In cancer biomarker development, a key objective is to evaluate whether a new biomarker, when combined with an established one, improves early cancer detection compared to using the established biomarker alone. Incremental value is often quantified by changes at specific points on the ROC curve, such as an increase in sensitivity at a fixed specificity, which is especially relevant in early cancer detection. Our research is motivated by the Early Detection Research Network (EDRN) biorepository studies, which aim to validate multiple cancer biomarkers across laboratories using specimens obtained from a centralized biorepository, under the constraint of limited specimen availability. To address this challenge, we propose a two-stage group sequential hypothesis testing framework for assessing incremental effects, allowing early stopping for futility or efficacy to conserve valuable samples. Our asymptotic results are derived under a logistic working model and remain valid even under model misspecification, ensuring robustness and broad applicability. We further integrate a rotating group membership design to facilitate validation of multiple candidate biomarkers across laboratories. Through extensive simulations, we demonstrate valid type I error control and efficient utilization of specimens. Finally, we apply our method to data from a multicenter EDRN pancreatic cancer reference set study and show how the proposed approach identifies promising candidate biomarkers that provide incremental performance when combined with CA19-9, while enabling efficient evaluation of a large number of such candidates.

翻译：在癌症生物标志物研发中，一个核心目标是评估新生物标志物与现有标志物联合使用时，是否比单独使用现有标志物更能提升早期癌症检测效能。增量价值通常通过ROC曲线上特定点的变化来量化，例如在固定特异度下敏感度的提升，这在早期癌症检测中尤为重要。本研究受早期检测研究网络（EDRN）生物样本库研究的启发，该研究旨在利用中央生物样本库提供的有限标本，跨实验室验证多种癌症生物标志物。为应对这一挑战，我们提出了一种两阶段成组序贯假设检验框架，用于评估增量效应，允许因无效或有效而提前终止试验以节约珍贵样本。我们的渐近结果基于逻辑斯蒂工作模型推导，即使在模型误设情况下仍保持有效，确保了方法的稳健性和广泛适用性。我们进一步整合了轮转组别成员设计，以促进跨实验室对多个候选生物标志物的验证。通过大量模拟实验，我们证明了该方法能有效控制Ⅰ类错误并高效利用标本。最后，我们将该方法应用于多中心EDRN胰腺癌参考集研究数据，展示了所提方法如何识别出与CA19-9联合使用时具有增量性能的潜力候选生物标志物，同时实现对大量此类候选标志物的高效评估。