Barbara Wendelberger, Thomas P Jensen, Melanie Quintana, Iain Stewart, Philip L. Molyneaux, Toby M. Maher, Justin M. Oldham, Simon R. Johnson, William A. Fahy, Fasihul Khan, Gauri Saini, Rayid Abdulqawi, Richard J. Allen, Bruno Guedes Baldi, N Chaudhuri, Tamera J Corte, Vincent Cottin, Manuela Funke-Chambour, Ian Glaspole, Anne E Holland, Kerri A. Johannson, Yet H. Khor, Michael Kreuter, Tejaswini Kulkarni, María Lorena Molina-Molina, Fernando J Martinez, Sydney B. Montesi, Steven D Nathan, Lucilla Piccari, Sujeet Rajan, Pilar Rivera-Ortega, Christopher J. Ryerson, Koji Sakamoto, Louise V. Wain, Athol U Wells, Wendy Adams, Letícia Kawano-Dourado, R Gisli Jenkins, Roger Lewis, Ahmed Fahim, Amanda Bravery, Amanda Goodwin, Ana Etges, Ana Sousa Marcelino Boshoff, Andreas Günther, Andrew Briggs, Andrew Palmer, Andrew Wilson, Anjali Crawshaw, Anna-Maria Hoffmann-Vold, Anne Bergeron, Anthony Gordon, Antje Prasse, Argyris Tzouvelekis, Athina Trachalaki, Avinash Anil Nair, Ayodeji Adegunsoye, Ben Hope-Gill, Bhavika Kaul, Bibek Gooptu, Bruno Crestani, Carisi Anne Polanczyk, Carlo Vancheri, Carlos Crobal, Charlotte Summers, Chris Grainge, Christophe von Garnier, Christopher Huntley, Claudia Ravaglia, Claudia Valenzuela, Conal Hayton, Cormac McCarthy, Daniel Chambers, Dapeng Wang, Daphne Babalis, David Thicket, David Turner, Deepak Talwar, Devaraj Anand, Devesh Dhasmana, Dhruv Parek, Diana Calaras, Diane Griffiths, Diego Castillo Villegas, Duncan Richards, Elisabeth Bendstrup, Elisabetta Balestro, Eliza Tsitoura, Emanuela Falaschetti, Ena Gupta, Erica Farrand, Felix Chua, Francesco Bonella, Francesco Lombardi, Gary M. Hunninghake, Gunnar Guðmundsson, Harold R. Collard, Haruyuki Ishii, Helen Parfrey, Helmut Prosch
RATIONALE: Fibrotic interstitial lung diseases (ILDs) cause loss of forced vital capacity (FVC) and increased risk of death over time. Most clinical trials aim to slow FVC decline and reduce mortality. However, the association of lower FVC with higher mortality will bias simple estimates of differences in FVC progression between groups. Therefore, both the time-dependent decline in FVC and increase in mortality should be jointly modeled. METHODS: We developed a Bayesian, joint mixed-effects disease progression model (DPM), using minimally informative prior distributions, for FVC trajectory and the hazard for ILD-related mortality over time. This model minimizes bias due to mortality in estimating differences in the rate of FVC decline and is suitable for use when characterizing populations or in estimating a treatment effect in a clinical trial. The DPM was applied to individual patient data from prospective cohort studies of fibrotic ILD. MEASUREMENTS AND MAIN RESULTS: The DPM yields a higher estimated rate of FVC decline (6.0% vs 4.7%/year) and a more precise fit than a linear mixed model of FVC alone, and replicates the nonlinear pattern in the observed data. By modeling the full FVC trajectory rather than only the change from baseline at a given time point, the DPM increases the information from each patient and reduces both the time to information and the effect of variability in baseline FVC measurements on the estimation of treatment effects. CONCLUSIONS: The joint DPM provides an integrated approach to minimizing bias in the estimation of treatment effects in clinical trials in fibrotic ILDs.