Throughout this report, there are descriptions of gaps in information and understanding about sickle cell disease (SCD) and sickle cell trait (SCT), the populations living with the disease and carrier status, the treatments used, the impact of SCD on the health care system, access to health care and other services, health outcomes, and the overall impact of SCD and SCT. To address what the committee perceives to be significant problems for those living with SCD, it will be necessary to collect reliable information to define the problems clearly, promote measurable changes to address them, and monitor the progress of these interventions and changes in the health system.
Data are often collected to gain insights into defined populations receiving clinical interventions or participating in local programs to understand outcomes across an entire health care system. Such analyses are of high value in generalizing to subpopulations with SCD who are similar to those studied, and these research efforts should be supported and promoted. This chapter focuses on efforts to ethically and efficiently collect reliable, high-utility data from whole populations or representative samples thereof and to use those data in improving health and health outcomes. Such data may have been originally gathered for other purposes (as with newborn screening [NBS] data or passive surveillance systems drawn from existing data sources), or efforts may be made to collect the most useful information from a wide variety of persons affected by SCD, as with a registry.
This chapter discusses these approaches and combined approaches and presents models of data gathering and use from other, similar diseases to provide context. All of the data gathering and investigations described here have the same goals: to better understand and thus be able to more effectively address the health, health outcomes, quality of life (QOL), and challenges to receiving quality care that face those with SCD and to better understand and advise those individuals on health and reproductive decision making.
The most successful example of the collection and use of population-wide data on SCD is NBS for SCD and SCT in the United States, which is now universal across all 50 states and the District of Columbia. NBS allows parents with SCD-positive newborns to gain quick access to knowledgeable hematologic care providers and should ensure that children receive standard-of-care treatment, such as prophylactic penicillin to prevent sepsis, appropriate immunizations, SCD screening to assess the risk of stroke, and hydroxyurea to reduce complications. NBS for SCT should help ensure that those with carrier status receive appropriate information as they reach reproductive age, and it may help health care providers monitor for health conditions associated with SCT. The promise of NBS is not consistently fulfilled, however. There is more to be done in sharing and translating positive results to caregivers and health care providers, and gaps remain in follow-up care.
Registries and surveillance systems have been in development for SCD for some time, and they show great promise for capturing much needed
information about those living with the disease, their care, and their outcomes. But there are challenges, merits, and deficits in collecting data for these important purposes. Furthermore, all efforts to gather health information face formidable ethical challenges and considerations; this chapter briefly discusses those considerations and concludes with suggestions for improving the collection, capture, and use of data from the different types of systems discussed.
This chapter is concerned with three approaches to gathering and analyzing information on those living with SCD and SCT. All three are ways of understanding the problem of SCD or SCT, but they address the disease and trait through different lenses and methodologies. The chapter uses the following definitions:
- Screening is the act of identifying the presence or absence of a disease or carrier state in a person. With respect to SCD in the United States, such screening typically takes place either at birth (NBS) or in the prenatal period. Screening may also be done for SCT at birth or any time throughout the life course. Symptomatic people who were not screened at birth may receive diagnostic testing for SCD.
- A disease registry is a system of data collection and communications with individuals affected by a particular disease. Such systems may be sponsored by government, disease advocacy organizations, pharmaceutical or device companies, or other entities. Patients typically consent to participate and share identifying and health information with the sponsor. Sponsors may provide benefits, such as education and information, access to health records, or information about clinical trials.
- Public health surveillance has been defined as “the ongoing, systematic collection, analysis, and interpretation of health-related data needed for the planning, implementation, and evaluation of public health practice” (CDC, 1986, p. ii). In particular, surveillance is aimed at evaluating and improving health at the population level and supporting and improving research and the care provided at the individual and clinical levels. Public health surveillance of SCD in the United States is typically conducted by state governments.
Screening has long been recognized as an important tool for early disease detection, and as technological advances have improved the ability to screen for an increasing number of diseases, screening rationales and criteria have also evolved. Even with these advances, however, it remains important to exercise caution and judgment beforehand and to make sure
that there are adequate resources for follow-up and treatment (NRC, 1975; Wilson and Jungner, 1968). During the early developmental stages of genetic and other types of screening, the proposed criteria typically included the importance of the condition, acceptability of the treatment, availability of care facilities, cost effectiveness, and an agreement on the progression of the condition (Andermann et al., 2008; Wilson and Jungner, 1968).
Over the past 40 years, researchers and providers have adapted these original criteria to reflect new knowledge of genetic diseases in order to increase the effectiveness of screening programs (Andermann et al., 2008; Grosse et al., 2010; Simopoulos and Committee for the Study of Inborn Errors of Metabolism, 2009). Newer criteria tend to emphasize equity, informed choice and autonomy, and evidence-based criteria (Andermann et al., 2008; Ross, 2012). More specifically, newer adaptations of the 1960s era Wilson and Jungner criteria take into account the effects on family members and parents, the importance of screening for rare diseases despite unfavorable cost–benefit analyses, the need for confidentiality concerning trait/disease status, and genetic counseling (Grosse et al., 2010). Although current programs vary in their methodologies and outputs, many describe their aim as providing results that can inform future reproductive choices, provide long-term care, and offer implications for family members (Andermann et al., 2008). The shift away from broad, blanket programs covering everyone to ensuring personalized, informed choice from all participants has sparked ethical debate and will continue to shape future genetic screening criteria (Grosse et al., 2010; NRC, 1975).
Types of Screening for SCD and SCT
The most common methods of screening include hemoglobin electrophoresis, isoelectric focusing (IEF), high-performance liquid chromatography (HPLC), and sickle solubility tests (Naik and Haywood, 2015). These tests all involve dried blood spots or whole liquid blood from a heel prick and check for red blood cell (RBC) count or hemoglobin variants. Electrophoresis is a classic method for identifying hemoglobinopathies; it uses an electric field to separate hemoglobins based on their charge. Further separation is possible by changing the pH and support medium. This method is the cheapest, but it is time and labor intensive (McGann and Hoppe, 2017). IEF and HPLC both separate hemoglobin based on net charge on a gel medium at particular pH levels. IEF requires more labor and time, whereas HPLC has rapid output and can be automated to run thousands of samples in minutes. However, HPLC is also cost intensive and requires high levels of technical expertise (McGann and Hoppe, 2017; Naik and Haywood, 2015). Because of issues with false positives and false negatives, confirmatory testing following the initial screening is generally
required (APHL and CDC, 2015). Sickle solubility tests may be unreliable and are known to yield false negatives in patients with severe anemia, in those with sickle hemoglobin (HbS) below a specific percentage, or in patients with high levels of fetal hemoglobin (HbF) (e.g., newborns less than 6 months old) (CDC, n.d.; Tubman and Field, 2015). Due to the cost and resources required for IEF, electrophoresis, and HPLC, they are usually not feasible options in low-resource settings. Point-of-care testing methods are being developed and may be particularly advantageous in both the United States and in settings with limited resources (McGann and Hoppe, 2017; Steele et al., 2019).
Screening for SCT and SCD involve similar sample collections; however, certain techniques are required to differentiate between SCT and SCD by discriminating among hemoglobin variants (Naik and Haywood, 2015). Solubility testing only detects the presence or absence of sickled hemoglobin and thus cannot discriminate between SCT and SCD (Tubman and Field, 2015). IEF, electrophoresis, and HPLC quantify hemoglobin and so can discriminate, making them the primary methods for NBS programs and confirmatory testing. Because these methods are more costly, they are usually not the first choice in low-resource settings. A study in Uganda found that the sickling test followed by confirmation with electrophoresis was a sensitive and cost-effective method for screening children (Okwi et al., 2009). Because of gaps in follow-up and the optimal communication of results both in the United States and globally, there is a pressing need for a point-of-care testing method to deliver results within minutes to hours, rather than days to weeks (McGann and Hoppe, 2017). Several point-of-care tests with high sensitivity and specificity in SCT and SCD detection have been developed in recent years and used in various low-resource countries (Alvarez et al., 2019; Nnodu et al., 2019; Segbena et al., 2018). Some continue to have the barrier of being unable to detect hemoglobins aside from HbS or normal hemoglobin, HbA (Mukherjee et al., 2019).
Prenatal diagnoses and other means of determining whether a fetus has SCD are medical procedures designed to inform parents so that they may prepare for raising the child or decide whether to terminate a pregnancy. In the United States, prenatal screening for SCD is not universal, and its occurrence depends on individual desires, insurance coverage, and the family’s history of disease (Gallo et al., 2010). The procedures used as part of prenatal screening include amniocentesis and chorionic villus sampling (CVS), both of which are invasive and conducted early in the pregnancy—between the 10th and 12th week of the pregnancy for CVS and the 14th and 20th week for amniocentesis (Yenilmez and Tuli, 2016). These tests
pose minor risks of miscarriage or complications; researchers have piloted new methods of non-invasive prenatal diagnosis, such as cell-free fetal DNA tests where fetal DNA that is found in the mother’s blood is tested for genetic conditions for use in prenatal SCD diagnosis. Infants born with SCD after such screening are identified and recorded as a part of routine NBS in the United States.
The results of prenatal screening and information about whether the pregnancy came to term may or may not be transferred to the state’s NBS program; practices differ by state. For example, California has a sickle cell surveillance program which compiles data from numerous sources, including NBS programs, Medicaid, emergency department (ED) admissions, clinic care, and vital records (Feuchtbaum et al., 2013). While prenatal diagnosis can be an important part of early pregnancy care, it is not yet useful as a data source for tracking SCD at a population level due to the small sample size and lack of integration with other medical records (Housten et al., 2016; Savage et al., 2015).
Because of the high morbidity and mortality associated with SCD, universal NBS offers substantial payoffs in addressing comorbidities and reducing mortality (Vichinsky et al., 1988). NBS followed by confirmatory screening is recommended by 2 months of age so that, if necessary, it is possible to initiate treatment and follow-up care promptly. Early prophylactic treatment with penicillin is essential to combat what would otherwise be a high rate of mortality from infections (Lin, 2009). More generally, it is crucial to establish care early in life to manage complications and build a continuum of care.
Among U.S. territories NBS began in the U.S. Virgin Islands in 1987 and in Puerto Rico in 1977 (Morales et al., 2009). By 2006 universal NBS screening was implemented in all 50 states and the District of Columbia (Benson and Therrell, 2010). Today, NBS has been highly successful in most states, providing critical information to parents, pediatricians, and pediatric hematology care providers that enables young children to avoid most of the severe complications, which are major contributors to infant and childhood mortality (AAP Newborn Screening Task Force, 2000). In particular, the high rate of uptake of prophylactic penicillin for young children has saved countless children; thus, universal NBS has proven to be a cost-effective, life-saving intervention in the United States (El-Haj and Hoppe, 2018). This screening can also provide valuable information on the incidence of SCD in that jurisdiction. On the other hand, screening is usually not intended to be longitudinal, nor does it capture information on treatments, complications, or other health outcomes for those diagnosed. NBS is also expensive, but
the cost is typically shared by state agencies and insurers, and it is seen to have a reasonable cost–benefit ratio in lives saved and health care resources conserved by keeping children healthy.
In most states, NBS also identifies newborns who are SCT carriers. Although it was initially thought that SCT status had virtually no clinical implications beyond reproductive decision making, recent studies have shown that some individuals with SCT are at risk for a variety of clinical complications (Alvarez, 2017; Alvarez et al., 2015; Elliott and Bruner, 2019; Naik and Haywood, 2015; Shetty and Matrana, 2014) (further addressed in Chapter 4). These complications include exertional rhabdomyolysis (muscle breakdown), cardiac dysfunction, sudden death, chronic renal disease, cancer, splenic infarction, and venous thromboembolism (Key et al., 2015; Naik and Haywood, 2015; Naik et al., 2018). Therefore, knowledge of carrier status is important to increase individuals’ awareness of these rare but serious potential complications and to help guide reproductive decisions in adulthood. Unfortunately, the transfer of knowledge from a state NBS program, parents, or providers to the teens and young adults who ultimately need it to make informed life choices is not systematic. Promoting knowledge of SCT carrier status in young adults should be a high priority, but no states are currently known to track the health status or reproductive outcomes of those with SCT.
SCD-related legislation and programs and federal funding vary by state. Studies show that 18 states had no legislation and that states received funding from a variety of federal agencies such as the National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and Centers for Disease Control and Prevention (CDC) (Benson and Therrell, 2010; Minkovitz et al., 2016).
According to information available from the Association of Public Health Laboratories’ (APHL’s) website, roughly half of U.S. states conduct some long-term follow-up care coordination when NBS identifies SCD (NewSTEPs, 2020). Practices vary widely, however, and persons with SCD are typically tracked up to 5 years—but only if they stay within the state of birth (APHL and CDC, 2015; NewSTEPs, 2020). Furthermore, there are no standard requirements for data storage for any specified length of time. For example, the Maryland Department of Health is required by law to keep newborn samples for 25 years so that tests can be replicated, if needed (Maryland Department of Health, n.d.). By comparison, dried blood spots in Texas may be kept by law for 2 years unless a parent provides consent for longer storage (Texas Department of State Health Services, 2019). California’s surveillance program was able to track individuals with SCD by location and report the prevalence of complications, health care use, and distribution of haplotypes from records between 2004 and 2008 (Feuchtbaum et al., 2013). Challenges in synthesizing all of these data include variability
in data source, duplicate records, and limited access to data sources conducive to research. Similar long-term program development in different states may face these same challenges of fragmentation and variability.
These inadequacies can be tied to the structural racism surrounding SCD, which results in fewer funding sources and incentives to develop interventions (Bediako and King-Meadows, 2016). Furthermore, there is high variability in state screening programs, although it is unclear whether this is influenced by differences in prevalence across states or specific structural factors (Minkovitz et al., 2016).
One study of postpartum women found a poor understanding of NBS, indicating a need to educate parents about NBS and its importance (Lang et al., 2009). In states with few state-led initiatives or policies, individuals, families, and the general public may not have a clear understanding of the necessity for screening and appropriate follow-up.
Subpopulation Screening for SCT
In light of the emerging knowledge of complications that may be associated with SCT, as discussed in Chapter 4, there are various subpopulations for whom screening for SCT makes particular sense.
A key subpopulation is pregnant women, given the current technologies that allow for genetic testing before birth. The discussion earlier in this chapter established the importance and opportunities to ensure that pregnant women are educated about SCD and SCT and know their status. Studies have found that pregnant women generally fall into three categories: those who wish to carry the child to term regardless of status, those who choose medical termination of a pregnancy with positive results, and those who do not wish to be screened at all (Gallo et al., 2010; Smith and Aguirre, 2012). The women who refuse screening may be basing this choice on the fear of being rejected by their partner, their religious beliefs, or the stigma surrounding discussing SCT status openly (Asgharian et al., 2003).1
Exertional sickling and exertional heat illnesses (EHIs) are also of great concern, particularly for members of the U.S. military. In the 1970s, the first military cases of exercise-induced death without a pre-existing condition were identified and classified as sudden death induced by sickling (Jones et al., 1970). Early studies of military recruits found that those with SCT had an increased risk of exercise-induced sudden death in basic training (Charache, 1988; Kark et al., 1987).
In recent years, as knowledge of the risks associated with SCT has grown, debates about how best to handle training for recruits with SCT
1 Both studies collected data on women in the United Kingdom rather than the United States.
have resumed (Mitchell, 2018). Case reports of the deaths of two soldiers with undetected SCT who collapsed as they attempted to finish a 2-mile run demonstrated that rhabdomyolysis caused by intense exercise could be fatal (Ferster and Eichner, 2012). A study of active-duty soldiers with SCT found an increased risk for exertional rhabdomyolysis, similar in magnitude to the effect of tobacco use (Nelson et al., 2016).
Currently, the U.S. military has no standardized protocol for dealing with service members with SCT; Air Force and Navy recruits wear armbands to indicate that they have SCT throughout training, for example, whereas Marine Corps recruits are not identified (Webber and Witkop, 2014). The U.S. Army currently uses SCT screening only for specific combat deployments and specialties, such as high-altitude work (Nelson et al., 2016). Furthermore, there are no protocols for handling physical activity or mitigating risk for identified individuals. Instead, the Army uses broad precautions to reduce the risk of dehydration and EHIs in all military personnel.
Even though the risks to military members with SCT are well understood, mandated screening is a highly contentious topic because of concerns about discrimination and stigmatization and because of doubts concerning the benefits of screening (Kark et al., 2010; Nelson et al., 2016; Singer et al., 2018b; Webber and Witkop, 2014). The theorized benefits of universal SCT testing include a reduction in exercise-induced sickling deaths, increased knowledge of SCT complications, and decreases in risky behaviors that can lead to exercise-induced illness. Proponents of mandatory military screening argue that knowledge of SCT status could lead recruits to change their behavior; an aware trainee would be more likely to end a workout early rather than persisting through the pain (Jones et al., 1970; Webber and Witkop, 2014). It is however important to note that at least one study of 48,000 soldiers, 3,500 of whom had SCT, found that while carrier status is associated with a higher risk of exertional rhabdomyolysis, it is not associated with a higher risk of death (Nelson et al., 2016).
National Collegiate Athletic Association (NCAA) student-athletes are another subpopulation targeted for SCT screening. In people with SCD, extreme exertion and heat and high altitudes can lead to sickling, which may present as normal exhaustion or heat-related illness (Anderson et al., 2011; Baker et al., 2018) but can result in mortality if it is not detected and treated appropriately. As discussed above, intense exercise can also lead to exertional rhabdomyolysis (Nelson et al., 2016). Between 2000 and 2011 there were 16 non-traumatic football deaths among NCAA athletes, of which 10 were attributed to exertional sickling (Anderson et al., 2011). Furthermore, in an examination of NCAA student-athletes, SCT was found to be associated with a 37-fold higher risk for exertional death (Harmon et al., 2012). Concerns over exertion-related deaths in
student-athletes led to an NCAA screening policy designed to identify SCT and prevent catastrophic consequences from acute sickling events associated with physical exertion.
A 2018 survey of NCAA staff and athletes found that staff members were more supportive of SCT screening than were student-athletes (Baker et al., 2018). The athletes’ concerns included relevance to their racial status, fear of being treated differently by coaches, and poor understanding of the necessity of screening. At least one student felt that athletes should know their trait status before college, rendering college screening unnecessary. In addition, many white athletes felt that they did not need to be screened because they believed SCT did not affect white individuals. The study also revealed various challenges to implementation, including the financial costs to institutions, variability in implementation and follow-up, and long wait times for the results (Baker et al., 2018). The coaches were most concerned that waiting for the test results would contribute to time lost for playing, conditioning, and practice. Several organizations have also raised concerns about athlete screening.
