Net benefit of diagnostic tests for multistate diseases: an indicator variables approach

A limitation of the common measures of diagnostic test performance, such as sensitivity and specificity, is that they do not consider the relative importance of false negative and false positive test results, which are likely to have different clinical consequences. Therefore, the use of classification or prediction measures alone to compare diagnostic tests or biomarkers can be inconclusive for clinicians. Comparing tests on net benefit can be more conclusive because clinical consequences of misdiagnoses are considered. The literature suggested evaluating the binary diagnostic tests based on net benefit, but did not consider diagnostic tests that classify more than two disease states, e.g., stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, stroke of undetermined etiology), skin lesion subtype, breast cancer subtypes (benign, mass, calcification, architectural distortion, etc.), METAVIR liver fibrosis state (F0- F4), histopathological classification of cervical intraepithelial neoplasia (CIN), prostate Gleason grade, brain injury (intracranial hemorrhage, mass effect, midline shift, cranial fracture). Other diseases have more than two stages, such as Alzheimer's disease (dementia due to Alzheimer's disease, mild cognitive disability (MCI) due to Alzheimer's disease, and preclinical presymptomatics due to Alzheimer's disease). In diseases with more than two states, the benefits and risks may vary between states. This paper extends the net-benefit approach of evaluating binary diagnostic tests to multi-state clinical conditions to rule-in or rule-out a clinical condition based on adverse consequences of work-up delay (due to false negative test result) and unnecessary workup (due to false positive test result). We demonstrate our approach with numerical examples and real data.