Fatigue Investigation Using Digital Outcomes

Percentage of Expected Smartwatch Wear Time Recorded Over Two Months

Passive compliance with continuous smartwatch data collection, as a measure of feasibility of long-term fatigue monitoring. Participants wear a smartwatch continuously for two months: a Garmin smartwatch (multiple sclerosis group), an Apple Watch (post-COVID-19 condition group), or either device (healthy controls). Expected wear time is the full duration of each participant's individual enrolment (approximately 60 days), so the denominator is calculated per participant rather than as a fixed period; charging periods are not excluded, so values are not expected to reach 100%. Compliance is calculated per participant as recorded wear time divided by expected wear time, multiplied by 100. Values range from 0% to 100%, with higher values indicating greater compliance. Compliance is also compared by group, disease characteristics and demographic factors, and baseline characteristics associated with lower compliance are described.

Percentage of Expected Armband Activity Monitor Wear Time Recorded Over Two Months

Passive compliance with continuous armband data collection, as a measure of feasibility of long-term fatigue monitoring. Participants wear an armband activity monitor (ActiGraph LEAP) continuously for two months. All participants wear the same device, so compliance can be compared between groups independently of device type. Expected wear time is the full duration of each participant's individual enrolment (approximately 60 days), so the denominator is calculated per participant rather than as a fixed period; charging periods are not excluded, so values are not expected to reach 100%. Compliance is calculated per participant as recorded wear time divided by expected wear time, multiplied by 100. Values range from 0% to 100%, with higher values indicating greater compliance. Compliance is also compared by group, disease characteristics and demographic factors, and baseline characteristics associated with lower compliance are described.

Percentage of Scheduled Study Application Questionnaires Completed Over Two Months

Active compliance with self-reported data collection, as a measure of feasibility of long-term fatigue monitoring. Participants complete short questionnaires in the study smartphone application (FIDO app) over two months, comprising cognitive and motor fatigue visual analogue scales prompted four times daily at random times, morning and evening sleep surveys daily, and the Fatigue Severity Scale weekly in the multiple sclerosis and healthy control groups. The number scheduled follows each participant's individual enrolment (approximately 60 days). Compliance is calculated per participant as the number of questionnaires completed divided by the number scheduled, multiplied by 100. Values range from 0% to 100%, with higher values indicating greater compliance. Compliance is reported per questionnaire type, compared by group, disease characteristics and demographic factors, and baseline characteristics associated with lower compliance are described. Response latency is also evaluated.

Percentage of Scheduled Study Application Performance Tasks Completed Over Two Months

Active compliance with task-based data collection, as a measure of feasibility of long-term fatigue monitoring. Participants complete two brief performance tasks in the FIDO app approximately every second day over two months: a cognitive fatigability test (cFAST) and a 30-second finger tapping task, together taking approximately seven minutes. The number scheduled follows each participant's individual enrolment (approximately 60 days). Compliance is calculated per participant as the number of sessions completed divided by the number scheduled, multiplied by 100. A session counts as completed if the participant finishes the full task protocol. Values range from 0% to 100%, with higher values indicating greater compliance. Compliance is reported per task, compared by group, disease characteristics and demographic factors, and baseline characteristics associated with lower compliance are described. Response latency is also evaluated.

Discriminative Accuracy of Cognitive Fatigability Test and Finger Tapping Test Performance for Participant Group, Stratified by Fatigue Level

Participants complete a cognitive fatigability test (cFAST) and a finger tapping test at the study visits and approximately every second day over two months. Performance measures are derived from each test during analysis and are not pre-specified. They are evaluated for their ability to discriminate patients from healthy controls, reported as the area under the receiver operating characteristic curve, from 0.5 (chance) to 1.0 (perfect discrimination), per test. Results are stratified by self-reported fatigue level on the corresponding subscale of the Fatigue Scale for Motor and Cognitive Functions (cognitive subscale for cFAST, motor subscale for tapping; scores 10 to 50, higher indicating greater fatigue). Baseline factors expected to influence this endpoint are age and disease status.

