ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients
Peter S. Cunningham, … , Andrew L. Hazel, John F. Blaikley
Peter S. Cunningham, … , Andrew L. Hazel, John F. Blaikley
Published December 20, 2022
Citation Information: J Clin Invest. 2023;133(4):e162775. https://doi.org/10.1172/JCI162775.
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Clinical Research and Public Health Inflammation

ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients

Abstract

Background Assessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.Methods We present ClinCirc. 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. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. ClinCirc was then evaluated in 13 intensive care unit (ICU) patients as well as in a separate cohort of 29 kidney-transplant recipients. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney-transplant recipients.Results ClinCirc had comparable performance to existing methods for analyzing simulated data or clock transcript expression of healthy volunteers. It had improved accuracy compared with the cosinor method in evaluating circadian parameters in PER2:luc cell lines. 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. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. 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.Conclusion ClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.Funding 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.

Authors

Peter S. Cunningham, Gareth B. Kitchen, Callum Jackson, Stavros Papachristos, Thomas Springthorpe, David van Dellen, Julie Gibbs, Timothy W. Felton, Anthony J. Wilson, Jonathan Bannard-Smith, Martin K. Rutter, Thomas House, Paul Dark, Titus Augustine, Ozgur E. Akman, Andrew L. Hazel, John F. Blaikley

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Figure 2

Inflammation is associated with reduced detection of circadian oscillations in the ICU.

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Inflammation is associated with reduced detection of circadian oscillati...
ICU patients were split into 2 groups based on whether ClinCirc detected unchanged or a reduced number of circadian oscillations in the peripheral blood molecular oscillator. (A) Heatmap displaying the proportion of patients in each group in whom ClinCirc detected a circadian oscillation in the measured inflammatory mediator. *P < 0.05, χ2 test. (B) Forty-eight–hour expression profiles for the 3 inflammatory mediators (MMP2, MMP3, and TSLP) that showed differential circadian oscillations between ICU patients who had standard or reduced detection of circadian oscillations. Data are represented as mean ± SEM. Traces were acrophase aligned. (C) Volcano plot showing differences in mean expression of 37 inflammatory mediators between ICU patients with standard or reduced detection of circadian oscillations. Positive fold change reveals that the mediator was elevated in patients in whom detection of circadian oscillations was reduced. Dotted line shows P = 0.05. Significant cytokines are labeled. Inflammatory mediators that were differentially regulated are IFN-α2, IFN-γ, IL-2, IL-8, IL-10, IL-11, IL-12 (p40), IL-19, IL-20, IL-26, IL-27 (p28), IL-28A, IL-29, IL-35, LIGHT, Pentraxin-3, and TSLP. (D) Difference in CRP expression between ICU patients grouped according to the detection of circadian oscillations and those who underwent kidney transplantation. **P < 0.01, ANOVA post hoc Tukey’s. (E) CRP expression in ICU patients was also plotted against the number of clock genes for that participant in which ClinCirc detected the presence of a circadian oscillation. r2 = 0.49 linear correlation. n = 13. For circadian rhythm analysis, data were only plotted if a circadian rhythm was detected.