Publications by authors named "Jane Hankins"

142 Publications

Quantitative Susceptibility Mapping Using a Multispectral Autoregressive Moving Average Model to Assess Hepatic Iron Overload.

J Magn Reson Imaging 2021 Feb 26. Epub 2021 Feb 26.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: R2*-MRI is clinically used to noninvasively assess hepatic iron content (HIC) to guide potential iron chelation therapy. However, coexisting pathologies, such as fibrosis and steatosis, affect R2* measurements and may thus confound HIC estimations.

Purpose: To evaluate whether a multispectral auto regressive moving average (ARMA) model can be used in conjunction with quantitative susceptibility mapping (QSM) to measure magnetic susceptibility as a confounder-free predictor of HIC.

Study Type: Phantom study and in vivo cohort.

Subjects: Nine iron phantoms covering clinically relevant R2* range (20-1200/second) and 48 patients (22 male, 26 female, median age 18 years).

Field Strength/sequence: Three-dimensional (3D) and two-dimensional (2D) multi-echo gradient echo (GRE) at 1.5 T.

Assessment: ARMA-QSM modeling was performed on the complex 3D GRE signal to estimate R2*, fat fraction (FF), and susceptibility measurements. R2*-based dry clinical HIC values were calculated from the 2D GRE acquisition using a published R2*-HIC calibration curve as reference standard.

Statistical Tests: Linear regression analysis was performed to compare ARMA R2* and susceptibility-based estimates to iron concentrations and dry clinical HIC values in phantoms and patients, respectively.

Results: In phantoms, the ARMA R2* and susceptibility values strongly correlated with iron concentrations (R  ≥ 0.9). In patients, the ARMA R2* values highly correlated (R = 0.97) with clinical HIC values with slope = 0.026, and the susceptibility values showed good correlation (R = 0.82) with clinical dry HIC values with slope = 3.3 and produced a dry-to-wet HIC ratio of 4.8.

Data Conclusion: This study shows the feasibility that ARMA-QSM can simultaneously estimate susceptibility-based wet HIC, R2*-based dry HIC and FFs from a single multi-echo GRE acquisition. Our results demonstrate that both, R2* and susceptibility-based wet HIC values estimated with ARMA-QSM showed good association with clinical dry HIC values with slopes similar to published R2*-biopsy HIC calibration and dry-to-wet tissue weight ratio, respectively. Hence, our study shows that ARMA-QSM can provide potentially confounder-free assessment of hepatic iron overload.

Level Of Evidence: 3 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27584DOI Listing
February 2021

Longitudinal effect of disease-modifying therapy on tricuspid regurgitant velocity in children with sickle cell anemia.

Blood Adv 2021 Jan;5(1):89-98

Department of Hematology, St Jude Children's Research Hospital, Memphis, TN.

Elevated tricuspid regurgitant velocity (TRV) ≥2.5 m/s is a predictor of disease severity in adults and children with sickle cell anemia (SCA), but how disease-modifying therapies (DMTs) affect this biomarker is incompletely understood. We investigated the effect of DMTs on TRV elevation in children. In a prospective single-center study, 204 subjects with HbSS or HbSβ0 thalassemia (mean age, 10.6 years; range, 5-18) had echocardiograms with assessment of TRV, with repeat evaluations after 2 years of observation. One-hundred and twelve participants received DMTs (hydroxyurea, n = 72; monthly erythrocyte transfusions, n = 40), 58 did not receive any DMT, and 34 were begun on hydroxyurea during this observation period. In the entire cohort, an increase in hemoglobin of 1.0 g/dL was associated with a 0.03-m/s decrease in TRV (P = .024), and a decrease in absolute reticulocyte count of 1.0 × 106/mL was associated with a 0.34-m/s decrease in TRV (P = .034). Compared with baseline, hydroxyurea exposure (continuous or newly started) was associated with an average 5% decline in mean TRV at the 2-year evaluation. Among participants newly started on hydroxyurea (mean treatment duration 1.2 ± 0.6 years), an increase in hemoglobin of 1.0 g/dL was associated with a 0.06-m/s decrease in TRV (P = .05). We conclude that hydroxyurea therapy may mitigate TRV elevation in children with SCA, possibly as a result of a reduction in hemolysis and improvement in anemia.
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http://dx.doi.org/10.1182/bloodadvances.2020003197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805333PMC
January 2021

Cognitive performance as a predictor of healthcare transition in sickle cell disease.

Br J Haematol 2021 Feb 11. Epub 2021 Feb 11.

Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Neurocognitive deficits in sickle cell disease (SCD) may impair adult care engagement. We investigated the relationship between neurocognitive functioning and socio-environmental factors with healthcare transition outcomes. Adolescents aged 15-18 years who had neurocognitive testing and completed a visit with an adult provider were included. Transition outcomes included transfer interval from paediatric to adult care and retention in adult care at 12 and 24 months. Eighty adolescents (59% male, 64% HbSS/HbSβ -thalassaemia) were included. Mean age at adult care transfer was 18·0 (±0·3) years and transfer interval was 2·0 (±2·3) months. Higher IQ (P = 0·02; P  = 0·05) and higher verbal comprehension (P = 0·008; P  = 0·024) were associated with <2 and <6 month transfer intervals respectively. Better performance on measures of attention was associated with higher adult care retention at 12 and 24 months (P = 0·009; P  = 0·05 and P = 0·04; P  = 0·12 respectively). Transfer intervals <6 months were associated with smaller households (P = 0·02; P  = 0·06) and households with fewer children (P = 0·02; P  = 0·06). Having a working parent was associated with less retention in adult care at 12 and 24 months (P = 0·01; P = 0·02 respectively). Lower IQ, verbal comprehension, attention difficulties and environmental factors may negatively impact transition outcomes. Neurocognitive function should be considered in transition planning for youth with SCD.
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http://dx.doi.org/10.1111/bjh.17351DOI Listing
February 2021

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of COVID-19 in Children and Adolescents.

J Pediatric Infect Dis Soc 2021 Jan 3. Epub 2021 Jan 3.

Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for two novel virus-neutralizing monoclonal antibody therapies, bamlanivimab, and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate COVID-19 in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.

Methods: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.

Results: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.

Conclusions: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence, and ensure implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.
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http://dx.doi.org/10.1093/jpids/piaa175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799019PMC
January 2021

Genetic variants associated with therapy-related cardiomyopathy among childhood cancer survivors of African ancestry.

Cancer Res 2020 Dec 7. Epub 2020 Dec 7.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital.

Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiation) (n=246) were compared to cardiotoxic-exposed survivors of European ancestry (n=1645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF [rs6689879*C: EF reduction=4.2%; P=2.8×10-8] in 246 survivors of African ancestry, which was successfully replicated in 1645 survivors of European ancestry but with attenuated magnitude (EF reduction=0.4%; P=0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2675DOI Listing
December 2020

Empirically Derived Profiles of Health-Related Quality of Life in Youth and Young Adults with Sickle Cell Disease.

J Pediatr Psychol 2020 Nov 29. Epub 2020 Nov 29.

Department of Psychology, St. Jude Children's Research Hospital, Memphis, TN.

Objective: Determining how the health-related quality of life (HRQOL) is impacted by living with Sickle Cell Disease (SCD) can inform psychosocial interventions. The purpose of the present study is to determine if demographic and treatment variables predict membership into empirically derived subgroups of HRQOL among youth and young adults with SCD.

Methods: Three hundred and seven youth and young adults with SCD (mean 17.63 years ± 3.74 years, 50.5% female) completed the Pediatric Quality of Life InventoryTM Sickle Cell Disease Module. Latent profile analysis examined subgroups/classes of HRQOL and relationships with demographic and treatment variables.

Results: Three distinct classes emerged: High HRQOL (34% of the sample), Moderate HRQOL (44% of the sample), and Low HRQOL (22% of the sample). Being female was associated with increased odds of being in the moderate or low groups. Living with more severe SCD (genotypes HbSS and HbSβ0 thalassemia) was associated with increased odds of being in the Low HRQOL group. Treatment with chronic red blood cell transfusion therapy was associated with increased odds of being in the High HRQOL group. Older age predicted a small increase in the odds of being in the Low versus High HRQOL group.

Conclusions: The present study adds to the literature on HRQOL in SCD by exploring person-centered, empirically derived groups of HRQOL. Identification of demographic and treatment factors that predict membership into those groups within a large sample assists in tailoring needed psychosocial interventions for youth with SCD.
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http://dx.doi.org/10.1093/jpepsy/jsaa104DOI Listing
November 2020

Use of Wise Device Technology to Measure Adherence to Hydroxyurea Therapy in Youth With Sickle Cell Disease.

J Pediatr Hematol Oncol 2021 Jan;43(1):e19-e25

Hematology, St. Jude Children's Research Hospital, Memphis, TN.

Despite broad support for hydroxyurea (HU) therapy, suboptimal adherence is reported for youth with sickle cell disease. Valid adherence measurement is crucial to understanding the relationship between medication behavior, disease response, and patient-centered health outcomes. The current pilot study examined the feasibility of the Wise electronic device for longitudinal HU adherence measurement in a sample of 36 youths prescribed HU. The study also explored the association between HU adherence, as measured by the Wise device, with other adherence measures (ie, family report, lab values, pill count, and medication possession ratio). A measure of family-reported acceptability was also completed. Overall, results supported the feasibility of the Wise device (rate of consent=82%, device use=75%, device failure=3%) for HU adherence measurement and most families rated their experience using their device positively (favorable responses ranged from 67% to 100%). Associations between HU adherence, as measured by the Wise device, and other adherence measures were not significant. Overall, the feasibility was supported. The Wise device allows longitudinal measurement of adherence with HU from initiation as a young child (ie, with liquid formulations) through adolescence and provides a novel means of adherence measurement for both clinical and research use.
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http://dx.doi.org/10.1097/MPH.0000000000001997DOI Listing
January 2021

Pain in Youth With Sickle Cell Disease: A Report From the Sickle Cell Clinical Research and Intervention Program.

Clin J Pain 2021 Jan;37(1):43-50

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta.

Objectives: Pain is prevalent among youth with sickle cell disease (SCD). However, previous research has been limited by small sample sizes and lacked examinations of developmental differences in pain, which are critical to minimizing the development of chronic pain as youth transition into adulthood. The primary aim of the current study was to compare pain and pain interference across 4 developmental groups in a large sample of youth with SCD. The secondary aim was to identify risk factors for greater pain and pain interference.

Materials And Methods: Utilizing a cross-sectional study design, the expression and predictors of pain and pain interference were compared across 4 developmental stages: toddlers/preschoolers (2 to 4 y), school-aged children (5 to 7 y), preadolescents (8 to 12 y), and adolescents (13 to 18 y). Participants included 386 youth with SCD and their caregivers.

Results: Caregiver-reported pain and pain interference and youth-reported pain interference increased across developmental groups and plateaued approaching adolescence (multivariate analyses of variance P=0.002 for pain and P<0.001 for pain interference). Elevated fatigue, anxiety, and perceived difficulties with pain management were the most robust predictors of higher youth- and caregiver-reported pain (βs ranging from 0.15 to 0.68; P<0.001) and pain interference (βs ranging from 0.18 to 0.64; P<0.001).

Discussion: Disease and treatment-related variables were not associated with pain. Self-reported pain was elevated in older versus younger developmental groups and was largely linked to anxiety, fatigue, and perceptions of pain management, thus highlighting the modifiable nature of factors influencing pain among youth with SCD.
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http://dx.doi.org/10.1097/AJP.0000000000000889DOI Listing
January 2021

Tackling adherence in sickle cell disease with mHealth.

Lancet Haematol 2020 10;7(10):e713-e714

Department of Pediatrics, Duke University, Durham, NC, USA.

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http://dx.doi.org/10.1016/S2352-3026(20)30299-4DOI Listing
October 2020

Intentional and unintentional nonadherence to hydroxyurea among people with sickle cell disease: a qualitative study.

Blood Adv 2020 09;4(18):4463-4473

Department of Psychology, St. Jude Children's Research Hospital, Memphis, TN.

Hydroxyurea is an efficacious treatment for sickle cell disease (SCD), but adoption is low among individuals with SCD. The objective of this study was to examine barriers to patients' adherence to hydroxyurea use regimens by using the intentional and unintentional medication nonadherence framework. We interviewed individuals with SCD age 15 to 49.9 years who were participants in the Sickle Cell Disease Implementation Consortium (SCDIC) Needs Assessment. The intentional and unintentional medication nonadherence framework explains barriers to using hydroxyurea and adds granularity to the understanding of medication adherence barriers unique to the SCD population. In total, 90 semi-structured interviews were completed across 5 of the 8 SCDIC sites. Among interviewed participants, 57.8% (n = 52) were currently taking hydroxyurea, 28.9% (n = 26) were former hydroxyurea users at the time of the interview, and 13.3% (n = 12) had never used hydroxyurea but were familiar with the medication. Using a constructivist grounded theory approach, we discovered important themes that contributed to nonadherence to hydroxyurea, which were categorized under unintentional (eg, Forgetfulness, External Influencers) and intentional (Negative Perceptions of Hydroxyurea, Aversion to Taking Any Medications) nonadherence types. Participants more frequently endorsed adherence barriers that fell into the unintentional nonadherence type (70%) vs intentional nonadherence type (30%). Results from this study will help SCD health care providers understand patient choices and decisions as being either unintentional or intentional, guide tailored clinical discussions regarding hydroxyurea therapy, and develop specific, more nuanced interventions to address nonadherence factors.
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http://dx.doi.org/10.1182/bloodadvances.2020001701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509876PMC
September 2020

A Survey-Based Needs Assessment of Barriers to Optimal Sickle Cell Disease Care in the Emergency Department.

Ann Emerg Med 2020 09;76(3S):S64-S72

Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Study Objective: Guided by an implementation science framework, this needs assessment identifies institutional-, provider-, and patient-level barriers to care of sickle cell disease (SCD) in the emergency department (ED) to inform future interventions conducted by the multicenter Sickle Cell Disease Implementation Consortium.

Methods: The consortium developed and implemented a validated needs assessment survey administered to a cross-sectional convenience sample of patients with SCD and ED providers caring for them. In total, 516 adolescents and adults with SCD and 243 ED providers from 7 and 5 regions of the United States, respectively, responded to the ED care delivery for SCD survey.

Results: Survey results demonstrated that 84.5% of respondents with SCD have an outpatient provider who treats many patients with SCD. In the ED, 54.3% reported not receiving care fast enough and 46.0% believed physicians did not care about them and believed similarly of nurses (34.9%). Consequently, 48.6% of respondents were "never" or "sometimes" satisfied with their ED care. Of surveyed ED providers, 75.1% were unaware of the National Heart, Lung, and Blood Institute recommendations for vaso-occlusive crises, yet 98.1% were confident in their knowledge about caring for patients with SCD. ED providers identified the following factors as barriers to care administration: opioid epidemic (62.1%), patient behavior (60.9%), crowding (58.0%), concern about addiction (47.3%), and implicit bias (37.0%).

Conclusion: The results underscore that many patients with SCD are dissatisfied with their ED care and highlight challenges to optimal care on the practice, provider, and patient levels. Exploring these differences may facilitate improvements in ED care.
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http://dx.doi.org/10.1016/j.annemergmed.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511000PMC
September 2020

A novel algorithm comprehensively characterizes human RH genes using whole-genome sequencing data.

Blood Adv 2020 09;4(18):4347-4357

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN.

RHD and RHCE genes encode Rh blood group antigens and exhibit extensive single-nucleotide polymorphisms and chromosome structural changes in patients with sickle cell disease (SCD). RH variation can drive loss of antigen epitopes or expression of new epitopes, predisposing patients with SCD to Rh alloimmunization. Serologic antigen typing is limited to common Rh antigens, necessitating a genetic approach to detect variant antigen expression. We developed a novel algorithm termed RHtyper for RH genotyping from existing whole-genome sequencing (WGS) data. RHtyper determined RH genotypes in an average of 3.4 and 3.3 minutes per sample for RHD and RHCE, respectively. In a validation cohort consisting of 57 patients with SCD, RHtyper achieved 100% accuracy for RHD and 98.2% accuracy for RHCE, when compared with genotypes obtained by RH BeadChip and targeted molecular assays and after verification by Sanger sequencing and independent next-generation sequencing assays. RHtyper was next applied to WGS data from an additional 827 patients with SCD. In the total cohort of 884 patients, RHtyper identified 38 RHD and 28 RHCE distinct alleles, including a novel RHD DAU allele, RHD* 602G, 733C, 744T 1136T. RHtyper provides comprehensive and high-throughput RH genotyping from WGS data, facilitating deconvolution of the extensive RH genetic variation among patients with SCD. We have implemented RHtyper as a cloud-based public access application in DNAnexus (https://platform.dnanexus.com/app/RHtyper), enabling clinicians and researchers to perform RH genotyping with next-generation sequencing data.
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http://dx.doi.org/10.1182/bloodadvances.2020002148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509869PMC
September 2020

Publication of data collection forms from NHLBI funded sickle cell disease implementation consortium (SCDIC) registry.

Orphanet J Rare Dis 2020 07 7;15(1):178. Epub 2020 Jul 7.

Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1620, New York, NY, 10029, USA.

Background: Sickle cell disease (SCD) is an autosomal recessive blood disorder affecting approximately 100,000 Americans and 3.1 million people globally. The scarcity of relevant knowledge and experience with rare diseases creates a unique need for cooperation and infrastructure to overcome challenges in translating basic research advances into clinical advances. Despite registry initiatives in SCD, the unavailability of descriptions of the selection process and copies of final data collection tools, coupled with incomplete representation of the SCD population hampers further research progress. This manuscript describes the SCDIC (Sickle Cell Disease Implementation Consortium) Registry development and makes the SCDIC Registry baseline and first follow-up data collection forms available for other SCD research efforts.

Results: Study data on 2400 enrolled patients across eight sites was stored and managed using Research Electronic Data Capture (REDCap). Standardized data collection instruments, recruitment and enrollment were refined through consensus of consortium sites. Data points included measures taken from a variety of validated sources (PHENX, PROMIS and others). Surveys were directly administered by research staff and longitudinal follow-up was coordinated through the DCC. Appended registry forms track medical records, event-related patient invalidation, pregnancy, lab reporting, cardiopulmonary and renal functions.

Conclusions: The SCDIC Registry strives to provide an accurate, updated characterization of the adult and adolescent SCD population as well as standardized, validated data collecting tools to guide evidence-based research and practice.
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http://dx.doi.org/10.1186/s13023-020-01457-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341606PMC
July 2020

Association between hospital admissions and healthcare provider communication for individuals with sickle cell disease.

