1. High-accuracy determination of internal circadian time from a single blood sample
- Author
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Frederik Bes, Sebastian Kadener, Bharath Ananthasubramaniam, Reut Ashwal-Fluss, Claudia Nowozin, Charlotte Weschke, Hedwig Lammert, Osnat Bartok, Nicole Wittenbrink, Jan de Zeeuw, Bert Maier, Barbara Koller, Achim Kramer, Hanspeter Herzel, Mirjam Münch, Mandy Zaleska, Sophia Wisniewski, Amely Wahnschaffe, Dieter Kunz, and Michael Hummel
- Subjects
Adult ,Genetic Markers ,Male ,0301 basic medicine ,Time Factors ,Circadian clock ,Computational biology ,Models, Biological ,Monocytes ,Cohort Studies ,Machine Learning ,Melatonin ,Young Adult ,03 medical and health sciences ,Genetic predisposition ,Humans ,Medicine ,Circadian rhythm ,Precision Medicine ,Chronotherapy ,business.industry ,Gene Expression Profiling ,Chronotype ,General Medicine ,Gold standard (test) ,Healthy Volunteers ,Circadian Rhythm ,Gene expression profiling ,030104 developmental biology ,Biomarker (medicine) ,Clinical Medicine ,business ,Biomarkers ,medicine.drug - Abstract
Background The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing. Methods To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes. Results We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost. Conclusion The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock. Funding This study was supported by the Bundesministerium fur Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.
- Published
- 2018