NIHRDataInsights/HRCSData huggingface dataset:
Title: An investigation into the use of shrinkage methods to alleviate over-fitting of prognostic models for independent and clustered data with few events
Funder: Medical Research Council

Abstract: Prognostic models are increasingly used by clinicians and policy makers to predict health outcomes for public and patients. These models are used to guide the clinical management of patients, help patients make informed decisions about their treatment and compare institutional performances after adjusting for patient case-mix. However, accurate and reliable prognostic models can be difficult to develop if the disease or event of interest is rare. Model overfitting is a problem in this situation, and is typically handled using variable selection approaches based on P-values. However, variable selection has problems, which are exacerbated in sparse data, including model instability in terms of the selected predictors. Additional complexity arises with multi-centre data as patients within a centre are more likely to be similar compared to patients across centres, leading to clustered (correlated) data. Penalised maximum likelihood methods, which apply shrinkage to regression coefficients, have been proposed to address the model overfitting problem. However, these methods have not been adequately evaluated for scenarios that typically occur in the clinical areas of public health, epidemiology and health services research. Moreover little work has been done to develop shrinkage methods for clustered data. It is important to conduct research to identify appropriate methods that enables the development of reliable prognostic models in the clinical settings described above. This research will conduct a thorough investigation of the performance of existing methods for binary and survival health outcomes through the evaluation of their theoretical properties and performance in simulation studies. The overreaching aim is to make recommendations to health researchers regarding the use of appropriate methods in prognostic modelling studies in these settings, and to facilitate their use by providing an overview of available software and developing routines where required.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Development of statistical methods for the analysis of single patient data
Funder: Medical Research Council

Abstract: This project is to develop effective statistical methods for comparing a single patient with a control population. The fundamental questions are whether the patient could be part of the control population and the degree to which the patient is unusual. In recent years a body of work has addressed these questions in a variety of situations, in most of which comparison is based on a single measure. This work will be extended to handle further situations, focusing on those involving two or more measures. Such situations arise commonly as multiple measurements are typically taken on patients, but appropriate statistical methods for their analysis are largely lacking. The methods that are developed will enable a broader range of more flexible hypotheses to be examined by researchers, allowing them to handle multiple indicators, quantify the uncertainty over results using confidence/credible intervals, and take account of covariates. The new methods will use both frequentist and Bayesian ideas, and combinations of the two that yield Bayesian-based methods with good frequentist properties. Probability-matching priors are one approach that will be considered. Also, the frequentist distributions of statistics from Bayesian posterior distributions will be derived and bias-correction methods examined. A Bayesian equivalent of double-bootstrapping will also be explored as another bias-correction mechanism. Simulation will be used to examine both the properties of methods and the sensitivity of methods to departures from the modelling assumptions. User-friendly software that implements the new methods will be written and made freely available.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: A Statistically Rigorous Framework for the Analysis of Biological Mass Spectrometry Data
Funder: Medical Research Council

Abstract: The aim of this study is to develop statistical tools that will allow experimentalists to quantify the uncertainty associated with biological mass spectrometry measurements. Current methods for the analysis of such data are of a rather poor statistical standard, as they do not allow for the use of well-established statistical procedures such as hypothesis testing and maximum likelihood estimation. Recent work by the applicant has demonstrated that such tools can be used when the statistical distribution of the data can be described mathematically, but at present this constrains their use to a small subset of the data-analytical problems encountered. Through improved statistical modelling we hope to expand the scope of their applicability. Various aspects of the instruments must be characterised as part of this study. These include the shapes of mass peaks, and the uncertainty inherent to the detection system. We will investigate these features by means of direct experiments using the mass spectrometry facilities at Swansea and Johns Hopkins and through the use of software tools. Should direct mathematical characterisation prove too difficult, we will explore the use of statistical procedures that can accommodate for the lack of this information. We will use the resulting model to solve a number of central problems that arise in the analysis of time-of-flight mass spectrometry data. Mass spectrometry is used in numerous areas of medical research, ranging from disease diagnostics to basic cellular research. All areas in which it is used would benefit from sound statistical methods for accounting for the uncertainty in the data as well as from potential improvements in the accuracy with which measurements can be made. If the study is successful in demonstrating the benefit to the statistical analysis of detailed instrument modelling, it could have an impact on instrumental design of both mass spectrometers and other scientific instruments.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Novel model-based designs for early phase trials of medicines for children
Funder: Medical Research Council

