Fan Xiaoyin Frank, DeMets David L, Lan K K Gordon
Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486, USA.
J Biopharm Stat. 2004 May;14(2):505-30. doi: 10.1081/bip-120037195.
Repeated significance testing in a sequential experiment not only increases the overall type I error rate of the false positive conclusion but also causes biases in estimating the unknown parameter. In general, the test statistics in a sequential trial can be properly approximated by a Brownian motion with a drift parameter at interim looks. The unadjusted maximum likelihood estimator can be potentially very biased due to the possible early stopping rule at any interim. In this paper, we investigate the conditional and marginal biases with focus on the conditional one upon the stopping time in estimating the Brownian motion drift parameter. It is found that the conditional bias may be very serious for existing point estimation methods, even if the unconditional bias is satisfactory. New conditional estimators are thus proposed, which can significantly reduce the conditional bias from unconditional estimators. The results of Monte-Carlo studies show that the proposed estimators can provide a much smaller conditional bias and MSE than the naive MLE and a Whitebead's bias reduced estimator.
在序贯实验中重复进行显著性检验,不仅会增加得出假阳性结论的总体一类错误率,还会在估计未知参数时导致偏差。一般来说,序贯试验中的检验统计量在中期观察时可以用带有漂移参数的布朗运动来恰当近似。由于在任何中期可能存在提前停止规则,未经调整的最大似然估计量可能会有很大偏差。在本文中,我们研究条件偏差和边际偏差,重点关注在估计布朗运动漂移参数时基于停止时间的条件偏差。研究发现,对于现有的点估计方法,即使无条件偏差令人满意,条件偏差也可能非常严重。因此提出了新的条件估计量,它们可以显著降低无条件估计量的条件偏差。蒙特卡罗研究结果表明,与朴素最大似然估计量和怀特比德偏差减少估计量相比,所提出的估计量能提供小得多的条件偏差和均方误差。