A perfect correlate does not a surrogate make.
A perfect correlate does not a surrogate make.
复制标题
DOI：
10.1186/1471-2288-3-16
复制
发表时间：
2003-09-09
影响因子：
4
通讯作者：
Kramer, Barnett S
中科院分区：
文献类型：
--
作者：
Baker, Stuart G;Kramer, Barnett S
背景：一些医学研究人员普遍认为，如果潜在替代终点与真实终点高度相关，那么随机分组之间潜在替代终点的正（或负）差异意味着随机分组之间未观察到的真实终点的正（或负）差异。当潜在的替代终点和未观察到的真实终点在每个随机分组中完全相关时，我们研究了这种信念。方法：我们采用图形方法。纵轴是未观察到的真实端点，横轴是潜在的代理端点。每个随机化组内的完全相关意味着，对于每个随机化组，潜在替代终点和真实终点呈直线相关。在这种情况下，调查人员不知道斜率或截距。我们考虑一个貌似合理的例子，其中实验组的直线斜率高于对照组。结果：在我们的未知线示例中，从对照组到实验组的平均潜在替代终点的减少对应于从对照组到实验组的平均真实终点的增加。因此，潜在的代理端点给出了错误的推断。类似的结果适用于二元潜在替代结果和真实结果（尽管相关性的概念不适用）。如果(i)两组的未知线重合，这意味着以潜在替代终点为条件的真终点分布不依赖于治疗组，这被称为Prentice标准，或者（ii）如果可以根据先前研究的数据准确预测线，则潜在替代终点将给出正确的推断。结论：随机分组中潜在替代终点和未观察到的真实结果之间的完全相关并不能保证基于潜在替代终点的正确推断。即使在早期试验中，研究者也不应该将结论建立在潜在的替代终点上，因为在一个群体中，唯一的验证是与真实终点高度相关。
BACKGROUND: There is common belief among some medical researchers that if a potential surrogate endpoint is highly correlated with a true endpoint, then a positive (or negative) difference in potential surrogate endpoints between randomization groups would imply a positive (or negative) difference in unobserved true endpoints between randomization groups. We investigate this belief when the potential surrogate and unobserved true endpoints are perfectly correlated within each randomization group.METHODS: We use a graphical approach. The vertical axis is the unobserved true endpoint and the horizontal axis is the potential surrogate endpoint. Perfect correlation within each randomization group implies that, for each randomization group, potential surrogate and true endpoints are related by a straight line. In this scenario the investigator does not know the slopes or intercepts. We consider a plausible example where the slope of the line is higher for the experimental group than for the control group.RESULTS: In our example with unknown lines, a decrease in mean potential surrogate endpoints from control to experimental groups corresponds to an increase in mean true endpoint from control to experimental groups. Thus the potential surrogate endpoints give the wrong inference. Similar results hold for binary potential surrogate and true outcomes (although the notion of correlation does not apply). The potential surrogate endpoint would give the correct inference if either (i) the unknown lines for the two group coincided, which means that the distribution of true endpoint conditional on potential surrogate endpoint does not depend on treatment group, which is called the Prentice Criterion or (ii) if one could accurately predict the lines based on data from prior studies.CONCLUSION: Perfect correlation between potential surrogate and unobserved true outcomes within randomized groups does not guarantee correct inference based on a potential surrogate endpoint. Even in early phase trials, investigators should not base conclusions on potential surrogate endpoints in which the only validation is high correlation with the true endpoint within a group.