Hematology 2020 Dec;25(1):229-240

Department of Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

To test the hypothesis that caregivers' or adult participants' low ratings of provider communication are associated with more hospital admissions among adults and children with sickle cell disease (SCD), respectively. Secondarily, we determined whether there was an association between the caregivers' or participants' health literacy and rating of providers' communication. Primary data were collected from participants through surveys between 2014 and 2016, across six sickle cell centers throughout the U.S. In this cross-sectional cohort study, 211 adults with SCD and 331 caregivers of children with SCD completed surveys evaluating provider communication using the Consumer Assessment of Healthcare Providers and Systems (CAHPS), healthcare utilization, health literacy, and other sociodemographic and behavioral variables. Analyses included descriptive statistics, bivariate analyses, and logistic regression. Participants with better ratings of provider communication were less likely to be hospitalized (odds ratio (OR) = 0.54, 95% confidence interval (CI) = [0.35, 0.83]). Positive ratings of provider communication were associated with fewer readmissions for children (OR = 0.23, 95% CI = [0.09, 0.57]). Participants with better ratings of provider communication were less likely to rate their health literacy as lower (regression coefficient (B) = -0.28, 95% CI = [-0.46, -0.10]). Low ratings of provider communication were associated with more hospitalizations and readmissions in SCD, suggesting the need for interventions targeted at improving patient-provider communication which could decrease hospitalizations for this population.
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http://dx.doi.org/10.1080/16078454.2020.1780737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440685PMC
December 2020

Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease.

Blood 2020 07;136(5):623-626

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.
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http://dx.doi.org/10.1182/blood.2020005687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393258PMC
July 2020

Perceptions of US Adolescents and Adults With Sickle Cell Disease on Their Quality of Care.

JAMA Netw Open 2020 05 1;3(5):e206016. Epub 2020 May 1.

University of California, San Francisco, Benioff Children's Hospital Oakland, Oakland.

Importance: Sickle cell disease (SCD) is the most common inherited red blood cell disorder in the United States, and previous studies have shown that individuals with SCD are affected by multiple health disparities, including stigmatization, inequities in funding, and worse health outcomes, which may preclude their ability to access quality health care. This needs assessment was performed as part of the Sickle Cell Disease Implementation Consortium (SCDIC) to assess barriers to care that may be faced by individuals with SCD.

Objective: To assess the SCD-related medical care experience of adolescents and adults with SCD.

Design, Setting, And Participants: This one-time survey study evaluated pain interference, quality of health care, and self-efficacy of 440 adults and adolescents (aged 15 to 50 years) with SCD of all genotypes and assessed how these variables were associated with their perceptions of outpatient and emergency department (ED) care. The surveys were administered once during office visits by trained study coordinators at 7 of 8 SCDIC sites in 2018.

Results: The SCDIC sites did not report the number of individuals approached to participate in this study; thus, a response rate could not be calculated. In addition, respondents were not required to answer every question in the survey; thus, the response rate per question differed for each variable. Of 440 individuals with SCD, participants were primarily female (245 [55.7%]) and African American (428 [97.3%]) individuals, with a mean (SD) age of 27.8 (8.6) years. The majority of participants (306 of 435 [70.3%]) had hemoglobin SS or hemoglobin S β0-thalassemia. Most respondents (361 of 437 [82.6%]) reported access to nonacute (usual) SCD care, and the majority of respondents (382 of 413 [92.1%]) noted satisfaction with their usual care physician. Of 435 participants, 287 (66.0%) reported requiring an ED visit for acute pain in the previous year. Respondents were less pleased with their ED care than their usual care clinician, with approximately half (146 of 287 [50.9%]) being satisfied with or perceiving having adequate quality care in the ED. Participants also noted that when they experienced severe pain or clinician lack of empathy, this was associated with a negative quality of care. Age group was associated with ED satisfaction, with younger patients (<19 vs 19-30 and 31-50 years) reporting better ED experiences.

Conclusions And Relevance: These results suggested that a negative perception of care may be a barrier for patients seeking care. These findings underscore the necessity of implementation studies to improve access to quality care for this population, especially in the acute care setting.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260622PMC
May 2020

Integration of Mobile Health Into Sickle Cell Disease Care to Increase Hydroxyurea Utilization: Protocol for an Efficacy and Implementation Study.

JMIR Res Protoc 2020 Jul 14;9(7):e16319. Epub 2020 Jul 14.

Bethesda, MA, United States.

Background: Hydroxyurea prevents disease complications among patients with sickle cell disease (SCD). Although its efficacy has been endorsed by the National Health Lung and Blood Institute evidence-based guidelines, its adoption is low, both by patients with SCD and providers. Mobile health (mHealth) apps provide benefits in improving medication adherence and self-efficacy among patients with chronic diseases and have facilitated prescription among medical providers. However, mHealth has not been systematically tested as a tool to increase hydroxyurea adherence nor has the combination of mHealth been assessed at both patient and provider levels to increase hydroxyurea utilization.

Objective: This study aims to increase hydroxyurea utilization through a combined two-level mHealth intervention for both patients with SCD and their providers with the goals of increasing adherence to hydroxyurea among patients and improve hydroxyurea prescribing behavior among providers.

