Novel Circadian Biomarkers in Medical ICU Patients

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PROJECT SUMMARY To better understand and treat the pathophysiology of sleep and circadian disruption in critical illness, practical and accurate measures of circadian time (i.e., circadian phase) are needed. Sleep homeostasis and circadian rhythms are fundamental, interdependent physiologic processes. The high prevalence of severe sleep and circadian disruption is well established in critically ill patients. Current measures of circadian time are resource intensive, requiring frequent (e.g., hourly) sampling of blood, saliva, or urine for ≥24 hours. Thus, a key gap in investigating critical illness sleep and circadian disruption is the lack of practical and accurate measures of circadian time that can be applied efficiently to larger numbers of patients and followed longitudinally. Recently, two transcriptional biomarkers of circadian time were developed and tested in normal subjects: TimeSignature (TimeS) and BodyTime (BodyT). These biomarkers accurately estimate melatonin onset and require only 1 or 2 blood samples per day. The accuracy of TimeS and BodyT has not been tested in critically ill subjects who have a high degree of circadian disruption. This project’s overall objective is to test the accuracy of novel circadian biomarkers in a critically ill patient cohort. The central hypothesis is that these novel circadian biomarkers, TimeS and BodyT, will accurately estimate melatonin onset in critically ill patients. Our rationale for testing these biomarkers is their convenient blood draw schedule, low blood volume requirements, and accuracy in estimating time of melatonin onset among healthy subjects. The central hypothesis will be tested via the following specific aims: Aim 1 - Establish the accuracy of TimeS in estimating time of melatonin onset relative to urine 6- sulfatoxymelatonin (aMT6s) acrophase in critically ill patients at the time of medical intensive care unit (MICU) admission; and Aim 2 - Establish the accuracy of BodyT in estimating time of melatonin onset relative to urine aMT6s acrophase in critically ill patients at the time of MICU admission. The aims will be tested in an observational cohort of MICU patients who undergo parallel sampling of urine aMT6s (hourly) and blood for transcriptional biomarker analysis (every 6 hours) for 24 hours. Urine aMT6s acrophase (i.e., time of fitted peak level aMT6s) will be the circadian time reference. Analysis will include tests for overall accuracy and a comparison of accuracy among subjects with circadian misalignment. For each biomarker, melatonin onset can be estimated using 2 of the 4 available samples; thus, each biomarker will have multiple sample pairs for analysis. These additional sample pairs will be used to compare accuracy based on sample timing relative to each subject’s individual circadian time. The proposed work is significant because establishing the accuracy of either or both biomarkers in this challenging population fills a significant gap that currently slows the field and provides key data for the next investigation aimed at improving outcomes by promoting sleep and circadian function in critically ill patients.