NIHRDataInsights/HRCSData huggingface dataset:
Title: How is the current crisis reshaping Brazil's health system? Strengthening health workforce and provision of services in São Paulo and Maranhão
Funder: Medical Research Council

Abstract: Brazil has been in economic recession for the last two years, and the Government is starting to introduce measures to limit public spending on social sectors and deregulate the health insurance market. We propose a theory-based conceptual framework to understand the multiple reverberations of the crisis on health system and health workers. The specific objectives of the study are: (a) to analyse the available data on health financing and medical workforce; (b) generate hypotheses on how the current economic crisis and associated policy responses will affect the health workforce; (c) test quantitatively such hypotheses in a representative sample of physicians, and; (d) organise policy dialogues to discuss the study findings and suitable policy options. Existing health financing and medical demography datasets will be explored through descriptive and multivariate analysis to establish a relationship between the health financing, health system outputs, and service utilisation. Semi-structured and in-depth interviews will be conducted in São Paulo and Maranhão states with health professionals, policy-makers and hospital managers. Theory-driven content analysis will be used to qualitatively analyse interviews' contents. Two surveys will be conducted in a representative sample of physicians to test the hypotheses on the impact of the crisis on Brazil's health workforce. Data will be collected through telephone interviews on: (1) Physicians' characteristics; (2) Changes in time allocation and outputs; (3) Changes in private sector and dual practice engagement; (4) Intentions to leave the public sector and retire. Ordinal and logistic regression models will be used to link such changes with physicians' characteristics and health workers' perceptions of the crisis. Two policy dialogue workshops facilitated by PAHO will be organised with national and international health stakeholders to disseminate the study findings, and inform the development of policy measures.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Unpacking the effect of the national pay for performance scheme (PMAQ) on inequalities in the financing and delivery of primary care in Brazil.
Funder: Medical Research Council

Abstract: Pay for performance (P4P) schemes, i.e. financial rewards based on the achievement of pre-specified performance indicators, are employed to improve the availability, quality and utilisation of essential health services globally. Although the design of P4P schemes may be key to understanding the variations in programme effectiveness, we know very little about how incentive designs affect performance and inequalities in outcomes. This project will investigate how Brazil's national P4P scheme for improving primary care access and quality (PMAQ) has affected socioeconomic inequalities in the financing and delivery of primary care and the extent to which different incentive designs affect these outcomes. The Brazilian experience provides a unique opportunity to explore this question as: 1) municipalities have autonomy in the design and delivery of incentives to providers in their area, 2) there is extensive secondary data available on socio-economic status, financing and quality of care, and 3) the scheme is the largest in the world, with substantial heterogeneity between areas. We will review the incentive designs adopted by municipalities nationally and develop a typology of designs. We will then investigate whether PMAQ affects inequalities in the distribution of funding across teams and if this differs by incentive design using routine data. We will also examine whether PMAQ funding is a substitute or complement to other health sector funding. We will examine the relationship between socio-economic inequalities and structure and process quality of care using data from the PMAQ External Evaluation. Finally, we will conduct 20 in-depth municipality level case studies in 2 states, varying in context and incentive design, to evaluate the mechanisms through which PMAQ affects inequalities in funding and quality of primary care. The study will promote knowledge exchange between researches in the United Kingdom and in Brazil.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Influence of vitamin D on non-communicable disease outcomes in South African schoolchildren: the ViDiKids-NCD sub-study
Funder: Medical Research Council

Abstract: 1. Background Laboratory investigations and observational studies suggest that vitamin D has favourable effects on calcium homeostasis, muscle function and metabolism that may translate into improved bone mineral density, increased lean mass and improved physical fitness. Randomised controlled trials (RCTs) powered to test minimum clinically important differences in these outcomes in children are lacking. 2. Aim and Objectives We aim to determine the effect of a 3-year course of oral vitamin D supplementation on diverse non-communicable disease (NCD) outcomes in South African schoolchildren by conducting a sub-study nested within the MRC-funded ViDiKids study - a n=5,400 RCT of vitamin D for the prevention of TB infection. Our objective is to conduct a sub-study (n=400 children aged 9-10 years at baseline, 12-13 years at follow-up) to evaluate: i) bone mineral density (primary outcome, measured by DXA) ii) physical fitness (VO2max derived from results of a 20 metre multi-stage shuttle run test) iii) muscle strength (grip strength and explosive leg strength, assessed with grip dynamometry and long jump from standing respectively) iv) body composition (fat mass and mean fat-free soft tissue mass, measured by DXA) v) biochemical parameters (serum concentrations of 25(OH)D, PTH, ALP, P1NP and CTX). 3. Application of results Vitamin D supplementation is cheap and safe. Positive findings from this research could have a major public health impact: 1 billion people worldwide are estimated to have inadequate vitamin D status, and an epidemic of osteroporosis is emerging in many low- and middle-income countries.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Improving the effectiveness and efficiency of Health and social care services for vulnerable Older Brazilians (IHOB).
Funder: Medical Research Council

