Platform Science ACF Projects 2021

A list of ACF 2021 projects within the speciality of Respiratory Medicine.

Lead: Professor Salman Siddiqui  ss338@le.ac.uk

Co-applicant: Professor Chris Brightling  ceb17@le.ac.uk

Co-applicant: Professor Paul Monks   paul.monks@leicester.ac.uk

Co-applicant: Professor Toru Suzuki   tsuzuki@leicester.ac.uk

Co-applicant: Professor Paul Thomas– University of Loughborough, C.L.P.Thomas@lboro.ac.uk

Three project areas are available for the ACF. All three projects combine breath discovery science, quantitative methods, opportunities in trial design, opportunities in qualitative assessment of near patient breath testing and evidence synthesis methods e.g. systematic review methodology.

 

Several partners in the EMBER pathology node are capable of hosting trainees during industry placement including Owlstone Medical (Cambridge-UK), as well as opportunities to travel to partnering EU and US institutions active in the breathomics field for research placements.

 

 

(i) Breath signatures in severe asthma – stratification of biologic therapies

Current high costs therapies in airway disease such as severe asthma cost the NHS 1Billion Pa, however these therapies fail in 1 in 4 patients and the current biomarkers used to stratify them are imprecise (e.g. blood eosinophils) or affected by standard treatment such as inhaled steroids (exhaled nitric oxide). Treatment failure leads to ongoing harm to patients through oral steroids exposure and life-threatening attacks leading to hospital admission. The EMBER program has developed several early and promising biomarker signatures using breathomics of biologic therapy response (anti-IL-5, anti-IL-5 receptor therapies) in severe asthma that appear to (i) identify with high precision (sensitivity and specificity > 90%) patients that will fail treatment at initiation of therapy and (ii) allow monitoring of airway inflammation in a corticosteroid treatment effect independent manner.

 

The ACF/CL will develop research programs deploying these markers into clinical trials of biologic response considering all current biologic agents, supporting the design of these trials, positioning of the optimal sampling methods and breath analysis platform e.g. eNOSE vs GCxGC-MS for signature validation.

 

The projects are aligned to ongoing EU/UK severe asthma trials consortia (3TR-IMI-ADON, NIHR BEAT-SA) and offer opportunities for research placement within industry e.g. Owlstone Medical (Cambridge, UK).

 

(ii) Ex vivo, in vitro systems for breath biomarker validation

An important gap in the breath research field is to underpin breath volatile signatures to mechanisms of disease, enabling the development of future stratified medicines and robust biomarkers. Within the EMBER pathology node in vitro systems have been developed and are being optimised for sampling of headspace volatiles in primary cell cultures e.g. activated eosinophils and bacterial cultures and native matrices to the lung such as sputum.           The use of pharmacological antagonists for specific enzymatic pathways within cells and stable transfection methods e.g. lentivirus that target (overexpress/knockout) enzymes of key interest found in target cells provide a power method of identifying causal pathways of breath volatiles. The projects will focus on antimicrobial strategies that modify the microbiome and high cost therapies.

 

The ACF/CL will be trained in primary cell/matrix headspace volatile capture and analysis. Training in cell culture, stable transfection will be provided in the Leicester BRC. Access to large repositories of data within biologic and infection trials programs/observational cohort studies in EMBER will enable robust ‘lookup and validation’ of in vitro signatures identified in patients and clinical trials. The potential for secondments to industry partners within the EMBER partnership will be explored in this project (GSK, AZ and Chiesi).

 

(iii) Multi-metabolomics approaches in cardio respiratory disease

Acute cardio respiratory disease accounts for approximately 70% of emergency admissions in the NHS. Diagnostic uncertainty remains in 30% of patients despite available tools such as imaging and current pathology markers e.g. BNP, CRP. It is recognised that diagnostic uncertainty is related to adverse outcomes with prolonged length of stay, increased rates of treatment failure and increased morbidity and mortality. The EMBER program has identified promising breath volatile and plasma metabolomics signatures (> 550 patients, pragmatic Breathomics, GCxGC-MS acute care study) in patients with severe cardio respiratory admissions and high levels of diagnostic uncertainty – primarily presenting with overlap syndrome of acute heart failure, respiratory infection and COPD.  The further development and validation of these metabolomic signatures using near patient breath testing (e.g. eNOSE) and further molecular pathology e.g. sputum metagenomics in cases where infection is suspected, echocardiography in cases of suspected heart failure, will enable the development of potential point of care signatures at triage.