Abstract: The evidence basis for medicines prescribed to children is often limited with efficacy and dosage extrapolated from data generated by clinical trials in adults. Extrapolation is not straightforward as differences in physiology and function, not just size, separate children and adults; this may lead to dose recommendations being either inefficacious or so high as to be unacceptably toxic. The primary aim of this project is to develop novel dose-finding procedures to estimate the optimal dose of a medicine in children which can formally borrow strength from existing data in adults or data on a different indication in children. Further project aims are to engage with key stakeholders in the clinical trials community (regulators; industry; publicly funded clinical trials units; clinical pharmacologists; clinicians) to increase the relevance of this work. Dose-finding procedures will use Bayesian non-linear hierarchical models to synthesise available data on dose, pharmacokinetics and pharmacodynamics with the aim of identifying a quantile of the implied dose-response relationship. As each new participant enters the trial dose-assignments are made according to a Bayesian decision theoretic criterion. The performance of procedures will be evaluated. Within the Bayesian paradigm, formal use of existing information on drug behaviour in adults is possible. For the hierarchical model, prior distributions will be constructed for model forms and parameters which correctly reflect the information contributed by adult data. Extensions to dose-finding procedures include incorporating covariates such as age, and relaxing constraints initially made by the hierarchical model. Trials which progress seamlessly to tests of efficacy on termination of dose-finding will be considered, combining information accrued in both stages to make a final decision. Opportunities for applying the proposed methodology to different therapeutic areas will be actively sought throughout the Fellowship.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of OCRL1 in endocytic membrane traffic
Funder: Medical Research Council

Abstract: Phosphoinositide (PI) lipids are vitally important for a multitude of cellular processes ranging from intracellular signaling to membrane traffic. The abundance and distribution of PIs is under tight control by kinase and phosphatase enzymes that consequently are important for normal cellular and organismal physiology. One such enzyme is OCRL1, a PI 5-phosphatase whose mutation causes two disorders in humans, Lowe syndrome and Dent-2 disease. OCRL1 has a role within the endocytic pathway, where it regulates receptor recycling, but how it carries out this function is poorly understood and consequently the mechanisms underlying Lowe syndrome and Dent disease are ill defined. Endocytosis is a universally important trafficking pathway present in all eukaryotes. Its dysregulation results in disease, and it is often exploited by bacterial and viral pathogens to cause infection. We have recently identified IPIP27A as a novel OCRL1 interactor with a key role in endocytic recycling. We have gone on to identify the cellular machinery to which IPIP27A binds, which includes several trafficking components associated with the actin cytoskeleton. These findings strongly support a model whereby OCRL1, IPIP27A and its associated proteins regulate the formation of carriers that mediate endocytic recycling. The aim of this proposal is to test this model and define the mechanisms by which OCRL1, IPIP27A and its actin-associated interactors function in carrier formation. To achieve this aim, a variety of cell-based approaches will be used, including trafficking assays, live cell microscopy and electron microscopy. Together our studies will provide significant insight into how membrane traffic within the endocytic pathway is regulated by PIs, and how defects in this process cause disease in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of miRNA regulation of early embryonic development
Funder: Medical Research Council

Abstract: Understanding the regulatory networks underlying pluripotency and differentiation is essential to effectively use stem cells for therapeutic applications. Two distinct phases of pluripotency have been proposed, a naïve state and a primed state and these states are thought to be regulated by different mechanisms microRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression and have been shown to be required to for proper proliferation and exit of the naïve pluripotent state. However little is known about their roles in the primed phase of pluripotency. In preliminary work to this proposal we have found that in contrast to the naïve pluripotent state, miRNAs regulate cell survival and neural differentiation of primed pluripotent cells. The main focus of this project is to understand how miRNAs regulate these processes. Dicer is an enzyme that is essential for the production of mature microRNAs. We will first establish the functional requirements of miRNAs in the epiblast by analysing embryos in which Dicer has been specifically deleted in primed pluripotent cells or in derivatives of each of the germ layers. These studies will be complemented with the analysis of the effects that Dicer deletion has on the survival and differentiation of epiblast stem cells (EpiSCs). Next we will identify what microRNAs regulate the primed pluripotent state by determining which miRNAs can rescue the defects of Dicer deleted EpiSCs. Finally we will establish the miRNA-mRNA target interactions that regulate primed epiblast pluripotency. For this we will transfect single miRNAs into Dicer deleted EpiSCs and study what genes become downregulated. These genes will be compared to those obtained by bioinformatic prediction of microRNA targets. The best candidate genes will be validated by mutation of the microRNA target site in them to establish which interactions are functionally important.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Determining how global genome nucleotide excision repair promotes efficient removal of DNA damage from chromatin
Funder: Medical Research Council

