ITEM 7.    Describe the reference standard and its rationale.

Example

The e-4 allele of the gene encoding apolipoprotein E (ApoE) is strongly associated with Alzheimer’s disease, but its value in the diagnosis remains uncertain. (…) Using the pathological diagnosis of Alzheimer’s disease as the standard, we compared the sensitivity and specificity of the clinical diagnosis of Alzheimer’s disease, the ApoE genotype, and the clinical diagnosis and ApoE genotype determined sequentially.[1]

In studies of diagnostic accuracy, the reference standard is used to distinguish patients with the target condition from those without it. Some target conditions cannot be defined unambiguously. Depending on the study question, clinical relevance, management decisions or prognosis, or pathological diagnosis may define the target condition.[2]

When it is not possible to subject all patients to the reference standard for practical or ethical reasons, authors often use a composite reference standard. The components may reflect different definitions of the target condition or different strategies for diagnosing the target condition. One example comes from studies of using nuchal translucency in the first trimester of pregnancy as a marker for Down syndrome.[3] In several of those studies, positive test results were verified with karyotyping, whereas negative results were verified by awaiting delivery. Studies in which the decision to perform fetal karyotyping depended on the result of nuchal translucency measurement considerably overestimated the sensitivity of nuchal translucency.[3]

Authors should clearly define the reference standard and how the choice of the reference standard relates to the study question.

In the example, the authors use a neuropathological diagnosis after postmortem examination as the reference standard in patients referred to Alzheimer’s disease centers for evaluations of dementia. Although pathological assessment is considered to be the gold standard of Alzheimer’s disease diagnosis, the correlation of the clinical and pathological data is by no means perfect. Nor does every pathologist render the same diagnosis from a given set of tissue sections.[4]

References