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Development of mechanistic models for analysis and interpretation of cough challenge test data.

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  • Full or part time
    Dr K Ogungbenro
    Prof L Aarons
    Prof Jacky Smith
  • Application Deadline
    Applications accepted all year round

Project Description

Cough is the most common reason for which medical advice is sought both at primary and secondary health care levels. Despite the prevalence of cough, understanding of the mechanisms that lead to coughing in different diseases is poorly understood; this has made drug development for treatment of cough even more difficult. Cough challenge test using inhalation agents such as capsaicin has been used to induce and quantify cough with the aim of understanding the mechanisms that underline cough and assess efficacy of antitussive therapies. Capsaicin cough challenge test has been designed and tested by a multi-disciplinary research team (lead by Prof Jacky Smith) at the Manchester University NHS Foundation Trust, Wythenshawe.

The objective of this project is to develop mechanistic models for describing the data obtained from capsaicin cough challenge test. This model will allow better interpretation of the test, provide insight into the mechanisms of cough and boosts developments of antitussive therapies. It will also help to refine statistical design of the test.

During capsaicin cough challenge, to evoke cough individuals are administered four inhalations of doubling doses of capsaicin within a specified range of doses. The data from this study (number of coughs after each dose of capsaicin inhalation) is a discrete type of data and requires special technique for its analysis. Recently a mixed-effect model approach (Satia et al) was applied to this data taking into account its discrete nature, dose-response type and the drop-out by individuals at different doses of capsaicin. This model characterised capsaicin dose-response in patients with chronic cough, asthmatic patients, and healthy volunteers and was superior to traditional method of analysing this data. This research will explore other models that have been proposed for count data; also correlation between counts will be explored by using Markov models.

Entry Requirements
Applicants are expected to hold or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in pharmacy, pharmacology, mathematics, statistics, biological sciences, engineering or a related biological/physical science area. A strong mathematical background and/or a Masters degree in relevant subject area are desirable. Previous experience of data analysis and mathematical/computational modelling would be an advantage.

If you are interested, please make direct contact with the Supervisor to discuss the project. You MUST also submit an online application form - choose PhD Pharmacy and Pharmaceutical Sciences. Applications will close when a suitable candidate is found so please apply as soon as possible.

Funding Notes

This project is funded by The Faculty of Biology, Medicine and Health at the University of Manchester. Studentship funding is for a duration of four years to commence in September 2019 and covers UK/EU tuition fees and a UKRI stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Satia, I., Tsamandouras, N., Holt, K., Badri, H., Woodhead, M., Ogungbenro, K., Felton, T.W., O'Byrne, P.M., Fowler, S.J., Smith, J.A. (2017). Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction. J. Allergy Clin. Immunol. 139(3): 771-779

Belvisi, M.G., Birrell, M.A., Wortley, M.A., Maher, S.A., Satia, I., Badri H., Holt, K., Round, P., McGarvey, L., Ford, J., Smith, J.A. (2017). XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough. Am. J. Respir. Crit. Care Med. 196(10):1255-1263

Hilton, E.C., Baverel, P.G., Woodcock, A., Van Der Graaf, P.H., Smith, J.A. (2013). Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point. J Allergy Clin Immunol. 132(4): 847-55

Musuamba, F.T., Manolis, E., Holford, N., Cheung, S., Friberg, L.E., Ogungbenro, K., Posch, M., Yates, J., Berry, S., Thomas, N., Corriol-Rohou, S., Bornkamp, B., Bretz, F., Hooker, A.C., Van der Graaf, P.H., Standing, J.F., Hay, J., Cole, S., Gigante, V., Karlsson, K., Dumortier, T., Benda, N., Serone, F., Das, S., Brochot, A., Ehmann, F., Hemmings, R., Rusten, I.S. (2017). Advanced methods for dose and regimen finding during drug development: summary of the EMA/EFPIA workshop on dose finding (London 4-5 December 2014). CPT Pharmacometrics Syst Pharmacol. 6(7): 418-429



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