Using time-varying models to estimate post-transplant survival in pediatric liver transplant recipients

Purpose
To distinguish clinical factors that have time-varying (as opposed to constant) impact upon patient and graft survival among pediatric liver transplant recipients.
Methods
Using national data from 2002 through 2013, we examined potential clinical and demographic covariates using Gray’s piecewise constant time-varying coefficients (TVC) models. For both patient and graft survival, we estimated univariable and multivariable Gray’s TVC, retaining significant covariates based on backward selection. We then estimated the same specification using traditional Cox proportional hazards (PH) models and compared our findings.
Results
For patient survival, covariates included recipient diagnosis, age, race/ethnicity, ventilator support, encephalopathy, creatinine levels, use of living donor, and donor age. Only the effects of recipient diagnosis and donor age were constant; effects of other covariates varied over time. We retained identical covariates in the graft survival model but found several differences in their impact.
Conclusion
The flexibility afforded by Gray’s TVC estimation methods identify several covariates that do not satisfy constant proportionality assumptions of the Cox PH model. Incorporating better survival estimates is critical for improving risk prediction tools used by the transplant community to inform organ allocation decisions.

研究目的：
明确对儿童肝移植受者的患者与移植物存活具有时变（而非恒定）影响的临床因素。

研究方法：
本研究采用2002至2013年的全国性数据，运用Gray分段恒定时变系数（time-varying coefficients, TVC）模型对潜在的临床与人口统计学协变量进行分析。针对患者存活与移植物存活两种结局，分别构建单变量与多变量Gray时变系数模型，并基于向后剔除法保留具有统计学意义的协变量。随后采用传统的Cox比例风险（proportional hazards, PH）模型开展相同设定的分析，并对两种模型的研究结果进行对比。

研究结果：
在患者存活模型中，纳入的协变量包括受者诊断、年龄、种族/族裔、呼吸机支持情况、脑病状态、肌酐水平、活体供者使用情况以及供者年龄。其中仅受者诊断与供者年龄的影响为恒定不变；其余协变量的效应均随时间发生变化。移植物存活模型中保留了完全一致的协变量，但发现各协变量的影响模式存在多处差异。

研究结论：
Gray时变系数估计方法所具备的灵活性，可识别出若干不满足Cox比例风险模型恒定比例性假设的协变量。优化生存结局估计对于改进移植学界用于指导器官分配决策的风险预测工具而言，具有至关重要的意义。