Abstract: The main objectives of the work are to determine how the GG-NER process is organised and initiated throughout the genome in response to UV damage, and to determine how the GG-NER complex functions during chromatin remodeling to promote efficient repair in the genome. We will use chromatin immunoprecipitation on microarrays [ChIP-Chip] to measure DNA repair factor binding throughout the yeast genome both before and after UV. We will also use this approach to measure epigenetic changes in the nucleosomes of chromatin in response to UV damage. Next generation sequencing on the ABI / Illumina platforms will be used to examine nucleosome mapping/chromatin remodeling in response to UV damage. We have direct access to the ABI SOLiD 5500 next generation sequencing system available via the Wales Gene Park and supported by a NISCHR funded BRU post in my laboratory. We have access also to the Illumina platform via our collaborator T. Owen-Hughes. We have developed new technology to examine the frequency of DNA damage at high resolution throughout entire genomes (Teng, et al 2011 A novel method for the genome-wide high resolution analysis of DNA damage. Nucleic Acids Research, January; 39(2). The method was developed employing S.cerevsiae as a model organism. Via our approach we can measure DNA damage and its repair in the entire S.cerevisiae genome. This method allows us to determine how DNA damage is repaired in the context of chromatin. We will relate the repair events to changes in chromatin that facilitate DNA repair such as covalent histone modifications and chromatin remodeling activities as described in the proposal. Biochemical studies on the in vitro activities of the GG-NER complex will involve the purification of native and recombinant proteins from yeast and bacteria. The biochemical activities of these proteins will be analysed using the in vitro experiments described in the case for support.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Future-Proofing the Sustainability of the MRC High Throughput Sequencing Hub in Scotland
Funder: Medical Research Council

Abstract: During the first three years of the MRC High Throughput Sequencing Hubs programme, the GenePool invested in training highly-skilled wet-lab and bioinformatics teams and installing leading high-throughput technologies to deliver bespoke genomics collaborations across our science and geographical area. We propose further investment in personnel and in outreach and training to consolidate the Hub at the core of nextgen genomics in our area, to build nextgen genomics analytic capacity across Scotland and the UK, and to transition to a fully cost-recovered financial model. We will develop a portfolio of training and outreach activities, including a new training post delivering master classes and summer schools in next gen genomics, the very successful Next Generation Bioinformatics User Group meetings and MRC 'spokes' bioinformaticians training. We will deliver proactive NextGen Clinics across Scotland, allowing prospective collaborators to discuss ideas directly with GenePool staff. The training bioinformatics post will be held jointly with our sister MRC Hub in Liverpool, linking the two facilities. We will produce promotional materials, and distribute these, including via our web and social media presences. We will beta-test and develop standard operating procedures for new applications, including testing of new commercial kits and reagents, and working with collaborators to bed in new ways of using the technology. We will enhance our collaborators' experience by improving the operation of the facility, appointing a laboratory manager and a business manager. This will streamline the processing of user data, freeing the scientific manager and director to focus on speeding the transformation of researchers' ideas into viable projects, well analysed studies and high-impact publications. At the end of the two year renewal period, the GenePool MRC HTS Hub will be fully transitioned to cost recovery on staff, reagents and equipment renewal.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre for Genomic Research: Genomics Hub Renewal
Funder: Medical Research Council

