Johnson Kent R, Freemantle Nick, Anthony Danielle M, Lassere Marissa N D
Department of Clinical Pharmacology, University of Newcastle, Mater Hospital, Waratah NSW 2298, Australia.
J Clin Epidemiol. 2009 Mar;62(3):328-36. doi: 10.1016/j.jclinepi.2008.06.004. Epub 2008 Oct 1.
We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials.
We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit.
In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L.
In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers.
我们描述了一种名为替代阈值效应（STE）的新统计方法，该方法可估计临床试验中预测目标临床结局获益所需的替代指标的阈值水平。在本文中，我们将此方法应用于他汀类药物试验中的低密度脂蛋白胆固醇生物标志物替代指标和生存获益目标结局。
我们确定了比较他汀类药物治疗与安慰剂治疗或不治疗并报告全因死亡率和心血管死亡率的随机试验。至少有一组全因死亡少于5例的试验被排除。多元回归将全因死亡率和心血管死亡率的降低建模为低密度脂蛋白胆固醇差异的函数。计算并绘制95%置信区间和95%预测区间，以确定预测无生存获益的最低低密度脂蛋白胆固醇差异（替代阈值）。
在16项符合条件的试验中，回归分析得出了一个全因死亡率模型，其预测区间表明，当低密度脂蛋白胆固醇差异值低于1.5 mmol/L时，总体生存率没有提高。心血管死亡率模型得出的预测区间表明，当低密度脂蛋白胆固醇差异值低于1.4 mmol/L时，没有心血管生存获益。
在多试验环境中，STE方法是一种评估生物标志物替代有效性的有前景且简单的统计方法。
