Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries.

Venous thrombosis is a common adverse effect of modern therapy for acute lymphoblastic leukemia (ALL). Prior studies to identify risks of thrombosis in pediatric ALL have been limited by genetic screens of pre-identified genetic variants or genome- wide association studies (GWAS) in ancestrally uniform populations. To address this, we performed a retrospective cohort evaluation of thrombosis risk in 1,005 children treated for newly diagnosed ALL. Genetic risk factors were comprehensively evaluated from genome-wide single nucleotide polymorphism (SNP) arrays and were evaluated using Cox regression adjusting for identified clinical risk factors and genetic ancestry. The cumulative incidence of thrombosis was 7.8%. In multivariate analysis, older age, T-lineage ALL, and non-O blood group were associated with increased thrombosis while non-low-risk treatment and higher presenting white blood cell count trended toward increased thrombosis. No SNP reached genome-wide significance. The SNP most strongly associated with thrombosis was rs2874964 near RFXAP (G risk allele; P=4x10-7; hazard ratio [HR] =2.8). In patients of non-European ancestry, rs55689276 near the α globin cluster (P=1.28x10-6; HR=27) was most strongly associated with thrombosis. Among GWAS catalogue SNP reported to be associated with thrombosis, rs2519093 (T risk allele, P=4.8x10-4; HR=2.1), an intronic variant in ABO, was most strongly associated with risk in this cohort. Classic thrombophilia risks were not associated with thrombosis. Our study confirms known clinical risk features associated with thrombosis risk in children with ALL. In this ancestrally diverse cohort, genetic risks linked to thrombosis risk aggregated in erythrocyte-related SNP, suggesting the critical role of this tissue in thrombosis risk.

Genetic Variation and Sickle Cell Disease Severity: A Systematic Review and Meta-Analysis.

Importance: Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood. Objective: To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations. Data Sources: PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications. Study Selection: At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls. Data Extraction and Synthesis: Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted. Main Outcomes and Measures: Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity. Results: The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas. Conclusions and Relevance: The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

Barriers and Facilitators of Premarital Genetic Counseling for Sickle Cell Disease in Northern Nigeria.

In high-income countries, premarital genetic counseling for Sickle Cell Disease (SCD) is a standard practice. However, in Nigeria, there is no formal premarital genetic counseling program available for SCD. We conducted a series of focus group discussions with health care professionals, patients with SCD, and parents of the patients with or without SCD to gain an understanding of their attitudes and beliefs towards SCD/Sickle Cell Trait and premarital genetic counseling for SCD. Data were analyzed using Charmaz's constructivist grounded theory approach. Two themes were highlighted in the analysis as follows: (1) the difference between the perception of premarital sickle cell screening among individuals with SCD versus the general population, and (2) the personal beliefs and physical challenges that could lead to the avoidance of premarital screening within the general community. Lack of disease-related knowledge, testing facilities, transportation, and stigma associated with the disease were the most commonly perceived barriers to premarital testing. Also, a willingness to receive premarital testing for SCD exists within our community to reduce the spread of the disease and advocate for improved health-related quality of life of patients with SCD. The content and structure of a premarital genetic counseling program in Kano, Northern Nigeria, needs to be developed.

Leveraging mathematical modeling to analyze nonadherence for hydroxyurea therapy in sickle cell disease.

Nonadherence is common in individuals with sickle cell disease (SCD) on hydroxyurea therapy and can be observed with waning improvements in hematologic parameters or biomarkers like mean cell volume and fetal hemoglobin level over time. We modeled the impact of hydroxyurea nonadherence on longitudinal biomarker profiles. We estimated the potential nonadherent days in individuals exhibiting a drop in biomarker levels by modifying the dosing profile using a probabilistic approach. Incorporating additional nonadherence using our approach besides existing ones in the dosing profile improves the model fits. We also studied how different patterns in adherence give rise to various physiological profiles of biomarkers. The key finding is consecutive days of nonadherence are less favorable than when nonadherence is interspersed. These findings improve our understanding of nonadherence and how appropriate intervention strategies can be applied for individuals with SCD susceptible to the severe impacts of nonadherence.

Working memory and school readiness in preschool children with sickle cell disease compared to demographically matched controls.

