Missing for too long: a narrative review of what the sickle cell community can learn from patient registries in hemophilia and cystic fibrosis

Introduction

Background

Sickle cell disease (SCD) is a complex highly morbid inherited blood disorder associated with an estimated 20-year reduction in life expectancy (1,2). Although the underlying genetic cause of SCD—pathogenic variants in the gene encoding the β globin subunit of hemoglobin—was first identified in 1949 (3), the health and life expectancy of people with SCD in the United States did not extend into adulthood until after 1972, when the National Sickle Cell Anemia Control Act was passed and funds were allocated for the establishment of comprehensive sickle cell centers, newborn screening and education, and dedicated research funding (4,5). This foundational act paved the way for improvements in infection prevention (e.g., penicillin prophylaxis) and stroke management. Two decades later, hydroxyurea was introduced as the first pharmacologic therapy for treatment of adults and then children with SCD, and with all these advancements, the life expectancy for people with SCD extended from teenage years into the 40s and 50s (4,6,7). Another two decades would pass before the introduction of three novel pharmacologic therapies in the 2010s, one of which is seldom used and two of which were withdrawn from some or all markets within several years (8,9). Alongside the slow introduction of viable therapies for SCD, life expectancy plateaued from the early 1990s into the 2000s (10,11).

The stuttering trajectory of improvement in the care for people with SCD contrasts with that seen for hemophilia and cystic fibrosis (CF), two inherited diseases with prevalence and morbidity on the order of that for SCD, which have benefited from new therapies and innovations in care at a seemingly ever-increasing pace (12-14). This is often attributed, at least in part, to the substantially lower investment in biomedical research for SCD from both public and private funding sources relative to these comparator diseases (15) compounding a history of stigma and discrimination toward people living with SCD, the overwhelming majority of whom in the USA identify as Black (16-19). Related to and compounding these disparities has been a longstanding paucity of population-level, contemporary data on people living with SCD compared to CF or hemophilia. Both CF and hemophilia have benefited from patient registries since the 1970s and 1980s, respectively; registries have been instrumental both in improving our understanding of these diseases and in leading to life-changing discoveries. The current sustained patient registry efforts for SCD were not begun until the 2010s, and there are now several distinct efforts ongoing. Given the relative nascency of population-level data collection in SCD, here we first examine the history and achievements of registries for hemophilia and CF, with an eye for what these efforts can teach us about implementation and quality improvement in SCD as its registries mature.

Objective

In this review, we first summarize the history and accomplishments of the major registries for hemophilia and CF in the USA (summarized in Table 1) before surveying the landscape of registry or other large-scale data collection efforts for SCD (summarized in Table 2). Though there are numerous registry efforts for these diseases outside the USA (e.g., in the UK there is the UK CF Foundation and the National Hemoglobinopathy Register), we focus this review within the USA, as the differences in social, political, and economic contexts between countries are significant enough that successes in one setting are not necessarily informative in others. We then consider ways in which the SCD community in the USA can learn from the experiences of hemophilia and CF patient communities, providers, and researchers to improve the strength and usefulness of registry data for SCD, with the ultimate goal of advancing our understanding of the disease and improving the care provided to the contemporary patient living with SCD. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-35/rc).

Methods

The search strategy for this narrative review is summarized in Table 3. Briefly, the literature review was conducted from April 2025 through July 2025. Initial journal article searches were conducted in PubMed, Google Scholar, and Scopus, with substantive focus on the history, development, and accomplishments of registries for hemophilia, CF, and SCD in the USA (see Appendix 1 for example search strategy). Additional articles were identified by backward reference searching. Given the focus on registries, additional searches were conducted of websites for identified registries in hemophilia, CF, and SCD, as well as archives of registry funding entities (foundations, CDC, federal funding announcements). No date exclusion was placed on articles; language was restricted to English. Findings were synthesized into a narrative review.

Hemophilia

Hemophilia A and hemophilia B are X chromosome-linked inherited bleeding disorders caused by variants in the genes encoding Factor VIII or Factor IX, respectively (20). Recent estimates of the prevalence of hemophilia (A and B combined) range from 15.7 to 24.6 cases per 100,000 males, with a total American population estimated at 30,000 individuals (21-23).