In 2012 the American Society of Hematology (ASH) issued a policy statement that opposed mandatory screening by the NCAA, citing concerns over stigmatizing individuals and recommending universal interventions to prevent exertion-related deaths instead, regardless of carrier status. Another frequently raised concern is genetic discrimination, especially because the NCAA is not covered under federal genetic anti-discrimination laws (Jordan et al., 2011). Invasions of genetic privacy are also possible, given that mandatory testing of athletes reveals their genetic status and information on the carrier status of their parents and relatives (Jordan et al., 2011). A recent study found that mandated screening could identify only up to one-third of individuals with SCT who were at risk for EHIs (Singer et al., 2018a). Critics of universal screening point to potential inefficiency, discrimination, and the lack of evidence-based research to support such a policy (Singer et al., 2018a; Webber and Witkop, 2014).
Missed Opportunities for Screening
There are specific groups that can be—and often are—missed within the spectrum of SCD care, especially screening. For instance, immigrants to the United States are not often screened in their respective countries, and the United States lacks a cohesive policy on screening immigrants for sickle cell status, so data are limited on the follow-up of immigrant adults and children (Faro et al., 2016). In some countries, such as Germany, rising immigration rates corresponding with increasing prevalence of SCD have prompted calls for increased screening of immigrants and general education for providers (Kunz et al., 2017). The ethical and legal implications of
such policies are currently being debated, as the German Genetic Testing Act allows individuals the right to know—and to not know—their individual genetic status for a particular disease. Furthermore, health care in Germany is not currently set up to handle SCD care, and thus a functioning infrastructure must be developed before adopting any SCD-specific screening policy (Frommel et al., 2014). In the Netherlands a study found that approximately 27 percent of new pediatric patients were immigrants, a majority of whom were diagnosed in the Netherlands for the first time (Peters et al., 2010). The lack of data on SCD and SCT in immigrant populations is a known information gap. Global immigration patterns should inform policies in the United States and other countries in order to effectively screen and treat immigrants in need of care and follow-up.
In addition, individuals born in the United States before the adoption of NBS protocols are at risk of falling through the cracks if they are not screened as adults. Research shows that most adults are not aware of their personal SCT status and that many do not wish to be screened, indicating that there is a need to reach out to older populations to assess their risk (Harrison et al., 2017). In the case of individuals unaware of their status, it may be effective to have them screened by ED providers when they present for any condition (Wright et al., 1994).
Adult screening for SCT can be problematic. For example, researchers found that in St. Louis “no coordinated agency exists to provide systematic trait testing or genetic counseling for individuals at risk for SCT” (Housten et al., 2016, p. 2). The same researchers also found that 10.5 percent of adults recruited at eight different community sites who were asked to participate in a screening test for SCT declined (Housten et al., 2016). Additionally, follow-up with genetic counseling did not routinely occur; in the sample only 56 percent of those tested chose to meet with a genetic counselor. Study participants under the age of 30 were least likely to follow up with genetic counseling (Housten et al., 2016).
Despite the importance of effectively screening and following up on SCD and SCT screening results, there is a notable lack of guidelines and policies advising providers on how to effectively communicate disease or carrier status to affected people or their parents. Initially, NBS was not designed to communicate carrier status, and identifying SCT was solely a by-product of SCD testing (Pecker and Naik, 2018). Consequently, there was little direction given to clinicians about communicating SCT status discovered during NBS. Today, the communication of neonatal screening results on SCD (and on SCT where conducted) varies by state, with many states providing the results to providers but not to parents.
Once a dried blood spot from NBS is sent to the laboratory, the tests are generally performed within 72 hours, followed, if necessary, by confirmatory testing. The results are then sent to the primary care provider (PCP), who is left to decide the appropriate way to communicate with the family and specialists (El-Haj and Hoppe, 2018). One study of NBS programs found that only 40 percent and 37 percent of families were directly informed of their child’s SCD or SCT status, respectively (Kavanagh et al., 2008). However, most NBS programs shared results with primary care clinicians (100 percent and 88 percent for SCD and SCT, respectively) and with the hospitals of birth (73 percent and 63 percent for SCD and SCT, respectively) so that they could give the results to the families (Kavanagh et al., 2008). Family notification rates varied widely from state to state, indicating greater issues with communicating screening results in some birth locations.
Effective communication of SCD and SCT testing results is extremely important because parents who discover that their child tested positive will often experience mental distress, ranging from anxiety to depression (Farrell and Christopher, 2013). Studies indicate that providers may use a great deal of scientific jargon, which hampers parental understanding and limits effective decision making (Farrell and Christopher, 2013). It has been suggested that communicating SCT status to parents could be more effective if PCPs treated SCT as more than an incidental finding and if an effort was made to connect providers with families through calls (Christopher et al., 2012). Following up on screening results has been found to require minimal effort if NBS programs have adequate funding to connect families with local providers.
In addition, a community-based screening program was found to be effective in increasing knowledge of SCT/SCD status and increasing the likelihood of follow-up genetic counseling, indicating that such interventions may be beneficial if tailored to specific communities (Housten et al., 2016). State programs looking to build patient registries and increase their capacity for patient–data linkage have explored linking medical records (Abhyankar et al., 2010; Hinton et al., 2014; Posnack, 2015). Health care professionals are now focusing on standardizing an approach to care due to the current gaps in patient follow-up, the lack of information on the impact of screening and treatment, and the absence of a cohesive policy on communicating genetic screening results (Abhyankar et al., 2010; Hinton et al., 2014, 2016; Hoots, 2010). This standardization will help to reduce miscommunications among laboratories, providers, and patients and improve care. One proposed method would be to link individuals’ screening results to their birth certificates (Hinton et al., 2016; Posnack, 2015; Zuckerman, 2009). This could potentially decrease the loss to follow-up that occurs across state lines. It would also provide records of
population-level information and allow for potential access to data on usage and socioeconomic information. Although current screening communication is inadequate in terms of its outreach and quality, standardizing protocols for screening and collecting data could improve the efficiency of care and communication.
State-Level Approaches to Screening and Communicating Results
State-funded screening programs usually source money from third-party programs, such as Medicaid, Title V, or federal allocations (Blood-Siegfried et al., 2006). This results in great variability in screening and communication procedures (Blood-Siegfried et al., 2006; Hoff and Hoyt, 2006; Kavanagh et al., 2008). As Table 3-1 shows, this variation means that numerous stakeholders are not informed about SCT and SCD results, including hematologists, PCPs, and families (Kavanagh et al., 2008). Of those providers who do communicate results, a small percentage report that they lack the competency to adequately do so.
The National Academies SCD committee contacted APHL to obtain updated results on states’ follow-up procedures for SCD- and SCT-positive screens. In response, APHL fielded a brief survey (see Appendix D) to members of their hemoglobinopathies workgroup and obtained responses from six state NBS programs (Colorado, Connecticut, Florida, New Jersey, Tennessee, and Washington). All of the programs that took part in the survey had standardized protocols (written/formal versus informal) for SCD screening, turnaround time for communicating results, and follow-up (see Appendix D). Although communication protocols varied, all programs had a turnaround time ranging from 1 day to a few weeks. Furthermore, 98–100 percent of babies who screened positive for SCD received followup within 1 year. All six NBS programs had a standardized protocol for informing parents of their children’s SCT status, and five programs had a required turnaround time (1–6 weeks).
The five NBS programs with follow-up protocols for SCT were not able to provide the percent of newborns who screen positive and receive follow-up in 1 year. These programs distribute letters to parents or PCPs or both, and the NBS program does not receive additional information after that. One program provides SCT results to requests from any properly authorized university or organization. These preliminary findings show possible improvements in screening procedures since 2008. Larger and more comprehensive studies are needed to confirm this and to fill the knowledge gaps about state NBS screening procedures. Further research will also help identify areas that still need to be addressed to optimize the quality and impact of NBS.
