This is a longitudinal observational cohort study, with all study activities taking place remotely over a 12-week period. Apple Health Kit (Apple Inc) and survey data will be collected and stored using a third-party digital health and research platform (Figure 1) approved by the Stanford University Institutional Review Board (IRB-77005). Study design includes multiple layers of data collection (eg, self-report measures, smartwatch metrics, and task-based measures), all of which are essential for biosignature development. Self-report measures encompass current gold-standard metrics of the pain experience and are crucial for biosignature validation. Smartwatch technology leverages the widespread adoption of wearables to capture real-time fluctuations across multiple body systems, which is critical for ensuring a holistic and longitudinal understanding of the pain experience. Task-based measures, such as the online Trier Social Stress Test and 30-second sit-to-stand task (30-s STS), are included as secondary metrics to facilitate participant comparison across standardized challenges. As understood through the biopsychosocial model of pain, multiple systems contribute to the pain experience. Therefore, it is vital to collect multiple layers of data for biosignature development. Machine learning methods are critical to the study design, facilitating an improved interpretation of multidimensional data and enhanced detection of nuanced fluctuations in pain status.

Up to 500 youth and adolescents with chronic primary or secondary MSK pain [21,22] will be enrolled in this study. Individuals are eligible to participate if they are between 14 and 24 years old and experience MSK pain (pain in muscles, tendons, bones, joints) in one or more anatomic regions that has persisted or recurred for ≥ 3 months and is associated with significant emotional distress or functional disability. Individuals are excluded if they report only headache, orofacial, or visceral pain, have been hospitalized in the past 30 days for something other than pain, have a significant cognitive impairment that would prevent study participation (eg, severe brain injury), are currently undergoing treatment for cancer, or are pregnant or expect to become pregnant over the study period. This study is listed at ClinicalTrials.gov (NCT06867757) and preregistered on Open Science Framework (10.17605/OSF.IO/EN69C).

Participants are recruited nationwide through a multipronged recruitment strategy to ensure a representative sample. Recruitment within the Stanford health care system occurs through the Research Participation and Engagement Program (RPEP) and Stanford Children’s Health Pediatric Pain Management Clinic. Nationwide recruitment occurs through a custom-designed study website, community advertisements to pediatric multidisciplinary pain clinics in the United States, advertisements sent via postal mail, and patient advocacy networks (eg, US Pain Foundation, American Chronic Pain Association, and The Ehlers-Danlos Society). Interested participants are directed to complete a web-based study interest form as the first step of the eligibility screening. Potentially eligible participants are then contacted by the study team for additional screening based on the previously described eligibility criteria.

The participants—and their legally authorized representatives, if applicable—complete an IRB-approved assent/consent process before completing any study activities. All study data, including digital health information, shared medical records, and video submissions, are collected, stored, and shared according to strict confidentiality requirements of the Stanford University IRB (IRB-77005).

The study design is outlined in Figure 2. Once enrolled, participants complete a battery of baseline surveys through the third-party app. Baseline surveys include self-report measures assessing pain and pain interference [23-27], fatigue [28,29], mood [30-32], stress [33], sleep [34], and physical activity [35] (Table 1).

Once the baseline surveys have been completed, the participants begin to receive “daily check-in” surveys, deployed at 5 pm (participant’s local time) and available to complete until 11:59 pm, for the duration of the 12-week study. Participants receive daily prompts through the app interface to complete these “daily check-in” surveys, which include short versions of self-report measures to quantify daily pain interference, pain, fatigue, mood, stress, sleep, and physical activity (Table 1). The daily check-in also asks participants to report whether they had a pain flare that day (“yes/no”) and to describe its characteristics. A pain-flare [10,11] is described to participants using the following language: “A temporary but noticeable worsening of your usual pain and/or symptoms (eg, fatigue, stiffness, and emotional distress) that feels more intense than what you typically deal with. Pain flares typically meet the following criteria: (1) are disruptive, (2) last longer than usual pain spikes, (3) affect more than just pain, (4) may be linked to a trigger, and (5) are bigger than normal pain changes.” Participants also have the option to initiate an unprompted retrospective or real-time pain flare report outside of the time-based daily check-in. The daily check-in also includes a daily diary for participants to note any exciting or stressful daily events (eg, academic stress, medical appointment) and any pain wellness strategies used (eg, deep breathing, pacing, journaling). The daily self-report measures are used as the gold standard (ie, ground truth) to which novel physiological markers are compared and thus are essential to ensure the clinical relevance of the biosignature.

If participants do not have an iPhone compatible with iOS 14.1 or later and an Apple Watch compatible with iOS 15 or later, they are mailed study-provided devices (iPhone SE Gen 2, Apple Watch Series 9s) as needed. Once the devices are received, the participants are invited to enroll in the study through an app-based third-party digital health and research platform. Upon study discharge, the participants are required to return any borrowed devices. The following steps are implemented to encourage device return: (1) participants receive a prepaid return envelope and instructions for returning the device(s) upon study discharge; (2) participants explicitly agree to return device(s) as part of the consent process; and (3) frequent touch points with the study team are intended to promote good rapport and increase the likelihood of follow through on agreed returns.

The participants are instructed to wear the Apple Watch for at least 18 hours per day during the 12-week observation period. Apple Health Kit data are collected, uploaded, and stored through the third-party digital health and research platform. Metrics of interest include those related to respiratory function (eg, respiratory rate), heart activity (eg, heart rate, heart rate variability), physical activity (eg, steps, bouts of activity, standing time), sleep (eg, in-bed time, sleep phases), and mobility (eg, gait speed, walking asymmetry, step length) (Table 1). Survey completion rate and adherence to required watch wear times are monitored by the study team. Participants receive notifications from the study team to encourage high levels of adherence based on completion standards selected a priori (eg, number of daily check-ins completed each week and daily and nightly hours of wear). Participants receive weekly monetary incentives for completing each component of the study, with up to US $210 total. Those who do not meet adherence standards may not be eligible to receive a given week’s compensation. Furthermore, those consistently not meeting standards within the first few weeks of the study may be withdrawn in an effort to allocate research team time to adherent participants and prevent excessive amounts of missing data. At the end of the 12-week observation period, the participants complete an additional battery of discharge surveys, once again deployed through the third-party app (Table 1). They also complete a series of task-based measures prior to study discharge.

The purpose of this study is to develop a digital biosignature of the pain experience in youth and adolescents with chronic MSK pain. Self-report measures are the current gold standard for monitoring the pain experience and informing clinical decision-making. The purpose of developing a digital biosignature is to overcome the limitations of self-report, specifically the tendency to represent a single point in time and its inherent vulnerability to recall bias. A digital biosignature will provide real-time, objective measures of the pain experience through a holistic, multisystem lens.

This study is expected to result in several clinical benefits. First, the development and validation of digital clinical end points facilitates more robust assessment of novel therapeutics and treatment paradigms for youth with chronic MSK pain. The precise monitoring of treatment response would enhance the rigor and effectiveness of clinical trial design, leading to improved treatments, especially for those refractory to existing therapies. Second, a digital biosignature will give clinicians a deeper understanding of their patients’ individual pain experience through real-time, longitudinal monitoring of symptom fluctuations. These insights will enhance clinical decision-making and support a shift toward individually tailored interventions. Real-time tracking will also facilitate expedited shifts in a prescribed treatment plan, saving time and resources in helping patients to find the best treatment option for their specific pain presentation. Additionally, an objective biosignature may improve patients’ pain experience and interactions with clinicians by reducing the need to repeatedly recount severe pain events, an act that itself may be distressing. Finally, not only will a digital biosignature inform clinical practice, but it will also empower patients to have more control over their symptoms. Specifically, Phase 2 addresses this last point through enhanced “wellness alerts” for improved self-efficacy in living with chronic pain.

To further the impact of the digital biosignature that will be developed in this study, we expect to conduct a second phase of the study. The goals of Phase 2 are twofold: (1) assess clinical validation of the digital biosignature in a novel sample and (2) evaluate the accuracy of a predictive “wellness alert” system.

Phase 2 includes recruitment of a novel cohort of up to 400 youth with MSK pain. Recruitment criteria will mirror those described in this study. To ensure relevance of the digital biosignature for a representative set of adolescents, this phase will have a particular focus on recruitment of youth experiencing health disparities (eg, rural youth with limited access to tertiary pain clinics and racial and ethnic minorities). Once again, a multipronged recruitment strategy will be implemented as described in this study. Stanford Medicine’s Trial Innovation Network will provide additional support for the recruitment of youth and adolescents experiencing health disparities. Participants will use an iPhone and Apple Watch for 12 weeks to monitor physiological, sleep, and physical activity data. Devices will be provided as needed. Metrics such as AUROC, AUPRC, F₁-score, positive predictive value, and negative predictive value will be used in this study phase for prospective validation of the digital biosignature. As in Phase 1, we expect that participants’ self-reported pain flare onset will be used as the primary outcome to which the digital biosignature is compared.

Participants enrolled in Phase 2 also have the opportunity to receive enhanced “wellness alerts,” which would be triggered by a deterioration in the pain experience as detected through abnormal smartwatch readings. The goal of these “wellness alerts” is to prompt users toward proactive self-management strategies (eg, pacing, sleep hygiene) in an effort to prevent or reduce the severity of the predicted pain flare. Patient and advocacy partners recommended positive framing of these “wellness alerts” (ie, opportunities for enhanced wellness strategies) as opposed to “pain flare predictions,” which may be negatively interpreted and lead to increased anxiety and hypervigilance. The accuracy of the enhanced “wellness alerts” will be assessed via comparison to self-reported pain flare onset through measures of accuracy, precision, and true positive and false negative rates. This “wellness alert” system is expected to empower patients by reducing feelings of helplessness surrounding unpredictable fluctuations in pain status. In addition, the alerts may serve as an additional tool to promote pain-related self-efficacy, which may serve as a protective factor in youth with chronic pain [45].

Although this study uses the Apple Smartwatch as a wearable technology of choice, the algorithms developed can be expanded across multiple monitoring options to promote broader dissemination and encourage improved access to study innovations. This study will introduce opportunities for open-access analysis tools that can be deployed across different wearable devices for improved dissemination. Furthermore, the identification of key physiological features may suggest that simpler, more economical fitness technologies (eg, pedometer or heart rate monitor chest strap) are sufficient for characterizing the pain experience in this population.

The TRAC-Pain study leverages the widespread adoption of consumer wearables to overcome limitations of self-report as the current gold standard for monitoring the pain experience in youth with chronic MSK pain. This study is unique in its multipronged recruitment strategy and intentional collaboration with patient and advocacy partners from the beginning of the study design process. Clinical impacts are expected to span multiple aspects of care, impacting researchers, clinicians, and patients. In terms of research, the development of digital clinical end points will enhance the rigor of clinical trials for the development of improved therapeutics. For clinicians, a longitudinal, real-time assessment of the pain experience will introduce opportunities for individually tailored treatments. Finally, this study is an important step toward promoting patient empowerment through opportunities for proactive self-management and enhanced self-efficacy in living with chronic pain.