Development of hemophilia registry in the USA

The Community Counts Public Health Surveillance of Bleeding Disorders project [formerly known as the Universal Data Collection (UDC) surveillance system] is the primary registry for people with hemophilia in the USA. Its history is closely linked to the history of hemophilia treatment centers (HTCs) in the USA. In 1975, the American Congress allocated funds to the Health Resources and Services Administration (HRSA) for the establishment of a regional network of specialized treatment centers for hemophilia, which would ultimately become the modern hemophilia treatment center network (HTCN) (24). HTCs provide comprehensive care to people with hemophilia, including access to relevant specialists, disease-relevant diagnostics, and other support services (25).

In response to the emerging human immunodeficiency virus (HIV) epidemic in the 1980s, and the recognition that blood-derived (especially pooled) products carried a significant risk for HIV, the CDC partnered with HTCs with the aim of preventing the spread of HIV to people with severe hemophilia, who frequently received such products. This partnership resulted in the development of the Hemophilia Minimal Dataset to track delivery of HIV risk-reduction services at HTCs, which expanded over time to include more detailed demographic and health services data of the people receiving care at these HTCs (26). The partnership between the CDC and the bleeding disorders community deepened in the 1990s, and Congress allocated funding to the CDC to establish a public health effort to reduce complications of bleeding disorders. This laid the groundwork for what would be the UDC program, a unified dataset across HTCs that monitored epidemiologic and clinical trends in hemophilia (primarily joint and infectious diseases) and provided surveillance of blood safety. Development and pilot testing of the UDC was carried out over several years, and included development of data collection tools (by way of a multidisciplinary team comprising health care workers and representatives from the hemophilia community), refinement of logistics involved in shipping and processing blood specimens, and ultimately pilot testing of data and blood sample collection.

In 1998, the UDC was established and data collection officially began. As of 2010, roughly 85% of all HTC hemophilia patients had participated in the UDC program, and more than 70,000 blood samples had been collected. In 2010, the CDC met with stakeholders in the bleeding disorder community to gather perspectives on emerging priorities for the future. This meeting informed the development of the next iteration of the UDC, which was called the Community Counts Public Health Surveillance of Bleeding Disorders project, or Community Counts (27). Community Counts expanded on the UDC to include more complications of hemophilia (such as inhibitors to treatment products) and additional health and comorbidity information, which was taking on increased salience as treatment advancements facilitated a growing and aging population of people with hemophilia.

The funding structure for UDC and Community Counts has changed over time (27). Initially, UDC was funded via cooperative agreements between the CDC and the 12 HTC regional centers in the US; this continued for award cycles in 1996, 2001, and 2006. With the evolution to Community Counts, the funding structure changed, such that the CDC established a cooperative agreement with the nonprofit American Thrombosis and Hemostasis Network (ATHN). The ATHN administers subcontracts to HTC regional core centers, which then administer contracts to individual HTCs. ATHN also provides the infrastructure that HTCs use to record their registry data electronically.

Community Counts is comprised of several distinct surveillance components. The registry component includes patients’ clinical data, such as demographics, family history, and details regarding treatment regimens, bleeding episodes, chronic pain, health care utilization, and comorbid conditions. In addition, Community Counts encompasses laboratory specimens that are used for tests that fall under CDC’s surveillance mission, such as testing for HIV, hepatitis C virus (HCV), or inhibitors against treatment products. There is also a mortality component, which reports cause of death and characteristics of individuals who have died. Finally, there is a population profile component, in which HTCs submit basic information on the entire hemophilia population who received care in a given year, which allows for an estimate of the proportion of the hemophilia population have participated in the registry. These data are hand-curated into the registry by staff at HTCs. Of note, Community Counts is classified as non-research public health surveillance, so consent is not strictly required, but it is the practice of Community Counts to require participant authorization for inclusion in the registry.