|State||Sickle Cell Disease||Sickle Cell Trait|
|Alabama||PCP, heme., hospital, sickle cell org.||PCP, public health nurse, sickle cell org.|
|Alaska||PCPa, heme.,a hospitalb||PCP,a hospitalb|
|Arizona||PCP, heme., family, sickle cell org.||PCP, family, sickle cell org.|
|Arkansas||PCP, heme., hospital||PCP, family, hospital|
|California||PCP, heme., family, hospital||PCP, family, hospital|
|Colorado||PCP, heme., family||PCP|
|Connecticut||PCP, heme., family||PCP, family, hospital, sickle cell org|
|Delaware||PCP, heme., family, hospital, Child Development Watch (with permission)||PCP, family, hospital|
|District of Columbia||PCP, heme., family, hospital, sickle cell org.||PCP, heme., family, hospital, sickle cell org.|
|Florida||PCP, heme., family, hospital||Family|
|Georgia (Grady)||PCP, public health nurse|
|Georgia (MCG)||PCP, public health nurse|
|Hawaii||PCP,a heme.,a public health RN,a family,a hospital,b Hawaii Community Genetics||PCP,a hospitalb|
|Idaho||PCP,a heme.,a hospitalb||PCP,a hospitalb|
|Illinois||PCP, sickle cell org.||PCP, sickle cell org.|
|Indiana||PCP, heme., family, hospital, sickle cell org.||PCP, sickle cell org.|
|Iowa||PCP, heme., hospital||PCP, heme., hospital|
|Kentucky||PCP, heme., hospital||PCP, hospital|
|Louisiana||PCP, heme., family, hospital, sickle cell org.||Family|
|Maine||PCP, heme., hospital||PCP, heme., hospital|
|Maryland||PCP, heme., family, hospitalb||PCP,b hospitalb|
|Massachusetts||PCP, heme., hospital||PCP, family, hospital|
|Michigan||PCP, heme., family, hospital, sickle cell org||PCP, family, hospital, sickle cell org.|
|Minnesota||PCP, heme., hospital||PCP, hospital|
|Mississippi||PCP, heme., public health RN, family, hospitalb||PCP, public health RN, family, hospitalb|
|Missouri||PCP, heme., family, hospital||PCP, heme., family, hospital|
TABLE 3-1 Continued
|State||Sickle Cell Disease||Sickle Cell Trait|
|Nebraska||PCP, heme., hospital||PCP, family, hospital|
|Nevada||PCP,a heme.,a hospitala||PCPa|
|New Jersey||PCP, heme., family, hospitalb||family, hospitalb|
|New Mexico||PCP, heme., public health RN, family, hospital, sickle cell org.||PCP, public health RN, hospital, sickle cell org.|
|New York||PCP, heme., public health RN, hospital||PCP, hospital|
|North Carolina||PCP, sickle cell org., sickle cell educator||PCP,b sickle cell org.,b sickle cell educator|
|North Dakota||PCP,a heme.a||PCP,a heme.a|
|Ohio||PCP, heme., hospital||PCP, hospital, sickle cell org|
|Oklahoma||PCP, heme., hospital, sickle cell org.||PCP, family, sickle cell org|
|Oregon||PCP, heme., hospital||PCP, hospital|
|Pennsylvania||PCP, heme., hospital||PCPa, heme.a|
|Rhode Island||PCP, heme.||PCP|
|South Carolina||PCP, hospital||PCP, hospital, sickle cell org.b|
|South Dakota||PCPa, heme.,a hospitalb||PCP,a heme.,a hospitalb|
|Tennessee||PCP, heme, family, hospital||PCP, family, hospital|
|Texas||PCP, public health RN, family, hospital||PCP,b hospitalb|
|Utah||PCP, hospital||PCP, hospital|
|Vermont||PCP, heme., family||PCP, hospital|
|Virginia||PCP, heme., hospital,b sickle cell org.||PCP, family|
|Washington||PCP, heme., hospital, sickle cell org.||PCP, hospital, sickle cell org.|
|West Virginia||PCP, heme.||PCP, family|
|Wisconsin||PCP, heme., public health RN, hospital||PCP, hospital|
|Wyoming||PCP, heme., family||PCP|
NOTE: heme. = hematologist; MCG = Medical College of Georgia; org. = organization; PCP = primary care provider; RN = registered nurse.
a Contracts with outside laboratory/program.
b Information provided by state laboratory only.
SOURCE: Kavanagh et al., 2008.
A lack of funds can also be a significant barrier to screening; the patient can incur a cost ranging from relatively low (e.g., $10) to a high of $130, depending on the state (Blood-Siegfried et al., 2006). Budget cuts to health programs mean that state-level priorities for SCD- and SCT-related activities are low compared with other public health investments, and improving the quality of neonatal care for SCD may require greater advocacy (Minkovitz et al., 2016).
NBS data can be used in a variety of ways to improve the lives of individuals with SCD and SCT. Doing so will require that the information is made available to all of those who should receive it, including family members and relevant clinicians, and that the people who do receive it understand what it means and are equipped to make effective decisions based on it.
If parents are to understand the implications of SCD and SCT for their children and themselves, it is important that they receive screening for hemoglobinopathy and genetic counseling (Chudleigh et al., 2016). As noted in the previous section, while providers, hospitals, or even families may be informed of a child’s status, there is little indication for how these individuals are referred to genetic counselors or for communicating information about their status from birth through adolescence and adulthood, especially for SCT (Taylor et al., 2014). A study conducted in Michigan to examine the prevalence of genetic counseling provided by PCPs found that the physicians surveyed reported that they were more likely to provide some genetic counseling to parents of children who are cystic fibrosis carriers (CFCs) than to parents of children with SCT (92 percent versus 80 percent; p < 0.01) (Moseley et al., 2013). Parents of children with CFC were also more likely to be counseled by genetic counselors or specialty centers than parents of children with SCT (85 percent versus 60 percent; p < 0.01) (Moseley et al., 2013). A lack of available counselors, parents declining counseling, and the physician not recommending counseling were all cited as reasons that contributed to the disparities.
Reproductive Decision Making
Because SCD is life threatening, it has important implications for reproductive decisions. With the advent of prenatal genetic testing for SCD, parents with SCT can now learn relatively early in a pregnancy whether their child will have SCD, which offers them options, including medical
termination. Parents must carefully weigh this decision based on their assessment of their potential child’s likely QOL and their personal values. Both prenatal and postnatal counseling must be provided appropriately, taking into account the child’s SCD and SCT status and specific follow-up and treatment needs. Whether or not parents choose to terminate an SCD-positive fetus, they should receive appropriate counseling to deal with the impacts of their decision (Pecker and Naik, 2018).
There are various barriers to parents making informed decisions. One issue is the vast amount of misinformation and misunderstanding that surrounds the topic, some of which may be perpetuated by health care providers. A Hispanic participant in a qualitative interpretive meta-synthesis study reported that her health care provider had told her that SCD was an African American disease (Smith and Aguirre, 2012). Additionally, some men denied their SCT status and tried to convince women that they were not positive, perhaps because of the history of discrimination associated with the disease and a fear of stigma if their status was revealed (Smith and Aguirre, 2012). One study that examined health beliefs regarding counseling and testing found that African American women strongly believed in the severity of SCD and the benefits of counseling but did not believe that they were at risk of having a child with SCD (Gustafson et al., 2007). Genetic counseling offers a missed opportunity for educating individuals with SCT and their families and providers about the benefits of counseling and standardizing referrals to counselors.
Some parents avoid prenatal genetic testing because of the cost or because of a fear that the test might be painful (Gustafson et al., 2007). When designing interventions to increase genetic screening rates, fee waivers and effective reproductive counseling strategies may help eliminate concerns about financial burden or pain (Mayo-Gamble et al., 2018).
Additionally, it is important for all prospective parents to understand and be aware of the potential to use pre-implantation genetic diagnosis (PGD) in conjunction with in vitro fertilization (IVF). Hemoglobinopathies can be diagnosed very early with PGD via a cell biopsy from the embryo or zygote (Vrettou et al., 2018), making it possible to decide whether to implant an embryo based on the results of the test. The first published case of a successful unaffected pregnancy using PGD in conjunction with IVF was in the late 1990s (Xu et al., 1999). Since then, this procedure has remained an option for informed pregnancies and also makes it possible for families that already have affected children to have another child who is a potential match as a donor for human stem cell transplantation (Vrettou et al., 2018).
Families are, however, confronted with a major financial hurdle with this option because public and private insurance coverage for PGD is variable and may be tied to coverage for infertility treatment, leaving some couples to cover the test out of pocket. Currently, only 16 states in the
United States have laws that require insurers to cover or offer coverage for infertility treatment (NCSL, 2019). A qualitative study with 18 genetic high-risk couples found that the study participants were concerned about the costs associated with PGD but ultimately prioritized the opportunity to not pass on a genetic disorder to their offspring (Drazba et al., 2014). Most families who have a child with SCD report an interest in learning about PGD and say that they would consider using it in a future pregnancy (Darbari et al., 2018).
Parents who oppose IVF with PGD often cite ethical or religious concerns (Schultz et al., 2014). Unfortunately, a small study of 19 parents with a child with SCD in the United States found that less than half (44 percent) of the parents surveyed knew about PGD as an option (Darbari et al., 2018). Thus, providing access to preconception counseling and education on both PGD and IVF may be an important future direction for parents with SCT.
Long-Term Follow-Up for SCT- and SCD-Positive Individuals
The long-term follow-up of individuals with SCT represents a significant gap in the overall spectrum of care and also a public health problem, as these individuals have a lifelong risk of passing on the sickle cell variant to their children or having children affected by SCD. These individuals may be predisposed to the emerging risk of certain conditions (discussed in Chapter 4) (Grant et al., 2011). Children with SCD are sometimes followed as long as they remain within the state, but they are no longer tracked if they cross state lines. State-level tracking of individuals with SCT is extremely disjointed, and there is little communication between states (Kavanagh et al., 2008; Minkovitz et al., 2016).
The accessibility of SCT status results later in life varies across states as well, but the committee was unable to find documentation about specific state practices. The committee was also unable to find any known long-term follow-up of health conditions or outcomes for those with positive SCT status in the United States, despite growing evidence of an increased risk for certain chronic health conditions (Alvarez, 2017; Alvarez et al., 2015; Elliott and Bruner, 2019; Naik and Haywood, 2015; Naik et al., 2018; Shetty and Matrana, 2014). While a first priority should be population-based surveillance for those living with SCD, given the severity of the disease, a focus on SCT as an emerging public health problem may be an important future policy initiative. Framing SCT as a public health concern may help increase funding, advocacy, and research for both SCD and SCT.
Even when NBS programs are highly effective, comprehensive follow-up and care for those diagnosed with SCD (SCD-positive individuals) are still required to ensure that these individuals receive quality care to reduce SCD-related morbidity. Assessing the quality of this care is important in
order to develop and implement policies universally. A 2016 study identified key indicators that could be used to assess the quality of care for individuals with SCD and SCT (Faro et al., 2016). High-quality care provided early genetic counseling, timely reporting of results, screening for immigrants, and penicillin prophylaxis. A 1998 study in California, Illinois, and New York found that follow-up from NBS was lacking in the areas of treatment and compliance (CDC, 2000). Antibiotics are still underused, and there are adherence issues being reported (Cober and Phelps, 2010; Reeves et al., 2018; Teach et al., 1998).
