Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease.

IMPORTANCE: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN: Cross-sectional. SETTING: St. Jude Children's Research Hospital. PARTICIPANTS: Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES: Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills.

Perinatal risk factors and neurocognitive outcomes in children and adolescents with sickle cell disease.

BACKGROUND: The literature on cognitive and academic outcomes for children with sickle cell disease (SCD) who experience perinatal risk factors is limited. We aimed to evaluate if low birthweight (LBW), gestational age, and history of neonatal intensive care unit (NICU) admission were associated with neurocognitive functioning, grade retention, or receipt of early intervention or formal educational support in children with SCD. PROCEDURES: This prospective birth cohort study included 336 participants, ages 8-18, with SCD, who received cognitive testing as part of standard of care and whose caregivers completed behavioral rating scales. Multivariable generalized linear regression models were used to examine associations between perinatal risks and outcome variables, after adjusting for demographic and medical covariates. RESULTS: The prevalence of NICU admission and LBW were 12.03% and 13.50%, respectively. Lower birthweight, earlier gestational age, and NICU admission were associated with worse working memory performance and receipt of early intervention services. Lower birthweight and NICU admission were also associated with slower processing speed. History of NICU admission was associated with caregiver ratings of hyperactivity and emotional dysregulation. The effects of perinatal risk factors on neurocognitive, academic, or educational outcomes were not dependent on SCD genotype. CONCLUSIONS: History of LBW or NICU admission was associated with worse cognitive outcomes and increased use of early intervention services among children with SCD. Early identification of perinatal risk factors will help identify children who will benefit from formal developmental or neuropsychological evaluations to manage the comorbidity of SCD and perinatal risks and facilitate increased intervention.

Impact of an Individualized Pain Plan to Treat Sickle Cell Disease Vaso-occlusive Episodes in the Emergency Department.

To address acute vaso-occlusive episodes (VOEs), the leading cause of Emergency Department (ED) visits among individuals with sickle cell disease (SCD), we conducted the clinical study, An Individualized Pain Plan with Patient and Provider Access for Emergency Department care of SCD (ALIGN), across eight sites. We hypothesized an improvement of 0.5 standard deviations in perceived quality of ED pain treatment of a VOE after implementing individualized pain plans (IPPs) accessible to both patients and providers. Patients with SCD were 18-45, owned a cell phone, and had an ED VOE visit within 90 days prior. Patients completed perceived quality of care surveys at baseline and within 96 hours after a VOE ED visit. Providers completed surveys regarding comfort managing VOEs at baseline and after managing an enrolled patient. Most of the 153 patients were African American (95.4%), female (64.7%) and had Hb SS/Sß0 genotype (71.9%). The perceived quality of ED pain treatment was high at both baseline and post implementation of IPPs; our primary outcome hypothesis was not met, as no statistically significant change in patient perceived quality ED treatment ocurred. A total of 135 providers completed baseline and follow-up surveys. On a scale of 1-7, with 7 being extremely comfortable managing VOEs, 60.5% reported a score ≥6 post IPP implementation vs. 57.8% at baseline. Almost all (97.6%) ordered the recommended medication, and 94.7% intend to use IPPs. In this implementation protocol, all sites successfully implemented IPPs . Patients and ED providers both endorsed the use of IPPs.

Gaps during pediatric to adult care transfer escalate acute resource utilization in sickle cell disease.