Abstract: This study will support policy and practice to reduce unneeded admissions of older people to hospitals and care homes, and reduce unnecessarily long stays. We will develop and apply a new concept, "avoidable displacement from home" (ADH), and apply it in the Brazilian context. Drawing on a systematic review and interviews with policymakers and practitioners, we will identify criteria for defining ADHs (admissions to hospitals/care homes that could have been realistically averted or shortened) which are applicable in Brazil. Using survey data, supplemented by in-depth, multi-method case studies in Belo Horizonte (BH) and Fortaleza (FZ), we will assess the prevalence of ADH nationally and in specific settings. Likewise, we will identify key predictors of ADH, with a particular focus on more vulnerable older people and their families. We will identify potential interventions to reduce rates of ADH in different parts of Brazil. This will draw on the systematic review, an evaluation of an intervention in BH and the implementation of a validation/feasibility study in FZ. The BH intervention provides frail older people with a week of intensive home care, serving both as respite for family carers and to build family carer capacity. We will apply a mixed method evaluation of process and outcome, drawing on interviews with key informants, practitioners and users and data linking diagnostic related groups and admissions. We will develop a version of this intervention (contingent on BH evaluation results) in FZ, with a view to full pilot and evaluation in a further funded study. We will produce a national report and develop an ADH toolkit for Brazilian policymakers and practitioners including definitional criteria for ADHs, predictors of ADH and evidence-based strategies to reduce ADH. We will engage intensively with policy networks in the UK and globally, assessing the wider conceptual and operational relevance of ADH.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Variational Approximation Approaches for Efficient Clinical Predictions
Funder: Medical Research Council

Abstract: Methodology Development: The project will involve four distinct stages. In the first 9 months of the fellowship I will derive MFVB approximations for MGLMMs. Current MFVB methods for mixed models only consider a single longitudinal marker. I will derive the MFVB approximations for continuous, binary and count longitudinal variables when jointly modelled in a MGLMM. During months 9-21 of the fellowship I will derive MFVB approximations for joint models of multiple longitudinal markers of different types and time-to-event data. I propose using the MGLMM methodology developed in Stage 1 and combining it with a proportional hazards model (as is standard in joint modelling). I will derive the approximations to the hazard model in order to approximate the full likelihood. I will perform substantial assessment of the utility of the MFVB methods I develop. Specifically I will assess (i) the accuracy of the model parameter estimates compared to alternative joint model methodology (MCMC or frequentist approaches), (ii) the speed of model fitting (iii) the gain in fitting models to large datasets compared to using only a small subsample of the patients. The performance of the MFVB joint model will assessed using various real datasets including both large and smaller datasets and through rigorous simulation analysis. Months 22-30 of this fellowship would be used to derive dynamic predictions from the multivariate joint models derived in the previous Workstage. This will allow dynamic predictions of a patient's risk of experiencing an event that can be updated each time new information is available. Software Development: The final 6 months of the fellowship will be used to develop user friendly code to fit the models developed during the first 3 stages. I will create functions in R to calculate MGLMMs and multivariate joint models as well as functions to assess predictive accuracy and graphically represent the predictions. These functions will be freely available R package.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: NIRG: Taming the skew - empowering Mendelian randomization trials by controlling stratification bias
Funder: Medical Research Council

