Value of composite reference standards in diagnostic research.

A common challenge in diagnostic studies is to obtain a correct final diagnosis in all participants. Ideally, a single error-free reference test, known as a gold standard, is used to determine the final diagnosis and estimate the accuracy of the test or diagnostic model under evaluation. If the reference standard does not perfectly correspond to true target disease status, estimates of the accuracy of the test or model under study (index test), such as sensitivity, specificity, predictive values, or area under the curve, can be biased. This is known as imperfect reference standard bias. One method to reduce this bias is to use a fixed rule to combine results of several imperfect tests into a composite reference standard. When the combination of several component tests provides a better perspective on disease than any of the individual tests alone, accuracy estimates of the test under evaluation (the index test) will be less biased than if only one imperfect test is used as the reference standard. Comparing the index test against each component test separately and then averaging the accuracy estimates is not recommended; it is better to insightfully combine component tests together into a composite reference standard. The hallmark of composite reference standards is that each combination of test results leads to a particular final diagnosis; in its simplest form, disease present or absent. For example, in a study on the accuracy of a rapid antigen test for detecting trichomoniasis, researchers decided against using the traditional gold standard of culture because it probably misses some cases. As they believed that microscopy picks up additional true cases, they instead considered patients as diseased if either microscopy or culture results were abnormal. Table 1⇓ gives further examples. Although the choice of component tests and the rules used to combine them affects the estimates of accuracy of the test under study, little guidance exists on how to develop and define a composite reference standard. Additionally, there is a lack of consensus in the way the term composite reference standard is used and reporting of results is generally poor. To address these problems, we provide an explanation of the methods for composite reference standards and make recommendations for development and reporting. What is a composite reference standard?