ABSTRACT: Guidelines recommend transfer to adult health care within 6 months of completing pediatric care; however, this has not been studied in sickle cell disease (SCD). We hypothesized that longer transfer gaps are associated with increased resource utilization. Transfer gaps were defined as the time between the last pediatric and first adult visits. We estimated the association between varying transfer gaps and the rates of inpatient, emergency department (ED), and outpatient visits, using negative binomial regression. Health care utilization was evaluated in a mid-south comprehensive program for a follow-up period of up to 8 years (2012-2020) and was restricted to the first 2 years of adult health care. In total, 183 young adults (YAs) with SCD (51% male, 67% HbSS/HbSß0-thalassemia) were transferred to adult health care between 2012 and 2018. YAs with transfer gaps ≥6 months compared with <2 months had 2.01 (95% confidence interval [CI], 1.31-3.11) times the rate of hospitalizations in the 8-year follow-up and 1.89 (95% CI, 1.17-3.04) when restricted to the first 2 years of adult health care. In the first 2 years of adult care, those with transfer gaps ≥6 months compared with <2 months, had 1.75 (95% CI, 1.10-2.80) times the rate of ED encounters. Those with gaps ≥2 to <6 months compared with <2 months had 0.71 (95 % CI, 0.53-0.95) times the rate of outpatient visits. Among YAs with SCD, a longer transfer gap was associated with increased inpatient and decreased outpatient encounters in adult health care and more ED encounters in the first 2 years of adult health care. Strategies to reduce the transfer gaps are needed.

Impact of hematopoietic cell transplantation on myocardial fibrosis in young patients with sickle cell disease.

ABSTRACT: Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.gov as #NCT04362293.

Awareness, access, and communication: provider perspectives on early intervention services for children with sickle cell disease.

Purpose: This study aimed to identify determinants influencing the utilization of early intervention services among young children with sickle cell disease (SCD) based on perspectives from medical and early intervention providers. Design and methods: Early intervention and medical providers from the catchment area surrounding St. Jude Children's Research Hospital and Washington University were recruited (20 total providers). Interviews were completed over the phone and audio recorded. All interviews were transcribed verbatim, coded, and analyzed using inductive thematic analysis. Results: Three overarching themes were identified from both groups: Awareness (e.g., lack of awareness about the EI system and SCD), Access (e.g., difficulties accessing services), and Communication (e.g., limited communication between medical and early intervention providers, and between providers and families). Although these three themes were shared by medical and early intervention providers, the differing perspectives of each produced subthemes unique to the two professional fields. Conclusions: Early intervention services can limit the neurodevelopmental deficits experienced by young children with SCD; however, most children with SCD do not receive these services. The perspectives of early intervention and medical providers highlight several potential solutions to increase early intervention utilization among young children with SCD.

Empirically derived profiles of neurocognitive functioning in youth and young adults with sickle cell disease.

OBJECTIVE: Sickle cell disease (SCD) is an inherited blood disorder associated with neurocognitive deficits. In contrast to variable-centered approaches, no known research has utilized person-centered strategies to identify multidimensional patterns of neurocognitive functioning of an individual with SCD. The purpose of the present study was to create empirically derived profiles and identify predictors of neurocognitive functioning subgroups among youth and young adults with SCD. METHODS: Individuals with SCD (N = 393, mean age 14.05 years, age range 8-24, 50.4% female/49.6% male) completed neurocognitive assessments. Latent profile analysis derived subgroups/classes of neurocognitive functioning and determined relations with demographic and medical variables. RESULTS: Three latent classes emerged: average functioning (n = 102, 27%), low average functioning (n = 225, 60%), and exceptionally low functioning (n = 46, 12%). Older age was associated with membership in the low average and exceptionally low functioning groups (relative to the average group). Being prescribed hydroxyurea was associated with membership in the average functioning group (relative to the low average group) and absence of hydroxyurea use was associated with membership in the exceptionally low group (relative to the low average group). Lower social vulnerability was associated with membership in the average functioning group compared to the low average and exceptionally low groups. CONCLUSIONS: Clinicians can help reduce disparities in cognitive development for individuals with SCD by promoting early treatment with hydroxyurea and implementing methods to reduce social vulnerabilities that can interfere with access to evidence-based care.

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.

Consensus of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) and the Brazilian Ministry of Health - General management of blood and blood products on the tests necessary for the release of exceptional medicines for sickle cell disease

Abstract To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

Machine learning to optimize automated RH genotyping using whole-exome sequencing data.