Registry achievements

The depth, scope, and longevity of the Community Counts and UDC surveillance programs has allowed for numerous achievements in advancing knowledge and health care for people with hemophilia. For example, blood samples collected in the UDC have been used for important evaluations of blood product safety in the USA, including finding evidence of Parvovirus B19 transmission risk associated with plasma-derived treatment products but not with recombinant treatment (28-30). The clinical data have facilitated detailed analyses of joint complications among people with Hemophilia, including the observation that increased BMI was associated with accelerated decline in joint function (31-33), as well as the impact of inhibitors on a population level (34).

Critically, these surveillance data have also been used to examine patterns in health care for people with hemophilia and to identify opportunities to improve that care. After a randomized controlled trial in 2007 demonstrated superior prevention of joint disease among young children with hemophilia who used prophylactic treatment compared to on-demand treatment (35), data from the UDC were used to investigate whether practice patterns changed in response to the study. An analysis of HTCs’ rates of prescription of prophylaxis to children with severe hemophilia age 2 to 14 years found an increase in the average proportion of the population on prophylaxis from 67.4% in 2006 and 2007 to 73% in 2008 and 2009, suggesting a change in practice patterns in response to the trial (36). Researchers subsequently compared rates of prophylaxis use across each modest-sized HTC (with at least ten participants), observing a large degree of variation in rates, including several HTCs in which all young patients were using prophylaxis and several in which no young patients were using prophylaxis. These analyses allowed for the identification of HTCs with room for improvement. Identified sites could then be targeted for interventions to address these deficiencies, and then outcomes of those efforts could be evaluated. Such strategies can iteratively improve care for people with hemophilia (36).

CF

CF is an autosomal recessive genetic disorder caused by variants in the gene encoding a transmembrane chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR) (37). Dysfunction of the CFTR leads to complications in numerous organ systems, including impaired airway clearance and increased risk of pulmonary infection, pancreatic insufficiency, liver disease, and impaired sweat gland function. CF affects an estimated 1 in 2,500 births in the USA, with a higher prevalence among White newborns, and the number of people with CF in the USA is estimated to be approximately 40,000 people (38,39).

Development of CF registry in the USA

The origin of the major patient registry for CF in the USA dates to the early years of the Cystic Fibrosis Foundation (CFF). The CFF was founded in 1955 by parents of children with CF in order to support development of treatments for CF and ultimately to develop a cure (40). In 1961, the CFF established a network of accredited health care centers to care for people with CF. The foundation subsequently initiated the CFF Patient Registry (CFFPR) in 1966, which began collecting health information about CF patients seen at CFF-accredited centers. Since then, the CFFPR has evolved from a basic registry on patient demographics to a comprehensive database of people with CF providing data for epidemiological, clinical, and policy research (41).

Initially, the CFFPR was used for basic—and previously unknown—descriptions of the population of people living with CF (41). In its early stages, CFFPR data were comprised of annual paper questionnaires that collected basic demographic, treatment, and disease exacerbation data (42). Subsequent developments in the CFFPR sparked new opportunities for investigation for CF researchers. In 1995, the CFF funded and tasked centers participating in the CFFPR with providing quarterly updates on growth, lung function, treatment, and disease complications among their population, expanding opportunities for epidemiological research on CF (41).

In 2003, the CFFPR transitioned from paper-based annual summary instrument to the current web-based encounter-level system called Port CF (41). Port CF allowed users streamlined access to data at both individual and population levels, in raw format or in prespecified reports. Individual data can serve as a useful tool in the clinical setting for providers to review longitudinal microbiology, nutrition, and lung function measures. Providers can also share these summaries with patients for purposes of education and discussions of management decisions. Population-level data are useful for quality improvement and population health efforts, such as identifying patients who are overdue for clinic visits, or patients who may be eligible for clinical trials or specific therapies. Finally, the data in Port CF can also be downloaded as data files for use in statistical software, so that care center teams can conduct their own queries and analyses as appropriate for their center and patient population (41).

