Circadian Measures and Misalignment in Patients: Toward a Trait-State Framework for Personalized Circadian Intervention

Circadian measures are increasingly used in sleep medicine and aging research, but different measures do not capture the same aspect of circadian biology. Chronotype questionnaires, sleep diaries, actigraphy, dim light melatonin onset, patient-derived cellular rhythms, and blood-based omics profiles each provide different types of information. Wearable-derived or sensor-derived rhythms mainly describe the patient’s current rhythm state in daily life. Controlled in vivo markers such as dim light melatonin onset estimate internal circadian phase. Patient-derived cellular period measured under controlled ex vivo conditions may reflect endogenous, trait-like circadian properties. Blood-based transcriptomic, metabolomic, and proteomic approaches may estimate molecular body time, but they also reflect systemic biological state. This review summarizes these circadian measures and discusses how they may be interpreted along a trait-state continuum. It also discusses how different measures may be compared to understand circadian misalignment, including phase-related, period-related, zeitgeber-related, central-peripheral, and trait-state misalignment. These concepts are not yet validated clinical biomarkers. However, they may help organize hypotheses for individualized interventions, including timed light, melatonin, sleep-wake scheduling, activity timing, meal timing, social rhythm stabilization, and treatment timing. A cautious integration of multiple circadian measures may support a systems-level interpretation of patient-specific temporal biology and contribute to personalized circadian intervention as one component of precision medicine.