Abstract: Randomised controlled trials (RCT) are the "gold standard" for testing a new treatment or identifying causal risk factors for disease, however they are not always feasible. Mendelian randomization (MR) is an alternative tool to RCT, which uses common genetic variants as surrogates for an exposure of interest to statistically estimate the causal effect of an exposure on a disease. MR assumes that there is no confounding between the genetic polymorphism and the disease outcome. If population stratification occurs due to mismatched ancestries, then this assumption will be violated and any estimates will be biased. Within single studies where researchers have access to individual level data, ancestry may be accounted for to some extent by adjusting for principle components. However, MR requires large sample sizes, which introduces genetic heterogeneity. In the case of two sample MR, which uses summary statistics from two study sets, population stratification will unlikely be adequately controlled for. Capturing the global population structure is the Holy Grail of population genetics. Currently, no approach exists that captures the population structure in a fast, accurate, and unbiased way in Big Data. We aim to develop new statistical and computational solutions to control for population stratification bias, particularly in MR, using mega datasets, such as the UK BioBank data. We will test these methods using simulated and real datasets, recommend when and how they should be used, and produce computer code to allow their execution by non-specialists. More specifically, we will: 1) develop a fine-scale model of the genetic structure in human populations; 2) optimise case-control matches based on genetics and demographic criteria; 3) measure the bias in using summary statistics in meta-analysing GWAS data; 4) test how this approach improves MR in testing two open questions using the UK BioBank.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: HOD1: Comparative Effectiveness Research using Observational Data:Methodological Developments and a Roadmap (CER-OBS)
Funder: Medical Research Council

Abstract: The potential gains for enhancing comparative effectiveness research (CER) by exploiting linked health-related databases are indisputable. However, the potential pitfalls that may arise from not properly accounting for the administrative nature of this information have fuelled a debate on its utility. A promising approach that addresses (some of) these concerns advocates the implementation of trial design principles when exploiting observational data in CER. It consists of emulating the trial that would be designed to study the effectiveness of a treatment by specifying the target population and target comparative measures, and then handling/analysing the observational data to replicate them. There are still several unmet challenges for a robust adoption of this approach, however: Study design: Erroneous decisions at any step of the construction of the emulated trial may affect the robustness of the reported evidence. Awareness of potential methodological pitfalls is essential for the interpretation and delivery of evidence. Data quality: The coarseness often affecting observational data and the likely dependence of the timing of the observations on factors related to the disease evolution, impact on the robustness of the adopted estimation approach. Estimation: Most CER involves treatments sustained over time and requires implementing g-methods for estimation. G-estimation of structural nested models is the most flexible, particularly for dealing with multiple confounders and/or time-points, but has not been fully exploited in applications, nor extended to deal with data coarseness and dependent follow-up. Given these challenges, this application aims to: A) Create a roadmap for the assessment and robust delivery of evidence that adopts the "emulate the target trial" approach. B) Extend g-estimation to deal with data coarseness and dependent follow-up. C) Use clinically relevant exemplars to illustrate both approach and methodological developments.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Vast-scale linear mixed modelling genetic discovery approaches for genome- and exome-wide association analyses to enable therapeutic target validation
Funder: Medical Research Council

Abstract: To address the objectives of the fellowship, we will further develop DISSECT (PMID: 26657010). This is a software tool developed within the group, which was designed to overcome the compute and memory limitations of single compute nodes by taking advantage of the aggregate power of the thousands of processor cores and large distributed memory available on supercomputers or large compute clusters. For this purpose, DISSECT distributes the available data over the multiple nodes. At any given time, each node has access to only a small portion of the data on which it performs local computations. When the algorithm requires access to blocks of data currently held on other nodes, the nodes communicate to coordinate data redistribution. This approach provides access to much larger computational resources for a single analysis (i.e. increases the scalability) than standard tools that can only use the resources of a single compute node for each analysis, even when running on similar computer clusters environments. In addition, using as a basis our current development, we will further develop, evaluate and implement previous approaches (PMID: 25642633, 21465547) that propose to perform approximations to reduce the computational cost of fitting these models on large datasets, and find a balance between speed, accuracy, and computation requirements. The proposed analyses will be run on Tier-1 and Tier-2 High Performance Computing Centres such as ARCHER (https://www.archer.ac.uk) and CIRRUS (http://www.cirrus.ac.uk).