Beginning in 2006, some of the data on CFFPR centers’ quality metrics were also made available to the public, in order to increase transparency and further build trust with the CF community (41). These metrics are also incorporated into the CFF website via the CF Care Center search, so patients and families of patients with CF who are considering where to receive care could see how every CFF-accredited center compares to national averages across several key metrics, as well as the patient population size (43).

The CFF provides ongoing infrastructure and support for the CFFPR in order to facilitate high-quality data collection. The CFF offers technical support to accredited centers for data collection into the CFFPR in the form of user manuals, data entry guidelines, training sessions, and other user support (42). The CFF also initiated an audit program of the CFFPR to assess data quality in the key domains of accuracy (registry data matching the medical record) and completeness (lack of missing data). The Port CF data entry system incorporates several strategies to limit erroneous data entries, including highlighting previous values to note possible large deviations from expected values, and implausible values are reviewed manually. The CFF also independently verifies death dates and any other suspicious important variables such as date of birth (42). Funding for the CFFPR comes from the CFF (42). The CFF provides funds to accredited care centers, a portion of which is determined by the number of patients enrolled in the CFFPR at that center and the completeness of their data.

Registry achievements

One of the greatest strengths of the CFFPR is its coverage and representation of the CF population in the USA. In 2023 there were more than 33,000 individuals included in the CFFPR (44). Prior research estimated that 81-84% of the CF population nationally was seen at a CFF-accredited center and consented to their data inclusion in the CFFPR (42).

The CFFPR has played a critical role in advancing our understanding of CF and improving the standard of care for people with CF. An early example of this was an analysis of survival data for people with CF that demonstrated improved survival among people seen at comprehensive care centers, supporting the spread of the comprehensive care model (45). With the expansion of the CFFPR’s scope in 1995 to more detailed quarterly data collection, researchers had increasing opportunity to examine risk factors associated with individual variation in disease severity, such as gender, socioeconomic status, air pollution, and acquisition of different microbial species in patients’ airways (46-49).

Beginning in the late 1990s, CFF-accredited centers increased their focus on quality improvement in the care for CF by examining variations between different centers’ practices and outcomes (50). Reports for various outcomes of interest across CFF-accredited centers were provided to the center directors and CF providers (41). As for hemophilia care, these center-level data provided by the CFFPR allowed for identification of high-performing centers in various quality measures relevant to CF, such as average BMI or rate of diabetes screening, which were in turn examined for processes and systems that could be adopted at other centers to improve those outcomes. Similarly, center directors and CF providers could assess whether their center was substantially underperforming for any outcomes and target quality improvement efforts toward those lagging areas. This iterative refinement in care for chronic illness is only possible with a comprehensive multi-site patient-level registry.

SCD

In contrast to the history of registries for hemophilia and CF in the USA, there is no single longstanding, universal patient registry for SCD. There are numerous factors contributing to this discrepancy, perhaps most saliently a history of marginalization of people living with SCD and an associated lack of a single motivated and well-resourced funding source such as a patient advocacy foundation for CF or a federal mandate for hemophilia (15,17). There have been numerous efforts toward large-scale data collection on people with SCD, each with its own mission and varying implementation strategies, often limited by funding and sustainability concerns. The following section will summarize each of these efforts and highlight related achievements before looking forward to consider how large-scale data collection for SCD can improve and maximize opportunity in the future.

Cooperative Study of Sickle Cell Disease (CSSCD)

One of the earliest efforts to study SCD at a large scale was the CSSCD. CSSCD was a multicenter prospective cohort study initiated in 1977 with the primary goal of describing the natural history of SCD and factors associated with morbidity and mortality (51,52). In phase 1 of CSSCD, a total of 4,085 individuals ranging in age from newborns to adults were enrolled over a 10-year period. Subsequent phases included follow-up of pediatric and adult cohorts for several years. The last exit interviews of study participants were completed in 1993.

While the CSSCD did not evolve into a longstanding patient registry, it highlighted the benefit of a detailed, longitudinal cohort in advancing our understanding of SCD and its complications. A cohort of infants was followed prospectively for 10 years, allowing for a description of the early natural course of SCD and its heterogeneity both between and within genotypes (53,54). Other studies examined in detail various manifestations of SCD and their associated risk factors, such as acute chest syndrome, stroke, heart disease, venous thromboembolism, retinopathy, and alloimmunization (55-60). The size of the cohort also allowed for study of outcomes during less common circumstances such as pregnancy and surgery, and identification of factors that increased or mitigated risk of negative outcomes during those periods (61,62). However, it is worth recalling that the entire lifespan of this critical registry preceded the era of hydroxyurea use, in adults [1995] (7) and then in children (1999, HUG-KIDS and 2011, BABY HUG) (63,64), in addition to widespread chronic transfusions, and so is less relevant to the modern patient living with SCD.

Sickle Cell Data Collection (SCDC) program

The SCDC program is a surveillance effort begun in 2015 by the Centers for Disease Control and Prevention (CDC) (65). The SCDC program was designed to collect and integrate health information from multiple sources to determine the prevalence of SCD in each participating state and to better understand the health needs of people with SCD, in order to inform policy decisions concerning resource allocation and targeted interventions. SCDC is primarily operated at a state level, with CDC providing grant funding in partnership with state health agencies and academic institutions. State SCDC teams incorporate data from newborn screening, hospital discharge and emergency department records, clinic records from participating clinical sites, and state Medicaid programs (66). SCDC began with two states, California and Georgia, and over time with additional funding has expanded to 16 states with varying degrees of capacity and data completeness, providing an incomplete but useful snapshot.

The SCDC surveillance data has been used extensively for epidemiological SCD research. The surveillance program methodology and results were published in detail for California and Georgia (66), and other states have shared their surveillance results publicly online as they complete data collection and integration (67,68). State teams collaborated to estimate the birth prevalence of SCD across 11 states from 2016 to 2020, also noting that the majority of mothers of newborns with SCD lived in areas of high social vulnerability (69). Additionally, SCDC data have been used to examine numerous aspects of health care for people with SCD, such as adherence to guideline therapies and immunization in the pediatric population, Medicaid coverage for children with SCD, access to hematology care, and emergency department utilization (70-73). These analyses have benefited from the surveillance nature of the SCDC data, capturing essentially the full population of people with SCD in each state. The results of SCDC surveillance have also been leveraged to increase resources for SCD care: Colorado and Indiana increased legislative funding for SCD in response to data shared from their state SCDC teams, and in California the SCDC data were instrumental in identifying poor outcomes for people with SCD, successfully arguing for funding to establish a network of adult SCD clinics across the state (74).

Globin Research Network for Data and Discovery (GRNDaD)

The GRNDaD began in 2016 as a collaboration between providers at sickle cell centers to prospectively collect data on a cohort of people with SCD, cared for at a range of sites across the USA (75). Its stated goals were to describe natural history, inform guideline development, and iteratively assess quality of care and guideline adherence at participating clinical sites. The registry required IRB consent, and uses the REDCap database platform comprising over 300 individual data elements that have been curated by the study’s investigators. Clinical data are manually extracted from the medical record in annual updates, and REDCap allows for direct entry of patient reported outcome (PRO) surveys. Data quality assessments are actively being introduced via an annual 10-item data audit to validate data completeness and accuracy against the medical record.

GRNDaD has been adopted as the national patient registry for the National Alliance of Sickle Cell Centers (NASCC), a nonprofit formed in 2020 to support sickle cell centers in the delivery of comprehensive high quality care (76). NASCC is composed of over 100 member clinical sites that meet criteria to qualify as comprehensive sickle cell centers (77-79). All NASCC member sites are required to use GRNDaD for data collection on at least a subset of their patients, with the goal of better understanding care gaps that can be targeted across comprehensive sickle cell center sites. As a result, GRNDaD has expanded from approximately 2,000 participants in 2022 to over 5,000 participants in summer 2025 (75). Uneven funding presents a barrier for GRNDaD, as it is currently funded by a patchwork of independent investigator grants and contracts. Therefore, since participation is highly dependent on local resources, the depth of commitment to GRNDaD varies across participating sites, affecting data quality and completeness.

