Lessons learned in the Apple Heart Study and implications for the data management of future digital clinical trials.

The digital clinical trial is fast emerging as a pragmatic trial that can improve a trial's design including recruitment and retention, data collection and analytics. To that end, digital platforms such as electronic health records or wearable technologies that enable passive data collection can be leveraged, alleviating burden from the participant and study coordinator. However, there are challenges. For example, many of these data sources not originally intended for research may be noisier than traditionally obtained measures. Further, the secure flow of passively collected data and their integration for analysis is non-trivial. The Apple Heart Study was a prospective, single-arm, site-less digital trial designed to evaluate the ability of an app to detect atrial fibrillation. The study was designed with pragmatic features, such as an app for enrollment, a wearable device (the Apple Watch) for data collection, and electronic surveys for participant-reported outcomes that enabled a high volume of patient enrollment and accompanying data. These elements led to challenges including identifying the number of unique participants, maintaining participant-level linkage of multiple complex data streams, and participant adherence and engagement. Novel solutions were derived that inform future designs with an emphasis on data management. We build upon the excellent framework of the Clinical Trials Transformation Initiative to provide a comprehensive set of guidelines for data management of the digital clinical trial that include an increased role of collaborative data scientists in the design and conduct of the modern digital trial.

The development of a mobile app-focused deduplication strategy for the Apple Heart Study that informs recommendations for future digital trials.

An app-based clinical trial enrolment process can contribute to duplicated records, carrying data management implications. Our objective was to identify duplicated records in real time in the Apple Heart Study (AHS). We leveraged personal identifiable information (PII) to develop a dissimilarity score (DS) using the Damerau-Levenshtein distance. For computational efficiency, we focused on four types of records at the highest risk of duplication. We used the receiver operating curve (ROC) and resampling methods to derive and validate a decision rule to classify duplicated records. We identified 16,398 (4%) duplicated participants, resulting in 419,297 unique participants out of a total of 438,435 possible. Our decision rule yielded a high positive predictive value (96%) with negligible impact on the trial's original findings. Our findings provide principled solutions for future digital trials. When establishing deduplication procedures for digital trials, we recommend collecting device identifiers in addition to participant identifiers; collecting and ensuring secure access to PII; conducting a pilot study to identify reasons for duplicated records; establishing an initial deduplication algorithm that can be refined; creating a data quality plan that informs refinement; and embedding the initial deduplication algorithm in the enrolment platform to ensure unique enrolment and linkage to previous records.

Arrhythmias Other Than Atrial Fibrillation in Those With an Irregular Pulse Detected With a Smartwatch: Findings From the Apple Heart Study.

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Utilizing a novel unified healthcare model to compare practice patterns between telemedicine and in-person visits.

OBJECTIVE: Telemedicine practice has been shown to vary from clinical guidelines. Variations in practice patterns may be caused by disruptions in the continuity of care between traditional and telemedicine providers. This study compares virtual and in-person visits in Stanford's ClickWell Care (CWC) - where patients see the same provider for both visit modalities. METHODS: Clinical data for two years of patient encounters at CWC from January 2015-2017 (5772 visits) were obtained through Stanford STRIDE. For the 20 most common visit categories, including 17 specific diagnoses, we compared the frequency of prescriptions, labs, procedures, and images ordered, as well as rates of repeat visits. RESULTS: For the 17 specific diagnoses, there are no differences in labs ordered. Two diagnoses show differences in images ordered, and four differences in prescriptions. Overall, there are more labs (0.16 virtual, 0.33 in-person p < 0.0001) and images ordered (0.07 virtual, 0.16 in-person, p < 0.0001) for in-person visits - due mainly to general medical exam visits. Repeat visits were more likely after in-person visits (19% virtual, 38% in-person, p < 0.0001), 10 out of 17 specific diagnoses showed differences in visit frequency between visit modalities. Visits for both anxiety (5.3x, p < 0.0001) and depression (5.1x, p < 0.0001) were much more frequent in the virtual setting. CONCLUSIONS: Prescriptions, labs, and images ordered were similar between in-person and virtual visits for most diagnoses. Overall however, for in-person visits we find increased orders for labs and images, primarily from general medical exams. Finally, for anxiety and depression patients show clear preferences for virtual visits.

Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation.

BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown. METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10. RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events. CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

Healthcare Service Utilization under a New Virtual Primary Care Delivery Model.

Background:Telemedicine holds great promise for changing healthcare delivery. While telemedicine has been used significantly in the direct-to-consumer setting, the use of telemedicine in a preventive primary care setting is not well studied.Introduction:ClickWell Care (CWC) is the first known implementation of a technology-enabled primary care model. We wanted to quantify healthcare utilization of primary care by patient characteristics and modality of care delivery.Materials and Methods:Our study population included those who completed a visit to a CWC clinic between January 1, 2015 and September 30, 2015. We compared patients based on utilization of CWCs in-person and virtual visits across the following domains: patient demographics, distance from clinic, responses to a Health Risk Assessment, and top 10 conditions treated.Results:Thousand two hundred seven patients completed a visit with a CWC physician in 2015. Nearly three-quarters of our patients were ≤40 years and sex was significantly different (p = 0.015) between visit cohorts. The greatest representation of men (47%) was seen in the virtual-only cohort. Patients' proximity to the clinic was also significantly different across visit cohorts (p = 0.018) with 44% of in-person-only and 34% of virtual-only patients living within 5 miles of Stanford Hospital.Discussion:We found men were more likely to engage in virtual-only care. Young patients are willing to accept virtual care although many prefer to complete an in-person visit first.Conclusions:Our findings suggest that a "bricks-and-clicks" care model where telemedicine is supported by a brick-and-mortar location may be an effective way to leverage telemedicine to deliver primary care.

New Delivery Model for Rising-Risk Patients: The Forgotten Lot?

BACKGROUND: Shared-risk models encourage providers to engage young patients early. Telemedicine may be well suited for younger, healthier patients although it is unclear how best to incorporate telemedicine into routine clinical care. INTRODUCTION: We test the assumptions surrounding the use of telemedicine, younger and rising-risk patients, and primary care in ClickWell Care (CWC), a care model developed at our institution for our own accountable care organization. MATERIALS AND METHODS: CWC's team of physicians and wellness coaches work together to provide comprehensive primary care through in-person, phone, and video visits. This study examines usage of the clinic over its initial year in operation. RESULTS: 1,464 unique patients conducted a total of 3,907 visits. 2,294 (58.7%) visits were completed virtually (1,382 [35.4%] by phone and 912 [23.3%] by video). Patients were more inclined to see the physician in-person for a new visit (1,065 visits [70.5%] vs. 362 [24%] phone and 83 [6%] video) and more likely to see the physician virtually for a return visit (606 [43.2%] phone and 249 [17.7%] video vs. 548 [39.1%] in-person), a statistically significant difference (X2 = 306.7, p < 0.00001). CONCLUSION: This new care model successfully engaged a younger population of patients. However, our data suggest young patients may not be inclined to establish care with a primary care physician virtually and, in fact, choose an initial in-person touch point, although many are willing to conduct return visits virtually. This new model of care could have a large impact on how care is delivered to low- and rising-risk patients.

An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis.

BACKGROUND: Evaluation of the efficacy of molecular treatment strategies for lymphatic vascular insufficiency requires a suitable preclinical animal model. Ideally, the model should closely replicate the untreated human disease in its pathogenesis and pathological expression. OBJECTIVE: We have undertaken a study of the time course of the development and resolution of acquired, experimental lymphedema and of its responses to vascular endothelial growth factor (VEGF)-C lymphangiogenesis in the mouse tail model. STUDY DESIGN: We provoked post-surgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C. Quantitative assessment of immune traffic function was performed through sequential in vivo bioluminescent imaging. RESULTS: In untreated lymphedema, tail edema was sustained until day 21. Exogenous administration of human recombinant VEGF-C produced a significant decrease in volume. Untreated lymphedema in the mouse tail model was characterized by the presence of dilated cutaneous lymphatics, marked acute inflammatory changes, and hypercellularity; VEGF-C produced a substantial reversion to the normal pattern, with notable regression in the size and number of cutaneous lymphatic vessels that express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). In vivo imaging confirmed the presence of an impairment of immune traffic in lymphedema that was ameliorated after VEGF-C administration. CONCLUSION: The post-surgical murine tail model of lymphedema closely simulates attributes of human lymphedema and provides the requisite sensitivity to detect therapeutically induced functional and structural alterations. It can, therefore, be used as an investigative platform to assess mechanisms of disease and its responses to candidate therapies, such as therapeutic lymphangiogenesis.

Inflammatory manifestations of experimental lymphatic insufficiency.

BACKGROUND: Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. METHODS AND FINDINGS: We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. CONCLUSIONS: We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.