A Composite Reference Standard for COVID-19 Diagnostic Accuracy Studies: a roadmap

Abstract

Clinical studies are in planning or currently underway and aim to evaluate the in-context diagnostic accuracy of novel diagnostic tests. These novel tests have the potential to be useful diagnostic tools during the next phases of the pandemic and for the differential diagnosis during the endemic phase. Real time reverse transcriptase polymerase chain reaction (rRT-PCR) is currently the reference standard for the diagnosis of COVID-19, but a high false negative rate has been reported.[1-3] Many of these diagnostic accuracy studies compare the new tests with rRT-PCR, an imperfect reference standard. The effect of this is underestimation of the specificity of the new tests. The authors propose the development and use of a composite reference standard, with predefined diagnostic criteria or levels of diagnostic uncertainty, to allow a comparison with evidence from up to date literature with regards to diagnostic accuracy, but also with current clinical practice in disease management. Multiple composite reference standards can be developed/adapted for specific clinical settings in order to take into account feasibility of use in practice (e.g. evaluations in the community settings cannot rely on radiological examinations). However, the focus in this article was on the development of a composite reference standard to be used in hospital studies.