Bobo, William V.

ABSTRACT Consumer‐grade wearables, including smartwatches, fitness trackers, and smart rings, are accessible tools for studying pharmacologic responses in real‐time, monitoring participant health in decentralized clinical trials, optimizing outcome measures, and delivering digital interventions that promote behavior change. However, incorporating consumer wearables into clinical studies is not as straightforward as simply purchasing devices and providing them to participants. It requires engaging with a complex engineering ecosystem with multiple investigator decisions on device selection, associated data management practices, and patient/participant engagement and technical support. This tutorial, based on experience running large clinical trials using consumer wearables, outlines the wearables market landscape across varying form factors and manufacturers as well as the data management software products supporting wearable use. It delineates the major decision processes involved in designing studies that incorporate wearables and presents a structured framework to guide the selection of devices and supporting data tools according to study objectives.

Introduction Sleep is routinely assessed in the management of mental health conditions. Wearable technologies like smartwatches offer a non-intrusive method to quantitatively measure sleep. However, there are limited empirical benchmarks for sleep duration and sleep quality measured by wearables against user reports. This study aims to evaluate the concordance between user-reported and smartwatch-measured hours of sleep and sleep quality. Methods Participants were recruited from two decentralized digital health well-being studies and completed a 7-day sleep diary while simultaneously wearing their smartwatch to sleep (November 7, 2023 - June 30, 2024). Participants self-reported sleep timestamps and perceived sleep quality using the Sleep Quality Scale. Sleep timestamps and quality were also derived from their smartwatches (Garmin Vívoactive 4 2019, Garmin Venu 2 Plus 2022, and Garmin Venu 3/3S 2023). Statistical analyses included paired t-tests, equipercentile linking, and chi-square tests to assess agreement between smartwatch and self-reported sleep parameters. Exploratory analyses established the difference between reported and recorded sleep duration in healthcare shift workers. Results From 841 sleep instances reported by 130 participants wearing three different generation smartwatches, the mean difference in sleep duration between smartwatch-recorded and participant-reported was 21.22 (Garmin Vívoactive), 11.67 (Garmin Venu 2 Plus), and 6.58 (Garmin Venu 3/3S) minutes, respectively. There were statistically significant between-group differences in mean sleep durations assessed by participant self-report vs. Vívoactive 4 smartwatches, but not self-report vs. Venu 2 Plus or Venu 3/3S smartwatches. Equipercentile linking revealed concordance between smartwatch sleep scores and self-reported sleep quality using the Sleep Quality Scale (SQS) between 4 and 7, with disagreements observed at the SQS ranges from 0–4 and 7-10. Conclusions These results suggest that wearables can reliably measure sleep duration, and future research warrants improvements in algorithms that estimate sleep quality with validations across different wearable vendors.

Importance The potential utility of real-time digital therapeutics that identify impending behavioral outbursts to proactively apply evidence-based interventions for managing children with disruptive behavior disorder has not been tested. Objectives To evaluate feasibility and adherence of a digitally augmented, real-time, proactive behavioral intervention (smartwatch) for children with disruptive behaviors. Design, Setting, and Participants This randomized clinical trial was conducted between March 1, 2022, and December 31, 2023, at Mayo Clinic in Rochester, Minnesota. The study enrolled children aged 3 to 7 years with externalizing behavior problems rated above the clinically significant range (I score ≥120; T score ≥60) on the Eyberg Child Behavior Inventory (ECBI). Interventions Twelve weekly sessions of parent-child interaction therapy (PCIT) (treatment as usual [TAU] arm) vs artificial intelligence (AI)–enhanced PCIT augmented with real-time behavioral outburst alerts (PCIT-AI arm). Main Outcomes and Measures The primary outcome was achieving the a priori feasibility benchmark set at greater than 70% for both completion of PCIT sessions and daily smartwatch wear. Parental reaction time to behavior prompts was measured in seconds. Secondary outcomes were percentage changes in ECBI and Pediatric Sleep Questionnaire scores. Behavioral outburst duration was examined based on parental logs of start and end times of observed tantrums using a smartphone application. Result This study enrolled 50 children (median [IQR] age, 5.0 [4.0-6.0] years; 34 [68%] male and 16 [32%] female; 28 randomized to the PCIT-AI arm and 22 to the PCIT-TAU arm). Of these children, 37 (74%; 21 in the PCIT-AI arm and 16 in the PCIT-TAU arm) completed PCIT, with children wearing the watch a median (IQR) 75.7% (67.8%-82.9%) of the time, thus achieving the feasibility benchmark (primary outcome). Median (IQR) response time to behavior prompts in the PCIT-AI arm was 3.65 (2.07-7.08) seconds. Assessing between-group differences, there was no statistically significantly greater numerical improvement in ECBI-intensity percentage change (13.86%; 95% CI, −1.41% to 29.14%), ECBI-problem percentage change subscale scores (38.59%; 95% CI, −1.22% to 78.40%), or absolute change in Pediatric Sleep Questionnaire scores (−0.16; 95% CI, −1.85 to 1.53) with the PCIT-AI arm than with the PCIT-TAU arm. Children in the PCIT-AI arm had significantly shorter mean (SD) tantrum durations (10.4 [20.8] minutes vs 22.1 [30.0] minutes; P < .001) and lower odds of tantrums lasting for 15 minutes or more (odds ratio, 3.66; 95% CI, 2.72-4.95). Conclusions and Relevance In this randomized clinical trial, both recruitment and technology feasibility benchmarks were achieved. The findings inform the design of fully powered efficacy study of wearable, digitally augmented PCIT for children with disruptive behaviors. Trial Registration ClinicalTrials.gov Identifier: NCT05077722

ABSTRACTObjectivesPrior studies have raised concerns about postpartum hemorrhage (PPH) risk associated with selective serotonin and serotonin‐norepinephrine reuptake inhibitors (SSRIs and SNRIs), although limitations include possible confounding by maternal indications. The current study examined the risk of PPH associated with prenatal S/NRIs accounting for diagnosed maternal depression during pregnancy.MethodsThe current study is a secondary analysis of data from a cohort of 2213 pregnancies (1997–2010) identified from a large electronic medical record‐linkage system. Exposures were identified from electronic prescriptions records and resulted in three main groups: S/NRI‐exposed pregnancies (S/NRI users), antidepressant‐unexposed pregnancies (non‐users), and S/NRI exposure in the year prior to (but not during) pregnancy (former users). Data used to identify PPH occurrences included obstetrician chart diagnoses, diagnosis codes, and recorded estimated blood loss (EBL). The risk of PPH by exposure group was estimated using unadjusted, minimally adjusted (maternal age at delivery, delivery year, parity, and maternal smoking), and depression‐adjusted models (previous covariates and maternal depression). Supplemental analyses included an examination of PPH risk with prenatal bupropion monotherapy.ResultsThe study cohort consisted of 837 S/NRI users, 401 former users, and 786 non‐users, as well as 114 bupropion users identified for additional analyses. The frequency of PPH was 11.6% in the overall cohort, and was 14.7% for S/NRI users, 10.2% for former users, and 8.7% for non‐users. The risk of PPH was significantly higher for S/NRI users than non‐users in unadjusted (OR 1.82 [95% CI 1.33, 2.49]), minimally adjusted (aOR 1.66 [1.19, 2.31]), and depression‐adjusted models (aOR 1.46 [1.02, 2.10]). The risk of PPH was also higher for S/NRI former users than non‐users in unadjusted models (OR 1.54 [1.05, 2.26]) but not minimally adjusted (aOR 1.42 [0.95, 2.11]) or depression‐adjusted models (aOR 1.41 [0.95, 2.10]). No significant differences in PPH risk were observed between S/NRI users and former users, between bupropion users and non‐users, or between S/NRI users and bupropion users.ConclusionsPrenatal S/NRI exposure was associated with an increased risk of PPH after adjusting for maternal depression, although residual confounding and confounding by other factors (including unmeasured factors) may be possible, as the risk of PPH appeared to be similar between S/NRI users and former users. Best‐practice PPH risk management strategies should be adhered to for depressed patients, especially those who require treatment with antidepressants during pregnancy.