Methods: We will test the efficacy of 2 mHealth interventions to increase both patient and provider utilization and knowledge of hydroxyurea in 8 clinical sites of the NHLBI-funded Sickle Cell Disease Implementation Consortium (SCDIC). The patient mHealth intervention, InCharge Health, includes multiple components that address memory, motivation, and knowledge barriers to hydroxyurea use. The provider mHealth intervention, Hydroxyurea Toolbox (HU Toolbox), addresses the clinical knowledge barriers in prescribing and monitoring hydroxyurea. The primary hypothesis is that among adolescents and adults with SCD, adherence to hydroxyurea, as measured by the proportion of days covered (the ratio of the number of days the patient is covered by the medication to the number of days in the treatment period), will increase by at least 20% after 24 weeks of receiving the InCharge Health app, compared with their adherence at baseline. As secondary objectives, we will (1) examine the change in health-related quality of life, acute disease complications, perceived health literacy, and perceived self-efficacy in taking hydroxyurea among patients who use InCharge Health and (2) examine potential increases in the awareness of hydroxyurea benefits and risks, appropriate prescribing, and perceived self-efficacy to correctly administer hydroxyurea therapy among SCD providers between baseline and 9 months of using the HU Toolbox app. We will measure the reach, adoption, implementation, and maintenance of both the InCharge Health and the HU Toolbox apps using the reach, effectiveness, adoption, implementation, and maintenance framework and qualitatively evaluate the implementation of both mHealth interventions.

Results: The study is currently enrolling study participants. Recruitment is anticipated to be completed by mid-2021.

Conclusions: If this two-level intervention, that is, the combined use of InCharge Health and HU Toolbox apps, demonstrates efficacy in increasing adherence to hydroxyurea and prescribing behavior in patients with SCD and their providers, respectively, both apps will be offered to other institutions outside the SCDIC through a future large-scale implementation-effectiveness study.

Trial Registration: ClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167.

International Registered Report Identifier (irrid): DERR1-10.2196/16319.
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http://dx.doi.org/10.2196/16319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388044PMC
July 2020

Using Machine Learning to Predict Early Onset Acute Organ Failure in Critically Ill Intensive Care Unit Patients With Sickle Cell Disease: Retrospective Study.

J Med Internet Res 2020 05 13;22(5):e14693. Epub 2020 May 13.

Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States.

Background: Sickle cell disease (SCD) is a genetic disorder of the red blood cells, resulting in multiple acute and chronic complications, including pain episodes, stroke, and kidney disease. Patients with SCD develop chronic organ dysfunction, which may progress to organ failure during disease exacerbations. Early detection of acute physiological deterioration leading to organ failure is not always attainable. Machine learning techniques that allow for prediction of organ failure may enable early identification and treatment and potentially reduce mortality.

Objective: The aim of this study was to test the hypothesis that machine learning physiomarkers can predict the development of organ dysfunction in a sample of adult patients with SCD admitted to intensive care units (ICUs).

Methods: We applied diverse machine learning methods, statistical methods, and data visualization techniques to develop classification models to distinguish SCD from controls.

Results: We studied 63 sequential SCD patients admitted to ICUs with 163 patient encounters (mean age 30.7 years, SD 9.8 years). A subset of these patient encounters, 22.7% (37/163), met the sequential organ failure assessment criteria. The other 126 SCD patient encounters served as controls. A set of signal processing features (such as fast Fourier transform, energy, and continuous wavelet transform) derived from heart rate, blood pressure, and respiratory rate was identified to distinguish patients with SCD who developed acute physiological deterioration leading to organ failure from patients with SCD who did not meet the criteria. A multilayer perceptron model accurately predicted organ failure up to 6 hours before onset, with an average sensitivity and specificity of 96% and 98%, respectively.

Conclusions: This retrospective study demonstrated the viability of using machine learning to predict acute organ failure among hospitalized adults with SCD. The discovery of salient physiomarkers through machine learning techniques has the potential to further accelerate the development and implementation of innovative care delivery protocols and strategies for medically vulnerable patients.
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http://dx.doi.org/10.2196/14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254279PMC
May 2020

Measuring hydroxyurea adherence by pharmacy and laboratory data compared with video observation in children with sickle cell disease.

Pediatr Blood Cancer 2020 08 9;67(8):e28250. Epub 2020 May 9.

Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.

Background: Hydroxyurea nonadherence is common among children with sickle cell disease (SCD), but it is unclear if current adherence measures are valid compared with video directly observed therapy (VDOT), a reference method. The objectives were to evaluate if hydroxyurea adherence by pharmacy records, urine assay, mean corpuscular volume (MCV), and/or fetal hemoglobin (HbF) correlated with and was sensitive and specific compared with VDOT.

