Recruitment Strategies in the Integration of Mobile Health Into Sickle Cell Disease Care to Increase Hydroxyurea Utilization Study (meSH): Multicenter Survey Study.

BACKGROUND: Hydroxyurea is an evidence-based disease-modifying therapy for sickle cell disease (SCD) but is underutilized. The Integration of Mobile Health into Sickle Cell Disease Care to Increase Hydroxyurea Utilization (meSH) multicenter study leveraged mHealth to deliver targeted interventions to patients and providers. SCD studies often underenroll; and recruitment strategies in the SCD population are not widely studied. Unanticipated events can negatively impact enrollment, making it important to study strategies that ensure adequate study accrual. OBJECTIVE: The goal of this study was to evaluate enrollment barriers and the impact of modified recruitment strategies among patients and providers in the meSH study in response to a global emergency. METHODS: Recruitment was anticipated to last 2 months for providers and 6 months for patients. The recruitment strategies used with patients and providers, new recruitment strategies, and recruitment rates were captured and compared. To document recruitment adaptations and their reasons, study staff responsible for recruitment completed an open-ended 9-item questionnaire eliciting challenges to recruitment and strategies used. Themes were extrapolated using thematic content analysis. RESULTS: Total enrollment across the 7 sites included 89 providers and 293 patients. The study acceptance rate was 85.5% (382/447) for both patients and providers. The reasons patients declined participation were most frequently a lack of time and interest in research, while providers mostly declined because of self-perceived high levels of SCD expertise, believing they did not need the intervention. Initially, recruitment involved an in-person invitation to participate during clinic visits (patients), staff meetings (providers), or within the office (providers). We identified several important recruitment challenges, including (1) lack of interest in research, (2) lack of human resources, (3) unavailable physical space for recruitment activities, and (4) lack of documentation to verify eligibility. Adaptive strategies were crucial to alleviate enrollment disruptions due to the COVID-19 pandemic. These included remote approaching and consenting (eg, telehealth, email, and telephone) for patients and providers. Additionally, for patients, recruitment was enriched by simplification of enrollment procedures (eg, directly approaching patients without a referral from the provider) and a multitouch method (ie, warm introductions with flyers, texts, and patient portal messages). We found that patient recruitment rates were similar between in-person and adapted (virtual with multitouch) approaches (167/200, 83.5% and 126/143, 88.1%, respectively; P=.23). However, for providers, recruitment was significantly higher for in-person vs remote recruitment (48/50, 96% and 41/54, 76%, respectively, P<.001). CONCLUSIONS: We found that timely adaptation in recruitment strategies secured high recruitment rates using an assortment of enriched remote recruitment strategies. Flexibility in approach and reducing the burden of enrollment procedures for participants aided enrollment. It is important to continue identifying effective recruitment strategies in studies involving patients with SCD and their providers and the impact and navigation of recruitment challenges. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03380351; https://clinicaltrials.gov/study/NCT03380351. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16319.

Epigenetic Aging Associations With Psychoneurological Symptoms and Social Functioning in Adults With Sickle Cell Disease.

Objective: Sickle cell disease (SCD), the most common inherited blood disorder in the United States, is associated with severe psychoneurological symptoms. While epigenetic age acceleration has been linked to psychoneurological symptom burden in other diseases, this connection is unexplored in SCD. This study aimed to assess the association between epigenetic age acceleration and psychoneurological symptom burden in SCD. Methods: In this cross-sectional study, emotional impact, pain impact, sleep impact, social functioning, and cognitive function were assessed in 87 adults living with SCD. DNA methylation data were generated from blood specimens and used to calculate epigenetic age using five clocks (Horvath, Hannum, PhenoAge, GrimAge, & DunedinPACE). Associations between epigenetic age acceleration and symptoms were assessed. Results: The sample (N = 87) had a mean (SD) chronologic age was 30.6 (8.1) years. Epigenetic age acceleration was associated with several symptom outcomes. GrimAge age acceleration (ß = -0.49, p = .03) and increased DunedinPACE (ß = -2.23, p = .004) were associated with worse emotional impact scores. PhenoAge (ß = -0.32, p = .04) and the GrimAge (ß = -0.48, p = .05) age acceleration were associated with worse pain impact scores. Increased DunedinPACE (ß = -2.07 p = .04) were associated with worse sleep impact scores. Increased DunedinPACE (ß = -2.87, p = .005) was associated with worse social functioning scores. We did not find associations between epigenetic age acceleration and cognitive function in this sample. Conclusion: Epigenetic age acceleration was associated with worse symptom experiences, suggesting the potential for epigenetic age acceleration as a biomarker to aid in risk stratification or targets for intervention to mitigate symptom burden in SCD.

Cost-Effectiveness of Lovotibeglogene Autotemcel (Lovo-Cel) Gene Therapy for Patients with Sickle Cell Disease and Recurrent Vaso-Occlusive Events in the United States.

BACKGROUND AND OBJECTIVE: Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥ 12 years with ≥ 4 vaso-occlusive events (VOEs) in the past 24 months. METHODS: We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase 1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses. RESULTS: Patients treated with lovo-cel were predicted to survive 23.84 years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40 years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs. CONCLUSIONS: Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.

Opioid Use Among Children and Adults With Sickle Cell Disease in North Carolina Medicaid Enrollees in the Era of Opioid Harm Reduction.

Adults and children with sickle cell disease (SCD) are predominantly African American, with pain-related health disparities. We examined opioid prescription fill patterns in adults and children with SCD and compared factors associated with fills in North Carolina Medicaid enrollees. Our retrospective cohort study included 955 enrollees diagnosed with SCD having at least one opioid fill. Associations were measured between two cohorts (12 and 24 mo of continuous enrollment) for the following characteristics: sex, age, enrollee residence, hydroxyurea adherence, comanagement, enrollment in Community Care North Carolina, prescription for short versus short and long-acting opioids, and emergency department reliance. The majority of individuals did not have an opioid claim over a 12 or 24-month period. Claims increased at ages 10 to 17, peaking at ages 18 to 30. The increased number of claims was associated with the following factors: increasing age, male, short versus long-acting opioids, and Medicaid enrollment for 24 versus 12 months. Community Care North Carolina enrollees in the 12-month cohort had higher opioid days of supply per month; the inverse was true of the 24-month cohort.

Mortality in adults with sickle cell disease: Results from the sickle cell disease implementation consortium (SCDIC) registry.

The cause of death in people affected by sickle cell disease (SCD) is often challenging to define as prior studies have used retrospective or administrative data for analysis. We used a prospective longitudinal registry to assess mortality and clinical co-morbidities among subjects enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. At enrollment, we collected the following data: patient-reported demographics, SCD phenotype, baseline laboratory values, comorbidities, and current medications. Subjects were followed for a median of 4.7 years before the present analysis. The relationship of clinical co-morbidities (at time of enrollment) to mortality was determined using survival analysis, adjusting for SCD phenotype and gender. There was a total of 2439 people with SCD enrolled in the SCDIC registry. One hundred and twenty-eight participants (5%) died during the observation period (2017-2022). Six people died from trauma and were excluded from further analysis. Proximate cause of death was unwitnessed in 17% of the deaths, but commonest causes of death include cardiac (18%), acute chest or respiratory failure (11%), sudden unexplained death (8%). Enrollment characteristics of the individuals who died (n = 122) were compared to those of survivors (n = 2317). Several co-morbidities at enrollment increased the odds of death on univariate analysis. All co-morbidities were included in a multivariable model. After backward elimination, iron overload, pulmonary hypertension, and depression, remained statistically significant predictors of the risk of death. SCD reduces life expectancy. Improved comprehensive and supportive care to prevent end-organ damage and address comorbidities is needed for this population.

Mental health, pain and likelihood of opioid misuse among adults with sickle cell disease.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

Supporting data driven translational patient-centered care using network analysis to visualize symptom distress in children with serious illness.

PURPOSE: There are an increasing number of techniques and tools to improve the capacity for children to relay their perceptions of their symptom experience while undergoing blood and marrow transplant (BMT). Network analysis (NA) is a tool that can illustrate associations between symptoms and the distress they cause. We aimed to develop a biopsychosocial assessment clinical analytic tool to examine symptom relationships for children undergoing BMT to find actionable relationships for intervention to improve clinical outcomes including mood. DESIGN AND METHODS: This pilot study used an analytical mobile application tool to support a wide scope of 15 biopsychosocial symptom distress levels and five mood assessments. Children recorded their symptom distress and mood using the app. NA was used to explore relationships between symptom distress and mood. RESULTS: Four children, 11-14 years old, undergoing BMT used the app daily during hospitalization. We found a strong presence of emotional distress and its associations symptom distress and mood. Multiple symptom associations were identified including associations between the set of symptoms difficulty breathing and fever (0.557), sad and worried (0.429). Of note, pain distress had a strong capacity to bridge other symptoms and was connected directly to many symptoms. PRACTICE IMPLICATIONS: We found the significance of patient struggles with emotional and symptom distress and the importance of this relationship to other clinical outcomes. This provides valuable insights and an improved understanding of the child's symptoms. Our findings support early assessment, intervention, and improved symptom communication to enhance sense of well-being and the child's care experience.

Characterizing epigenetic aging in an adult sickle cell disease cohort.

ABSTRACT: Sickle cell disease (SCD) affects ∼100 000 predominantly African American individuals in the United States, causing significant cellular damage, increased disease complications, and premature death. However, the contribution of epigenetic factors to SCD pathophysiology remains relatively unexplored. DNA methylation (DNAm), a primary epigenetic mechanism for regulating gene expression in response to the environment, is an important driver of normal cellular aging. Several DNAm epigenetic clocks have been developed to serve as a proxy for cellular aging. We calculated the epigenetic ages of 89 adults with SCD (mean age, 30.64 years; 60.64% female) using 5 published epigenetic clocks: Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE. We hypothesized that in chronic disease, such as SCD, individuals would demonstrate epigenetic age acceleration, but the results differed depending on the clock used. Recently developed clocks more consistently demonstrated acceleration (GrimAge, DunedinPACE). Additional demographic and clinical phenotypes were analyzed to explore their association with epigenetic age estimates. Chronological age was significantly correlated with epigenetic age in all clocks (Horvath, r = 0.88; Hannum, r = 0.89; PhenoAge, r = 0.85; GrimAge, r = 0.88; DunedinPACE, r = 0.34). The SCD genotype was associated with 2 clocks (PhenoAge, P = .02; DunedinPACE, P < .001). Genetic ancestry, biological sex, ß-globin haplotypes, BCL11A rs11886868, and SCD severity were not associated. These findings, among the first to interrogate epigenetic aging in adults with SCD, demonstrate epigenetic age acceleration with recently developed epigenetic clocks but not older-generation clocks. Further development of epigenetic clocks may improve their predictive ability and utility for chronic diseases such as SCD.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Use of consumer wearables to monitor and predict pain in patients with sickle cell disease.

Background: In sickle cell disease (SCD), unpredictable episodes of acute severe pain, known as vaso-occlusive crises (VOC), disrupt school, work activities and family life and ultimately lead to multiple hospitalizations. The ability to predict VOCs would allow a timely and adequate intervention. The first step towards this ultimate goal is to use patient-friendly and accessible technology to collect relevant data that helps infer a patient's pain experience during VOC. This study aims to: (1) determine the feasibility of remotely monitoring with a consumer wearable during hospitalization for VOC and up to 30 days after discharge, and (2) evaluate the accuracy of pain prediction using machine learning models based on physiological parameters measured by a consumer wearable. Methods: Patients with SCD (≥18 years) who were admitted for a vaso-occlusive crisis were enrolled at a single academic center. Participants were instructed to report daily pain scores (0-10) in a mobile app (Nanbar) and to continuously wear an Apple Watch up to 30 days after discharge. Data included heart rate (in rest, average and variability) and step count. Demographics, SCD genotype, and details of hospitalization including pain scores reported to nurses, were extracted from electronic medical records. Physiological data from the wearable were associated with pain scores to fit 3 different machine learning classification models. The performance of the machine learning models was evaluated using: accuracy, F1, root-mean-square error and area under the receiver-operating curve. Results: Between April and June 2022, 19 patients (74% HbSS genotype) were included in this study and followed for a median time of 28 days [IQR 22-34], yielding a dataset of 2,395 pain data points. Ten participants were enrolled while hospitalized for VOC. The metrics of the best performing model, the random forest model, were micro-averaged accuracy of 92%, micro-averaged F1-score of 0.63, root-mean-square error of 1.1, and area under the receiving operating characteristic curve of 0.9. Conclusion: Our random forest model accurately predicts high pain scores during admission for VOC and after discharge. The Apple Watch was a feasible method to collect physiologic data and provided accuracy in prediction of pain scores.

Preferences for potential benefits and risks for gene therapy in the treatment of sickle cell disease.

Objective of this study is to quantify benefit-risk tradeoffs pertaining to potential gene therapies among adults and parents/caregivers of children with sickle cell disease (SCD). A discrete-choice experiment survey was developed in which respondents selected their preferred treatment alternatives in a series of experimentally controlled pairs of hypothetical gene therapies and a "no gene therapy" option. Gene therapy alternatives were defined based on the chance of eliminating SCD symptoms, expected increases in life expectancy they could offer, treatment-related risk of death, and potential increases in lifetime cancer risk. Respondents made selections based on their current disease severity and in the context of expectations of worsened disease. Three clinical sites and 1 patient organization recruited 174 adult patients and 109 parents of children with SCD to complete the survey. Adult and parent respondents were generally willing to choose gene therapies, but the adults required higher expected levels of efficacy (ie, higher chance of eliminating symptoms) than parents to choose gene therapies that conferred mortality risks of ≥10%. When adults and parents of children with less severe symptoms were asked to consider scenarios of higher levels of disease severity, the increased risk tolerance, and the lowest acceptable level of efficacy for gene therapies with mortality risks dropped by >50%. Baseline SCD symptoms are a major driver of gene therapy acceptability. Adults and parents of patients with milder symptoms may prefer other treatment options; however, an expectation of symptoms deterioration triggers strong reassessment of the acceptable benefit-risk balance of this novel technology.

Monitoring and responding to signals of suicidal ideation in pragmatic clinical trials: Lessons from the GRACE trial for Chronic Sickle Cell Disease Pain.

Sickle cell disease (SCD) is a hemoglobin disorder and the most common genetic disorder that affects 100,000 Americans and millions worldwide. Adults living with SCD have pain so severe that it often requires opioids to keep it in control. Depression is a major global public health concern associated with an increased risk in chronic medical disorders, including in adults living with sickle cell disease (SCD). A strong relationship exists between suicidal ideation, suicide attempts, and depression. Researchers enrolling adults living with SCD in pragmatic clinical trials are obligated to design their methods to deliberately monitor and respond to symptoms related to depression and suicidal ideation. This will offer increased protection for their participants and help clinical investigators meet their fiduciary duties. This article presents a review of this sociotechnical milieu that highlights, analyzes, and offers recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

A multilevel mHealth intervention boosts adherence to hydroxyurea in individuals with sickle cell disease.

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSß0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167.

Feasibility of Implementation of a Mobile Digital Personal Health Record to Coordinate Care for Children and Youth With Special Health Care Needs in Primary Care: Protocol for a Mixed Methods Study.

BACKGROUND: Electronic health record (EHR)-integrated digital personal health records (PHRs) via Fast Healthcare Interoperability Resources (FHIR) are promising digital health tools to support care coordination (CC) for children and youth with special health care needs but remain widely unadopted; as their adoption grows, mixed methods and implementation research could guide real-world implementation and evaluation. OBJECTIVE: This study (1) evaluates the feasibility of an FHIR-enabled digital PHR app for CC for children and youth with special health care needs, (2) characterizes determinants of implementation, and (3) explores associations between adoption and patient- or family-reported outcomes. METHODS: This nonrandomized, single-arm, prospective feasibility trial will test an FHIR-enabled digital PHR app's use among families of children and youth with special health care needs in primary care settings. Key app features are FHIR-enabled access to structured data from the child's medical record, families' abilities to longitudinally track patient- or family-centered care goals, and sharing progress toward care goals with the child's primary care provider via a clinician dashboard. We shall enroll 40 parents or caregivers of children and youth with special health care needs to use the app for 6 months. Inclusion criteria for children and youth with special health care needs are age 0-16 years; primary care at a participating site; complex needs benefiting from CC; high hospitalization risk in the next 6 months; English speaking; having requisite technology at home (internet access, Apple iOS mobile device); and an active web-based EHR patient portal account to which a parent or caregiver has full proxy access. Digital prescriptions will be used to disseminate study recruitment materials directly to eligible participants via their existing EHR patient portal accounts. We will apply an intervention mixed methods design to link quantitative and qualitative (semistructured interviews and family engagement panels with parents of children and youth with special health care needs) data and characterize implementation determinants. Two CC frameworks (Pediatric Care Coordination Framework; Patient-Centered Medical Home) and 2 evaluation frameworks (Consolidated Framework for Implementation Research; Technology Acceptance Model) provide theoretical foundations for this study. RESULTS: Participant recruitment began in fall 2022, before which we identified >300 potentially eligible patients in EHR data. A family engagement panel in fall 2021 generated formative feedback from family partners. Integrated analysis of pretrial quantitative and qualitative data informed family-centered enhancements to study procedures. CONCLUSIONS: Our findings will inform how to integrate an FHIR-enabled digital PHR app for children and youth with special health care needs into clinical care. Mixed methods and implementation research will help strengthen implementation in diverse clinical settings. The study is positioned to advance knowledge of how to use digital health innovations for improving care and outcomes for children and youth with special health care needs and their families. TRIAL REGISTRATION: ClinicalTrials.gov NCT05513235; https://clinicaltrials.gov/study/NCT05513235. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46847.

Outcomes of End-User Testing of a Care Coordination Mobile App With Families of Children With Special Health Care Needs: Simulation Study.

BACKGROUND: Care for children with special health care needs relies on a network of providers who work to address the medical, behavioral, developmental, educational, social, and economic needs of the child and their family. Family-directed, manually created visual depictions of care team composition (ie, care mapping) and detailed note-taking curated by caregivers (eg, care binders) have been shown to enhance care coordination for families of these children, but they are difficult to implement in clinical settings owing to a lack of integration with electronic health records and limited visibility of family-generated insights for care providers. Caremap is an electronic health record-integrated digital personal health record mobile app designed to integrate the benefits of care mapping and care binders. Currently, there is sparse literature describing end-user participation in the co-design of digital health tools. In this paper, we describe a project that evaluated the usability and proof of concept of the Caremap app through end-user simulation. OBJECTIVE: This study aimed to conduct proof-of-concept testing of the Caremap app to coordinate care for children with special health care needs and explore early end-user engagement in simulation testing. The specific aims included engaging end users in app co-design via app simulation, evaluating the usability of the app using validated measures, and exploring user perspectives on how to make further improvements to the app. METHODS: Caregivers of children with special health care needs were recruited to participate in a simulation exercise using Caremap to coordinate care for a simulated case of a child with complex medical and behavioral needs. Participants completed a postsimulation questionnaire adapted from 2 validated surveys: the Pediatric Integrated Care Survey (PICS) and the user version of the Mobile Application Rating Scale (uMARS). A key informant interview was also conducted with a liaison to Spanish-speaking families regarding app accessibility for non-English-speaking users. RESULTS: A Caremap simulation was successfully developed in partnership with families of children with special health care needs. Overall, 38 families recruited from 19 different US states participated in the simulation exercise and completed the survey. The average rating for the survey adapted from the PICS was 4.1 (SD 0.82) out of 5, and the average rating for the adapted uMARS survey was 4 (SD 0.83) out of 5. The highest-rated app feature was the ability to track progress toward short-term, patient- and family-defined care goals. CONCLUSIONS: Internet-based simulation successfully facilitated end-user engagement and feedback for a digital health care coordination app for families of children with special health care needs. The families who completed simulation with Caremap rated it highly across several domains related to care coordination. The simulation study results elucidated key areas for improvement that translated into actionable next steps in app development.

Developing an Implementation Blueprint for the NIH HEAL Initiative GRACE Trial: Perspectives on Acupuncture and Guided Relaxation for Chronic Sickle Cell Disease Pain.

Objective: This study aimed to explore perspectives of people living with sickle cell disease (SCD) and SCD clinic providers and staff about the use of acupuncture and guided relaxation for treating chronic SCD pain. Data obtained were to inform an implementation blueprint for an effectiveness implementation clinical trial (GRACE Trial) testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care. Design: Qualitative research design. Methods: We conducted 33 semistructured interviews with people with SCD and SCD clinic providers and staff. Interviews were transcribed and coded. A deductive content analysis process was used to identify themes. Results: Four themes were identified: Receptivity to Acupuncture and Guided Relaxation, Limited Awareness, Complementary and Integrative Health (CIH) Therapy Preference, and Access Barriers. Both patients and clinic providers and staff were open to the use of acupuncture and guided relaxation for chronic pain treatment. After learning about these CIH therapies, some patients expressed a preference for one therapy over the other. They also discussed their ability to successfully engage with each therapy. There is a need to dispel misconceptions about the therapies by increasing understanding of how each therapy is implemented and functions to reduce pain. We identified several potential barriers that might affect the success of the trial and future health system integration, including time, transportation, and technology. Conclusion: This study is one of the first to present perspectives of both patients with SCD and clinic providers and staff on the use of acupuncture and guided relaxation for chronic SCD pain. Stakeholders' early input and perspectives highlighted that they welcome nonpharmacological CIH therapies. Implementation of a clinical trial and future health system integration will require the addressing misinformation and identifying strategies to overcome access barriers. Clinical trial registration number: NCT04906447.

Infertility and treatment-seeking practices among females and males with sickle cell disease in the Sickle Cell Disease Implementation Consortium registry.

OBJECTIVE: To describe the prevalence of infertility and infertility treatment seeking among people enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry and identify sociodemographic and clinical correlates of infertility. DESIGN: Cross-sectional. PARTICIPANTS: The study population included 2108 women and men (≥18 years of age) enrolled in the SCDIC registry who completed the fertility questionnaire. RESULTS: All participants who completed the infertility-specific questions were included in the analysis (1224 females; 884 males). Of these, 16.9% of males and 23.7% of females reported infertility, in contrast to rates in the general population (12% of males; 11% of females). Only 22.8% of this subgroup had sought a fertility consultation; of these, 41% received infertility testing and 58% received advice, yet only a few received specific treatment: ovulation medication (19.1%), fallopian tubal surgery (4.8%), other female treatment (17.5%), varicocelectomy (8.1%), or other male treatment (10.8%). Increasing age, employment status, and interaction between gender and single marital status are associated with reported infertility. We did not observe differences between groups relative to sickle cell disease (SCD) genotype, a broad category of self-reported hydroxyurea use any time during life, type of medical insurance, income, or education. CONCLUSION: To our knowledge, this is the first study to examine self-reported identification of and treatment for infertility among a large sample of people with SCD. These findings suggest that (a) infertility occurs at a higher rate, but fertility care treatment seeking is less frequent than in the general public; and (b) sociodemographic and clinical differences between individuals who report experiencing infertility and those who do not did not emerge in this study.

Predicting Pain in People With Sickle Cell Disease in the Day Hospital Using the Commercial Wearable Apple Watch: Feasibility Study.

BACKGROUND: Sickle cell disease (SCD) is a genetic red blood cell disorder associated with severe complications including chronic anemia, stroke, and vaso-occlusive crises (VOCs). VOCs are unpredictable, difficult to treat, and the leading cause of hospitalization. Recent efforts have focused on the use of mobile health technology to develop algorithms to predict pain in people with sickle cell disease. Combining the data collection abilities of a consumer wearable, such as the Apple Watch, and machine learning techniques may help us better understand the pain experience and find trends to predict pain from VOCs. OBJECTIVE: The aim of this study is to (1) determine the feasibility of using the Apple Watch to predict the pain scores in people with sickle cell disease admitted to the Duke University SCD Day Hospital, referred to as the Day Hospital, and (2) build and evaluate machine learning algorithms to predict the pain scores of VOCs with the Apple Watch. METHODS: Following approval of the institutional review board, patients with sickle cell disease, older than 18 years, and admitted to Day Hospital for a VOC between July 2021 and September 2021 were approached to participate in the study. Participants were provided with an Apple Watch Series 3, which is to be worn for the duration of their visit. Data collected from the Apple Watch included heart rate, heart rate variability (calculated), and calories. Pain scores and vital signs were collected from the electronic medical record. Data were analyzed using 3 different machine learning models: multinomial logistic regression, gradient boosting, and random forest, and 2 null models, to assess the accuracy of pain scores. The evaluation metrics considered were accuracy (F1-score), area under the receiving operating characteristic curve, and root-mean-square error (RMSE). RESULTS: We enrolled 20 patients with sickle cell disease, all of whom identified as Black or African American and consisted of 12 (60%) females and 8 (40%) males. There were 14 individuals diagnosed with hemoglobin type SS (70%). The median age of the population was 35.5 (IQR 30-41) years. The median time each individual spent wearing the Apple Watch was 2 hours and 17 minutes and a total of 15,683 data points were collected across the population. All models outperformed the null models, and the best-performing model was the random forest model, which was able to predict the pain scores with an accuracy of 84.5%, and a RMSE of 0.84. CONCLUSIONS: The strong performance of the model in all metrics validates feasibility and the ability to use data collected from a noninvasive device, the Apple Watch, to predict the pain scores during VOCs. It is a novel and feasible approach and presents a low-cost method that could benefit clinicians and individuals with sickle cell disease in the treatment of VOCs.

Hybrid effectiveness-implementation trial of guided relaxation and acupuncture for chronic sickle cell disease pain (GRACE): A protocol.

Background: People with sickle cell disease frequently use complementary and integrative therapies to cope with their pain, yet few studies have evaluated their effectiveness. The 3-arm, 3-site pragmatic Hybrid Effectiveness-implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain (GRACE) has 3 priorities: (1) evaluate guided relaxation and acupuncture to improve pain control; (2) determine the most appropriate and effective treatment sequence for any given patient based on their unique characteristics; and (3) describe the processes and structures required to implement guided relaxation and acupuncture within health care systems. Methods: Participants (N = 366) are being recruited and randomized 1:1:1 to one of 2 intervention groups or usual care. The acupuncture intervention group receives 10 sessions over approximately 5 weeks. The guided relaxation intervention group receives access to video sessions ranging from 2 to 20 min each viewed daily over 5 weeks. The usual care group receives the standard of clinical care for sickle cell disease. Participants are re-randomized at 6 weeks depending on their pain impact score. Assessments occur at 6 weeks, 12 weeks, and 24 weeks. The primary outcome is the change in pain impact score and secondary measures include opioid use, anxiety, depression, sleep, pain catastrophizing, substance use, global impression of change, constipation, and hospitalizations. The GRACE study uses the Consolidated Framework for Implementation Research to plan, execute, and evaluate the associated implementation processes. Conclusion: The results from GRACE will represent a critical step toward improving management of pain affecting patients with sickle cell disease.ClinicalTrials.gov Identifier: NCT04906447.