Flexible designs for diagnostic studies - from diagnostic accuracy to personalized medicine

诊断试验评价研究，即诊断研究，是临床试验的一种重要形式。毕竟，正确的诊断是成功治疗的先决条件。此外，诊断性研究是个性化医疗研究的基本组成部分，因为其目的是只应用有理由期望个别效果的疗法（例如由于遗传易感性或由于疾病的亚型）。诊断性测试的发展与治疗学的发展一样，遵循几个阶段。关键的开发阶段包括验证性诊断准确性研究和随机诊断研究。诊断准确性研究的一个特点是有两个共同主要终点（真阳性率和真阴性率），而在随机诊断研究中，选择一个患者相关终点（例如死亡率）。诊断准确性研究和随机诊断研究一样，需要计算样本量。样本量计算基于既往研究和/或文献得出的假设。如果这些假设是错误的，这将导致高估或低估所需的样本量。因此，采用灵活（自适应）研究设计是合理的，该设计允许根据中期分析结果对样本量进行后续调整。适应性设计具有很高的实际意义，因为它们可以减少研究的时间和成本，并增加研究成功的机会。已开发用于治疗研究的各种自适应设计方法仅在诊断研究中有有限的用途。特别是关于诊断研究的适应性设计的主题，方法学研究还很少，要求的项目目标是开发和评估诊断研究中各种问题的适应性研究设计方法。区分诊断准确性研究和随机诊断研究，区分关于真实疾病状态的揭盲和未揭盲的中期分析，以及区分有和无标准试验作为对照的研究。此外，还应开发和评估诊断研究的自适应无缝设计方法。在这种非常有效的研究设计中，可以将两个研究阶段联系起来，从而可以更快地应用有用的诊断测试。为了实际应用所开发的方法，应编写所有设计的计算机程序（R和/或SAS），并向公众提供。

Studies for the evaluation of diagnostic tests, i.e. diagnostic studies, are an important form of clinical trials. After all, a correct diagnosis is the prerequisite for a successful therapy. In addition, diagnostic studies are an elementary component of research in the field of personalized medicine, as its aim is to apply only therapies which give reasons to expect an effect individually (for example because of a genetic predisposition or because of the subtype of the disease).The development of a diagnostic test follows, just like the development of therapeutics, several phases. The crucial development phases include confirmatory diagnostic accuracy studies and randomized diagnostic studies. A special characteristic of diagnostic accuracy studies is that there are two co-primary endpoints (true positive and true negative rate), while in randomized diagnostic studies a patient-relevant endpoint (for example mortality) is selected.Diagnostic accuracy studies as well as randomized diagnostic studies require a sample size calculation. Sample size calculations are based on assumptions derived from previous studies and/or from the literature. If these assumptions are wrong, this leads to an over- or underestimation of the required sample size. Hence it is reasonable to apply a flexible (adaptive) study design which allows for a subsequent adjustment of the sample size as a result of an interim analysis. Adaptive designs have a high practical relevance as they can reduce time and costs of a study and the chance of a successful study can be increased. The various methods for adaptive designs that have been developed for therapeutic studies are only of limited use for diagnostic studies. Particularly on the topic of adaptive designs for diagnostic studies, only very little methodological research has been done yet.The requested project aims are developing and evaluating methods for adaptive study designs for various questions in diagnostic studies. A distinction is made between diagnostic accuracy studies and randomized diagnostic studies, between interim analyses with and without unblinding regarding the true disease state and between studies with and without a standard test as comparator. Moreover, methods for adaptive seamless designs for diagnostic studies shall be developed and evaluated. In this very efficient study design, two study phases can be linked and thus a helpful diagnostic test can be applied more quickly. For practical application of the methods developed, computer programs (R and/or SAS) shall be written for all designs and be provided for the public.