The diagnostic biomarker problem in amyotrophic lateral sclerosis

In the effort to reduce the long diagnostic delay in amyotrophic lateral sclerosis, an often overlooked problem derives from confusion around the concept of diagnostic biomarkers and the type of data required to develop such tools. A useful diagnostic biomarker is one that can correctly differentiate individuals with, from those without, the disease of interest - and importantly, at a point in time when the diagnosis is otherwise uncertain. This requires a test with a high positive predictive value (the proportion of positive test results that are true positives), a high negative predictive value (the proportion of negative test results that are true negatives), or ideally both. Critically, positive and negative predictive values depend on the context of use for the diagnostic, which determines the prevalence of disease in the population in which the diagnostic test will be used. Almost all diagnostic biomarker studies in amyotrophic lateral sclerosis get this wrong - focusing on data and samples from patients for whom there is no diagnostic uncertainty. This Update distinguishes disease state biomarkers from diagnostic biomarkers; highlights the data required to clinically validate a diagnostic biomarker; underscores the critical importance of understanding the clinical context in which the diagnostic biomarker will be used; and outlines potential strategies for developing diagnostic biomarkers that might be clinically useful.