ABSTRACT: Rh phenotype matching reduces but does not eliminate alloimmunization in patients with sickle cell disease (SCD) due to RH genetic diversity that is not distinguishable by serological typing. RH genotype matching can potentially mitigate Rh alloimmunization but comprehensive and accessible genotyping methods are needed. We developed RHtyper as an automated algorithm to predict RH genotypes using whole-genome sequencing (WGS) data with high accuracy. Here, we adapted RHtyper for whole-exome sequencing (WES) data, which are more affordable but challenged by uneven sequencing coverage and exacerbated sequencing read misalignment, resulting in uncertain predictions for (1) RHD zygosity and hybrid alleles, (2) RHCE∗C vs. RHCE∗c alleles, (3) RHD c.1136C>T zygosity, and (4) RHCE c.48G>C zygosity. We optimized RHtyper to accurately predict RHD and RHCE genotypes using WES data by leveraging machine learning models and improved the concordance of WES with WGS predictions from 90.8% to 97.2% for RHD and 96.3% to 98.2% for RHCE among 396 patients in the Sickle Cell Clinical Research and Intervention Program. In a second validation cohort of 3030 cancer survivors (15.2% Black or African Americans) from the St. Jude Lifetime Cohort Study, the optimized RHtyper reached concordance rates between WES and WGS predications to 96.3% for RHD and 94.6% for RHCE. Machine learning improved the accuracy of RH predication using WES data. RHtyper has the potential, once implemented, to provide a precision medicine-based approach to facilitate RH genotype-matched transfusion and improve transfusion safety for patients with SCD. This study used data from clinical trials registered at ClinicalTrials.gov as #NCT02098863 and NCT00760656.

Description of a national, multi-center registry of patients with sickle cell disease and SARS-CoV-2 infection: Data from the Pediatric COVID-19 United States Registry.

Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS-CoV-2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID-19 United States Registry who developed acute COVID-19 due to SARS-CoV-2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS-C; n = 4). Nearly half of hospitalized children with SCD and SARS-CoV-2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS-C required ICU admission. Children with SCD are at risk of severe disease with SARS-CoV-2 infection, highlighting the importance of vaccination in this vulnerable population.

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.

Consensus of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) and the Brazilian Ministry of Health - General management of blood and blood products on the tests necessary for the release of exceptional medicines for sickle cell disease.

To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

Translation, transcultural adaptation, and validation of PedsQL 3.0 Sickle Cell Disease Module into Brazilian Portuguese.

INTRODUCTION: Despite the high prevalence of sickle cell disease (SCD) in Brazil, no studies have described the validation of an SCD-specific health-related quality-of-life (HRQoL) instrument in children. We validated PedsQL 3.0 Sickle Cell Disease Module (PedsQL-SCD) for Brazilian Portuguese, and cross-validated it with PedsQL 4.0 Generic Core Scale (PedsQL-GCS) in children with SCD. METHODS: PedsQL-SCD was translated and culturally adapted using forward and reverse translations. PedsQL-SCD and PedsQL-GCS were tested in children and adolescents with SCD aged 2-18 years and their caregivers. Validity was assessed using the Pearson and intraclass correlation coefficients, and reliability measured with Cronbach's alpha. RESULTS: PedsQL-SCD was validated in 206 children with SCD (median age 14 years, range: 8-18) and 201 caregivers. Among patients and caregivers, the mean total score for PedsQL-SCD was 65.7 and 64.1, respectively. The mean total score for PedsQL-GCS was 73.1 and 68.9 among patients and caregivers, respectively. The internal consistency for PedsQL-SCD and PedsQL-GCS was good; Cronbach's alpha coefficients ranged from .59-.93 to .64-.83 among patients and from .60-.95 to .65-.85 among caregivers, respectively. Most intercorrelations between PedsQL-SCD and PedsQL-GCS, for patients and caregivers, had medium to large effect sizes (range: .23-.63 and .27-.64, respectively). Pain and pain impact domains of PedsQL-SCD and physical dimension of PedsQL-GCS had the highest cross-correlation (.63 and .6 for patients; .63 and .64 for caregivers, respectively), confirming convergent construct validity. CONCLUSION: PedsQL-SCD is a valid, culturally appropriate measure to assess HRQoL in children with SCD in Brazil and is well-correlated PedsQL-GCS.

