弥合两阶段模型与联合模型之间的差距:以肿瘤生长抑制和总生存模型为例。
Bridging the gap between two-stage and joint models: The case of tumor growth inhibition and overall survival models.
作者信息
Alvares Danilo, Mercier François
机构信息
MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
Modeling and Simulation, Roche Innovation Center, Basel, Switzerland.
出版信息
Stat Med. 2024 Jul 30;43(17):3280-3293. doi: 10.1002/sim.10128. Epub 2024 Jun 3.
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.
许多临床试验会同时产生纵向生物标志物数据和事件发生时间数据。我们可能会对它们之间的关系感兴趣,比如在肿瘤学药物研发中肿瘤大小与总生存期的关系。现有许多成熟的方法可用于分析此类数据,这些方法可以是序贯分析(两阶段模型),也可以是同时分析(联合模型)。两阶段建模(2stgM)受到了挑战,原因如下:(i)它没有认识到生物标志物是生存子模型的内生协变量;(ii)它没有将纵向生物标志物子模型的不确定性传递到生存子模型。另一方面,联合建模(JM)虽然恰当地规避了这两个问题,但却因耗时且在实际应用中难以使用而受到批评。在本文中,我们探索了第三种方法,即新型两阶段建模(N2stgM)。该策略在不影响参数估计准确性的情况下降低了模型复杂性。我们阐述了三种方法(2stgM、JM和N2stgM),并考虑使用贝叶斯框架来实现它们。我们使用真实数据和模拟数据来分析这些方法的性能。在所有情况下,我们提出的方法对参数的估计与JM大致相同,但计算成本较低,而2stgM产生了有偏差的结果。