Fatigue Investigation Using Digital Outcomes

FIDO is an exploratory, multicenter, observational study evaluating whether fatigue in neurological and post-infectious conditions can be characterized using digital outcomes derived from wearable sensors, smartphone-based performance tests, and self-report collected in free-living conditions. Fatigue is among the most disabling symptoms reported in multiple sclerosis (MS) and post-COVID-19 condition (long COVID), yet it is assessed almost exclusively through questionnaires administered at single time points in clinic. Such instruments capture neither day-to-day fluctuation nor the exertion-dependent component of fatigue that patients describe. FIDO combines continuous physiological and behavioral monitoring with repeated at-home cognitive and motor testing to examine whether these signals track fatigue as it is experienced in daily life. The primary focus of the study is feasibility: whether participants in these populations can sustain the required device wear and application-based tasks over an eight-week monitoring period, and how completeness and timeliness of data vary within and between participants. Secondary objectives address the relationship between digital measures and established clinical and self-reported assessments of fatigue, fatigability, autonomic function, and cognition. Further exploratory objectives examine sleep, post-exertional malaise, menstrual cycle phase, gut microbiome composition, machine learning models for estimating and predicting fatigue, the effect of reduced data quantity and resolution on derived measures, and participants' experience and perceived usability of the study tools. DESIGN AND SETTING Prospective observational cohort study with three parallel groups and no allocation or intervention. Each participant takes part for approximately eight weeks, comprising two on-site visits and a continuous home-based data collection phase between them. STUDY PROCEDURES Visit 1 (baseline). After written informed consent and assignment of a pseudonymized study identifier, participants complete a battery of questionnaires and clinical assessments. Instrumentation includes a 5-lead ECG Holter, an upper-arm blood pressure monitor, an ActiGraph LEAP armband, and a smartwatch. Autonomic function is assessed using a subset of an Ewing-based test battery: heart rate response to paced deep breathing at 0.1 Hz for 10 minutes; the 30:15 ratio on active standing; blood pressure and heart rate response to postural change at 1, 3, and 5 minutes standing; and blood pressure response to a sustained handgrip test at 30% of maximal voluntary contraction for 5 minutes, with blood pressure measured at 1, 3, and 5 minutes. After a two minutes break, blood pressure is measured again. Cognitive, memory, and dexterity assessments comprise the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test-Revised, and the Nine-Hole Peg Test. Participants also perform two administrations each of the smartphone-based cognitive fatigability test (cFAST) and a 30-second finger tapping task, separated by rest periods and preceded by a fatigue visual analogue scale, with the order of the two smartphone tasks counterbalanced. Participants receive the study application, wearable devices and chargers, stool collection kits, printed questionnaires, and device manuals. Eight-week remote monitoring. Participants wear an ActiGraph LEAP on the upper arm and a smartwatch on the wrist continuously, removing them only for showering and swimming, and synchronize data regularly. Participants with MS receive a Garmin smartwatch and participants with post-COVID-19 condition an Apple Watch; healthy controls receive either model. The application prompts cognitive and motor fatigue visual analogue scales four times daily at random times, morning and evening sleep surveys, and the cFAST and tapping tasks every second day (approximately seven minutes combined). Stress, food, activity, and symptom logging are available on a self-reported basis. The Fatigue Severity Scale is completed weekly by the MS and healthy control groups; it is not administered in the post-COVID-19 group, as the instrument was developed for MS and does not adequately capture fatigue in this population. A printed Fatigue Scale for Motor and Cognitive Functions is completed at week 4. Stool samples for gut microbiome analysis are collected at weeks 4 and 8 and returned by prepaid post. Visit 2 (final visit). Participants return to their site while continuing to wear the sensors and repeat a subset of the baseline questionnaires, assessments, and smartphone-based tasks. Usability and acceptability questionnaires (UEQ and MARS), completed at home beforehand, are returned, and participants give open verbal feedback during a semi-structured interview, which is audio-recorded. All study devices and chargers are returned at the end of the visit.