ABSTRACT Adherence in digital health studies with extended observation periods (≥ 12 months) is limited, and participant retention considerably reduces with time. The US Food and Drug Administration has issued guidelines for improving participant engagement, adherence, and diversity in digital health studies combined with decentralized procedures. A decentralized digital health study on well‐being was designed with protocolized procedures to study the feasibility of participant engagement and technology support to facilitate adherence (wearing the smartwatch ≥ 70% of time) sustained over a 12‐month period. At the end of the study, participants were asked about their ease of participation and free‐response questions about how wearing the smartwatches impacted their physical wellness. An inductive thematic analysis (ITA) was performed to assess themes of those responses and association with adherence. A total of 298 participants were recruited between 2022 and 2023 ( n = 129 in Cohort A in October 22, n = 169 in Cohort B in April 23), with 23% non‐white participants accrued. Among the 298 participants accrued, 273 (92% of accrued participants) completed the 12‐month study with an average overall adherence of 77.4% (SD = 32.64) wear‐time across 12 months. Median adherence of participants whose responses exemplified an ITA theme encompassing perceived behavior changes in sleep and physical activity was higher than those who did not have a response exemplifying that theme. Conversely, those expressing perceived discomfort or intrusiveness of the smartwatch had a statistically lower adherence. These results highlight the crucial roles of technology support and robust engagement efforts to enable sustained adherence over extended follow‐up periods in decentralized digital health studies.

Introduction: Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. Objectives: This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. Methods: A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Results: Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Conclusions: Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.

Abstract Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient‐specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health‐system‐wide, mixed‐methods study. Clinicians representing multiple practices and care settings ( N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient‐specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0–100 points) of each alert, the perceived impact of each alert on stress and decision‐making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision‐making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician‐guided design of PGx alerts in the era of digital medicine.

AbstractObjectivesInterpatient variability in bipolar I depression (BP‐D) symptoms challenges the ability to predict pharmacotherapeutic outcomes. A machine learning workflow was developed to predict remission after 8 weeks of pharmacotherapy (total score of ≤8 on the Montgomery Åsberg Depression Rating Scale [MADRS]).MethodsSupervised machine learning models were trained on data from BP‐D patients treated with olanzapine (N = 168) and were externally validated on patients treated with olanzapine/fluoxetine combination (OFC; N = 131) and lamotrigine (LTG; N = 126). Top predictors were used to develop a prognosis rule informing how many symptoms should change and by how much within 4 weeks to increase the odds of achieving remission.ResultsAn AUC of 0.76 (NIR:0.59; p = 0.17) was established to predict remission in olanzapine‐treated subjects. These trained models achieved AUCs of 0.70 with OFC (NIR:0.52; p < 0.03) and 0.73 with LTG (NIR:0.52; p < 0.003), demonstrating external replication of prediction performance. Week‐4 changes in four MADRS symptoms (reported sadness, reduced sleep, reduced appetite, and concentration difficulties) were top predictors of remission. Across all pharmacotherapies, three or more of these symptoms needed to improve by ≥2 points at Week‐4 to have a 65% chance of achieving remission at 8 weeks (OR: 3.74, 95% CI: 2.45–5.76; p < 9.3E‐11).ConclusionMachine learning strategies achieved cross‐trial and cross‐drug replication in predicting remission after 8 weeks of pharmacotherapy for BP‐D. Interpretable prognoses rules required only a limited number of depressive symptoms, providing a promising foundation for developing simple quantitative decision aids that may, in the future, serve as companions to clinical judgment at the point of care.

PURPOSE The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC ( BRCA1 and BRCA1) and LS ( MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.