Data from GRNDaD have already been used to advance our understanding of the natural history of individuals who are living with SCD in the modern era. For instance, an analysis of biopsychosocial factors associated with pain-related outcomes, using patient-reported outcomes (PROs) in GRNDaD, identified that pain impact was worse in older individuals and in those with lower social and emotional functioning (80), and that subgroups of individuals with chronic pain consistently reported worse pain impact than those without chronic pain (81). An analysis of kidney function noted that the development of albuminuria was associated with a drop in hemoglobin, a trend which had not previously been appreciated (82). Finally, a recent study of thrombotic risk associated with surgical splenectomy found a two-fold increased risk of both venous thromboembolism and stroke among those who had a surgical splenectomy relative to those who did not (83).

GRNDaD has also been used in outcomes and health services research. For instance, management of iron overload was not guideline based across sites, as <50% of transfused patients with a serum ferritin ≥1,000 µg/L had undergone the recommended hepatic iron quantification (84). That study validated a screening threshold of serum ferritin (≥1,000 µg/L), and identified a serum ferritin (2,500 µg/L) above which empiric chelation therapy could be considered. Separately, investigators used GRNDaD to survey treatment patterns, finding a substantial shift from hydroxyurea to chronic transfusion as people with SCA transitioned to adulthood, and noting overall low rates of hydroxyurea used at maximally tolerated dose (85,86).

American Society of Hematology Research Collaborative (ASH RC) Data Hub

The ASH founded the ASH RC in 2018 as a nonprofit organization with the goal of enhancing research and clinical practice for people with blood disorders (87), focusing initially on SCD and multiple myeloma.

One of the primary components of the ASH RC is the Data Hub, a repository of aggregated electronic health record (EHR) data of people with SCD. At present nearly 40 institutions are participating in the Data Hub SCD Program from across the USA (88), with substantial overlap with GRNDaD sites. Participating centers share EHR data of non-consented individuals with SCD using standardized data integration and submission protocols. Supplemental data that cannot be reliably extracted from EHRs—such as SCD genotype—can be submitted separately via an electronic case report form. An analysis by ASH RC investigators showed that genotypes submitted by site investigators closely matched genotype as determined by independent chart review, supporting this as a method for genotype identification (89). The case report forms can also be used to submit data from sites that are unable to link EHR data or to amend inaccurate or miscoded data. Data fidelity can be a challenge with this approach, as EHR data are documented by a range of clinical providers across a range of clinical settings.

The ASH RC released its first report this year, containing data submitted from 17 clinical sites, and encompassing patient encounters from January 1, 2015 to December 31, 2024 (90). The Data Hub included 23,580 active individuals during that period, 10,412 of whom had a physician-attested SCD diagnosis. The peak number of active individuals in a given year was 15,249 individuals, of whom 8,055 had a physician-attested diagnosis, in 2023. The report detailed information regarding the cohort’s demographics, SCD complications, disease-modifying therapy utilization, emergency department and inpatient encounters, and volume of laboratory testing. Due to variability between sites’ EHRs, the report discouraged inferences concerning medication and care utilization across sites or over time, and instead highlighted the breadth of available information contained in the Data Hub. The Data Hub has not yet produced extensive research publications outside of this report, but numerous projects are ongoing (88).

The current state of big data for SCD

Reviewing the history and accomplishments of major data collection efforts for SCD alongside registries for hemophilia and CF highlights several salient issues, discussed below.

First, SCD data collection is fragmented amongst distinct projects with overlapping but non-identical goals. The CDC’s SCDC program is primarily focused on surveillance and epidemiology—determining the prevalence of SCD, and understanding trends in the diagnosis, treatment, and vital statistics of the SCD population. GRNDaD is a patient registry designed to provide high-quality descriptive real-world data, including PROs, on the natural history of SCD and to provide a platform for study and implementation of quality improvement across clinical sites. The ASH RC SCD Data Hub is a registry and data repository for real-world evidence, with goals focusing on partnering with industry to facilitate more effective and efficient clinical trials and providing grants for academic researchers to make use of its data. Of these programs, the SCDC, with a unique focus on surveillance, stands somewhat apart, while there is significant overlap between GRNDaD and the SCD Data Hub. Both collect clinical data using disparate approaches and are well positioned to enable clinical, epidemiological, and health services research on SCD, but each has strengths and weaknesses.

