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.

Cumulative human exposure and environmental occurrence of phthalate esters: A global perspective.

In the current investigation, the distribution and extent of human exposure of phthalate esters (PAEs) have been reported on global extent based on computed indices. The proposed indices were calculated based on environmental concentrations, toxicity, occurrence, environmental fate, and transport of PAEs. The cumulative phthalate exposure index (PEI) based on the phthalate pollution index (PPI) was mapped on a global scale based on the existing data reported in the literature. The results revealed that the PAEs are heterogeneously distributed globally, and about 30% of total environmental PAEs are ultimately exposed to the average human being. The comparative distribution of PAEs in various environmental compartments including urban-rural, indoor-outdoor, home-dormitory-classroom, and their exposure likelihood were studied based on indices. More than 90% of total human exposure of PAEs was observed to be from indoor environmental compartments. Significantly high exposure was observed in the urban population as compared to the rural population. About 70% of the total phthalate pollution sub-index of dust was observed from home followed by a classroom of ∼15% and then a dormitory of ∼10%. In addition, the indices were equated with the current human development index (HDI), gross national income (GNI), and exposure of particulate matter of each country. Based on current findings, the population living in the areas where >20 µg/m3 of particulate matter has been reported are possibly exposed with higher PAEs. The indices were highly diversified at high HDI (0.9) values and between 40,000 and 50,000 $ per capita income due to different usage of phthalate-containing products, disposal, and extensive monitoring work carried out by the developed and developing countries.

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.

[Figure: see text].

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.).

Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study.

BACKGROUND: Smartwatch and fitness band wearable consumer electronics can passively measure pulse rate from the wrist using photoplethysmography (PPG). Identification of pulse irregularity or variability from these data has the potential to identify atrial fibrillation or atrial flutter (AF, collectively). The rapidly expanding consumer base of these devices allows for detection of undiagnosed AF at scale. METHODS: The Apple Heart Study is a prospective, single arm pragmatic study that has enrolled 419,093 participants (NCT03335800). The primary objective is to measure the proportion of participants with an irregular pulse detected by the Apple Watch (Apple Inc, Cupertino, CA) with AF on subsequent ambulatory ECG patch monitoring. The secondary objectives are to: 1) characterize the concordance of pulse irregularity notification episodes from the Apple Watch with simultaneously recorded ambulatory ECGs; 2) estimate the rate of initial contact with a health care provider within 3 months after notification of pulse irregularity. The study is conducted virtually, with screening, consent and data collection performed electronically from within an accompanying smartphone app. Study visits are performed by telehealth study physicians via video chat through the app, and ambulatory ECG patches are mailed to the participants. CONCLUSIONS: The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF. The Apple Heart Study will help provide a foundation for how wearable technology can inform the clinical approach to AF identification and screening.

Hyperbaric programs in the United States: Locations and capabilities of treating decompression sickness, arterial gas embolisms, and acute carbon monoxide poisoning: survey results.

Hyperbaric oxygen therapy is the primary treatment for arterial gas embolism, decompression sickness and acute carbon monoxide poisoning. Though there has been a proliferation of hyperbaric centers throughout the United States, a scarcity of centers equipped to treat emergency indications makes transport of patients necessary. To locate and characterize hyperbaric chambers capable of treating emergency cases, a survey of centers throughout the entire United States was conducted. Using Google, Yahoo, HyperbaricLink and the UHMS directory, a database for United States chambers was created. Four researchers called clinicians from the database to administer the survey. All centers were contacted for response until four calls went unreturned or a center declined to be included. The survey assessed chamber readiness to respond to high-acuity patients, including staff availability, use of medical equipment such as ventilators and intravenous infusion devices, and responding yes to treating hyperbaric emergencies within a 12-month period. Only 43 (11.9%, N = 361) centers had equipment, intravenous infusion pumps and ventilators, and staff necessary to treat high-acuity patients. Considering that a primary purpose of hyperbaric oxygen therapy is the treatment of arterial gas embolism and decompression sickness, more hyperbaric centers nationwide should be able to accommodate these emergency cases quickly and safely.