Dynamic predictive probabilities to monitor rapid cystic fibrosis disease progression

• Published in: Statistics in medicine 2020-03, Vol.39 (6), p.740-756
• Main Authors: Szczesniak, Rhonda D., Su, Weiji, Brokamp, Cole, Keogh, Ruth H., Pestian, John P., Seid, Michael, Diggle, Peter J., Clancy, John P.
• Format: Article
• Language: English
• Subjects: Cystic fibrosis; Cystic Fibrosis - diagnosis; Cystic Fibrosis - genetics; Disease Progression; Forced Expiratory Volume; Humans; longitudinal data analysis; Lung - diagnostic imaging; medical monitoring; nonstationary process; nowcasting; predictive probability distributions; Probability
• ISSN: 0277-6715; 1097-0258; 1097-0258
• DOI: 10.1002/sim.8443

Cystic fibrosis (CF) is a progressive, genetic disease characterized by frequent, prolonged drops in lung function. Accurately predicting rapid underlying lung‐function decline is essential for clinical decision support and timely intervention. Determining whether an individual is experiencing a period of rapid decline is complicated due to its heterogeneous timing and extent, and error component of the measured lung function. We construct individualized predictive probabilities for “nowcasting” rapid decline. We assume each patient's true longitudinal lung function, S(t), follows a nonlinear, nonstationary stochastic process, and accommodate between‐patient heterogeneity through random effects. Corresponding lung‐function decline at time t is defined as the rate of change, S′(t). We predict S′(t) conditional on observed covariate and measurement history by modeling a measured lung function as a noisy version of S(t). The method is applied to data on 30 879 US CF Registry patients. Results are contrasted with a currently employed decision rule using single‐center data on 212 individuals. Rapid decline is identified earlier using predictive probabilities than the center's currently employed decision rule (mean difference: 0.65 years; 95% confidence interval (CI): 0.41, 0.89). We constructed a bootstrapping algorithm to obtain CIs for predictive probabilities. We illustrate real‐time implementation with R Shiny. Predictive accuracy is investigated using empirical simulations, which suggest this approach more accurately detects peak decline, compared with a uniform threshold of rapid decline. Median area under the ROC curve estimates (Q1‐Q3) were 0.817 (0.814‐0.822) and 0.745 (0.741‐0.747), respectively, implying reasonable accuracy for both. This article demonstrates how individualized rate of change estimates can be coupled with probabilistic predictive inference and implementation for a useful medical‐monitoring approach.