GRNDaD’s relative strengths are its grassroots inception, well-defined and curated cohort, easy incorporation (and ongoing use) of PROs and other survey data, and integration with local quality improvement initiatives. Specifying clinical baseline data is also more straightforward in GRNDaD, which has established baseline data for each participant, compared to the SCD Data Hub, which requires algorithmic identification of baseline data, and is not yet available and validated. GRNDaD’s greatest challenge going forward likely comes from scalability. Time and effort on the part of staff at participating clinical sites are required to generate and input the data for GRNDaD, which, in the absence of sustained financial support, could limit the degree to which some sites participate in GRNDaD. In CF this issue was addressed by the CFF providing funds to CF centers. Unfortunately, there is not a similarly aligned and resourced organization in the SCD community, since ASH resources are directed elsewhere. NASCC is the most prominent non-profit organization focused on SCD care centers, but it does not yet have the level of financial support sufficient for sustained data collection at clinical sites.

The SCD Data Hub strength lies in EHR data collection and in financial and logistical support by ASH RC. The integration of monthly EHR data updates from participating sites into the Data Hub creates a large and valuable dataset for study. However, EHR data formats and reporting can vary across sites (or within the same site across time as EHR software changes), and some data—text (or unstructured) components in particular—are not readily extractible. EHR integration requires less staff labor on the part of participating sites to acquire data, but there is still a need for manual submission of certain data elements and for SCD diagnosis confirmation. The comprehensive nature of the data also necessitates significant algorithmic processing to separate baseline data from data obtained during an illness episode. The tradeoff between scale and accuracy underlies the current unavailability of unstructured data elements, such as measures typically enumerated in idiosyncratic procedure or imaging reports (e.g. tricuspid regurgitant velocity or liver iron concentration). The Data Hub’s potential for impact is substantially augmented by support from ASH; for example, the ASH RC has sponsored investigator-led research projects using the Data Hub, helping to develop clinical knowledge from the data and improve data quality efforts.

Second, SCD data lag behind comparator diseases in terms of coverage of the population. This is not surprising given the much older and more established registries for hemophilia and CF, which are estimated to include on the order of 80% to 90% of their national populations with at least basic clinical information. In contrast, SCD data collection efforts comprise only a small fraction of the national population. The number of people with SCD in the US is not clearly established, but a lower bound estimate of 100,000 individuals is regularly used by the CDC and others (65). Using this estimate, GRNDaD includes approximately 5%, and the ASH RC Data Hub roughly 10%, of the population. Both of these registries are growing, but scalability will present challenges. GRNDaD is dependent on the participation of clinical sites and support staff to carry out patient consents and data entry. Thus far the number of clinical sites participating in GRNDaD has increased at an encouraging rate, especially recently, from 12 sites in 2022 to 71 sites in 2025. The SCD Data Hub is less dependent on staff for data entry, but does currently still require sites’ manual submission of case reports to confirm the diagnosis of SCD and other important elements that are not readily extractable from EHR data. In their current forms, both GRNDaD and the Data Hub are comprised of data from sickle cell centers or major health systems; both will require innovative approaches to include patients who are not seen at sickle cell centers but are an important and often overlooked population in research to date.

Third, the hemophilia and CF communities benefited enormously from the integration of their primary patient registries into a network of comprehensive care centers, facilitating discoveries in care optimization and enabling quality improvement work at the centers. The SCD community stands to benefit in much the same way if it follows suit. Indeed, the early stages of this integration are taking place with GRNDaD’s adoption by NASCC and the requirement that member centers of NASCC participate in GRNDaD. However, this partnership will require further growth on the part of both GRNDaD and NASCC to approach the utility of the registries and comprehensive care networks in hemophilia and CF. ASH has not yet adopted this model of integration to the same degree; it has developed the SCD Research Network, comprised of ~50 participating clinical sites, but does not currently have a focus on quality improvement.

