Wearable computing devices allow collection of densely sampled real-time information on movement enabling researchers and medical experts to obtain objective and non-obtrusive records of actual activity of a subject in the real world over many days. Our interest here is motivated by the use of activity data for evaluating and monitoring the circadian rhythmicity of subjects for research in chronobiology and chronotherapeutic healthcare. In order to translate the information from such high-volume data arising we propose the use of a Markov modelling approach which (i) naturally captures the notable square wave form observed in activity data along with heterogeneous ultradian variances over the circadian cycle of human activity, (ii) thresholds activity into different states in a probabilistic way while respecting time dependence and (iii) gives rise to circadian rhythm parameter estimates, based on probabilities of transitions between rest and activity, that are interpretable and of interest to circadian research.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Experimental and epidemiologic studies have shown that circadian clocks disruption can play an important role in the development of cancer and metabolic diseases. The cellular clocks outside the brain are effectively coordinated by the body temperature rhythm. We hypothesized that concurrent measurements of body temperature and rest-activity rhythms would assess circadian clocks coordination in individual patients, thus enabling the integration of biological rhythms into precision medicine. Objective: The study aimed at the real-time demonstration of large inter-subject differences in the circadian clocks of people during their daily routine, using a mobile e-Health platform. Such critical step further aimed at the integration of circadian rhythm disorders diagnosis and treatments into precision e-medicine. Methods: Non-invasive real-time measurements of rest-activity and chest temperature rhythms were recorded during the subject’s daily life, using a dedicated new mobile e-health platform (PiCADo). It involved a chest sensor that jointly measured accelerations, 3D-orientation and skin surface temperature every 1-5 min, and relayed them out to a mobile gateway via Bluetooth-Low-Energy. The gateway tele-transmitted all stored data to a server via GPRS every 24 h. The technical capabilities of PiCADo were validated in 55 healthy subjects and 12 cancer patients, whose rhythms were e-monitored during their daily routine for 3-30 days. Spectral analyses enabled to compute rhythm parameters values, with their 90% confidence limits, and their dynamics in each subject. Results: All the individuals displayed a dominant circadian rhythm in activity with maxima occurring from 12:09 to 20:25. This was not the case for the dominant temperature period, which clustered around 24 h for 51 subjects (76.1%), and around 12 h for 13 others (19.4%). Statistically significant sex- and age- related differences in circadian coordination were identified in the non-cancerous subjects, based upon the range of variations in temperature rhythm amplitudes, maxima (acrophases), and phase relations with rest-activity. The circadian acrophase of chest temperature was located at night for the majority of people, but it occurred at daytime for 26% of the non-cancerous people and 33.3% of the cancer patients, hence supporting important inter-subject differences in circadian coordination. Sex, age and cancer significantly impacted on circadian coordination. Conclusions: Complementing rest-activity with chest temperature circadian e-monitoring revealed striking inter-subject differences regarding human circadian clocks coordination and timing during daily routine. To further delineate the clinical importance of such finding, the PiCADo platform is currently applied for both the assessment of health effects resulting from atypical work schedules, and the identification of the key determinants of circadian disruption in cancer patients.

The dichotomy index (I < O), a quantitative estimate of the circadian regulation of daytime activity and sleep, predicted overall cancer survival and emergency hospitalization, supporting its integration in a mHealth platform. Modifiable causes of I < O deterioration below 97.5%—(I < O)_low—were sought in 25 gastrointestinal cancer patients and 33 age- and sex-stratified controls. Rest-activity and temperature were tele-monitored with a wireless chest sensor, while daily activities, meals, and sleep were self-reported for one week. Salivary cortisol rhythm and dim light melatonin onset (DLMO) were determined. Circadian parameters were estimated using Hidden Markov modelling, and spectral analysis. Actionable predictors of (I < O)_low were identified through correlation and regression analyses. Median compliance with protocol exceeded 95%. Circadian disruption—(I < O)_low—was identified in 13 (52%) patients and four (12%) controls (p = 0.002). Cancer patients with (I < O)_low had lower median activity counts, worse fragmented sleep, and an abnormal or no circadian temperature rhythm compared to patients with I < O exceeding 97.5%—(I < O)_high—(p < 0.012). Six (I < O)_low patients had newly-diagnosed sleep conditions. Altered circadian coordination of rest-activity and chest surface temperature, physical inactivity, and irregular sleep were identified as modifiable determinants of (I < O)_low. Circadian rhythm and sleep tele-monitoring results support the design of specific interventions to improve outcomes within a patient-centered systems approach to health care.

BACKGROUND: Circadian timing of treatments can largely improve tolerability and efficacy in patients. Thus, drug metabolism and cell cycle are controlled by molecular clocks in each cell and coordinated by the core body temperature 24-hour rhythm, which is generated by the hypothalamic pacemaker. Individual circadian phase is currently estimated with questionnaire-based chronotype, center-of-rest time, dim light melatonin onset (DLMO), or timing of core body temperature (CBT) maximum (acrophase) or minimum (bathyphase). METHODS: We aimed at circadian phase determination and readout during daily routines in volunteers stratified by sex and age. We measured (a) chronotype, (b) every minute (q1min) CBT using 2 electronic pills swallowed 24 hours apart, (c) DLMO through hourly salivary samples from 1800 hours to bedtime, and (d) q1min accelerations and surface temperature at anterior chest level for 7 days, using a teletransmitting sensor. Circadian phases were computed using cosinor and hidden Markov modeling. Multivariate regression identified the combination of biomarkers that best predicted core temperature circadian bathyphase. RESULTS: Among the 33 participants, individual circadian phases were spread over 5 hours, 10 minutes (DLMO); 7 hours (CBT bathyphase); and 9 hours, 10 minutes (surface temperature acrophase). CBT bathyphase was accurately predicted, i.e., with an error less than 1 hour for 78.8% of the subjects, using a new digital health algorithm (INTime), combining time-invariant sex and chronotype score with computed center-of-rest time and surface temperature bathyphase (adjusted R ² = 0.637). CONCLUSION: INTime provided a continuous and reliable circadian phase estimate in real time. This model helps integrate circadian clocks into precision medicine and will enable treatment timing personalization following further validation. FUNDING: Medical Research Council, United Kingdom; AP-HP Foundation; and INSERM.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet

PurposeTo assess the impact of chronomodulated irinotecan fluorouracil-leucovorin and oxaliplatin (chronoIFLO4) delivered at home on the daily life of patients with cancer in real time using a home-based e-Health multifunction and multiuser platform. This involved multidimensional telemonitoring of circadian rest-activity rhythm (CircAct), sleep, patient-reported outcome measures, and body weight changes (BWCs).Patients and MethodsPatients received chronoIFLO4 fortnightly at home. Patients completed the 19-item MD Anderson Symptom Inventory on an interactive electronic screen, weighed themselves on a dedicated scale, and continuously wore a wrist accelerometer for CircAct and sleep monitoring. Daily data were securely teletransmitted to a specific server accessible by the hospital team. The clinically relevant CircAct parameter dichotomy index I < O and sleep efficiency (SE) were calculated. The dynamic patterns over time of patient-reported outcome measures, BWC, I < O, and SE informed the oncology team ...