Impact of imperfect diagnosis in ME/CFS association studies

ABSTRACTThe absence of an objective disease biomarker puts studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) under the curse of imperfect diagnosis. This problem leads to frequent reports that fail to reproduce prior published studies. To address the impact of imperfect diagnosis on the robustness of studies’ conclusions, we conducted a simulation study to quantify the statistical power to detect a disease association with a hypothetical binary factor in the presence of imperfect diagnosis. Using the classical case-control design, studies with sample sizes of less than 500 individuals per group could not reach the target power of at least 80% to detect realistic disease associations. We then recreated serological association studies in which the chance of imperfect diagnosis was combined with the probability of misclassifying a binary factor, as it happens in a typical serological association study. In this case, the target power of 80% could only be achieved for studies with more than 1000 individuals per group. Given the current sample sizes of ME/CFS studies, our results suggest that most studies are likely to be underpowered due to imperfect diagnosis alone. To increase reproducibility across studies, we provided some practical recommendations, such as the use of standard case definitions together with multi-centric study designs, and routine reporting of power calculations under a non-negligible chance of misdiagnosis. Our results can also inform the design of future studies under the assumption of misdiagnosis.