Children diagnosed with sickle cell disease (SCD) are at risk of the development of neurobehavioural problems early in life. Specific impairments in executive function skills, including working memory, have been documented in school-aged children with SCD. These executive skills are known to strongly contribute to early academic skills and preparedness for entering kindergarten. This study examined working memory and school readiness in preschool children with SCD compared to a healthy control group matched for race, sex and parent education. A total of 84 patients diagnosed with SCD (61.9% haemoglobin [Hb]SS/HbSß0 -thalassaemia) and 168 controls completed testing. The mean (SD) ages of patients and controls at testing were 4.53 (0.38) and 4.44 (0.65) years respectively. The SCD group performed worse than controls on measures of executive function, working memory and school readiness (p < 0.01; Cohen's D range: 0.32-0.39). Measures of working memory were associated with school readiness after accounting for early adaptive development. Multiple linear regression models among patients diagnosed with SCD revealed that college education of the primary caregiver was positively associated with school readiness (p < 0.001) after controlling for sex, genotype, age and early adaptive development. These results highlight the need to implement school readiness interventions in young children diagnosed with SCD emphasising executive function skills.

Mathematical Modeling of Hydroxyurea Therapy in Individuals with Sickle Cell Disease.

Sickle cell disease (SCD) is a chronic hemolytic anemia affecting millions worldwide with acute and chronic clinical manifestations and early mortality. While hydroxyurea (HU) and other treatment strategies managed to ameliorate disease severity, high inter-individual variability in clinical response and a lack of an ability to predict those variations need to be addressed to maximize the clinical efficacy of HU. We developed pharmacokinetics (PK) and pharmacodynamics (PD) models to study the dosing, efficacy, toxicity, and clinical response of HU treatment in more than eighty children with SCD. The clinical PK parameters were used to model the HU plasma concentration for a 24 h period, and the estimated daily average HU plasma concentration was used as an input to our PD models with approximately 1 to 9 years of data connecting drug exposure with drug response. We modeled the biomarkers mean cell volume and fetal hemoglobin to study treatment efficacy. For myelosuppression, we modeled red blood cells and absolute neutrophil count. Our models provided excellent fits for individuals with known or correctly inferred adherence. Our models can be used to determine the optimal dosing regimens and study the effect of non-adherence on HU-treated individuals.

PARIS and SPARTA: Finding the Achilles' Heel of SARS-CoV-2.

To understand reinfection rates and correlates of protection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we established eight different longitudinal cohorts in 2020 under the umbrella of the PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2)/SPARTA (SARS SeroPrevalence And Respiratory Tract Assessment) studies. Here, we describe the PARIS/SPARTA cohorts, the harmonized assays and analysis that are performed across the cohorts, as well as case definitions for SARS-CoV-2 infection and reinfection that have been established by the team of PARIS/SPARTA investigators. IMPORTANCE Determining reinfection rates and correlates of protection against SARS-CoV-2 infection induced by both natural infection and vaccination is of high significance for the prevention and control of coronavirus disease 2019 (COVID-19). Furthermore, understanding reinfections or infection after vaccination and the role immune escape plays in these scenarios will inform the need for updates of the current SARS-CoV-2 vaccines and help update guidelines suitable for the postpandemic world.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells.

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

Strategies to increase access to basic sickle cell disease care in low- and middle-income countries.

INTRODUCTION: Sickle cell disease (SCD) is the most common hemoglobinopathy in the world. Over 90% of those born with SCD live in low- and middle-income countries (LMICs), yet individuals in these settings have much poorer outcomes compared to those in high-income countries. AREAS COVERED: This manuscript provides an in-depth review of the cornerstones of basic SCD care, the barriers to implementing these in LMICs, and strategies to increase access in these regions. Publications in English language, peer-reviewed, and edited from 2000 to 2021 were identified on PubMed. Google search was used for gray literature. EXPERT OPINION: Outcomes for patients with SCD in high-income countries have improved over the last few decades due to the implementation of universal newborn screening programs and use of routine antimicrobial prophylaxis, increase in therapeutic and curative options, and the adoption of specific measures to decrease risk of stroke. This success has not translated to LMICs due to several reasons including resource constraints. A combination of several strategies is needed to increase access to basic SCD care for patients in these settings.

GMEPS: a fast and efficient likelihood approach for genome-wide mediation analysis under extreme phenotype sequencing.

Due to many advantages such as higher statistical power of detecting the association of genetic variants in human disorders and cost saving, extreme phenotype sequencing (EPS) is a rapidly emerging study design in epidemiological and clinical studies investigating how genetic variations associate with complex phenotypes. However, the investigation of the mediation effect of genetic variants on phenotypes is strictly restrictive under the EPS design because existing methods cannot well accommodate the non-random extreme tails sampling process incurred by the EPS design. In this paper, we propose a likelihood approach for testing the mediation effect of genetic variants through continuous and binary mediators on a continuous phenotype under the EPS design (GMEPS). Besides implementing in EPS design, it can also be utilized as a general mediation analysis procedure. Extensive simulations and two real data applications of a genome-wide association study of benign ethnic neutropenia under EPS design and a candidate-gene study of neurocognitive performance in patients with sickle cell disease under random sampling design demonstrate the superiority of GMEPS under the EPS design over widely used mediation analysis procedures, while demonstrating compatible capabilities under the general random sampling framework.