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Determining the causal links and clinical significance of rare genetic variants
Funder: Medical Research Council

Abstract: Large studies of disease outcomes combined with studies of intermediate phenotypes (transcriptome, proteome) in two-sample Mendelian randomisation (MR) can be used to provide evidence for a causal path from DNA variation through gene expression to disease outcome. Even so, their small phenotypic effect size makes common genetic variants detected by GWAS in cosmopolitan populations difficult to follow up functionally. Genetic variants of larger effects size are rare in populations of largely unrelated individuals, but may become detectable in isolate populations with higher levels of kinship. Such variants are unlikely to be captured by standard SNP genotyping and so require more genome sequence-level analysis. This project will identify novel and rare variants in whole-exome sequence data that have cis-acting effects on protein abundance in 8000 individuals from isolate populations from the Northern Isles of Scotland and from Croatia. Evidence for the role of protein expression in disease aetiology will be explored using two sample MR. These studies will include re-contact of cohort participants carrying rare variants with large predicted phenotypic effects for a more detailed phenotypic assessment and generation of tractable biological samples. Further study will include exploiting proteomic and other 'omic data to build graphical predictive models for individual traits or diseases incorporating multiple loci.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating lysosomal dysfunction as a unifying pathological mechanism in hereditary spastic paraplegia
Funder: Medical Research Council

Abstract: Axonal health is necessary for a functional nervous system and it is vital to understand how this is disrupted in axonopathies. Insights into this are provided by genetic conditions causing selective axonal degeneration, of which hereditary spastic paraplegias (HSPs) are exemplars; HSPs are characterised by distal "dying back" axonal degeneration in the corticospinal tracts. Through work funded by our present MRC grant, we discovered characteristic lysosomal abnormalities in several genetic subtypes of HSP, including the most common form, spastin-HSP. This led us to propose that lysosomal dysfunction underlies HSP axonopathy. Building on these findings, we aim to test the hypothesis that lysosomal dysfunction is a unifying and potentially treatable pathological mechanism in HSP. We will: i) Investigate how the lysosomal abnormality affects downstream cellular pathways that require functional lysosomes, thereby identifying mechanisms by which lysosomal dysfunction could cause axonopathy. We will prioritise effects on endosomal lipid metabolism, BMP signalling and autophagy, as preliminary evidence highlights these as strong candidate pathways to be involved in HSP. ii) Test a causal relationship between lysosomal dysfunction and axonopathy by determining whether strategies to improve lysosomal function can ameliorate abnormal lysosomal morphological phenotypes, effects on downstream lysosomal pathways [identified at i)] and HSP-associated axonal phenotypes. These experiments may also identify potential therapeutic approaches. iii) Determine whether lysosome dysfunction is a broadly unifying mechanism for HSP, by examining whether it is present in representative examples of additional key functional groups of HSP proteins, beyond those that we have already shown to be involved. Through this work we will better understand how lysosomal dysfunction contributes to HSP pathogenesis, and how this might be targeted therapeutic benefit.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Epigenome patterning in oocytes and its legacies in the embryo
Funder: Medical Research Council

Abstract: Transmission of epigenetic information from parent to offspring is generally precluded by multiple genome-wide reprogramming steps that occur from the specification of germ cells, during gametogenesis, in the preimplantation embryo, and with establishment of lineage-specific epigenomes from implantation. Yet the extent to which there is inter-generational transmission of epigenetic states is still unclear and of substantial interest, eg, in relation to factors such as the increase in maternal obesity and the programming of adverse metabolic outcomes in offspring, or whether epigenetic fidelity is compromised by procedures for assisted reproduction. Genomic imprinting provides the best paradigm for epigenetic inheritance, and which is fundamentally important for normal offspring growth, development and long-term health. Until recently, it appeared that there was a single modality of imprinting, determined by gamete-derived DNA methylation, but recent studies prompt us to develop a more nuanced view and to recognise additional pathways to imprinting, such as chromatin-determined imprinting. This programme will explore transcriptional control and how transcription patterns the epigenome in the oocyte and the legacies of these events in the embryo. It will investigate how DNA methylation-dependent and chromatin-dependent modes or imprinting are set up at different times in the female germline and how they contribute in different ways to developmental processes in the embryo and extra-embryonic lineages. It will assess general principles at the genome-wide scale, but also work at the level of specific loci to test mechanistic details and functional impacts of the different modes of imprinting. It will explore variation in DNA methylation in human preimplantation embryos, how this variation can be traced back to methylation variation in oocytes and seek to eludiate the genetic basis and pathophysiological correlates of such variation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE