Use and development of statistical mediation techniques to understand the survival gap between males and females with cystic fibrosis

Cystic Fibrosis (CF) is a life limiting genetic disorder affecting over 70,000 people worldwide. It is caused by a mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene which supplies the instructions for the cystic fibrosis transmembrane conductance regulator protein which acts as a channel to transport chloride and bicarbonate ions across cell membranes. This impaired transport results in thickened and dehydrated mucus covering the cells that both interferes with normal functioning and is prone to colonisation by pathogens causing progressive damage in many organ systems of the body including the pancreas, lungs, kidneys and digestive system, and ultimately leads to a reduced life-span.

Current treatments concentrate on mitigating the damage caused by CF since currently there are no treatments that can cure CF. For babies born in 2019 in the UK, median survival is predicted to be 51.6 years for males and 45.7 years for females. This survival gap between males and females has been present in recorded data over recent decades even as survival times have increased and it has also been observed in other countries. There is as yet no clear explanation for this survival gap and it provides the motivation for this project. It seems likely that sex impacts on several aspects of disease progression through the life course, which in turn affects survival. Previous research has shown that: females with CF first acquire many pathogens at an earlier age than males, females infected with particular pathogens have increased mortality compared to men, after the age of 40 females have greater decline in FEV% predicted (the proportion of Forced Expiratory Volume compared to a person without CF of the same age, sex, height and ethnicity) than males and also that, of those with severe CFTR genotypes, females have higher prevalence of cystic fibrosis related diabetes. The hypothesis is that these and other aspects of disease progression affected by sex are, in combination, responsible for the survival disparity.

The project will use longitudinal data from the UK Cystic Fibrosis Registry which was set up in 1995. It is a centralised database managed by the Cystic Fibrosis Trust. Over 99% of people with CF in the UK have consented to their data being submitted to the database. The database is a large data set not only in containing records from over 13,000 people and over 140,000 records from annual patient reviews but also in terms of the width and complexity of the records with data collected on over 250 variables at each annual review. The project will use data up to 2018.

One aim of the project is to understand which variables show divergence between the sexes by summarising sex differences in key variables. The main aim of the project, however, is to understand how the effect of sex on survival may act through intermediate variables by using mediation analysis and so further the understanding of the causal pathways leading to this survival disparity. The mediators considered will be of different types: categorical, continuous and time-to-event, and all are repeatedly measured. There has been considerable recent development in statistical methodology for mediation analysis where there are multiple mediators and also where the outcome is time-to-event and this project presents an exciting opportunity to use and develop these techniques.
The project will allow me to gain skills in:
- Handling and analysing longitudinal data from a large observational patient registry
- Applying state of the art statistical mediation analysis and other causal inference methodology to a substantive research question
- Developing statistical methodology and assessment of methods using simulation studies
- Liaising with clinical advisors and data experts to refine the research questions