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

Peter Cunningham; Gareth Kitchen; Callum Jackson; Stavros Papachristos; Thomas Springthorpe; David Van Dellen; Julie Gibbs; Timothy Felton; Anthony Wilson; Jonathan Bannard-Smith; Martin K. Rutter; Thomas House; Paul Dark; Titus Augustine; Ozgur Akman; Andrew Hazel; John Blaikley

doi:10.1172/JCI162775

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe 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.ResultsClinCirc 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.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK 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.

Original language	English
Article number	e162775
Journal	The Journal of clinical investigation
Volume	133
Issue number	4
Early online date	20 Dec 2022
DOIs	https://doi.org/10.1172/JCI162775
Publication status	Published - 15 Feb 2023

Keywords

Algorithms
Cell Line
Circadian Rhythm/physiology
Glucocorticoids/pharmacology
Humans
Intensive Care Units
Kidney Transplantation/adverse effects
Retrospective Studies

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10.1172/JCI162775Licence: CC BY

Cite this

Cunningham, P., Kitchen, G., Jackson, C., Papachristos, S., Springthorpe, T., Van Dellen, D., Gibbs, J., Felton, T., Wilson, A., Bannard-Smith, J., Rutter, M. K., House, T., Dark, P., Augustine, T., Akman, O., Hazel, A., & Blaikley, J. (2023). ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients. The Journal of clinical investigation, 133(4), Article e162775. https://doi.org/10.1172/JCI162775

@article{0567f1f00d124431b90dd5731850e232,

title = "ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients",

abstract = "BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe 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.ResultsClinCirc 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.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK 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.",

keywords = "Algorithms, Cell Line, Circadian Rhythm/physiology, Glucocorticoids/pharmacology, Humans, Intensive Care Units, Kidney Transplantation/adverse effects, Retrospective Studies",

author = "Peter Cunningham and Gareth Kitchen and Callum Jackson and Stavros Papachristos and Thomas Springthorpe and {Van Dellen}, David and Julie Gibbs and Timothy Felton and Anthony Wilson and Jonathan Bannard-Smith and Rutter, {Martin K.} and Thomas House and Paul Dark and Titus Augustine and Ozgur Akman and Andrew Hazel and John Blaikley",

note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Cunningham et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2023",

month = feb,

day = "15",

doi = "10.1172/JCI162775",

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Cunningham, P, Kitchen, G, Jackson, C, Papachristos, S, Springthorpe, T, Van Dellen, D, Gibbs, J , Felton, T, Wilson, A, Bannard-Smith, J , Rutter, MK , House, T , Dark, P , Augustine, T, Akman, O, Hazel, A & Blaikley, J 2023, 'ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients', The Journal of clinical investigation, vol. 133, no. 4, e162775. https://doi.org/10.1172/JCI162775

TY - JOUR

T1 - ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients

AU - Cunningham, Peter

AU - Kitchen, Gareth

AU - Jackson, Callum

AU - Papachristos, Stavros

AU - Springthorpe, Thomas

AU - Van Dellen, David

AU - Gibbs, Julie

AU - Felton, Timothy

AU - Wilson, Anthony

AU - Bannard-Smith, Jonathan

AU - Rutter, Martin K.

AU - House, Thomas

AU - Dark, Paul

AU - Augustine, Titus

AU - Akman, Ozgur

AU - Hazel, Andrew

AU - Blaikley, John

PY - 2023/2/15

Y1 - 2023/2/15

N2 - BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe 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.ResultsClinCirc 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.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK 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.

AB - BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe 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.ResultsClinCirc 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.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK 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.

KW - Algorithms

KW - Cell Line

KW - Circadian Rhythm/physiology

KW - Glucocorticoids/pharmacology

KW - Humans

KW - Intensive Care Units

KW - Kidney Transplantation/adverse effects

KW - Retrospective Studies

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DO - 10.1172/JCI162775

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JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

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ER -

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

Abstract

Keywords

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Inflammatory arthritis - time to reveal the bigger picture

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

Inflammatory arthritis - time to reveal the bigger picture

Centre for Biological Timing

MRC Transition Support CSF John Blaikley

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