Methods: This was a cross-sectional analysis of adherence data from 34 children with SCD on a single-arm, six-month hydroxyurea adherence study. Spearman correlation coefficient compared participants' adherence by pharmacy records, MCV, and HbF to adherence by VDOT. The sensitivity and specificity of ≥80% adherence by pharmacy records, two urine samples with hydroxyurea, MCV ≥100 fl/L, and HbF ≥20% compared with ≥80% VDOT adherence were also calculated.

Results: Median pharmacy and VDOT adherence rates were similar (87.8% vs 88.1%, P = 0.75) and mildly correlated (r  = 0.45; P = 0.008) but the sensitivity of ≥80% adherence by pharmacy records was 72.7% and specificity was 45.5%. MCV (r = -0.02, P = 0.92) and HbF (r = -0.2, P = 0.33) did not significantly correlate with VDOT adherence. Sensitivity and specificity were 83.3% and 33.3% for having two urine samples with hydroxyurea, 35% and 71.4% for MCV ≥100 fl/L, and 75% and 0% for HbF ≥20%, respectively.

Conclusions: Commonly used tools to measure hydroxyurea adherence may not correlate with or be valid compared with video adherence. Future studies to refine these measures are needed to effectively target adherence interventions to children with SCD who have the potential to benefit. (ClinicalTrials.gov NCT02578017).
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http://dx.doi.org/10.1002/pbc.28250DOI Listing
August 2020

Development of the InCharge Health Mobile App to Improve Adherence to Hydroxyurea in Patients With Sickle Cell Disease: User-Centered Design Approach.

JMIR Mhealth Uhealth 2020 05 8;8(5):e14884. Epub 2020 May 8.

Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, United States.

Background: Sickle cell disease (SCD) is an inherited blood disorder causing acute complications and chronic progressive end organ damage. SCD is associated with significant morbidity, early mortality, impaired health-related quality of life, and increased acute health care utilization. Hydroxyurea is a US Food and Drug Administration-approved medication that reduces disease complications, acute health care utilization, and costs. However, adherence to hydroxyurea is suboptimal. Mobile health (mHealth) interventions have the potential to improve hydroxyurea adherence, but few examples exist that are specific to the SCD population.

Objective: This study aimed to design a mHealth intervention for individuals with SCD to improve adherence to hydroxyurea, using a user-centered design that was informed by specific barriers to hydroxyurea adherence and utilization in this population.

Methods: This study consisted of 4 phases. In phase 1, individuals with SCD and health care providers participated in an optimization digital workshop. In phase 2, patients completed surveys pertaining to their interest in mHealth use, barriers and facilitators to hydroxyurea use, and health literacy. Phases 3 and 4 involved semistructured interviews and focus groups, respectively, and used the Health Belief Model (HBM) as the framework to investigate drivers of poor hydroxyurea adherence and to inform the development of an app prototype. In addition, in phase 4, we have incorporated the patients' feedback on the preliminary app prototype and its features.

Results: Barriers to hydroxyurea adherence were consistent with the literature and included forgetfulness and several specific thoughts and emotions associated with hydroxyurea use (eg, fear of side effects, depression, stigma, and hopelessness). In addition, more than half of the participants reported potentially low health literacy. Preferred patient app features included 7 key components, namely (1) medication reminders and tracker, (2) disease education, (3) communication, (4) personalization, (5) motivation, (6) support during pain episodes, and (7) social support. Utilizing a user-centered design approach, data obtained from patients and providers were translated into features within the app, mapping to components of the HBM and the specific drivers of hydroxyurea adherence and matching the literacy level of the population, resulting in the development of a novel mobile app called InCharge Health.

Conclusions: The InCharge Health app is an mHealth intervention developed with substantial input from users and by mapping the HBM as the framework that guided the choice for its components. InCharge Health is a customized product for the SCD population aimed at optimizing medication adherence, with the end goal of improving quality of life and health outcomes among patients with SCD. The efficacy and implementation of the InCharge Health app as an mHealth intervention to promote hydroxyurea adherence will be tested in a future stepped-wedge multicenter trial for adolescents and adults with SCD.
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http://dx.doi.org/10.2196/14884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245000PMC
May 2020

Vaccine Design Informed by Virus-Induced Immunity.

Viral Immunol 2020 05 5;33(4):342-350. Epub 2020 May 5.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

When an individual is exposed to a viral pathogen for the first time, the adaptive immune system is naive and cannot prevent virus replication. The consequence may be severe disease. At the same time, the host may rapidly generate a pathogen-specific immune response that will prevent disease if the virus is encountered again. Parvovirus B19 provides one such example. Children with sickle cell disease can experience life-threatening transient aplastic crisis when first exposed to parvovirus B19, but an effective immune response confers lifelong protection. We briefly examine the induction and benefits of virus-induced immunity. We focus on three human viruses for which there are no licensed vaccines (respiratory syncytial virus, human immunodeficiency virus type 1, and parvovirus B19) and consider how virus-induced immunity may inform successful vaccine design.
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http://dx.doi.org/10.1089/vim.2019.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247049PMC
May 2020

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease.