In a national CDC study, 76 percent of doctors reported providing penicillin prophylaxis, but only 44 percent of patients followed through (CDC, 2000). Several other studies found similar trends in treatment and adherence among providers and patients, respectively (Cober and Phelps, 2010; Reeves et al., 2018; Teach et al., 1998). A study synthesizing the effects of NBS programs found that surveillance information was needed to obtain longitudinal data and carry out follow-up programs (Yusuf et al., 2011). One NBS program in New York had a 12 percent loss to follow-up among children, indicating that these gaps in follow-up care must be addressed to ensure the effectiveness of these programs (Yusuf et al., 2011).
Other Approaches to Educating the Public About SCD
One way to communicate the importance for SCD and SCT screening is to include it within public health education focused on other areas. One program in Zambia, for instance, integrated screening into a dental hygiene program that provided free toothbrushes and toothpaste and informed rural residents of tooth decay (Chunda-Liyoka et al., 2018). Combining several health interventions within a single program or roll-out allows for increased reach and access that a single program might not have. Other possible education methods would be to work through registered nurses, who are already heavily involved in the care and case management of individuals with SCD (Arhin, 2019), or with community-based organizations (CBOs) and patient advocacy groups.
Patient disease registries, which vary widely in their structure, scope, and purpose, are distinguished by their common approach: they collect information from a subset of people with a particular disease to develop a generalizable picture of who has the disease, what effects they are experiencing, and how they are being cared for (AHRQ, 2014). That information typically includes the registrants’ characteristics, clinical data and test results, and health status over time. Like clinical trial databases, registries
typically aim to collect highly reliable and precise data. Depending on the sponsorship and intended goal, patient registries are likely to provide valuable information to researchers, drug and device developers, clinicians, and sometimes the patients themselves (AHRQ, 2014).
Registries typically require a high level of resources to recruit, consent, and collect detailed data. Registries may be sponsored and funded by grants or government contracts, pharmaceutical companies or device developers, professional associations, or CBOs. There can be significant overlap between patient registries and clinical trial data collection in the types of data collected and their use (Forrest et al., 2011). Registries may or may not be long-term or longitudinal, and the sponsors may or may not widely share the results of data analysis.
Registry participants may be rewarded in various ways, including receiving a stipend for their time, being connected with clinical trials, or receiving education or support in forums or from trained community health workers. Registries for rare diseases that include clinical data can be helpful for researchers tracking clinical outcomes related to specific treatments or preventative measures.
By their nature, registries collect identifiable and sensitive information about patients and are typically designed so that patients (or their legal guardians) must explicitly consent to take part by sharing their information directly or providing access to their medical records. Although some registries capture information from the majority of patients (e.g., state cancer registries), there are always nonparticipants—due to challenges related to consent, access to the registry portal or the data collection interview, or simple unwillingness—and this can create bias in results derived from registry data if those results are assumed to apply to all of those living with the disease.
Examples of SCD Patient Registries
Multisite clinical registries have been used to track the specific outcomes or sequelae of the complications of SCD. These may be considered extensions of the clinical trial model.
A granting agency may conceive and fund federally supported registries, with research institutions performing the work of obtaining patient consent, collecting data, analyzing the data, and disseminating the results. These efforts may be funded to develop methodologies through pilot programs or to implement registry systems on a larger scale. NIH’s National Heart, Lung, and Blood Institute (NHLBI) implemented the Comprehensive Sickle Cell Centers Collaborative Data collection effort from 2005 to 2008, which gathered data from 3,640 persons with SCD nationwide via clinical interviews and medical record extraction (Dampier et al., 2011; NHLBI, 2007). NHLBI currently supports the Sickle Cell Disease Implementation
Consortium, begun in 2016, which includes a patient registry with participants recruited from the participating centers. The goal of this SCD registry is to collect data on 2,400 adolescent and adult patients (SCDIC, n.d.).
Multiple Private-Sector Efforts to Collect and Use Data on Individuals with SCD
CBOs frequently collect records of the health of their clients, whether formally or informally. For example, the Sickle Cell Disease Association of America (SCDAA), the largest national CBO focused on SCD, launched its patient registry, Get Connected, in 2018 with multiple aims: providing patients with the storage of and easy access to their medical information, offering information and resources to patients and their families, and helping with clinical research planning and recruitment. As of June 2018, the registry, which had been promoted by SCDAA since 2015, had collected data on nearly 6,128 persons, 4,984 of whom had SCD and another 633 with SCT. The remaining enrollees are non-patients (Pena, 2018).
Professional organizations may also support or host data collection systems for those affected by the focal conditions. In 2018, for example, ASH launched the ASH Research Collaborative (RC) Data Hub, which functions as a data repository with information on hematologic diseases and which was set up to facilitate clinicians’ and researchers’ access to patient data. This effort may be of particular use to researchers studying rare hematologic diseases, which may not otherwise have a centralized data collection system. The RC Data Hub can collect prospective and retrospective data from both U.S. and international sources, including inpatient and outpatient clinical systems, industry and government datasets, patients, and other existing registries (ASH RC, 2019). The data include genomic or molecular correlates, clinical and laboratory data, patient-reported outcomes, information on population health, and social determinants. The RC Data Hub automates data collection when necessary and allows for information on new diseases to be captured. In addition, automation allows researchers and medical personnel to promptly retrieve data that can be used to answer certain research questions through advanced querying.
In 2019, ASH launched the Sickle Cell Disease Clinical Trials Network, which provides a framework for finding and categorizing patient cohorts for clinical trials, placing trial sponsors with sites, and recruiting eligible patients. It collects information from the RC Data Hub to assist with identifying areas of research and treatment that could benefit from additional data. The mission of the network is to “improve outcomes for individuals with SCD by expediting therapy development and facilitating innovation in clinical trial research” (ASH RC, 2018).
In countries that are disproportionately affected by a specific genetic disease, registries may be sponsored by the national government; one such example is Greece’s hemoglobinopathy registry, established in 2009. Because this registry includes everyone diagnosed with SCD and follows these individuals over time with the goal of conducting longitudinal surveillance, it may be considered a public health surveillance effort; in this context, it offers a possible model for developing state- or even national-level universal registries in the United States (Voskaridou et al., 2019). There are similar registries within the United States for other severe diseases, which have been successful in gathering data on nearly all affected patients and tracking them over their lifetimes. An example is the cystic fibrosis (CF) registry, which includes nearly every person with the disease living in the United States. Registrants are monitored by staff at clinical sites, which ensures that the patient data are entered into the system accurately and in a timely manner. The registry receives support from private funding, including the Cystic Fibrosis Foundation, and other sources (CFF, 2018).
Hemophilia treatment centers (HTCs), sites of high-quality care for those living with hemophilia in the United States, also participate in a lifelong data collection system, Community Counts. This effort is a collaboration among HTCs participating in the U.S. Hemophilia Treatment Center Network, CDC, HRSA, and the American Thrombosis and Hemostasis Network. The system tracks the clinical visits of those living with hemophilia through the HTC Population Profile and tracks these individuals over their life course (including mortality) through the Registry for Bleeding Disorders Surveillance (Manco-Johnson et al., 2018).
Standardizing Data Collection and Patient Registries
Researchers developing registries, data collection systems for clinical research, and other systems for outcomes data may be frustrated with the lack of standardization and comparability across such efforts. If patient outcomes are defined differently in different settings, it is difficult to compare the results of interventions or methods changes. NHLBI convened a steering committee of those involved in SCD research to develop standards for data collection as a part of the PhenX Toolkit (consensus measures for Phenotypes and eXposures) (Eckman et al., 2017; Hamilton et al., 2011). All researchers and scientists participating in SCD-related data collection efforts are encouraged to design their measures around these common data elements and standards to improve data usefulness and consistency.
As noted above, public health surveillance is the ongoing and systematic collection, analysis, and interpretation of health-related data, with a particular emphasis on the timely dissemination of the data and results in order to make them as useful as possible (Foege et al., 1976; Thacker and Berkelman, 1988). Wide-ranging surveillance efforts provide data on a large number of patients, typically with low bias in the cohort examined (i.e., nearly everyone is captured, with little difference in characteristics between those followed and those not). Depending on the methodologies used, surveillance systems can provide excellent “bird’s eye view” data on population-level disease prevalence, health outcomes, mortality, access to care, and cost of care. Such data can augment other data collection efforts, such as NBS or registries (Choi, 2012).
Suggested surveillance systems as described here can be distinguished from many registries by the former’s aim to be universal in scope, capturing all of those with the disease of interest along with longitudinal data on the population, and by the relatively low resources needed to establish surveillance systems (compared to far-reaching registries). However, the data used to define the population living with SCD were not originally intended for surveillance and do not approach the reliability of clinical trials data or registries. Furthermore, surveillance systems’ purpose and scope vary from those of registries. Specifics such as laboratory values, biomarkers, and QOL measures (e.g., employment or educational achievement) are generally not known, and there are different gaps in data in every system across states or regions. Administrative data may also be more prone to errors than NBS or registry data, although such errors are unlikely to be biased (and thus are unlikely to affect conclusions). Complete information on the cost of care and treatments that may not be billed (e.g., clinical trials or charity care) or bundled as part of managed care may be missing.
