Explaining the Sex Effect on Survival in Cystic Fibrosis: a Joint Modeling Study of UK Registry Data

Male sex is associated with better lung function and survival in people with cystic fibrosis but it is unclear whether the survival benefit is solely due to the sex-effect on lung function. METHODS: This study analyzes data between 1996 and 2015 from the longitudinal registry study of the UK Cystic Fibrosis Registry. We jointly analyze repeated measurements and time-to-event outcomes to assess how much of the sex effect on lung function also explains survival. These novel methods allow examination of association between percent of forced expiratory volume in 1 second (%FEV1) and covariates such as sex and genotype, and survival, in the same modeling framework. We estimate the probability of surviving one more year with a probit model. RESULTS: The dataset includes 81,129 lung function measurements of %FEV1 on 9,741 patients seen between 1996 and 2015 and captures 1,543 deaths. Males compared with females experienced a more gradual decline in %FEV1 (difference 0.11 per year 95% confidence interval [CI] = 0.08, 0.14). After adjusting for confounders, both overall level of %FEV1 and %FEV1 rate of change are associated with the concurrent hazard for death. There was evidence of a male survival advantage (probit coefficient 0.15; 95% CI = 0.10, 0.19) which changed little after adjustment for %FEV1 using conventional approaches but was attenuated by 37% on adjustment for %FEV1 level and slope in the joint model (0.09; 95% CI = 0.06, 0.12). CONCLUSIONS: We estimate that about 37% of the association of sex on survival in cystic fibrosis is mediated through lung function.