Evaluation of strategies for reducing the burden of COPD in the UK using Bayesian methods

Chronic obstructive pulmonary disease (COPD) is responsible for 5.3% of all deaths and 1.7% of all hospital admissions in the UK. This thesis focuses on strategies to reduce COPD burden by targeting three aspects across the public healthcare system: prevention, emergency treatment, and long-term management. Analyses were performed in a Bayesian framework to exploit its flexibility in modelling uncertainty and the incorporation of prior knowledge. First, I assessed whether communication of personalised disease risk in primary care is an effective smoking cessation intervention, using cost-effectiveness and value of information analyses based on various data sources across the literature. The odds ratio for the effectiveness of communication of personalised disease risk was 1.48 (95%CrI:0.91-2.26). While I found a probability of cost-effectiveness of about 90%, further research up to a maximum of £27 million is justified to reduce the uncertainty around this estimate. Secondly, I assessed whether case ascertainment affects the detection of poorly performing hospital trusts in the treatment of acute exacerbation of COPD (AECOPD) in secondary care, using data from the National Asthma and COPD Audit Programme. Case ascertainment was associated with 30-day mortality (OR:1.74; 1.25-2.41) and adjusting for it impacted the findings, with 5 trusts becoming outliers and 2 trusts no longer classified as outliers. Finally, using general practice data from Clinical Practice Research Datalink, I assessed whether new guidelines suggesting triple therapy (long-acting beta-2 agonists, LABA + long-acting muscarinic antagonists, LAMA + inhaled corticosteroids, ICS) for the treatment of those with poorly-controlled COPD on LABA+LAMA dual therapy improves disease outcomes. Triple therapy was not associated with severe AECOPD (IRR:1.00; 0.93-1.07) or mortality (IRR:0.95; 0.86-1.06), but was associated with increased risk of pneumonia (IRR:1.19; 1.05-1.35). This thesis applied sophisticated Bayesian methods to increase understanding of how COPD burden could be reduced in different areas of the public healthcare system.Open Acces

BIMAM—a tool for imputing variables missing across datasets using a Bayesian imputation and analysis model

Motivation Combination of multiple datasets is routine in modern epidemiology. However, studies may have measured different sets of variables; this is often inefficiently dealt with by excluding studies or dropping variables. Multilevel multiple imputation methods to impute these ‘systematically’ missing data (as opposed to ‘sporadically’ missing data within a study) are available, but problems may arise when many random effects are needed to allow for heterogeneity across studies. We show that the Bayesian IMputation and Analysis Model (BIMAM) implemented in our tool works well in this situation. General features BIMAM performs imputation and analysis simultaneously. It imputes both binary and continuous systematically and sporadically missing data, and analyses binary and continuous outcomes. BIMAM is a user-friendly, freely available tool that does not require knowledge of Bayesian methods. BIMAM is an R Shiny application. It is downloadable to a local machine and it automatically installs the required freely available packages (R packages, including R2MultiBUGS and MultiBUGS). Availability BIMAM is available at [www.alecstudy.org/bimam]

Moisture sensitivity examination of asphalt mixtures using thermodynamic, direct adhesion peel and compacted mixture mechanical tests

Moisture damage in asphalt mixtures is a complicated mode of pavement distress that results in the loss of stiffness and structural strength of the asphalt pavement layers. This paper evaluated the moisture sensitivity of different aggregate–bitumen combinations through three different approaches: surface energy, peel adhesion and the Saturation Ageing Tensile Stiffness (SATS) tests. In addition, the results obtained from these three tests were compared so as to characterise the relationship between the thermodynamic and the mechanical tests. The surface energy tests showed that the work of adhesion in dry conditions was bitumen type dependent, which is in agreement with the peel test. After moisture damage, all of these three tests found that the moisture sensitivity of aggregate–bitumen combinations were mainly aggregate type dependent. Based on the peel test, the moisture absorption and mineralogical compositions of aggregate were considered as two important factors to moisture sensitivity. This phenomenon suggests that in a susceptible asphalt mixture, the effect of aggregate may be more influential than the effect of bitumen. The SATS test and the peel test showed similar moisture sensitivity results demonstrating the good correlation between these two mechanical tests. However, the surface energy tests and the mechanical tests cannot correlate in terms of moisture sensitivity evaluation

Understanding Polarized Foreground from Dust: Towards Reliable Measurements of CMB Polarization

Science opportunities and recommendations concerning optical/infrared polarimetry for the upcoming decade in the field of cosmology. Community-based White Paper to Astro2010 in response to the call for such papers.Comment: White Paper to the Cosmology and Fundamental Physics (GCT) Science Frontiers Panel of the Astro2010 Decadal Surve

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials