidence of gestational diabetes, and among women of normal or high BMI, increased birth weight. The aim of the study proposed here is to determine whether it has improved the health and capacity of the children at the age of 6 years. The study has already started (from Sept 2013) so as not to miss the age window in the earliest-born children. Ethical approval was obtained from JJ Hospital, Mumbai. Families are visited by health workers to explain the study. As close as possible to their 6th birthday, the child and both parents attend a research clinic at the Centre for the Study of Social Change in Bandra, Mumbai, after an overnight fast. Detailed body measurements of the parents and child are performed. A fasting blood sample is taken from the child for glucose, insulin and lipids, and further samples drawn at 30 and 120 minutes after an oral glucose load. Blood pressure and hand grip strength are measured. Fat, lean and bone mass are measured using DXA. Cognitive function is measured using the Kaufman Assessment Battery and other tests validated for Indian children and designed to measure multiple domains. Parents' fasting glucose is measured. DNA and RNA samples for future genetic/epigenetic analyses are collected from children and parents, and frozen. 110 children have been studied so far, and over 3 years we expect to study ~1500 (80%) of the surviving children from the original 1962 births. We will have 80% power to detect a difference of 0.14 SDs in continuous outcomes between treatment and control groups at 5% significance. This equates, for example, to approximately 1.4 mmHg of systolic blood pressure.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional relationships in Bayesian evidence synthesis of multiple outcomes
Funder: Medical Research Council

Abstract: Health Technology Assessments usually include systematic reviews of randomised controlled trials and evidence syntheses which are then embedded in economic models. While pair-wise meta-analysis has been extended to mixed treatment comparisons (MTC, also termed network meta-analysis) for multiple treatments, less progress has been made in synthesis of multiple outcomes, both within and between trials. A single, coherent analysis using all the available data on all outcomes is preferable to separate outcome-specific analyses. The commonly recommended approach, multivariate meta-analysis, requires only correlations between outcomes at the within- and between-trial levels, but models are technically difficult to fit, especially when there are more than 3 or 4 outcomes, and/or when the data are sparse. However, there is often prior knowledge on the nature of the relationships between outcomes and there is a need for models which capture these relationships. We will develop models that express functional relationships between outcomes, and which typically have fewer parameters. However, these models make stronger assumptions, so the issue of model fit is critical. Trial data in different areas of medicine displays a wide variety of functional relationships between outcomes. We will focus on a very common occurring evidence structures that feature multiple outcomes subject to either measurement error (for example, patient- or clinician-rated outcomes) or variability (weight, blood pressure), reported in different formats and/ or at multiple time points. We will develop a framework, applicable to all multiple outcome structures, for identifying, fitting, and evaluating functional relationships. We will apply the framework to several illustrative, real-life clinical examples. Models will be implemented by extending current Bayesian methods for MTC, of which standard (two-treatment) meta-analysis is a special case.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: Model Based Network Meta-Analysis for Pharmacometrics and Drug-Development
Funder: Medical Research Council

Abstract: Early phase trials compare drugs at different doses with placebo and/or other active drugs, often with repeated outcome measures over time. Drug development decisions are often informed by a meta-analysis of such studies. Recently methods have been developed to incorporate relationships with dose and time, termed Model-Based Meta-Analysis (MBMA). However, there may be more than one comparator drug, and the comparators may also have been measured at various different doses and times. Network meta-analysis is a technique that allows relative effects to be estimated across multiple treatments that have been compared in trials that form a connected network of treatment comparisons. Dose can be incorporated as a separate treatment, but this may lead to sparsely populated networks. This study aims to incorporate models for dose and time within a network meta-analysis framework. This will allow us to combine information from studies comparing different drugs at different doses and different times, even though those studies may not have included the same dose and times. Furthermore, we will explore the possibility of also incorporating evidence from single arm studies, and/or studies that compare drugs that we are not directly interested in, but that could help us understand the form of the relationships over dose and time. The models we develop may require some strong assumptions. It is therefore important to check whether those assumptions hold, and a key part of this work will be to look at methods to check model fit, validity of model assumptions, in particular checks for inconsistency. The methods developed will allow the synthesis of all the relevant available evidence, and assessment of the robustness of the model predictions, to better inform drug-development decisions. The industry project partner Pfizer will ensure that the methods developed will be relevant to the needs of drug-development organisations, facilitating the impact of the research.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: HMT: Accuracy vs Precision - Developing optimal estimators for trials with multiple hypothesis tests
Funder: Medical Research Council

Abstract: Accurate estimation of a treatment's effect is vital for expressing its true worth. This is important in early phase trials as this information is routinely used to decide whether further study is warranted and to power future studies. Additionally, health bodies require accurate estimation of the treatment effect to make informed choices about cost-effectiveness relative to alternative options as well as benefit risk assessment. The treatment effect is usually reported as the maximum likelihood estimator (MLE) which is a precise and readily available estimator. For designs that include interim analyses, it is, however, typically biased since it ignores the sequential nature of the trial. Additional bias is introduced by selecting treatments, subgroups or endpoints based on observed effect sizes. To address this problem, several classes of estimation procedures have been proposed, most methods are, however, limited to two-stage designs and normally distributed observations. Additionally few estimators offer corresponding confidence intervals, limiting their usefulness in practice. This project aims to thoroughly evaluate the extent of bias of the MLE in studies in which multiple hypothesis tests are conducted and develop novel approaches for point and interval estimation. Specific objectives, which will be discussed in more detail below, are to: - evaluate the extent of bias for a range of statistical designs; - develop graphical approaches for displaying treatment effects for correlated hypotheses; - develop point and interval estimates that yield an optimal trade-off of precision and accuracy; - develop bias-reducing methods for estimating effects for time-to-event endpoints; - develop open-source software and associated training tailored to clinical trialists and applied statisticians working on clinical trials. To ensure practical relevance, the overall research programme will be overseen by an advisory board.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mathematical and Statistical Modelling to Optimise Paediatric Medicines Research
Funder: Medical Research Council

Abstract: This project aims to improve methods for modelling drug effects in the following three scenarios: effect is difficult to observe directly; effect is measured by a disease score or composite measure; effect is a clear biomarker. The methods will be developed using example applications. Where effect is difficult to observe, the example scenario is bacterial infection where serial cultures are rarely available in patients. In vitro hollow fibre infection model data will be combined with clinical dose-concentration data and a joint model formulated. Where effect is a disease score, the example scenarios will be taken from measures of sedation and toxicity used in paediatric critical care. Item response theory will be used to allow for pooling of different types of information , and again estimated jointly with dose-concentration data. Where effect is a clear biomarker the example scenario will be in immune reconstitution following transplant and antiretroviral initiation. Mechanistic differential equation models will be used to gain insight into drug, age and disease-related effects at the model parameter level. Mathematical models will be non-linear and mixed effects will be used to account for parameter and between occasion variability modelling. Optimal design of in vitro experiments will also be undertaken, and final optimum therapeutic guidelines derived using decision theory-based minimisation of loss function type approaches. The software for parameter estimation will be NONMEM and optimal design PoPED or PFIM. Scientific opportunities will mainly be the development and implementation of these methods in a paediatric setting. Medical opportunities will be development of dosing guidelines for some antimicrobials in children, developing sedation dosing guidelines for paediatric critical care, and improved understanding of interventions affecting immune reconstitution.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Newcastle University Single Cell Functional Genomics Unit (NUSCU)
Funder: Medical Research Council

Abstract: Foundations for the Newcastle University Single Cell Functional Genomics Unit are already in place, incl >£1M investment in 2012-13 in 18-colour fluorescent cell sorting (FACSAria Fusion), analysis (LSRFortessa), image flow cytometry (Image Stream), quantitative multiplex RNA analysis (Nanostring), and >£75K/yr on personnel and maintenance. Although this enables the isolation of cell types and a limited number of functional analyses, the comprehensive analysis of the whole genome, transcriptome, epigenome and a substantial component of the cell proteome is not currently possible in the North East of England. We seek to enable the work described above, through: (i) isolation of single cells from tissue section and suspension for whole genome sequencing and gene expression studies; (ii) in-house whole-genome DNA and RNA sequencing and linked epigenetic analysis; (iii) high throughput single-cell proteomics; (iv) a dedicated bioinformatic infrastructure. It is critical to establish this equipment on-site, as the research proposed will use patient tissue or fragile stem cell populations/cell lines which cannot be transported. We request Cell and sub-cellular trapping from solid tissues by laser micro dissection with optical tweezers (Zeuss PALM CombiSystem) Single-cell targeted gene expression analysis, global transcriptome analysis, mRNA sequencing, and genome amplification for whole-genome sequencing (Fluidigm C1 & BioMark system) Whole genome and transcriptome next-generation sequencing and linked epigenetic analysis (Illumina HiSeq 2500, linked sample preparation equipment, robotics and qPCR validation of RNAseq data) High throughput single cell proteomics with mass spectrometry based cytometry (Cytometry by Time Of Flight, CyTOF) Dedicated computational and bioinformatic infrastructure, enabling data processing and storage using newly developed algorithms (5 high-performance computer nodes @1TB/32core), which will complement our existing computing infrast


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: A National Centre for Translational Hyperpolarised Magnetic Resonance
Funder: Medical Research Council

Abstract: The technique of "spin hyperpolarised" Magnetic Resonance (MR) has the potential to provide a safe and uniquely versatile high-sensitivity tool for medical research, drug discovery and clinical diagnostics. By employing the "Signal Amplification by Reversible Exchange" ("SABRE") method, developed in York, spin hyperpolarisation is delivered in seconds in a continuous low-cost mode to 1H, 31P, 19F, 13C and 15N nuclei, which are ubiquitous to drugs, metabolites and biomarkers, offering distinct advantages over other hyperpolarisation methods. The in vivo detection of these biochemical probes through relatively low-cost, in-vivo molecular MR measurement in conventional hospital scanners can empower both clinical diagnosis and improve treatment in a wide range of conditions. In this joint bid, the Universities of Leeds and York, supported by clinical and industry partners, aim to establish a National Centre for Translational Hyperpolarised Magnetic Resonance to take SABRE hyperpolarisation from bench to bedside within 5 years. Target conditions in the areas of cancer, cardiovascular and musculoskeletal disease, all areas of international excellence in Leeds, will be investigated. Challenges of clinical compound generation and delivery will be addressed with close MHRA oversight and in collaboration with partners working on alternative hyperpolarisation methods, especially Dynamic Nuclear Polarisation, which is already entering clinical trials. Achieving our aim of clinical translation of the SABRE hyperpolarisation method would significantly advance the UK's prominence in exploring new areas in clinical research and address major scientific challenges relating to both the stratification of diseases and experimental studies in man.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cytochrome c oxidase: structure, function and malfunction
Funder: Medical Research Council

Abstract: The aim of this project is to elucidate the pumping mechanism of CcO and to investigate the effect of allosteric factors and isoforms on catalysis, using, for the first time, a yeast system that allows production and large scale purification of mitochondrial mutant forms of the enzyme. We will also start developing yeast as a platform for the construction of a chimeric yeast/human CcO. Initial focus will be put on identifying the internal hydrophilic pathway responsible for proton pumping. This will involve accurate measurements of ADP/Oxygen ratios on preparations of intact mitochondria from mutant strains. We will then address the coupling mechanism using time-resolved FTIR spectroscopy to detect concerted movements of key amino acids and water molecules on chosen reaction steps with the purified CcO. This will be done on photolysis of the fully reduced CO-bound enzyme, comparing the signals recorded for the wild-type and mutant forms and, subsequently, be extended to redox reactions. We will investigate how long range factors can regulate catalysis. For instance, we will follow by FTIR spectroscopy the structural changes induced by the binding of ADP or ATP to allosteric sites on yeast supernumerary subunits. This will include the design of a range of mutants to mimic post-translational modifications such as phosphorylation. We will aim to crystallise the yeast CcO and resolve its 3D X-ray structure. Finally, we will use our yeast system to investigate the effect of human disease-related mutations in CcO. We will use a range of biochemical methods to determine level of expression/stability, turnover number, affinity for its substrate, ability to pump proton and at which stoichiometry. If required, more advanced biophysical techniques including FTIR spectroscopy and fast kinetics recording will be used. Ultimately, as the project develops, we will look at the effect of such alterations on a chimeric yeast/human enzyme.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the genetic and activity-dependent instructions for striatal circuit development
Funder: Medical Research Council

Abstract: The aim of the proposed study is to dissect out the role of genetic and activity-dependent factors in coordinating the development of recurrent inhibitory connectivity between striatal medium spiny projection neurons (MSNs), which is shown to be disrupted in a variety of basal ganglia disorders. I will employ in vitro and in vivo electrophysiology in mice to define the development of synaptic connectivity between MSNs under baseline conditions and after disruption of early activity patterns. Furthermore, I will genetically label different types of MSN with fluorescent probes to investigate the role of genes in coordinating striatal recurrent connectivity. These complementary experiments will define critical factors and processes in the development of the striatum and can guide new rationales and identify targets for intervention in a range of basal ganglia disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding TGF beta activation in health and disease
Funder: Medical Research Council

Abstract: This grant aims to investigate the structural and functional significance of the dynamic C-terminus of human LTBP1 and its interaction with human fibrillin-1. We wish to establish the importance of this interaction in modulating the activation of TGF beta, which is covalently bound to LTBP via its propeptide LAP at a site adjacent to this C-terminal region. We will use the well established collaboration of Handford (biochemistry) and Redfield (biophysics) to investigate i) the structural basis of the LTBP/fibrillin-1 interaction for LTBP1 and other isoforms shown to bind to fibrillin-1 (using site-directed mutagenesis, NMR, SPR and related biophysical techniques), and ii) the functional importance of this interaction for TGFbeta activation, using an established TGFbeta reporter cell line in co-culture with normal and deficient fibroblast lines secreting fibrillin-1 and LTBP variants. These data will give new mechanistic insights into the role of extracellular matrix in regulating TGF beta activation, and molecular mechanisms underlying various connective tissue diseases which lead to over-activation of TGF beta. Furthermore these studies have the potential to direct further in vivo models as well as provide a rational basis for the design of novel antagonists /agonists. Results will be presented at international conferences on TGF beta signalling and disease, and any commercial exploitation will be handled by ISIS Innovation, University of Oxford.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Non-Enzymatic Glycation of Collagen: Role in Metabolic Disease and Inflammation
Funder: Medical Research Council

Abstract: We have discovered that necrosis of bone osteoblasts and vascular smooth muscle cells (VSMCs) results in poly(ADP ribose) (PAR) in the extracellular matrix (ECM). The ribose moiety at the end of a free PAR molecule is a potentially much more reactive sugar species for glycation than the sugar normally considered to be responsible for the majority of AGEs, namely glucose. Moreover, the finding of PAR in the ECM implied that damaging glycation could potentially occur in other pathologies where there is uncontrolled cell necrosis, not just in diabetic tissues. PAR is generated in cells from NAD+ by PAR polymerase (PARP) enzymes. Over-activation of PARPs, as happens as a result of cellular damage due to oxidative stress for instance, leads to cellular ATP and NAD+ depletion and drives cell necrosis. In other words, the oxidative stress that goes hand-in-hand with chronic inflammation and that can result in cell necrosis, may result in PAR - a potentially powerful glycator - in the surrounding ECM. In our pilot work, we found that as expected, ribose-based species react much faster to glycate proteins than does glucose, leading (amongst other things) to rapid formation of irreversible collagen cross-links which severely disrupt the collagen molecular structure, even for fibrillar collagen. As a result of this pilot work, we have formed a new hypothesis: that the most damaging glycating agent in oxidatively-stressed tissues is PAR and its degradation products, rather than glucose - the role of glucose is to create the oxidative stress conditions that drive the formation of PAR and cell necrosis. We will investigate this in in vitro oxidative stress models for bone and vascular tissue.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural and functional analyses of the multifunctional nontypeable Haemophilus influenzae SAP transporter
Funder: Medical Research Council

Abstract: No structural data is currently available for the nontypeable Haemophilus influenzae (NTHi) SAP transporter and the molecular mechanisms for the transport of haem and APs are unknown. We will use X-ray crystallography and electron microscopy to determine the molecular structure of the multi-protein SAP (and Trk) complex with the aim of identifying protein interactions that enable haem and AP transport. To obtain material for structural studies we will in parallel clone, express and purify all the components that make up the Sap/Trk complex (up to 8 individual proteins) with a focus on co-expression and co-purification to determine the structure of the complete Sap transporter. A unique collaboration will ensure that the fastest and most appropriate techniques are used - high throughput cloning/expression testing at the OPPF-UK, membrane protein focused biochemistry at the MPL , diffraction data collection at DLS beamlines, and cryo-EM and imaging at OPIC (U. Oxford) and the electron Bioimaging Facility eBIF (Diamond) when it comes online in 2015. Structural data obtained from Diamond MX beamlines and cryo-EM will be used to guide functional characterisation through use of site directed mutagenesis and will allow preliminary in silico design of small molecule inhibitors to disrupt transporter function (U. Oxford). The impact of impaired mutant Sap components will be assessed in vitro via the proteoliposome assay and in a murine model of NTHIi infection (MRC Harwell).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE