Methodologic issues in the validation of putative biomarkers and surrogate endpoints in treatment evaluation for systemic lupus erythematosus.
Methodologic issues in the validation of putative biomarkers and surrogate endpoints in treatment evaluation for systemic lupus erythematosus.
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DOI：
10.2174/187153009787582388
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发表时间：
2009-03
期刊：
影响因子：
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通讯作者：
Abrahamowicz M
中科院分区：
文献类型：
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作者：
Liang MH;Simard JF;Costenbader K;Dore BT;Ward M;Fortin PR;Illei GG;Manzi S;Mittleman B;Buyon J;Gupta S;Abrahamowicz M
过去 30 年来，FDA 尚未批准用于治疗系统性红斑狼疮 (SLE) 的新药，其中一个障碍是缺乏经过验证的生物标志物和替代终点。过去对 SLE 生物标志物的验证在方法上存在缺陷。我们提出了一个概念框架和五个关键标准，用于验证这种表现千变万化的异质多系统疾病中的假定生物标志物和生物替代物。以狼疮性肾炎终末期肾病的假定生物标志物为例，我们还进行了计算机模拟，以规划生物标志物生物存储库以支持验证过程。 “随机时间窗口”采样，即在从该受试者的总随访时间中随机选择的时间间隔内获得生物标志物，会产生严重的“生存偏差”。这种情况可以通过“固定日历窗口”设计来避免，即在同一预先指定的时间内测量所有在此期间仍处于危险中的队列成员的生物标志物。在狼疮性肾炎中，终末期肾病的发病率相对较低，若要积累300例终末期肾病高危患者，则需要对高危患者进行约5000人年的随访，这意味着平均对500名受试者进行约10年的随访。将每个受试者的生物标志物测定数量从 1 个增加到 5 个，所需的受试者数量减少了 10-15%，而进一步增加每个受试者的观察数量产生的收益要小得多。生物样本库需要大量受试者，因此必须最大限度地提高研究设计和分析的效率，并为合作和使用标准化措施确保可比性提供最有力的理由。
No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the FDA for the last 30 years and one barrier has been the lack of validated of biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and the five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage renal disease from lupus nephritis, we also performed computer simulations for planning a biomarker bio-repository to support the validation process. “Random time window” sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject yields serious ‘survival bias’. This can be avoided by the “fixed calendar window” design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases of the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.