 

The ACF/CL will conduct acute care triage studies in patients with high levels of diagnostic uncertainty at triage for biomarker validation use point of care breath testing devices e.g. eNOSE, CMS, coupled with ReCIVA sampling onto thermal desorption tubes for GCxGC-MS target validation. Testing burden, patient acceptability will be further studied using qualitative assessments (semi-structured interviews). Health economic evaluation (in conjunction with the UoL Health Sciences group) will be initiated by developing a model of the acute care pathway and optimal positioning of breath testing devices.

 

Excellent support is available to deliver acute care studies in the BRC, this includes an established acute care platform for acute observational and intervention studies hosted by the Leicester NIHR-CRF, study nurses capable of supporting acute care studies, breath testing device are well established in the cardio respiratory admissions unit at University Hospitals of Leicester and several informatics tools in EMBER support sample curation, tracking and linkage to clinical care data.

 

Prof Anna Hansell, Professor in Environmental Epidemiology, Director Centre for Environmental Health and Sustainability & the National Institute of Health Research Health Protection Research Unit in Environmental Exposures and Health at University of Leicester

Prof Matt Bown, Professor of Vascular Surgery

Prof Frank Dudbridge, Professor of Statistical Genetics

Dr Anna Guyatt, Research Fellow in Genetic and Observational Epidemiology

Project lead: Anna Hansell (ah618@leicester.ac.uk)

1. Air pollution in relation to abdominal aortic aneurysm prevalence and progression

Abdominal aortic aneurysm (AAA) was responsible for 4645 deaths in England in 2018. AAAs are usually asymptomatic, but rupture has a mortality of >80%, and is related to size. The NHS operates the National AAA Screening Programme (NAAASP, www.aaa.screening.nhs.uk/), and patients with small AAAs are monitored for increase in aneurysm diameter, with repair surgery offered to those with large AAAs. Patients with small AAAs identified through NAAASP have been enrolled in a prospective study led by Prof Bown at Leicester (United Kingdom Aneurysm Growth Study, UKAGS).

 

There is evidence of links between both short-term and long-term exposure to air pollution and various cardiovascular outcomes, however, there are almost no studies on AAA. Air pollution is a plausible risk factor: animal studies have suggested particulate matter promotes AAA formation, but there are almost no human studies investigating air pollution in relation to AAA prevalence or progression.

 

This project will consist of: i) a cross-sectional analysis of 10,000 men within NAAASP, investigating whether air pollution is associated with baseline aortic diameter, and ii) a longitudinal analysis of 4,000 men with small AAA (also within NAAASP), investigating whether air pollution exposure at baseline and/or over follow-up years is associated with AAA growth rate.

 

Environmental exposure data will be obtained from the Centre for Environmental Health and Sustainability (CEHS, Director: Prof Hansell), and will comprise air pollution estimates from state-of-the-art models for pollutants, including particulate matter and NO2, plus potential co-factors (e.g. traffic noise). Statistical techniques will include linear mixed modelling, considering bias from competing mortality and loss-to-follow-up. An extension could explore using models incorporating environmental data to improve prediction in aneurysm growth.

 

The proposed research will be based in the CEHS at the University of Leicester, and will include multi-disciplinary supervision from experts in environmental epidemiology, biostatistics and cardiovascular medicine. Prof Hansell (CEHS director) has conducted amongst the largest studies to date on air pollution and lung health (Doiron et al., 2019), and managed the team that led the integration of air pollution data into UK Biobank. The ACF/ACL will gain experience in integrating environmental datasets with cohort studies, considering relevant ethical issues, as well as training in epidemiology and statistics, with potential extensions relevant to precision medicine.

