A joint model for lung function and nutritional status decline with recurrent pulmonary exacerbations, death, and lung transplantation using cystic fibrosis patient Registry data

Objectives: CF primarily affects the lungs and digestive system. Direct associations between recurrent acute respiratory events, known as pulmonary exacerbations (PEs), and markers of lung function and nutritional decline have been reported, but have been limited to continuous longitudinal markers of lung function and nutrition with time-to-first PE, thus neglecting subsequent occurrences. This limitation is primarily caused by a lack of appropriate and robust statistical software, which may hinder CF epidemiologic studies of PE recurrence.
Methods: For this retrospective cohort study of the U.S. CF Foundation Patient Registry, we jointly model the association between lung function decline (FEV 1) and evolution of growth and nutritional status (BMI) with the risk of recurrent PE, and the risk of lung transplant or death by using all available data. We employ a novel approach to investigate how the underlying value and slope of FEV1 and BMI trajectories associate with mortality/transplantation and PE recurrence. We accommodate non-risk periods during care episodes and risk periods defined by the gap or calendar timescale. The developed joint model for multiple longitudinal outcomes, recurrent and terminal events is available in the R package JMbayes2.
Results: Preliminary results suggest that FEV 1 and BMI are associated with risks of experiencing either death/transplantation or PE. The model estimates an association of −0.02 (95%CI −0.03, −0.01) and 0.01 (95%CI −0.02, 0.04) between the risk of experiencing a PE and FEV1 or BMI, respectively.
Conclusion: Incorporating all recurrent events with multiple markers to represent lung function decline and nutritional status enhances our understanding of risks posed by PEs. Our implementation enables a more efficient use of all available Registry data. Therefore, it brings new insights into CF disease progression and contributes to precise monitoring and comprehensive treatment strategies.