Abstract: The CGR has acted as one of the MRC DNA-sequencing hubs for two years and in that time has tripled its turnover, significantly increased its laboratory workflow and sequencing capacity, developed higher throughput pipelines, implemented LIMS as well as instigating software and hardware solutions. In that time, it has also completed 394 sequencing and array projects for the UK community, with its user base currently including 75 Universities/Research Institutes and 17 groups working in the commercial sector. The CGR has a current staff of 19 persons and currently runs six different sequencing platforms: Ion Torrent PGM; 454 FLX+ and 454Jr; ABs SOLiD v4 and 5500xl; and the Illumina GAIIx. The CGR is completing the purchase of two Illumina HiSeq2000s. The CGR is aimed primarily at providing a service for small-to-medium sized projects to the UK research community. This proposal requests two additional years of reduced funding to allow the CGR to further to expand its market and complete the move to a fully self-sustainable business model. To achieve this, we request funds to (i) hire a Business Manager to drive a vigorous marketing campaign, (ii) run a training and outreach activities to encourage more research users and (iii) develop research projects with some of the largest research initiatives in the North of England. The CGR will also engage in a number of large collaborative research proposals that will ensure the CGR maintains an academic and research-led philosophy.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mitochondrial DNA copy number as a phenotypic trait for human diseases in genetic epidemiological studies
Funder: Medical Research Council

Abstract: Mitochondrial DNA (mtDNA) has been studied in relation to population genetics and human disease. Mutations and depletion of mtDNA have been related to a variety of diseases. There is evidence suggesting that depletion of mtDNA is associated with metabolic disorders such as obesity, diabetes and hyperlipidemia. However, variation of mtDNA copy number as a continuous trait in relation to genetic epidemiological studies is underexplored. The same applies to the study of nuclear genes exerting control in the genetic variation of mtDNA. Our aims here are i) to conduct association studies between mtDNA copy number and complex traits including adiposity, fasting glucose, insulin, lipids and cognitive function, aiming to identify relations between mtDNA copy number and these traits relevant to disease; and ii) to conduct a genomewide association scan (GWAS) aiming to identify nuclear genes controlling mtDNA copy number. To this end, we will determine mtDNA copy number in an established and densely phenotyped cohort (Avon Longitudinal Study of Parents and Children, ALSPAC, N = 20,000). The results from this project would open a new dimension on the study of obesity, diabetes, hyperlipidemia and cognitive risk traits, representing new basic knowledge and potential benefit for improving human health. If we demonstrate that mtDNA copy number can be used as a biomarker for obesity, diabetes, hyperlipidemia and cognitive risk traits, its use could also be applied to the study of other diseases.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: MRC strategic Award
Funder: Medical Research Council

Abstract: While numerous environmental and nutritional risk factors for disease and mortality have been identified, significantly less is known on how they affect health and longevity in whole populations. My proposed research programme will integrate methods and data from population and environmental sciences, statistics and epidemiology to create a quantitative risk-based characterization of the worldwide population health transitions, in the recent past and forecasted into the future. The focus will be on a number of important global environmental and nutritional risk factors.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Managing and exploiting high dimensionality in genetic epidemiology
Funder: Medical Research Council

Abstract: A salient characteristic of genetic epidemiology in recent years has been the high dimensionality of studies in terms of the number of genetic variants assayed, phenotypic outcomes analysed, and sample sizes attained. This leads for example to increased possibilities for false positive findings and in selection bias when focusing on the most significant results. However, high dimensionality can be usefully exploited by pooling information across multiple genes or phenotypes, which can improve power by means such as aggregating evidence across a biological pathway, estimating the total heritability explained by a genomewide association scan (GWAS), or eliciting stronger instruments for Mendelian randomisation (MR) analyses. The next generation of genetic epidemiology studies can be broadly dichotomised into 1) continued disease mapping efforts using larger sample sizes and complete DNA sequence data, focussing on rare mutations and structural variants; 2) efforts to gain insight from GWAS results by relating DNA variation to biological function. High dimensionality will continue to be a key feature in both cases. This research will address high dimensionality in both cases, which will continue to be a key feature. We will address genomewide significance for whole genome and exome sequencing studies, in diverse worldwide populations. We will develop improved methods for analysing the new generation of disease specific genotyping chips, which are optimised for the study of particular classes of disease, using empirical Bayes optimal discovery procedures. We will develop improved methods for analysing standard GWAS, including more powerful two-stage approaches within a single data set, and proper reporting of significance levels from replication studies. Finally we will study the use of whole genome instruments in Mendelian randomisation, by using shrinkage methods within two-stage least squares and inferring non-linear causal effects from observational data.


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