Komarzynski, Sandra, Bolborea, Matei, Huang, Qi, Finkenstädt, Bärbel and Lévi, Francis A. (2019) Predictability of individual circadian phase during daily routine for medical applications of circadian clocks. JCI Insight, 4 (18). e130423. doi:10.1172/jci.insight.130423 ISSN 2379-3708.

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Abstract

Background: Circadian 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 CBT maximum (acrophase) or minimum (bathyphase).
Methods: We aimed at circadian phase determination and read-out during daily routine in volunteers stratified by sex and age. We measured (i) chronotype; (ii) q1min CBT using two electronic pills swallowed 24-hours apart; (iii) DLMO through hourly salivary samples from 18:00 to bedtime; (iv) q1min accelerations and surface temperature at anterior chest level for seven days, using a tele-transmitting sensor. Circadian phases were computed using cosinor and Hidden-Markov modelling. Multivariate regression identified the combination of biomarkers that best predicted core temperature circadian bathyphase.
Results: Amongst the 33 participants, individual circadian phases were spread over 5h10min (DLMO), 7h (CBT bathyphase) and 9h10 min (surface temperature acrophase). CBT bathyphase was accurately predicted, i.e. with an error <1h 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 R-squared = 0.637).
Conclusion: INTime 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 personalisation following further validation.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Circadian rhythms, Drugs -- Metabolism, Cell cycle, Cell cycle -- Regulation
Journal or Publication Title:	JCI Insight
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Official Date:	19 September 2019
Dates:	Date Event 19 September 2019 Published 20 August 2019 Available 20 August 2019 Accepted
Volume:	4
Number:	18
Article Number:	e130423
DOI:	10.1172/jci.insight.130423
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	2 September 2019
Date of first compliant Open Access:	2 September 2019
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID UNSPECIFIED Medical Research Council http://dx.doi.org/10.13039/501100000265 UNSPECIFIED Assistance publique-Hôpitaux de Paris http://dx.doi.org/10.13039/501100009820 UNSPECIFIED Institut national de la santé et de la recherche médicale http://dx.doi.org/10.13039/501100001677

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