Fetal hemoglobin modulates neurocognitive performance in sickle cell anemia✰,✰✰.

PURPOSE OF THE STUDY: Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. PATIENTS AND METHODS: The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). RESULTS: HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. CONCLUSION: As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells.

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence and breakthrough infections have changed vaccine policy to include booster immunizations. However, the effect of diverse and repeated antigen exposures on SARS-CoV-2 memory T cells is poorly understood. Here, we utilize DNA-barcoded MHC-multimers combined with scRNAseq and scTCRseq to capture the ex vivo profile of SARS-CoV-2-responsive T cells within a cohort of individuals with one, two, or three antigen exposures, including vaccination, primary infection, and breakthrough infection. We found that the order of exposure determined the relative distribution between spike- and non-spike-specific responses, with vaccination after infection leading to further expansion of spike-specific T cells and differentiation to a CCR7-CD45RA+ effector phenotype. In contrast, individuals experiencing a breakthrough infection mount vigorous non-spike-specific responses. In-depth analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all types of exposures elicit diverse repertoires characterized by shared, dominant TCR motifs, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and that current vaccination protocols continue to expand and differentiate spike-specific memory responses.

Host Predictors of Broadly Cross-Reactive Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern Differ Between Infection and Vaccination.

BACKGROUND: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization.

Neurocognitive functioning in preschool children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. PROCEDURE: Sixty-two patients with SCD (60% HbSS/HbSß0 -thalassemia; 40% HbSC/HbSß+ -thalassemia) between the ages of 3 and 6 years (mean = 4.77 years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSß0 -thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45) years of age. The average dose was 28.8 mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. RESULTS: Patients with HbSS/HbSß0 -thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR ] < .05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR  > .05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR  < .05). Greater household socioeconomic status was positively associated with academic readiness. CONCLUSIONS: Preschoolers with severe SCD (HbSS/HbSß0 -thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed.

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

An Assessment of Serological Assays for SARS-CoV-2 as Surrogates for Authentic Virus Neutralization.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has since caused a global pandemic resulting in millions of cases and deaths. Diagnostic tools and serological assays are critical for controlling the outbreak, especially assays designed to quantitate neutralizing antibody levels, considered the best correlate of protection. As vaccines become increasingly available, it is important to identify reliable methods for measuring neutralizing antibody responses that correlate with authentic virus neutralization but can be performed outside biosafety level 3 (BSL3) laboratories. While many neutralizing assays using pseudotyped virus have been developed, there have been few studies comparing the different assays to each other as surrogates for authentic virus neutralization. Here, we characterized three enzyme-linked immunosorbent assays (ELISAs) and three pseudotyped vesicular stomatitis virus (VSV) neutralization assays and assessed their concordance with authentic virus neutralization. The most accurate assays for predicting authentic virus neutralization were luciferase- and secreted embryonic alkaline phosphatase (SEAP)-expressing pseudotyped virus neutralizations, followed by green fluorescent protein (GFP)-expressing pseudotyped virus neutralization, and then the ELISAs. IMPORTANCE The ongoing COVID-19 pandemic is caused by infection with severe acute respiratory syndrome virus 2 (SARS-CoV-2). Prior infection or vaccination can be detected by the presence of antibodies in the blood. Antibodies in the blood are also considered to be protective against future infections from the same virus. The "gold standard" assay for detecting protective antibodies against SARS-CoV-2 is neutralization of authentic SARS-CoV-2 virus. However, this assay can only be performed under highly restrictive biocontainment conditions. We therefore characterized six antibody-detecting assays for their correlation with authentic virus neutralization. The significance of our research is in outlining the advantages and disadvantages of the different assays and identifying the optimal surrogate assay for authentic virus neutralization. This will allow for more accurate assessments of protective immunity against SARS-CoV-2 following infection and vaccination.

A reanalysis of pain crises data from the pivotal l-glutamine in sickle cell disease trial.

The pivotal Endari trial in sickle cell disease showed a reduction in pain crises events. This reanalysis of the l-glutamine phase 3 trial using annual rates of pain crises, consistent with other SCD studies, supported the statistically significant outcomes of the original analysis. The observed 45% difference in the VOC rate is comparable to what was reported in other sickle cell therapeutics used to reduce the incidence of pain. The results presented in this communication are informative for clinicians evaluating treatment effects across available SCD therapeutic options based on studies that utilized VOC as the primary endpoint.