Wearable inertial measurement units (IMUs) provide an accessible means of monitoring fatigue-related changes in running biomechanics, yet most existing methods rely on limited feature sets, lack personalization, or fail to generalize across individuals. This study introduces a bioinformatics-inspired stride sequence modeling framework that integrates spectral-entropy features, sample entropy, frequency-domain descriptors, and mixed-effects statistical modeling to detect fatigue using a single lumbar-mounted IMU. Nineteen recreational runners completed non-fatigued and fatigued 400 m runs, from which we extracted stride-level features and evaluated (1) population-level fatigue classification via global leave-one-participant-out (LOPO) models and (2) individualized fatigue detection through supervised participant-specific models and non-fatigued-only anomaly detection. Mixed-effects models revealed robust and multidimensional fatigue effects across key biomechanical features, with large standardized effect sizes (Cohen`s d up to 1.35) and substantial variance uniquely explained by fatigue (partial R2 up to 0.31). Global LOPO machine learning models achieved modest accuracy (55%), highlighting strong inter-individual variability. In contrast, personalized supervised Random Forest classifiers achieved near-perfect performance (mean accuracy 97.7%; mean AUC 0.997), and NF-only One-Class SVMs detected fatigue as a deviation from individual baseline patterns (mean AUC 0.967). Entropy and stride-to-stride variability metrics further demonstrated consistent fatigue-linked increases in movement irregularity and reduced neuromuscular control. These findings show that IMU stride sequences contain highly informative, fatigue-sensitive biomechanical signatures, and that combining bioinformatics-inspired sequence analysis with hybrid statistical and personalized AI models enables both robust population-level insights and highly reliable individualized fatigue monitoring. The proposed framework supports future integration into sports analytics platforms, digital coaching systems, and real-time wearable fatigue detection technologies. This highlights the necessity of personalized fatigue-monitoring strategies in wearable systems.
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