Burden of employment loss and absenteeism in adults and caregivers of children with sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is a genetic disorder affecting 100 000 people with an estimated annual medical cost of $3 billion in the United States; however, the economic impact on patients is not well described. We aimed to examine the indirect economic burden and test the hypothesis that socioeconomic status and greater social vulnerability risks are associated with increased absenteeism and employment loss. We surveyed adults and caregivers of children with SCD at 5 US centers from 2014 to 2021. Logistic regression models were used to examine the associations of employment loss and missed days of work with demographics and social determinants. Indirect costs were estimated by multiplying the self-reported missed days of work and job loss by 2022 average wages by the state of the participating institution. Of the 244 participants, 10.3% reported employment loss in the last 5 years, and 17.5% reported missing 10 or more days of work. Adults had 3 times more employment loss compared with caregivers of children with SCD (OR, 3.18; 95% CI, 1.12-9.01) but fewer missed days of work (OR, 0.24; 95% CI, 0.11-0.0.51). Participants who did not live with a partner reported increased employment loss (OR, 4.70; 95% CI, 1.04-21.17) and more missed days of work (OR, 4.58; 95% CI, 1.04-20.15). The estimated annual indirect economic burden was $2 266 873 ($9290 per participant). Adults with SCD and caregivers of children with SCD commonly report employment loss and missed days of work as important risk factors. The high indirect economic burden suggests that future economic evaluations of SCD should include SCD-related indirect economic burden.

RH genotypes and red cell alloimmunization rates in chronically transfused patients with sickle cell disease: A multisite study in the USA.

BACKGROUND: Red cell alloimmunization remains a challenge for individuals with sickle cell disease (SCD) and contributes to increased risk of hemolytic transfusion reactions and associated comorbidities. Despite prophylactic serological matching for ABO, Rh, and K, red cell alloimmunization persists, in part, due to a high frequency of variant RH alleles in patients with SCD and Black blood donors. STUDY DESIGN AND METHODS: We compared RH genotypes and rates of alloimmunization in 342 pediatric and young adult patients with SCD on chronic transfusion therapy exposed to >90,000 red cell units at five sites across the USA. Genotyping was performed with RHD and RHCE BeadChip arrays and targeted assays. RESULTS: Prevalence of overall and Rh-specific alloimmunization varied among institutions, ranging from 5% to 41% (p = .0035) and 5%-33% (p = .0002), respectively. RH genotyping demonstrated that 33% RHD and 57% RHCE alleles were variant in this cohort. Patients with RHCE alleles encoding partial e antigens had higher rates of anti-e identified than those encoding at least one conventional e antigen (p = .0007). There was no difference in anti-D, anti-C, or anti-E formation among patients with predicted partial or altered antigen expression compared to those with conventional antigens, suggesting that variant Rh on donor cells may also stimulate alloimmunization to these antigens. DISCUSSION: These results highlight variability in alloimmunization rates and suggest that a molecular approach to Rh antigen matching may be necessary for optimal prevention of alloimmunization given the high prevalence of variant RH alleles among both patients and Black donors.

Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease.

PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States : A Cost-Effectiveness Analysis.

BACKGROUND: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. OBJECTIVE: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). DESIGN: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. DATA SOURCES: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. TARGET POPULATION: Persons eligible for gene therapy. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health care sector and societal. INTERVENTION: Gene therapy versus common care. OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. RESULTS OF BASE-CASE ANALYSIS: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. LIMITATION: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. CONCLUSION: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Agreement between youth and caregiver report of pain and functioning in pediatric sickle cell disease: PedsQL sickle cell disease module.

ABSTRACT: Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.