Missing values and estimands in diagnostic studies

被估量的概念最近已在治疗试验中得到应用。被估量代表潜在的研究问题，并由属性人群、治疗、用于测量个体治疗效果的变量、汇总统计量和并发事件定义。特别是，区别处理经常等同于违反协议的并发事件是新的要素。并发事件的一个例子是研究过程中的补救药物。此外，预先规定了处理并发事件的策略，例如，策略可以是在补救药物治疗后不使用结果（治疗期间策略）。根据策略和可能的缺失值的假设，一个合适的理论估计结果。在本例中，一个可能的估计量是平均治疗效果，因此在急救药物的情况下，仅考虑事先收集的数据。在诊断研究中，并发事件和缺失值以及处理它们的适当统计方法也是重要的主题。然而，对于诊断研究，被估量的概念还不存在，在处理缺失值的方法上仍存在很大的差距。因此，本项目旨在将被估量的概念从治疗性试验转移到诊断性试验。为此，被估量的属性和处理并发事件的策略将适用于诊断研究。此外，将在此基础上进一步发展处理缺失值的统计方法，以便得出适当的估计数。将在模拟研究和实例研究中评估被估量和处理缺失值的方法的联合概念。此外，将开发关于被估量和缺失值的诊断研究的自适应设计。适应性设计允许在研究过程中进行预先设定的调整，可以提高研究效率，但也有其局限性。因此，将开发和评价适应性设计，例如，允许基于并发事件或设计变更（意味着被估量的修改）的频率重新估计样本量。由于新的欧洲医疗器械法规，在不久的将来，诊断研究的要求将大大增加。该研究项目将提出建议，这些建议将以相应指导文件的形式在讲习班和专题讨论会上传播。此外，开发的方法将在可免费访问的软件中实现，从而易于应用。

The concept of estimands has recently been implemented in therapeutic trials. An estimand represents the underlying research question and is defined by the attributes population, treatments, variable for measuring the individual treatment effect, summary statistics and intercurrent events. In particular, the differentiated handling of intercurrent events, which are often equated with protocol violations, is the new element. An example of an intercurrent event would be a rescue medication during the course of the study. Furthermore, strategies for dealing with intercurrent events are prespecified, e.g. the strategy could be not to use the results after a rescue medication (while-on-treatment strategy). Depending on the strategy and the assumptions for possible missing values, a suitable theoretical estimator results. In the example, a possible estimator would be the mean treatment effect, whereby in the case of rescue medication, only the data collected beforehand are considered. In diagnostic studies, intercurrent events as well as missing values and appropriate statistical methods to deal with them are also important topics. However, for diagnostic studies the concept of estimands does not yet exist and there are still large gaps in methods for dealing with missing values. For this reason, the present project aims to transfer the concept of estimands from therapeutic to diagnostic trials. For this purpose, the attributes of the estimands and strategies for dealing with intercurrent events will be adapted for diagnostic studies. Furthermore, statistical methods for dealing with missing values will be further developed on this basis in order to arrive at suitable estimators. This joint concept of estimand and methods for handling missing values will be evaluated in simulation studies and for example studies.Furthermore, adaptive designs for diagnostic studies with regard to estimands and missing values will be developed. Adaptive designs allow prespecified adjustments in the course of the study and can lead to more efficient studies, but they also have their limitations. Therefore, adaptive designs will be developed and evaluated that allow, for example, sample size re-estimations based on frequencies of intercurrent events or design changes that imply modifications of the estimand. Due to the new European regulation of medical devices, the requirements for diagnostic studies will increase considerably in the near future. The research project will provide recommendations, which will be disseminated in the form of corresponding guidance documents and in workshops and at a symposium. In addition, the methods developed are to be implemented in freely accessible software, thus enabling easy application.