Circadian epidemiology: Structuring circadian causes of disease and practical implications.

That disruptions of the body's internal clockwork can lead to negative health consequences, including cancer, is a plausible hypothesis. Yet, despite strong mechanistic and animal support, the International Agency for Research on Cancer (IARC) experts considered epidemiological evidence as limited regarding the carcinogenicity of "shift-work involving circadian disruption" (2007) and "night shift work" (2019). We use directed acyclic graphs (DAGs) to outline a concept of circadian causes that discloses challenges when choosing appropriate exposure variables. On this basis, we propose to move beyond shift-work alone as a direct cause of disease. Instead, quantifying chronodisruption as individual doses can lead to interpretable circadian epidemiology. The hypothesis is that doses of chronodisruption cause disrupted circadian organisation by leading to desynchronization of circadian rhythms. Chronodisruption can be conceptualized as the split physiological nexus of internal and external times. Biological (or internal) night - an individual's intrinsically favoured sleep time window - could be the backbone of circadian epidemiology. In practice, individual doses that cause disrupted circadian organisation are derived from the intersection of time intervals of being awake and an individual's biological night. After numerous studies counted work shifts, chronobiology may now advance circadian epidemiology with more specific dose estimation - albeit with greater challenges in measurement (time-dependent individual data) and analysis (time-dependent confounding).