Repeated Handgrip Strength Variability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Separating Disease-Related Fatigability from Force Gradation

Background: Force production reflects neuromuscular capacity, central regulation, and sensory feedback, making performance-based testing vulnerable when disease-related limitations could be interpreted as reduced effort. Repeated handgrip strength (HGS) testing may quantify neuromuscular fatigability in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but interpretation of within-subject variability as an effort-validity marker remains controversial. We tested whether the coefficient of variation (CV) distinguishes ME/CFS-related impairment from deliberate submaximal performance and compared it with the sum of residuals (SR), a trajectory-aware metric. Methods: We analyzed three cohorts using the same repeated-HGS protocol: two 10-trial sessions separated by one hour. We included 211 ME/CFS participants and 170 controls, including 28 instructed to perform at 50% perceived maximum force. CV and SR were determined as HGS variability measures and compared by probability-density overlap and receiver operating characteristic analyses. The primary comparison was ME/CFS versus deliberately submaximal controls. Results: CV distributions showed substantial overlap between groups. SR improved group-level separation, increasing non-overlapping fractions from 0.217 to 0.326 in the Jaekel cohort and from 0.180 to 0.361 in the MIRACLE cohort. In ROC analyses, SR consistently yielded higher discrimination than CV across cohorts, sessions, and sex strata. A commonly used 15% CV cutoff classified 42-48% of ME/CFS participants as submaximal, while correctly identifying only 57-64% of deliberately submaximal controls. Conclusions: CV may conflate ME/CFS-related fatigability with irregular force modulation and should not be used as stand-alone evidence of submaximal effort. Trajectory-aware SR partly reduced this bias and indicated that ME/CFS-related force impairment is distinguishable from deliberate submaximal force production at the group level. However, neither metric should be used alone to diagnose ME/CFS or evaluate sincerity of effort.