Simultaneous statistical inference under order restrictions and its application to dose-response studies

公开释放建议概述在毒理学和生物药学研究中，为了研究化合物的影响，增加几个剂量水平通常与对照进行比较。对照可以是中性对照、安慰剂或主动对照，这是一种已知有效的标准药物。因此，剂量-反应实验通常以单向布局进行，所考虑的化合物的剂量被分配给不同的受试者组。在这些研究中有不同的担忧。在毒理学研究中，主要关注的是所考虑的毒素的安全性，目标是估计与对照没有显著差异的最高剂量。这一最高剂量通常被称为无统计学意义的趋势剂量或未观察到的不良事件水平剂量。然而，在药学研究中，主要目标是评估是否确实存在剂量-反应效应，这意味着与对照相比，至少有一种治疗有效。如果发现剂量反应效应，则确定产生比对照更理想的效果的最低剂量水平。这一最低剂量水平通常被称为最小有效剂量，即临床上明显好于中性对照组平均反应的剂量；也就是最低有效剂量：MID=Min{d(I)：m(I)&gt；m(0)+c}其中，c定义为实验人员预先分配的临床显著差异。对于疗效研究，确定最小有效剂量很重要，因为高剂量往往会产生不良副作用。本研究的目的是为回归曲线的各种先验信息构建最有效的统计推断程序。

SUMMARY OF PROPOSAL FOR PUBLIC RELEASE In toxicological and biopharmaceutical studies, to investigate the effect of a compound several increasing dose levels are usually compared with a control. The control may be a neutral control, a placebo, or an active control, a standard drug known to be effective. Therefore, dose-response experiments are often conducted in a one-way layout in which the doses of the compound under consideration are allocated to separate groups of subjects. There are different concerns in these studies. In toxicological studies, the main concern is the safety of the toxin under consideration and the goal is to estimate the highest dose that shows no significant difference from the control. This highest dose is generally called the no statistical significance for trend or no observed adverse event level dose. In pharmaceutical studies, however, the primary goal is to assess whether there is indeed a dose-response effect which means that at least one treatment is effective in comparison to the control. If a dose response effect is found, then to identify the lowest dose level producing a desirable effect over that of the control. This lowest dose level is commonly referred to as the minimum effective dose, the dose that is clinically significantly better than the mean response of the neutral control; that is         MED=min{d(i):m(i)>m(0) + c} where c is defined as a clinically significant difference preassigned by an experimenter. For efficacy studies, identifying the minimum effective dose is important since high doses often turn out to have undesirable side effects. The aim of this investigation is to construct most efficient statistical inference procedures for various kind of prior information concerning regression curves.