Clinical trials to test experimental treatments for Huntington's disease are expensive, so it is prudent to enroll subjects whose symptoms may be most impacted by the treatment during follow-up. However, modeling how symptoms progress to identify such subjects is problematic since time to diagnosis, a key covariate, can be censored. Imputation is an appealing strategy where censored covariates are replaced with their conditional means, the calculation of which requires estimating and integrating over its conditional survival function from the censored value to infinity. To flexibly estimate the survival function, existing approaches use the semiparametric Cox model with Breslow's estimator. Then, for integration, the trapezoidal rule is used, but the trapezoidal rule is not designed for indefinite integrals and leads to bias. We propose a conditional mean calculation that properly handles the indefinite integral with adaptive quadrature. Yet, even with adaptive quadrature, the integrand (the survival function) is undefined beyond the observed data, so we explore methods to extend it. In extensive simulation studies, we show that replacing the trapezoidal rule with adaptive quadrature corrects the bias seen with existing methods. We further illustrate how imputing with corrected conditional means can help prioritize patients for a new Huntington's disease trial.
翻译:测试亨廷顿病实验性治疗的临床试验费用昂贵, 因此谨慎的做法是将症状受后续治疗影响最大的患者纳入实验性治疗中。 但是, 模拟症状进展以辨别这些症状自诊断以来有问题, 可以进行检查。 验尸是一种有吸引力的战略, 被审查的同系异系用有条件的手段替换, 其计算方法要求从受审查的价值估算和整合其有条件的生存功能, 从受审查的价值到无限。 为了灵活估计生存功能, 现有的方法使用与布雷斯洛的估测器的半对称 Cox 模型。 然后, 为了整合, 使用捕捉性分裂性规则, 但捕捉性规则不是针对无限期的整体, 并导致偏差。 我们提出一个有条件的平均计算方法, 适当处理无限制的同适应性二次二次曲线的结合。 然而, 即使是适应性二次曲线( 生存功能) 也是没有定义的, 因此我们探索了扩展它的方法。 在广泛的模拟研究中, 我们展示了如何用适应性治疗性病的治疗方法 以新的二次决断系。