Basel Academy for Quality and Research in Medicine, Basel, Switzerland, & Department of Environmental Sciences, University of Basel, Basel, Switzerland.
Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Clin Epidemiol. 2021 Jan;129:51-59. doi: 10.1016/j.jclinepi.2020.09.019. Epub 2020 Sep 28.
New diagnostic tests to identify a well-established disease state must undergo a series of scientific studies from test construction to finally demonstrating a societal impact. Traditionally, these studies are performed with substantial time gaps in between, resulting in a long time period from the initial idea to roll out in clinical practice including reimbursement. Seamless designs allowing us to combine a sequence of studies in one protocol may hence accelerate this process. Currently, a systematic investigation of the potential of seamless designs in diagnostic research is lacking.
We identify major study types in diagnostic research and their basic characteristics with respect to the application of seamless designs. This information is used to identify major hurdles and opportunities for seamless designs.
The following major study types were identified: Variable construction studies, cut point finding studies, variable value studies, single-arm accuracy studies, comparative accuracy studies, change-in-management studies, observational discordant pair studies, randomized discordant pair studies, and randomized diagnostic studies. The following characteristics were identified: Type of recruitment (case-control vs. population-based), application of a reference standard, inclusion of a comparator, paired or unpaired application of a comparator, assessment of patient-relevant outcomes, and possibility for blinding of test results. Two basic hurdles could be identified: 1) Accuracy studies are hard to combine with postaccuracy studies in a seamless design for the following reasons. First, because the former are required to justify the latter and application of a reference test in outcome studies may be a threat to the integrity of the study. 2) Randomized diagnostic studies are probably best placed as singular studies at the end of the process, as all other questions should be clarified before performing such a study. However, otherwise there is a substantial potential for seamless designs. All steps from the construction to the comparison with the comparator can be combined in one protocol. This may include a switch from case-control to population-based recruitment as well as a switch from a single-arm study to a comparative accuracy study. In addition, change-in-management studies can be combined with an outcome study in discordant pairs.
There is a potential for seamless designs in diagnostic research. It is wise to have the whole sequence of necessary studies in mind and to plan a full programme than rather individual studies one by one.
为了识别一种既定的疾病状态，新的诊断测试必须经历从测试构建到最终展示社会影响的一系列科学研究。传统上，这些研究之间存在相当大的时间间隔，因此从最初的想法到在临床实践中实施，包括报销，需要很长的时间。无缝设计可以允许我们在一个方案中组合一系列研究，从而可能加速这一过程。目前，对诊断研究中无缝设计潜力的系统研究还很缺乏。
我们确定了诊断研究中的主要研究类型及其基本特征，以及无缝设计的应用。利用这些信息，可以确定无缝设计的主要障碍和机会。
确定了以下主要研究类型：变量构建研究、切点发现研究、变量值研究、单臂准确性研究、比较准确性研究、管理变化研究、观察性不一致对研究、随机不一致对研究和随机诊断研究。确定了以下特征：招募类型（病例对照与基于人群）、参考标准的应用、比较器的纳入、比较器的配对或非配对应用、患者相关结果的评估以及测试结果的盲法评估的可能性。可以确定两个基本障碍：1）准确性研究很难与无缝设计中的后准确性研究相结合，原因如下。首先，因为前者需要证明后者的合理性，并且在结果研究中应用参考测试可能会威胁到研究的完整性。2）随机诊断研究可能最好作为整个过程的最后一个独立研究，因为在进行此类研究之前，所有其他问题都应该得到澄清。然而，否则，无缝设计具有很大的潜力。从构建到与比较器的比较的所有步骤都可以在一个方案中组合。这可能包括从病例对照到基于人群的招募的转变，以及从单臂研究到比较准确性研究的转变。此外，可以将管理变化研究与不一致对中的结果研究相结合。
诊断研究中存在无缝设计的潜力。明智的做法是牢记整个必要研究序列，并计划一个完整的方案，而不是一个一个地进行个别研究。