 

2. Modifiers of the impact of air pollution on lung function

 

A recent study in UK Biobank (Doiron et al., 2019, led by Prof Hansell) found that higher air pollution exposure (inter-quartile range interval) was associated with the equivalent of ~8 months ageing of the lung, and a doubling of chronic obstructive pulmonary disease risk, as measured by spirometry.

 

As well as these environmental associations, lung function has an established genetic basis: members of the supervisory team were involved in the largest genome-wide association study (GWAS) of spirometric traits to date (Shrine et al., 2019), and identified 279 genetic signals for lung function.

 

Some of the impact of air pollution on lung function may be modified by genetic variants (a gene-by-environment interaction). Whilst these interactions have been explored for 279 known lung function variants, results were inconclusive. However, a review of small-scale studies (Minelli et al., 2011) has suggested potential interactions of known antioxidant genes with air pollution in relation to lung function. The proposed project would involve performing gene-by-environment interaction analyses in UK Biobank, using antioxidant candidate genes identified previously, allowing evidence for these associations to be assessed at scale. Further work could use Mendelian randomization, a causal inference technique in which genetic variants are used as unconfounded measures of modifiable exposures, to investigate causality between antioxidants (e.g. a potentially modifiable dietary exposure) and lung function.

 

This project will use ‘big data’ on air pollution, dietary data, genetics, and spirometry measures in UK Biobank. The ACF/ACL will be trained in high performance computing and statistics, including techniques fundamental to genetic epidemiology (genetic association and Mendelian randomization).

 

This project is based at the Centre for Environmental Health and Sustainability (CEHS) at the University of Leicester. The University is a world leader in air pollution research, and Prof Hansell (CEHS director) has conducted amongst the largest studies to date on air pollution and lung health, and managed the team that led the integration of air pollution data into UK Biobank. The Leicester genetic epidemiology group has particular strengths in respiratory genetics and statistics, including global experts in Mendelian randomization (Prof Dudbridge).

 

Overall, this project will leverage genetic, environmental and physiological data to investigate how genetic variation and lifestyle factors may modify the impact of air pollution on lung health, and to identify opportunities for mitigation via diet or potential drug targets.

 

3. Disentangling the relationships between environmental pollution, COPD and cardiovascular disease

Environmental risk factors such as air pollution are associated with common diseases with high morbidity and mortality, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) (Doiron et al., 2019; Cai et al., 2018, led by Prof Hansell). COPD and CVD commonly occur co-morbidly, and CVD has been reported as one of the major causes of death in people with COPD. Despite these interrelationships, the exact nature of the associations between COPD and CVD are yet to be established: for example, it is possible that the relationship between COPD and CVD is partially explained by measures of air pollution being a common cause of both conditions (confounding). This is not the only possible model: lung function impairment occurring as a consequence of pollution exposure may mediate the association between ambient air pollution and cardiovascular morbidity and mortality.

 

This project would provide the ACF/ACL with an opportunity to train in observational epidemiology, integrating ‘big data’ from UK Biobank, including pollutant data from state-of-the-art models for particulate matter and NO2, electronic healthcare records, and quantitative measures of lung function (spirometry). The trainee would first assess the extent to which air pollution may confound the lung function-CVD relationship, and could then consider lung function as a potential mediator between air pollution and CVD. Techniques would involve regression modelling, including survival analysis, and due consideration of bias by competing risks, confounding, and loss-to-follow-up, plus training in the use of statistical software (e.g. Stata or R).

 

This project is based at the Centre for Environmental Health and Sustainability (CEHS) at the University of Leicester. Prof Hansell (CEHS director) has conducted amongst the largest studies to date on air pollution, lung health and CVD, and Dr Guyatt is a fellow undertaking research in cardiorespiratory epidemiology. The work would take place in a highly multi-disciplinary setting, with additional access to experts in biostatistics, linked healthcare data, and multimorbidity. Understanding the nature of the relationships between air pollution, COPD and CVD would provide insight into potential preventative strategies for two common health conditions of major public health importance.


 

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