Biard L, Labopin M, Chevret S, Resche-Rigon M
1 Service de Biostatistique et Information Médicale, AP-HP Hôpital Saint-Louis, Paris, France.
2 Université Paris Diderot - Paris 7, Sorbonne Paris Cité UMR-S 1153, Paris, France.
Stat Methods Med Res. 2018 Mar;27(3):920-932. doi: 10.1177/0962280216647981. Epub 2016 May 10.
In survival analysis, assessing the existence of potential centre effects on the baseline hazard or on the effect of fixed covariates on the baseline hazard, such as treatment-by-centre interaction, is a frequent clinical concern in multicentre studies. Survival models with random effects on the baseline hazard and/or on the effect of the covariates of interest have been largely applied, for instance, to investigate potential centre effects. We aimed to develop a procedure to routinely test for multiple random effects in survival analyses. We propose a statistic and a permutation approach to test whether all or a subset of components of the variance-covariance matrix of random effects are non-zero in a mixed-effects Cox model framework. Performances of the proposed permutation tests are examined under different null hypotheses corresponding to the different components of the variance-covariance matrix, i.e ., to the different random effects considered on the baseline hazard and/or on the covariates effects. Several alternative hypotheses are evaluated using simulations. The results indicate that the permutation tests have valid type I error rates under the null and achieve satisfactory power under all alternatives. The procedure is applied to two European cohorts of haematological stem cell transplants in acute leukaemia to investigate the heterogeneity across centres in leukaemia-free survival and the potential heterogeneity in prognostic factors effects across centres.
在生存分析中，评估潜在中心效应是否存在于基线风险或固定协变量对基线风险的效应上，例如治疗与中心的交互作用，是多中心研究中常见的临床关注点。对基线风险和/或感兴趣的协变量效应具有随机效应的生存模型已被广泛应用，例如，用于研究潜在的中心效应。我们旨在开发一种在生存分析中常规检验多个随机效应的方法。我们提出一种统计量和一种置换方法，以检验在混合效应Cox模型框架下随机效应的方差协方差矩阵的所有或部分分量是否为非零。在对应于方差协方差矩阵不同分量的不同原假设下，即对应于在基线风险和/或协变量效应上考虑的不同随机效应，检验所提出的置换检验的性能。使用模拟评估几个备择假设。结果表明，置换检验在原假设下具有有效的I型错误率，并且在所有备择假设下都具有令人满意的检验功效。该方法应用于两个欧洲急性白血病血液干细胞移植队列，以研究各中心在无白血病生存率方面的异质性以及各中心预后因素效应的潜在异质性。