Conclusions

Looking to the future

How can the issues above be addressed? Within the SCD community, the most straightforward answer, and one that would see upsides immediately, is developing collaborations between the major data collection efforts: GRNDaD, SCD Data Hub, and SCDC. Collaboration could take different forms, but critical aspects should involve data sharing, linking participants across all the registries, and collective funding. This would allow the strengths of each database to combine and compensate for relative weaknesses. To illustrate with several examples, the SCD Data Hub faces a challenge with cohort identification, requiring manual case identification by staff at participating sites. GRNDaD benefits from a well-defined manually phenotyped cohort of people with SCD and from an engaged provider community. Inclusion of GRNDaD’s cohort in the SCD Data Hub would considerably boost its population and clarify uncertain cases, while allowing access to PROs that are not readily extractable from EHRs; from the viewpoint of GRNDaD, the addition of EHR data would increase the granularity and richness of the registry substantially. This collaboration could also take an administrative form. Both GRNDaD and SCD Data Hub require at least some local staff labor for data entry; these could be streamlined into the same staff at each clinical site, improving efficiency and concentrating technical expertise. Addition of data from SCDC would improve epidemiological research on SCD. Both GRNDaD and SCD Data Hub are cohorts that, although large, are not fully representative of the national population. Inclusion of surveillance data would help us to understand what proportion of the full population is covered by these registries, as well as information about how these populations differ. Finally, collaborative funding would help each entity to maximize its potential and jointly work toward the shared goal of better understanding the modern individual living with SCD and how to best provide health care to these individuals. This is especially important in a reality of capricious federal funding—by collaborating to fund data collection in these lean times, we would be laying the groundwork to capitalize in times of greater funding opportunities. Early efforts at collaboration between data collection efforts are underway, and it is our hope these will grow into longstanding partnerships.

We must do better as a community to serve individuals in the US who are facing daily struggles from SCD. The hemophilia and CF communities have a long history of building strong patient registries and using them to better understand the respective diseases and improve our systems of care for people living with them. This has resulted in real, meaningful improvement in scientific discovery, quality of life, and survival for affected people with these diseases. CF and hemophilia, afflicting largely White American populations, have benefitted from long-standing community and government resources that were not, until relatively recently, available to Black American communities, and the robustness of their respective registries reflects this. For too long people with SCD have been deprived of the benefits from an established mature registry that is integrated into patient care (Figure 1). Now, with several relatively nascent but sizable data collection efforts expanding within the SCD community, it is past time for us to work together, building on and maximizing each effort’s strengths. We must ensure that the SCD population has the same access to high-quality patient registry data, to improved disease understanding, and to benefits in clinical care and quality improvement, as do the hemophilia and CF populations. People living with SCD, their families, and communities, deserve better, and we must all work to achieve this.

Figure 1 Benefits of high-quality registries for sickle cell disease stakeholders. Schematic illustration of benefits of a high-quality patient registry for sickle cell disease across multiple stakeholder groups: people living with sickle cell disease, clinicians and researchers, and the community at large. SCD, sickle cell disease.

Acknowledgments

We thank Carolyn Hoppe for feedback on drafts of this manuscript.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (William B. Ershler and Sheinei Alan) for the series “Adult Sickle Cell Disease” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-35/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-35/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-35/coif). The series “Adult Sickle Cell Disease” was commissioned by the editorial office without any funding or sponsorship. J.G.R. reports grants from AHRQ, NHLBI and Agios Pharmaceuticals, unrelated to this review article. S.R.W. reports research grants from the ASH Research Collaborative, consulting fees from Solas BioVentures, Agios and Novo Nordisk, unrelated to this review article. He received honoraria for being a contributing editor of The Hematologist, the official journal of American Society of Hematology. J.A.L. reports grants from Doris Duke Foundation, Bluebird, Pfizer, Novartis, Novo-Nordisk, NHLBI and American Society of Hematology, unrelated to this review article. She is an unpaid advisory board member for NASCC, a unpaid co-Director of the GRNDaD registry. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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