论文标题

推出之前的外推在估算协变量时会减少偏差

Extrapolation before imputation reduces bias when imputing censored covariates

论文作者

Lotspeich, Sarah C., Garcia, Tanya P.

论文摘要

建模症状进展以确定新亨廷顿疾病临床试验的信息学科是有问题的,因为诊断时间(一个关键的协变量)可以受到大量审查。插补是一种吸引人的策略,在重大审查下,审查的协变量被其有条件的手段取代,但现有的方法在重大审查下占200%的偏见。计算这些条件均值良好需要估计然后整合从审查的协变量从审查值到Infinity的生存函数。为了灵活地估计生存功能,现有方法使用Breslow的估计器使用半参数COX模型,从而使整合有条件均值(估计的生存函数)未定义超出观察到的数据。然后,估计该积分为最大的观察到的协变量值,并且该近似值可以切断生存功能的尾巴并导致严重的偏见,尤其是在重度审查下。我们提出了一种混合方法,该方法将半参数存活率估计量拼接在一起,以参数扩展为止,从而可以将积分直至无穷大。在模拟研究中,我们提出的外推方法归类大大降低了现有的归因方法,即使参数扩展被误指定。我们进一步证明,采用校正后的有条件手段归类有助于将患者确定以后的临床试验。

Modeling symptom progression to identify informative subjects for a new Huntington's disease clinical trial is problematic since time to diagnosis, a key covariate, can be heavily censored. Imputation is an appealing strategy where censored covariates are replaced with their conditional means, but existing methods saw over 200% bias under heavy censoring. Calculating these conditional means well requires estimating and then integrating over the survival function of the censored covariate from the censored value to infinity. To estimate the survival function flexibly, existing methods use the semiparametric Cox model with Breslow's estimator, leaving the integrand for the conditional means (the estimated survival function) undefined beyond the observed data. The integral is then estimated up to the largest observed covariate value, and this approximation can cut off the tail of the survival function and lead to severe bias, particularly under heavy censoring. We propose a hybrid approach that splices together the semiparametric survival estimator with a parametric extension, making it possible to approximate the integral up to infinity. In simulation studies, our proposed approach of extrapolation then imputation substantially reduces the bias seen with existing imputation methods, even when the parametric extension was misspecified. We further demonstrate how imputing with corrected conditional means helps to prioritize patients for future clinical trials.

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