![]() This oscillator consists of 9 clock proteins regulated by a transcription-translation feedback loop (TTFL). An alternative approach is to measure the molecular oscillator, a core mechanism in circadian biology ( 9). However, these outputs may be influenced by noncircadian mechanisms ( 7, 8), causing them to be subject to confounding. It is possible to measure circadian outputs in order to assess circadian oscillations. In this paper, we adopt the latter approach to create a technique combining the best features from two widely used methods of periodic signal analysis, a technique that we term ClinCirc. Therefore, the development of new techniques, or using workflows that combine existing techniques, to identify circadian oscillations with increased accuracy could reveal new insights into the translational importance of circadian biology. One potential reason for this is the difficulty of determining whether an oscillation is circadian or noncircadian. The clinical relevance of these effects, however, remains opaque, since associations between clinical outcomes and the molecular oscillator ( 6), a key driver of circadian biology, remain scarce. ![]() Graphical AbstractĬircadian biology has profound effects on both outcome and pathophysiology ( 1) in many disease models ( 2– 5). UK Research and Innovation (UKRI), National Institute of Health Research (NIHR), Engineering and Physical Sciences Research Council (EPSRC), National Institute on Academic Anaesthesia (NIAA), Asthma+Lung UK, Kidneys for Life. ClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.įunding. This phase shift could explain why a significant complication of kidney transplantation (delayed graft dysfunction) oscillates according to the time of day kidney transplantation is performed.Ĭonclusion. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. In ICU patients, it was the only method investigated to suggest that loss of circadian oscillations in the peripheral oscillator was associated with inflammation, a feature widely reported in animal models. It had improved accuracy compared with the cosinor method in evaluating circadian parameters in PER2:luc cell lines. ClinCirc had comparable performance to existing methods for analyzing simulated data or clock transcript expression of healthy volunteers. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney-transplant recipients. ClinCirc was then evaluated in 13 intensive care unit (ICU) patients as well as in a separate cohort of 29 kidney-transplant recipients. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. This method combines 2 existing mathematical methods (Lomb-Scargle periodogram and cosinor) sequentially and is designed to measure circadian oscillations from infrequently sampled clinical data. Assessing circadian rhythmicity from infrequently sampled data is challenging however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.
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