Br J Haematol 2020 06 26;189(6):1192-1203. Epub 2020 Feb 26.

Departments of, Department of, Psychology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16-17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ thalassaemia; n = 52 HbSS/HbSβ thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ thalassaemia; n = 8 HbSS/HbSβ thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.
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http://dx.doi.org/10.1111/bjh.16519DOI Listing
June 2020

Attention difficulties are associated with lower engagement in adult care amongst youth with sickle cell disease.

Br J Haematol 2020 04 26;189(1):e27-e30. Epub 2020 Feb 26.

Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/bjh.16421DOI Listing
April 2020

Web-Based Technology to Improve Disease Knowledge Among Adolescents With Sickle Cell Disease: Pilot Study.

JMIR Pediatr Parent 2020 Jan 7;3(1):e15093. Epub 2020 Jan 7.

Department of Hematology, St Jude Children's Research Hospital, Memphis, TN, United States.

Background: Advancements in treatment have contributed to increased survivorship among children with sickle cell disease (SCD). Increased transition readiness, encompassing disease knowledge and self-management skills before transfer to adult care, is necessary to ensure optimal health outcomes. The Sickle Cell Transition E-Learning Program (STEP) is a public, Web-based, 6-module tool designed to increase transition readiness for youth with SCD.

Objective: The objective of our study was to investigate the participation rate of youth with SCD in STEP and its association with transition readiness.

Methods: This was a single-center, Institution Review Board-approved, retrospective cohort review. A total of 183 youths with SCD, aged between 12 and 15 years, were offered STEP as an adjunct to in-clinic disease education sessions. Participation rate (number of patients who used at least one STEP module divided by those approached) was calculated. The association among the number of STEP modules completed, disease knowledge, and self-management was explored.

Results: Overall, 53 of the 183 approached adolescents completed at least one STEP module, yielding a participation rate in STEP of 29.0%. Of the 53 participants, 37 and 39 adolescents had disease knowledge and self-management confidence rating available, respectively. A positive correlation (r=0.47) was found between the number of STEP modules completed and disease knowledge scores (P=.003). No association was found between the number of modules completed and self-management confidence ratings. Disease knowledge scores were significantly higher among participants who completed ≥3 STEP modules compared with those who completed <3 STEP modules (U=149.00; P=.007).

Conclusions: Improvement in disease knowledge in adolescence is critical to ensure the youth's ability to self-care during the period of transition to adult care. Despite low participation, the cumulative exposure to the STEP program suggested greater promotion of disease knowledge among adolescents with SCD before transfer to adult care.
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http://dx.doi.org/10.2196/15093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996770PMC
January 2020

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain.

Blood Adv 2019 12;3(23):3982-4001

Department of Pediatrics, Connecticut Children's/School of Medicine, University of Connecticut, Hartford, CT.

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
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http://dx.doi.org/10.1182/bloodadvances.2019000882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963237PMC
December 2019

A program of transition to adult care for sickle cell disease.

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):496-504

Departments of Hematology and.

Most children with sickle cell disease (SCD) today survive into adulthood. Among emerging adults, there is a marked increase in acute care utilization and a rise in mortality, which can be exacerbated by not establishing or remaining in adult care. Health care transition programs are therefore essential to prepare, transfer, and integrate emerging adults in the adult care setting. The Six Core Elements of Health Care Transition, created by the Center for Health Care Transition Improvement, define the basic components of health care transition support as follows: (1) transition policy, (2) tracking and monitoring progress, (3) assessing transition readiness, (4) planning for adult care, (5) transferring to adult care, and (6) integrating into adult care. Programs that implement the Six Core Elements have experienced significant declines in care abandonment during adolescence and young adulthood and higher early adult care engagement. Most of the core transition activities are not currently reimbursable, however, posing a challenge to sustain transition programs. Ongoing studies are investigating interventions in comparative effectiveness trials to improve health-related quality of life and reduce acute care utilization among emerging adults with SCD. Although these studies will identify best practices for health care transition, it is also important to define how the transition outcomes will be measured, as no consensus definition exists for successful health care transition in SCD. Future research is needed to define best practices for health care transition, systematically assess transition outcomes, and revise payment models to promote sustainability of health care transition programs.
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http://dx.doi.org/10.1182/hematology.2019000054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913425PMC
December 2019

and Liver Iron Content in Children with Sickle Cell Anemia and Iron Overload.

J Clin Med 2019 Nov 5;8(11). Epub 2019 Nov 5.

Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 () gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous deletion (-null; 7.8, SD±6.9, = 0.09). However, after >12 months of chelation, -null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for -null = 0.1 (SD±3.3); versus -0.3 (SD±3.0) and -1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, = 0.047). homozygous deletion may prevent effective chelation in children with SCA and iron overload.
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http://dx.doi.org/10.3390/jcm8111878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912836PMC
November 2019