Abstract
BACKGROUNDCircadian timing of treatments can largely improve tolerability and efficacy in patients. Thus, drug metabolism and cell cycle are controlled by molecular clocks in each cell and coordinated by the core body temperature 24-hour rhythm, which is generated by the hypothalamic pacemaker. Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of core body temperature (CBT) maximum (acrophase) or minimum (bathyphase).METHODSWe aimed at circadian phase determination and readout during daily routines in volunteers stratified by sex and age. We measured (a) chronotype, (b) every minute (q1min) CBT using 2 electronic pills swallowed 24 hours apart, (c) DLMO through hourly salivary samples from 1800 hours to bedtime, and (d) q1min accelerations and surface temperature at anterior chest level for 7 days, using a teletransmitting sensor. Circadian phases were computed using cosinor and hidden Markov modeling. Multivariate regression identified the combination of biomarkers that best predicted core temperature circadian bathyphase.RESULTSAmong the 33 participants, individual circadian phases were spread over 5 hours, 10 minutes (DLMO); 7 hours (CBT bathyphase); and 9 hours, 10 minutes (surface temperature acrophase). CBT bathyphase was accurately predicted, i.e., with an error less than 1 hour for 78.8% of the subjects, using a new digital health algorithm (INTime), combining time-invariant sex and chronotype score with computed center-of-rest time and surface temperature bathyphase (adjusted R2 = 0.637).CONCLUSIONINTime provided a continuous and reliable circadian phase estimate in real time. This model helps integrate circadian clocks into precision medicine and will enable treatment timing personalization following further validation.FUNDINGMedical Research Council, United Kingdom; AP-HP Foundation; and INSERM.
Highlights
The discovery of the molecular mechanisms of circadian clocks has highlighted a new potential for improving human health through the translation of circadian timing concepts to medical practice [1,2,3]
Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of core body temperature (CBT) maximum or minimum
Among the 33 participants, individual circadian phases were spread over 5 hours, 10 minutes (DLMO); 7 hours (CBT bathyphase); and 9 hours, 10 minutes
Summary
The discovery of the molecular mechanisms of circadian clocks has highlighted a new potential for improving human health through the translation of circadian timing concepts to medical practice [1,2,3]. The molecular clocks in the cells of all organs are coordinated by an array of physiological rhythms that are generated by the suprachiasmatic nuclei (SCN) in the hypothalamus [6]. The circadian rhythm in core body temperature and that in circulating glucocorticoids, which are controlled by the SCN, play a key role in the coordination of the molecular clocks outside the brain [7,8,9], while the melatonin secretion rhythm both informs on the circadian phase of the SCN and helps calibrate its period [10]. Drug metabolism and cell cycle are controlled by molecular clocks in each cell and coordinated by the core body temperature 24-hour rhythm, which is generated by the hypothalamic pacemaker. Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of core body temperature (CBT) maximum (acrophase) or minimum (bathyphase)
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