Keeping an eye on circadian time in clinical research and medicine

Abstract

Background: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms.

Content: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology.

Conclusion: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Keywords: chronobiology; chronomedicine; circadian; circadian medicine; daily; diurnal; human; time-of-day; translational.

FIGURE 1

Oscillatory and evoked components contribute to rhythmic outputs. Daily rhythms in physiology (such as blood pressure, glucose, hormone levels, and the rates of distribution, metabolism and excretion of substances) are a composite of both internal oscillatory components driven by cellular and molecular clocks and evoked components in response to external stimuli or behavioural change. Understanding these relative contributions allows for them to be targeted by circadian medicine. Adapted from Klerman and Czeisler Recent Progress in Hormone Research 1999.

FIGURE 2

Meal timing relative to the circadian clock influences blood glucose levels. Postprandial glucose profiles differ depending on whether a nutritionally identical meal is consumed in the biological morning (red) or biological evening (blue), with impacts not only on the temporal profile of blood glucose levels but also on the cumulative total blood glucose (area under curve shown in inset). This highlights the importance of circadian timing on human health and disease management (such as diabetes). Adapted from Morris, C. J., et al., Proceedings of the National Academy of Sciences 2015.

FIGURE 3

Melatonin levels are low during the daytime and begin to rise 1–3 h before habitual sleep onset. The dim light melatonin onset (DLMO) occurs when the endogenous melatonin levels rise above a low threshold such as 3 pg/ml for saliva or 2 standard deviations above the low baseline points.