Surveillance is typically defined geographically, with efforts at a state or national level. Rare disease surveillance is increasingly seen as a necessary tool to understand the complications, comorbidities, uptake of treatments, and health outcomes for diseases that may otherwise be difficult to track, given their small population sizes and widely dispersed care. In 2007 the American Society of Pediatric Hematology/Oncology convened the Sickle Cell Disease Summit, a meeting of stakeholders in hemoglobinopathies, to settle on a unified approach to health care and research disparities for SCD. One key finding was that there is a critical need for population-based surveillance to track outcomes (Hassell et al., 2009).
The creation of the Registry and Surveillance System for Hemoglobinopathies (RuSH), a cooperative agreement among CDC, NHLBI, and seven states with significant populations of people living with SCD and
thalassemia, was one outcome of this summit and its recommendations. This 2010–2012 effort was intended to develop and test methodologies for public health surveillance in these disorders at the state level. It was originally intended to be developed and validated over 4 years, but funding was ultimately provided for only 2 years. Although some states had already begun to gather data on their Medicaid populations or to follow NBS-diagnosed cases of SCD, RuSH was the first large-scale attempt to conduct public health surveillance for SCD in the United States. Information on incidence and prevalence in RuSH states produced by these efforts was novel and intended to be helpful to researchers and policy makers in those states (Hulihan et al., 2015; Paulukonis et al., 2014).
California, Georgia, and CDC have continued this work with the Sickle Cell Data Collection (SCDC) program, which has been funded privately by the CDC Foundation since 2015. The two states collect NBS-identified cases, hospital discharge data, ED data, vital records death data, Medicaid claims for all claimants with SCD diagnostic codes, and reports from SCD care clinics on patient genotype. These data are used to support policy decisions at the state and federal level, inform researchers and providers via published manuscripts, and educate those living with the disease, their families and communities, and health care providers on the disease and the latest research on it (Paulukonis et al., 2015).
Several states have also implemented or expanded public health surveillance of SCD. In 2019, CDC, through the CDC Foundation’s SCDC, awarded grants to train seven additional states—Alabama, Indiana, Michigan, Minnesota, North Carolina, Tennessee, and Virginia—on how to implement comprehensive data collection programs for SCD. No data will be collected under the grant, but the states will receive training on the conduct of longitudinal data collection and surveillance for SCD (CDC, 2019). Tennessee’s St. Jude Children’s Research Hospital gathers data from multiple sources and uses them to support research and policy (St. Jude Children’s Research Hospital, 2019).
Each state or other geographic region that attempts surveillance efforts in SCD or any rare disease will by necessity use varying methodologies. Access to data differs by location and the program’s relationship to data stewards, and the data sources, patient identifiers, and underlying programs vary widely. Still, most states that have attempted such an endeavor have found that it yields fruitful and novel information; improves communication across agencies, providers, insurers, and patients living with the disease; and supports policy change that can improve access to high-quality care and health outcomes for those with SCD. Collectively these surveillance programs have used data to publish manuscripts on epidemiology and health outcomes among those with SCD, to support grants, to connect health care providers with resources and support, and to support policy change (CDC, 2018).
Public health surveillance may use fewer resources than more intensive methods of gathering information on the SCD population, particularly when considered as cost per patient or per year of data included. It is best suited to provide information to support policy change and new research programs that can gather reliable individual-level data. The Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act of 2018 explicitly authorizes grants to conduct public health surveillance for SCD and other heritable blood disorders. Appropriations have not yet been made, however. Support of this law and its appropriate funding will be critical for public health surveillance in SCD in coming years.2
As noted above, organizations dealing with diseases similar to SCD have successfully integrated public health surveillance and registry approaches and data. When the majority of the affected population finds benefit in sharing health information and receives consistent, high-quality care, as with the CF and hemophilia communities (discussed in Chapter 8), the value of the registry data for tracking health care and health outcomes over time is dramatically increased. As SCD registry and surveillance systems in the United States become more established and successful, merging data and methods across these systems and incorporating information from NBS will be an ideal model for which to strive. A merged system would provide valuable information about individuals over the life course to participants, health care providers, researchers, and policy makers.
When individuals with SCD interact with clinicians or researchers, there are a variety of ethical and privacy issues that must be taken into account. The issues are particularly relevant for African Americans because of the history of medical and research establishments in the United States treating them unethically.
Perceptions of Who Is Affected
The widespread presence of SCT in people of African origin is due largely to an accident of evolutionary biology, as it confers a survival advantage in areas with a high prevalence of malaria. As many as 40 percent of individuals in parts of sub-Saharan Africa may be affected, but SCT may also be found in people in southern Europe, Saudi Arabia, and India—a result of centuries of genetic diffusion (Serjeant, 2013). The slave trade brought
2 Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention and Treatment Act of 2018, Public Law 115-327, 115th Congress (December 18, 2018).
vast numbers of people to the Americas and the Caribbean, parts of the world where the genetically conferred resistance was largely irrelevant but where the disease took root, with its greatest prevalence today among those with African ancestry.
However, the resulting widespread belief in the United States that SCD is an African American disease is not only incorrect but can create additional challenges (e.g., some people assume they can judge the likelihood of someone having SCT solely by looks). Skin color has been shown to be a poor marker of African descent (Crawford et al., 2017), and it is not uncommon for SCT to be found in people who do not present as African American, including Caucasians and Latinos. For these people, the notion that SCD is an African American disease may present special obstacles to care. See Box 3-1 for the perspective of a Hispanic individual living with SCD.
A History of Discrimination
Throughout the 19th century and more than halfway through the 20th century, diseases that particularly affected African Americans received significantly less attention than diseases that were of more concern to white Americans. For example, a historian of medicine wrote that at the outset of the 20th century, the sickle cell population was “clinically invisible” (Wailoo, 2017). After 1910, the disorder was understood to be caused by physically distorted RBCs. However, correct diagnosis was infrequent, and the common symptoms, such as infections and pain, were often attributed to other conditions, especially when diseases with similar symptoms were endemic, such as malaria in Memphis (Wailoo, 2001). World War II investigators in the growing field of molecular biology recognized that a corrective therapy for the hemoglobin molecule could theoretically be devised, but in practice providers relied mainly on antibiotics (Wailoo, 2017). Although the providers’ actions did decrease mortality, they did nothing to identify methods to treat the hemoglobin molecule directly.
Beginning in the 1960s, the civil rights movement, media coverage, and grassroots civic engagement, such as that of the Black Panthers, helped stimulate public awareness of SCD (Bassett, 2016). The new political and medical science environments led to the passage of the Sickle Cell Anemia Control Act of 1972. No longer clinically invisible, patients with SCD did benefit from longer life spans made possible by continually improving antibiotics. Nevertheless, the overall progress continues to be slow.
Furthermore, suggestions that those with the gene should be aggressively identified in order to prevent it from being passed on were reminiscent of earlier eugenic efforts (Bowman, 1996). Despite the benefits of PGD and genetic counseling discussed in earlier sections, these options need to
be approached with sensitivity in light of the history of racial discrimination in the United States. Elsewhere in the world, there have been such eugenics-type efforts. In Bahrain genotyping and counseling has reduced the births of affected infants (Almutawa and Alqamish, 2009), and mandatory premarital screening for couples has led to voluntary cancellations of marriage proposals in Saudi Arabia (Alotaibi, 2017). Such programs would raise complications in the United States, however, because of its history of racial discrimination.
In recent years, individuals living with SCD in the United States have been entangled in the controversy around pain management and opiates, with the added complication that pain reported by those perceived as African Americans has been taken less seriously than when reported by other patients (Hoffman et al., 2016). In addition, African Americans are particularly vulnerable to the stigma of suspected addictive behavior. Patients with SCD continue to encounter controversies and difficulties that are often more societal than scientific.
Patient Privacy Concerns
Patient privacy and confidentiality are core values of medical ethics. They are even cited in the Hippocratic Oath (Hajar, 2017). But unlike in the ancient world, where one clinician interacted with one patient, modern health care systems have extensive medical records combined with patient care provided by a health care team. This presents many opportunities for others to access personal health information. The Institute of Medicine defines privacy as follows:
Privacy addresses the question of who has access to personal information and under what conditions. Privacy is concerned with the collection, storage, and use of personal information, and examines whether data can be collected in the first place, as well as the justifications, if any, under which data collected for one purpose can be used for another (secondary) purpose. An important issue in privacy analysis is whether the individual has authorized particular uses of his or her personal information. (IOM, 2009)
Rarely are there objections to caregivers viewing necessary medical information to provide the best patient care, but illegitimate access must be prevented. Protecting against this may be especially important for patients who are members of historically discriminated groups or liable to be stigmatized because of their disease, both of which apply to many people affected by SCD.
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) safeguards the privacy of medical information in addition to ensuring that health coverage cannot be denied when someone loses or changes a job and providing protections against the denial of coverage because of certain diseases and pre-existing conditions (OCR, 2013). However, in practice HIPAA may also create confusion about information sharing among those with a “need to know” basis, particularly with regard to mental health information (IOM, 2009). In brief, a mental health professional may share information with a patient’s personal representative and also family, friends, or caregivers insofar as that information is relevant to the patient’s caregiving (and without patient objection). If the patient lacks or has impaired decision-making capabilities, a therapist may share relevant information with others who can make medical decisions based on the patient’s best interests.
