Background Cancer screening trials have required large sample-sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the “Intended Effect” (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control-arm, such as stored blood for multicancer detection (MCD) tests. Methods We simulated hypothetical MCD screening trials to compare power and sample-size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial (NLST), Minnesota Colon Cancer Control Study (MINN-FOBT-A), and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial—colorectal component (PLCO-CRC)). Results Compared to the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality p-values 5-fold (NLST), 33-fold (MINN-FOBT-A), or 14,160-fold (PLCO-CRC), or alternately, reduced sample-size (90% power) by 26% (NLST), 48% (MINN-FOBT-A), or 59% (PLCO-CRC). For potential MCD trial designs requiring 100,000 subjects per-arm to achieve 90% power for multi-cancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37,500-50,000 per arm, depending on assumptions concerning control-arm test-positives. Conclusions Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample-size or accelerate trials, and provide particularly strong power gains for MCD tests.

中文翻译：

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通过测试控制臂样本提高筛查试验的功效：在多种癌症检测筛查中的应用

背景癌症筛查试验需要大样本量和长期视野来证明癌症死亡率降低，这是癌症筛查的主要目标。我们通过利用测试控制臂样本的信息来检查假设和潜在的功率增益，我们将其称为“预期效果”（IE）分析，我们将在本文中详细解释。 IE 分析特别适合对控制臂中存储的样本进行的测试，例如用于多癌检测 (MCD) 测试的存储血液。方法 我们模拟了假设的 MCD 筛选试验，以比较标准分析与 IE 分析的功效和样本量。根据我们在此详述的两个假设，我们预测了 3 个现有筛查试验（国家肺部筛查试验 (NLST)、明尼苏达结肠癌控制研究 (MINN-FOBT-A) 以及前列腺癌、肺癌、结直肠癌、卵巢癌筛查）的 IE 分析试验——结直肠成分（PLCO-CRC））。结果 与 3 项现有试验的标准分析相比，IE 设计可将癌症特异性死亡率 p 值降低 5 倍 (NLST)、33 倍 (MINN-FOBT-A) 或 14,160 倍 (PLCO- CRC），或者将样本大小（90% 功效）减少 26% (NLST)、48% (MINN-FOBT-A) 或 59% (PLCO-CRC)。对于潜在的 MCD 试验设计，需要每组 100,000 名受试者才能达到标准分析的多种癌症死亡率的 90% 功效，IE 分析仅每组 37,500-50,000 名受试者就达到 90% 功效，具体取决于有关控制臂测试的假设 -积极的一面。结论 在筛选试验的控制臂中测试存储的样本以进行 IE 分析可以大大增加减少样本量或加速试验的功效，并为 MCD 测试提供特别强大的功效增益。