Reliability and Within-Participant Variability of Cognitive Fatigability Test and Finger Tapping Test Performance

Reliability of smartphone-based performance tests for repeated long-term monitoring. Performance measures are derived during analysis and are not pre-specified. Each test is administered twice in immediate succession, in counterbalanced order, at each of the two study visits, when fatigue is expected to remain stable, and repeated approximately every second day over two months, when fatigue is expected to fluctuate. Agreement across repeated administrations is reported as the intraclass correlation coefficient, from 0 to 1, higher values indicating greater consistency. The immediate-repeat estimate reflects measurement reliability; the two-month estimate reflects the proportion of variance attributable to stable differences between participants. Whether within-participant variation tracks concurrent fatigue is addressed by the corresponding association outcome. Results are reported per test. Baseline factors expected to influence this endpoint are age and disease status.

Agreement Between Cognitive Fatigability Test and Finger Tapping Test Performance and Established Fatigue and Functional Assessments

Agreement between smartphone-based performance tests and established fatigue and functional assessments. Performance measures are derived during analysis and are not pre-specified. A cognitive or motor fatigue visual analogue scale (0 to 10) is completed immediately before every test session. Performance is additionally compared with the fatigue and functional assessments specified in the protocol, including the Fatigue Severity Scale weekly in the multiple sclerosis and healthy control groups, the Fatigue Scale for Motor and Cognitive Functions at the study visits and at four weeks, the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test-Revised at the initial visit, handgrip strength and the Nine-Hole Peg Test. Associations are reported as correlation coefficients from -1 through 0 to +1, per test pairing. Baseline factors expected to influence this endpoint are age and disease status.

Association Between Digital Measurements Derived From Wearable Data and the Fatigue Scale for Motor and Cognitive Functions (FSMC)

Association between digital measurements derived from continuously recorded wearable data and the Fatigue Scale for Motor and Cognitive Functions (FSMC). Candidate measurements are derived during analysis from raw sensor signals recorded by an armband monitor and consumer smartwatch, including photoplethysmography, inertial, barometric and temperature signals; their scales are not pre-specified. Associations are reported as correlation coefficients from -1 through 0 to +1, separately for each group.

Autonomic Function and Symptoms in Participants With Multiple Sclerosis, Post-COVID-19 Condition and Healthy Controls

Characterisation of autonomic function and its variation between clinical groups. At both study visits participants undergo a standardised autonomic test battery based on Ewing's protocol, comprising heart rate response to paced deep breathing at 0.1 Hz, the 30:15 ratio on active standing, blood pressure response to postural change, and blood pressure response to sustained handgrip at 30% of maximal voluntary contraction, recorded using a 5-lead ECG Holter and blood pressure monitor. Autonomic symptoms are assessed by COMPASS-31 (weighted total 0 to 100, higher indicating greater symptom burden). Values from each component of the battery are compared between participants with multiple sclerosis, participants with post-COVID-19 condition and healthy controls.

Agreement Between Blood Pressure Estimated From the Armband Activity Monitor and Cuff-Measured Blood Pressure During Clinical Autonomic Testing

Whether blood pressure estimated from photoplethysmography by the armband activity monitor (ActiGraph LEAP), worn on the upper arm, agrees with cuff-measured blood pressure. Comparison is made only at the study visits, during the autonomic test battery, when cuff blood pressure is recorded in the supine position, at one, three and five minutes of standing, and before, during and after a five-minute sustained handgrip contraction at 30% of maximal voluntary contraction. Estimated and cuff-measured systolic and diastolic blood pressure are compared at each of these timepoints, in millimetres of mercury. Agreement is assessed using Bland-Altman analysis and reported as the mean difference between methods with 95% limits of agreement. Agreement during postural change and sustained contraction, when blood pressure is expected to vary, is examined separately.

Time From Notification to Completion of Scheduled Study Application Questionnaires and Performance Tasks Over Two Months

Responsiveness to scheduled prompts, as a measure of the effort required to sustain active data collection rather than whether it is completed at all. The FIDO app records the time at which each prompt is sent and the time at which the corresponding questionnaire or task is submitted; latency is the interval between these timestamps, in minutes, calculated per completed prompt, with longer intervals indicating slower responding. Prompts that are never completed are not assigned a latency and are captured by the completion rate outcomes. Latency is summarised per participant as the median and as within-participant variability over the two-month period, reported separately for each prompt type (fatigue visual analogue scale, sleep surveys, Fatigue Severity Scale, cognitive fatigability test, finger tapping task), and compared by group, disease characteristics and demographic factors.