Standard measures and common data elements for sickle cell disease (SCD) will improve the data quality and comparability necessary for cross-study analyses and the development of guidelines that support effective treatments and interventions. In 2014, the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) funded an Administrative Supplement to the PhenX Toolkit (consensus measures for Phenotypes and eXposures; https://www.phenxtoolkit.org/) to identify common measures to promote data comparability across SCD research. An 11-member Sickle Cell Disease Research and Scientific Panel provided guidance to the project, establishing a core collection of SCD-related measures and defining the scope of 2 specialty collections: (1) cardiovascular, pulmonary, and renal complications, and (2) neurology, quality-of-life, and health services. For each specialty collection, a working group of SCD experts selected high-priority measures using a consensus process that included scientific community input. The SCD measures were released into the Toolkit in August 2015. The 25 measures included in the core collection are recommended for use by all NHLBI-funded investigators performing human-subject SCD research. The 10 neurology, quality-of-life, and health services measures and 14 cardiovascular, pulmonary, and renal measures are recommended for use within these specialized research areas. For SCD and other researchers, PhenX measures will promote collaborations with clinicians and patients, facilitate cross-study analysis, accelerate translational research, and lead to greater understanding of SCD phenotypes and epigenetics. For clinicians, using PhenX measures will help elucidate the etiology, progression, and treatment of SCD, leading to improved patient care and quality of life.

Objectives: To assess current knowledge of National Heart, Lung and Blood Institutes (NHLBI) and Thalassemia International Federation (TIF) recommendations, blood banking practices and perceived challenges among transfusion services in the management of patients with haemoglobinopathies. Background: Previous reports have demonstrated variations in transfusion practices for sickle cell disease (SCD) and thalassemia patients. Recently, NHLBI/TIF have provided transfusion recommendations for patients with haemoglobinopathies. Methods: A cross-sectional survey was conducted of transfusion services from the state of Georgia previously identified as having SCD/thalassemia populations. The survey assessed transfusion service practices in pre-transfusion testing and blood product selection; awareness/implementation of NHLBI/TIF transfusion-based recommendations and perceived challenges in transfusing haemoglobinopathy patients. Results: Responses were received from 35 of 49 (71%) institutions. Only institutions indicating transfusing SCD or thalassemia patients (32) were included in analysis. Seventy-one percent of non-sickle cell treatment centres (SCTCs) and 20% of non-thalassemia treatment centres follow NHLBI and TIF recommendations to perform a red blood cell phenotype beyond ABO/Rh(D) and provide Rh and Kell prophylactically matched units for SCD and thalassemia patients, respectively. Forty percent of institutions (33% of non-SCTCs) employ RBC genotyping to evaluate the red cell phenotype for SCD patients. Over 77% of institutions do not utilise a reliable method to identify SCD patients prior to transfusion, such as a required question/answer field on type/screen or crossmatch orders. Conclusion: Many healthcare systems' transfusion practices for haemoglobinopathy patients are discordant with NHLBI/TIF recommendations. Efforts are needed to increase awareness and implementation of current recommendations among all transfusion services seeing these patients.

Background: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. Purpose: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. Methods: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. Results: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. Limitations: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. Lessons learned: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. Conclusions: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects.

In this study, the relationship of clinical differences among patients with sickle cell disease (SCD) was examined to understand the major contributors to early mortality in a contemporary cohort. Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed up for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis. Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sβ0 was 58 years and for Hb SC and Sβ+ was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM-1, and short-acting narcotics use were significantly associated with decreased survival. Forty-two percent of subjects were on hydroxyurea therapy, which was not associated with survival. SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ0 and SS. Not only were comorbidities individually associated with decreased survival but also an additive effect was observed, thus, those with a greater number of negative endpoints had worse survival (P<0.0001). The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial.

Background: Sickle cell disease patients are more likely than the general population to undergo surgery and usually do so at a younger age. Female sickle cell disease patients also have special gynecological and obstetric issues related to their disease. Methods: We collected data through standardized clinical report forms, patient interviews, and medical records from 509 adult sickle cell disease patients. Logistic regression was used to estimate the association between multiple variables and each of the surgery types. We also determined the prevalence and outcomes of pregnancy in 284 women with sickle cell disease in this population. Results: Almost 50% of patients aged 18-27 years had had a cholecystectomy. Mean corpuscular hemoglobin, total bilirubin, and lactate dehydrogenase were significantly higher in the postcholecystectomy group; 9.5% of 504 individuals had undergone splenectomy. Hematocrit, body mass index, and red blood cell count were significantly higher in the postsplenectomy group. Hip replacement had been performed in 9.2% of individuals, with the prevalence increasing as early as the fourth decade and continuing to increase through the sixth decade of life. A history of pregnancy was present in 190 women (67%). Of 410 pregnancies, only 53.9% resulted in live births, 16.6% were voluntarily terminated, and 29.5% were complicated by miscarriage, still birth, or ectopic implantation. Conclusions: Sickle cell disease continues to have a strong effect on the mean age for common surgeries and impacts pregnancy outcomes. We conclude that this population has a unique surgical and obstetric history that should be further studied to provide insight into potentially more effective preventive approaches to end-organ damage.

Renal failure occurs in 5-18% of sickle cell disease (SCD) patients and is associated with early mortality. At-risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The myosin, heavy chain 9, non-muscle (MYH9) and apolipoprotein L1 (APOL1) genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. We genotyped 26 single nucleotide polymorphisms (SNPs) in MYH9 and 2 SNPs in APOL1 (representing the G1 and G2 tags) in 521 unrelated adult (18-83years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Seven SNPs in MYH9 and one in APOL1 remained significantly associated with proteinuria after multiple testing correction (P<0·0025). An MYH9 risk haplotype (P=0·001) and the APOL1G1/G2 recessive model (P<0·0001) were strongly associated with proteinuria, even when accounting for the other. Glomerular filtration rate was negatively correlated with proteinuria (P<0·0001), and was significantly predicted by an interaction between MYH9 and APOL1 in age-adjusted analyses. Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk.