Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109-2029, USA.
Stat Med. 2010 Aug 15;29(18):1875-89. doi: 10.1002/sim.3931.
A biomarker (S) measured after randomization in a clinical trial can often provide information about the true endpoint (T) and hence the effect of treatment (Z). It can usually be measured earlier and more easily than T and as such may be useful to shorten the trial length. A potential use of S is to completely replace T as a surrogate endpoint to evaluate whether the treatment is effective. Another potential use of S is to serve as an auxiliary variable to help provide information and improve the inference on the treatment effect prediction when T is not completely observed. The objective of this report is to focus on its role as an auxiliary variable and to identify situations when S can be useful to increase efficiency in predicting the treatment effect in a new trial in a multiple-trial setting. Both S and T are continuous. We find that higher efficiency gain is associated with higher trial-level correlation but not individual-level correlation when only S, but not T is measured in a new trial; but, the amount of information recovery from S is usually negligible. However, when T is partially observed in the new trial and the individual-level correlation is relatively high, there is substantial efficiency gain by using S. For design purposes, our results suggest that it is often important to collect markers that have high adjusted individual-level correlation with T and at least a small amount of data on T. The results are illustrated using simulations and an example from a glaucoma clinical trial.
生物标志物 (S) 在临床试验随机分组后测量，通常可以提供关于真实终点 (T) 的信息，从而可以评估治疗效果 (Z)。S 通常可以更早、更容易地测量，因此可能有助于缩短试验的长度。S 的一个潜在用途是完全替代 T 作为替代终点，以评估治疗是否有效。S 的另一个潜在用途是作为辅助变量，有助于提供信息并提高 T 未完全观察时对治疗效果预测的推断。本报告的目的是重点关注其作为辅助变量的作用，并确定在多试验环境中，当 T 未完全观察时，S 可以在新试验中提高预测治疗效果的效率的情况。S 和 T 均为连续变量。我们发现，当仅在新试验中测量 S 而不是 T 时，与仅测量 T 相比，更高的效率增益与更高的试验水平相关性相关，但与个体水平相关性无关；但是，从 S 中恢复的信息量通常可以忽略不计。然而，当新试验中部分观察到 T 且个体水平相关性较高时，使用 S 可带来实质性的效率增益。出于设计目的，我们的结果表明，收集与 T 具有高调整个体水平相关性且至少有少量 T 数据的标志物通常很重要。模拟结果和青光眼临床试验的实例说明了这些结果。
