Repository logo
 

Bridging the gap between two-stage and joint models: the case of tumor growth inhibition and overall survival models

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Alvares, Danilo Alvares  ORCID logo  https://orcid.org/0000-0003-3764-0397
Mercier, François 

Abstract

Many clinical trials generate both longitudinal biomarker and time-to-event data. We might be interested in their relationship, as in the case of tumor size and overall survival in oncology drug development. Many well-established methods exist for analyzing such data either sequentially (two-stage models) or simultaneously (joint models). Two-stage modeling (2stgM) has been challenged (i) for not acknowledging that biomarkers are endogenous covariable to the survival submodel, and (ii) for not propagating the uncertainty of the longitudinal biomarker submodel to the survival submodel. On the other hand, joint modeling (JM), which properly circumvents both problems, has been criticized for being time-consuming, and difficult to use in practice. In this paper, we explore a third approach, referred to as a novel two-stage modeling (N2stgM). This strategy reduces the model complexity without compromising the parameter estimate accuracy. The three approaches (2stgM, JM, and N2stgM) are formulated, and a Bayesian framework is considered for their implementation. Both real and simulated data were used to analyze the performance of such approaches. In all scenarios, our proposal estimated the parameters approximately as JM but without being computationally expensive, while 2stgM produced biased results.

Description

Keywords

Journal Title

Statistics in Medicine

Conference Name

Journal ISSN

0277-6715
1097-0258

Volume Title

Publisher

John Wiley and Sons
Sponsorship
Medical Research Council, grant number: MC_UU_00002/5