Federal law specifically requires the confidentiality of SCD-related medical records that are held by the U.S. Department of Veterans Affairs.3 Patients should be confident that learning their SCD status from genetic testing will not subject them to discriminatory practices. This became a public issue in the early 1970s, when some states required that African Americans be tested to identify both carriers and SCD-positive individuals. In response, Congress enacted the National Sickle Cell Anemia Control Act in 1972, which withheld federal funds from states that mandated testing. Thus, the experience with SCD served as a precursor to the 2008 Genetic Information Nondiscrimination Act, which protects individuals
3 Veterans Health Administration. 2016. VHA Directive 1605.01. Privacy and Release of Information. Washington, DC: Veterans Health Administration, U.S. Department of Veterans Affairs. See https://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=5456 (accessed March 3, 2020).
from any sort of genetic discrimination in health insurance and employment (Feldman, 2012).
Data Protection Considerations
Neither participants in research studies nor patients in clinical care typically have ownership rights to any data collected from them; in particular, they do not have a financial interest in any commercial products that may be developed based on those data. Rather, the data in data banks and registries typically are owned by health care providers and insurance plans, funding agencies for registry projects, research institutions, and government agencies. However, following several legal cases, such as the Henrietta Lacks case (Shah, 2010), there is now widespread agreement that patients and research participants should at least be clearly informed, in advance, that they will not have rights to any data collected. It is also understood that the privacy and confidentiality of patients providing data should be carefully protected (e.g., by “de-identification”), which makes it difficult, if not impossible, for the information to be traced back to the patients.
In 1979, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued the Belmont Report, which offered three principles to guide research involving human participants: respect for persons, beneficence, and justice (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). These principles remain the core values of the U.S. biomedical research enterprise. In the context of data protection, respect requires that participants’ privacy and dignity be preserved and that patients should be able to give their informed consent for the way their data are collected and used. Beneficence requires that harm to participants and relevant groups be minimized and benefits maximized, including the harm and benefits of information in a data registry. Justice requires that no particular group be involved in the research enterprise more than any other and that the benefits of the research be shared equitably. Considering that the National Commission was partly a response to the controversy from the U.S. Public Health Service Syphilis Study (CDC, 2015), these principles have special resonance for African Americans, who suffer a disproportionate burden of SCD.
The movement for personalized medicine in the era of big data suggests that in the future it will be increasingly more difficult to distinguish regular clinical care from research. Data registries and machine-learning systems that use sophisticated and continuously revised algorithms will increasingly be part of the regular clinical experience. If the identification of people with SCD can be improved and their clinical experiences entered into these systems, those patients stand to benefit. Still, the ethical protections that apply to data protection should continue to be respected.
Public Health Surveillance and Research
Public health surveillance is crucial to tracking the distribution of a disease to improve access to health care resources in areas with health disparities. For SCD, improved surveillance is particularly important because of current data limitations, including the exact percentage of affected African Americans. Recognizing that SCD research and treatment lags behind research for other chronic illnesses, the Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act of 20184 reauthorized an SCD prevention and treatment program and provides grants for research, surveillance, prevention, and treatment of heritable blood disorders. As of the development of this report, the section of the legislation related to data collection on certain blood disorders had not yet been funded by Congress. Although the focus of public health surveillance is improving the well-being of populations, the ethics of public health also requires respecting the health and dignity of individuals.
While public health surveillance essentially consists of data collection and analysis that generates hypotheses (Thacker and Berkelman, 1988), public health research builds on that information to test which hypotheses provide the most effective interventions for population-level prevention and treatment. Individuals’ interests must be balanced against the value of a public health intervention to the community, taking into account the benefits and costs. Surveillance and research depend on each other to be effective in promoting population health (Lussier et al., 2012). Public trust is crucial for both approaches, so every reasonable effort should be made to communicate goals and explain the relevant practices to the affected population.
Especially in cases of chronic social vulnerability, as with the communities most likely to be affected by SCD, members of representative civic and religious organizations should be closely involved in every phase of the surveillance and intervention. Among African Americans, trust in the medical establishment has justifiably been a topic of intense concern, particularly considering the history of exploitive experiments and surveillance studies. Yet there is evidence that African Americans are interested in participating in clinical trials, though that interest may not be accommodated in enrollment processes. As for any subpopulation, appropriate arrangements should be made in the prior review (e.g., institutional review board representation) and consent phases (e.g., clarity about the prospects of commercializing any important research result) (Hamel et al., 2016).
NBS raises specific ethical and social issues. The World Health Organization recommends screening if diagnosis and treatment will benefit the
4 Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention and Treatment Act of 2018, Public Law 115-327, 115th Congress (December 18, 2018).
newborn. The classical example that meets this test is phenylketonuria screening. For selective screening to be useful, the affected communities must be part of the program (Avard et al., 2006).
Blood donations are sometimes screened for SCD as part of public health surveillance and to protect the blood supply. Incidental findings, such as the discovery of SCT, raise the question of whether donors should be informed of their status, about which they may not be aware. One option is to inform potential donors that their blood may be screened for SCT and give them the choice of whether to be notified, along with being informed about the medical and reproductive health implications of a positive result. Responsible regulatory agencies and community organizations need to collaborate to address concerns about stigma and discrimination while also protecting public health (Lee and Marks, 2014).
Electronic Informed Consent Issues
Electronic informed consent has been defined as “the use of electronic systems and processes that may employ multiple electronic media, including text, graphics, audio, video, podcasts, passive and interactive Web sites, biological recognition devices, and card readers, to convey information related to the study and to obtain and document informed consent” (FDA, 2016, p. 2). No matter how informed consent is obtained, the same ethical requirements apply. Specifically, the individual must have the capacity to give consent, the information provided must be complete and understandable enough that the patient can make an informed decision, and the participant’s or patient’s consent must be verified. Furthermore, with consent processes that involve only remote interactions by electronic means, care must be taken that the participant or patient has the same opportunities to have any questions and concerns addressed in person.
Conclusion 3-1: There are gaps in information for SCD that do not exist for similar diseases. Robust and well-supported longitudinal data collection systems that include the majority of those living with the disease will provide the information and evidence needed for decision making and facilitate the evaluation of changes in SCD care.
Conclusion 3-2: Communication of SCD results to parents/guardians, the pediatrician of record, a referred pediatric hematologist, and other relevant care providers as well as follow-up once diagnosed are inconsistent across state NBS programs.
Therefore, newborns with SCD and their families do not receive standardized quality care and familial support across different state programs in a timely manner.
Conclusion 3-3: Follow-up and communication of positive SCT status to parents, the pediatrician of record, other relevant care providers, and young adults seeking trait status from NBS systems are not consistent across state NBS programs. Thus, some people with SCT are unaware of their status despite a confirmed determination by NBS. This may affect future reproductive decisions and/or health.
AAP (American Academy of Pediatrics) Newborn Screening Task Force. 2000. Serving the family from birth to the medical home. Pediatrics 106(Suppl 2):389.
Abhyankar, S., M. A. Lloyd-Puryear, R. Goodwin, S. Copeland, J. Eichwald, B. L. Therrell, and C. J. McDonald. 2010. Standardizing newborn screening results for health information exchange. AMIA Annual Symposium Proceedings 2010:1–5.
AHRQ (Agency for Healthcare Research and Quality). 2014. AHRQ methods for effective health care. In R. E. Gliklich, N. A. Dreyer, and M. B. Leavy (eds.), Registries for evaluating patient outcomes: A user’s guide. Rockville, MD: Agency for Healthcare Research and Quality.
Almutawa, F. J., and J. R. Alqamish. 2009. Outcome of premarital counseling of hemoglobinopathy carrier couples attending premarital services in Bahrain. Journal of the Bahrain Medical Society 21(1):217–220.
Alotaibi, M. M. 2017. Sickle cell disease in Saudi Arabia: A challenge or not. Journal of Epidemiology and Global Health 7(2):99–101.
Alvarez, O. A. 2017. Renal medullary carcinoma: The kidney cancer that affects individuals with sickle cell trait and disease. Journal of Oncology Practice 13(7):424–425.
Alvarez, O., M. M. Rodriguez, L. Jordan, and S. Sarnaik. 2015. Renal medullary carcinoma and sickle cell trait: A systematic review. Pediatric Blood & Cancer 62(10):1694–1699.
Alvarez, O. A., T. Hustace, M. Voltaire, A. Mantero, U. Liberus, and R. Saint Fleur. 2019. Newborn screening for sickle cell disease using point-of-care testing in low-income setting. Pediatrics 144(4):e20184105.
Andermann, A., I. Blancquaert, S. Beauchamp, and V. Dery. 2008. Revisiting Wilson and Jungner in the genomic age: A review of screening criteria over the past 40 years. Bulletin of the World Health Organization 86(4):317–319.
Anderson, S. A., J. Doperak, and G. P. Chimes. 2011. Recommendations for routine sickle cell trait screening for NCAA Division I athletes. PM&R 3(2):168–174.
APHL (Association of Public Health Laboratories) and CDC (Centers for Disease Control and Prevention). 2015. Hemoglobinopathies: Current practices for screening, confirmation and follow-up. https://www.aphl.org/aboutAPHL/publications/Documents/NBS_HemoglobinopathyTesting_122015.pdf (accessed January 9, 2020).
Arhin, A. O. 2019. Knowledge deficit of sickle cell trait status: Can nurses help? Critical Care Nursing Quarterly 42(2):198–201.
Asgharian, A., K. A. Anie, and M. Berger. 2003. Women with sickle cell trait: Reproductive decision-making. Journal of Reproductive and Infant Psychology 21(1):23–34.
ASH RC (American Society of Hematology Research Collaboration). 2018. Sickle Cell Disease Clinical Trials Network. https://www.ashresearchcollaborative.org/sites/default/files/2018-12/ASH_Research_Collaborative_CTN_Handout.pdf (accessed March 10, 2020).
ASH RC. 2019. Data Hub. https://www.ashresearchcollaborative.org/s/data-hub (accessed March 10, 2020).
Avard, D., L. Kharaboyan, and B. Knoppers. 2006. Newborn screening for sickle cell disease: Socio-ethical implications. In S. A. M. McLean (ed.), First do no harm: Law, ethics and healthcare. Aldershot, England: Ashgate. Pp. 493–507.
Baker, C., J. Powell, D. Le, M. S. Creary, L. A. Daley, M. A. McDonald, and C. D. Royal. 2018. Implementation of the NCAA sickle cell trait screening policy: A survey of athletic staff and student-athletes. Journal of the National Medical Association 110(6):564–573.
Bassett, M. T. 2016. Beyond berets: The Black Panthers as health activists. American Journal of Public Health 106(10):1741–1743.
Bediako, S., and T. King-Meadows. 2016. Public support for sickle-cell disease funding: Does race matter? Race and Social Problems 8(2).
Benson, J. M., and B. L. Therrell, Jr. 2010. History and current status of newborn screening for hemoglobinopathies. Seminars in Perinatology 34(2):134–144.
Blood-Siegfried, J., H. S. Lieder, and K. Deary. 2006. To screen or not to screen: Complexities of newborn screening in the 21st century. Journal for Nurse Practitioners 2(5):300–307.
Bowman, J. E. 1996. The road to eugenics. The University of Chicago Law School Roundtable 3(2):7.
CDC (Centers for Disease Control and Prevention). 1986. Comprehensive plan for epidemiologic surveillance. Atlanta, GA: U.S. Department of Health and Human Services.
CDC. 2000. Update: Newborn screening for sickle cell disease—California, Illinois, and New York, 1998. Morbidity and Mortality Weekly Report 49(32):729–731.
CDC. 2015. U.S. Public Health Service syphilis study at Tuskegee: The Tuskegee timeline. https://www.cdc.gov/tuskegee/timeline.htm (accessed January 9, 2020).
CDC. 2018. Sickle cell data collection program report: Data to action introduction. https://www.cdc.gov/ncbddd/hemoglobinopathies/data-reports/2018-summer/index.html (accessed January 9, 2020).
CDC. 2019. CDC awards funds to learn more about people with sickle cell disease. https://www.cdc.gov/media/releases/2019/p0925-cdc-awards-funds-sickle-cell.html (accessed March 11, 2020).
CDC. n.d. Get screened to know your sickle cell status. https://www.cdc.gov/ncbddd/sicklecell/documents/Factsheet_ScickleCell_Status.pdf (accessed March 10, 2020).
CFF (Cystic Fibrosis Foundation). 2018. 2017 annual report. Bethesda, MD: Cystic Fibrosis Foundation.
Charache, S. 1988. Sudden death in sickle trait. American Journal of Medicine 84(3, Part 1):459–461.
Choi, B. C. 2012. The past, present, and future of public health surveillance. Scientifica (Cairo) 2012:875253.
Christopher, S. A., J. L. Collins, and M. H. Farrell. 2012. Effort required to contact primary care providers after newborn screening identifies sickle cell trait. Journal of the National Medical Association 104(11–12):528–534.
Chudleigh, J., S. Buckingham, J. Dignan, S. O’Driscoll, K. Johnson, D. Rees, H. Wyatt, and A. Metcalfe. 2016. Parents’ experiences of receiving the initial positive newborn screening (NBS) result for cystic fibrosis and sickle cell disease. Journal of Genetic Counseling 25(6):1215–1226.
Chunda-Liyoka, C., A. A. Kumar, P. Sambo, F. Lubinda, L. Nchimba, T. Humpton, P. Okuku, C. Miyanda, J. Im, K. Maguire, G. M. Whitesides, and T. P. Stossel. 2018. Application of a public health strategy to large-scale point-of-care screening for sickle cell disease in rural sub-Saharan Africa. Blood Advances 2(Suppl 1):1–3.
Cober, M. P., and S. J. Phelps. 2010. Penicillin prophylaxis in children with sickle cell disease. Journal of Pediatric Pharmacology and Therapeutics 15(3):152–159.
Crawford, N. G., et al. 2017. Loci associated with skin pigmentation identified in African populations. Science 358(6365):eaan8433.
Dampier, C., P. LeBeau, S. Rhee, S. Lieff, K. Kesler, S. Ballas, Z. Rogers, W. Wang, and Comprehensive Sickle Cell Centers Clinical Trial Consortium Site Investigators. 2011. Health-related quality of life in adults with sickle cell disease (SCD): A report from the Comprehensive Sickle Cell Centers Clinical Trial Consortium. American Journal of Hematology 86(2):203–205.
Darbari, I., J. E. O’Brien, S. J. Hardy, B. Speller-Brown, L. Thaniel, B. Martin, D. S. Darbari, and R. S. Nickel. 2018. Views of parents of children with sickle cell disease on preimplantation genetic diagnosis. Pediatric Blood & Cancer 65(8):e27102.
Drazba, K. T., M. A. Kelley, and P. E. Hershberger. 2014. A qualitative inquiry of the financial concerns of couples opting to use preimplantation genetic diagnosis to prevent the transmission of known genetic disorders. Journal of Genetic Counseling 23(2):202–211.
Eckman, J. R., K. L. Hassell, W. Huggins, E. M. Werner, E. S. Klings, R. J. Adams, J. A. Panepinto, and C. M. Hamilton. 2017. Standard measures for sickle cell disease research: The PhenX Toolkit sickle cell disease collections. Blood Advances 1(27):2703–2711.
El-Haj, N., and C. C. Hoppe. 2018. Newborn screening for SCD in the USA and Canada. International Journal of Neonatal Screening 4(4):36.
Elliott, A., and E. Bruner. 2019. Renal medullary carcinoma. Archives of Pathology and Laboratory Medicine 143(12):1556–1561.
Faro, E. Z., C. J. Wang, and S. O. Oyeku. 2016. Quality indicator development for positive screen follow-up for sickle cell disease and trait. American Journal of Preventive Medicine 51(1 Suppl 1):S48–S54.
Farrell, M. H., and S. A. Christopher. 2013. Frequency of high-quality communication behaviors used by primary care providers of heterozygous infants after newborn screening. Patient Education and Counseling 90(2):226–232.
FDA (U.S. Food and Drug Administration). 2016. Use of electronic informed consent questions and answers: Guidance for institutional review boards, investigators, and sponsors. https://www.fda.gov/media/116850/download (accessed January 9, 2020).
Feldman, E. A. 2012. The Genetic Information Nondiscrimination Act (GINA): Public policy and medical practice in the age of personalized medicine. Journal of General Internal Medicine 27(6):743–746.
Ferster, K., and E. R. Eichner. 2012. Exertional sickling deaths in army recruits with sickle cell trait. Military Medicine 177(1):56–59.
Feuchtbaum, L., S. Paulukonis, and N. Rosenthal. 2013. Sickle cell disease surveillance in California: Methods, findings, and challenges. In Newborn Screening and Genetic Testing Symposium. Atlanta, GA: Association of Public Health Laboratories.
Foege, W. H., R. C. Hogan, and L. H. Newton. 1976. Surveillance projects for selected diseases. International Journal of Epidemiology 5(1):29–37.
Forrest, C. B., R. J. Bartek, Y. Rubinstein, and S. C. Groft. 2011. The case for a global rare-diseases registry. The Lancet 377(9771):1057–1059.
Frommel, C., A. Brose, J. Klein, O. Blankenstein, and S. Lobitz. 2014. Newborn screening for sickle cell disease: Technical and legal aspects of a German pilot study with 38,220 participants. BioMed Research International 2014:695828.
Gallo, A. M., D. Wilkie, M. Suarez, R. Labotka, R. Molokie, A. Thocmpson, P. Hershberger, and B. Johnson. 2010. Reproductive decisions in people with sickle cell disease or sickle cell trait. Western Journal of Nursing Research 32(8):1073–1090.
Grant, A. M., C. S. Parker, L. B. Jordan, M. M. Hulihan, M. S. Creary, M. A. Lloyd-Puryear, J. C. Goldsmith, and H. K. Atrash. 2011. Public health implications of sickle cell trait: A report of the CDC meeting. American Journal of Preventive Medicine 41(6 Suppl 4):S435–S439.
Grosse, S. D., W. H. Rogowski, L. F. Ross, M. C. Cornel, W. J. Dondorp, and M. J. Khoury. 2010. Population screening for genetic disorders in the 21st century: Evidence, economics, and ethics. Public Health Genomics 13(2):106–115.
Gustafson, S. L., E. A. Gettig, M. Watt-Morse, and L. Krishnamurti. 2007. Health beliefs among African American women regarding genetic testing and counseling for sickle cell disease. Genetics in Medicine 9(5):303–310.
Hajar, R. 2017. The physician’s oath: Historical perspectives. Heart Views 18(4):154–159.
Hamel, L. M., L. A. Penner, T. L. Albrecht, E. Heath, C. K. Gwede, and S. Eggly. 2016. Barriers to clinical trial enrollment in racial and ethnic minority patients with cancer. Cancer Control 23(4):327–337.
Hamilton, C. M., L. C. Strader, J. G. Pratt, D. Maiese, T. Hendershot, R. K. Kwok, J. A. Hammond, W. Huggins, D. Jackman, H. Pan, D. S. Nettles, T. H. Beaty, L. A. Farrer, P. Kraft, M. L. Marazita, J. M. Ordovas, C. N. Pato, M. R. Spitz, D. Wagener, M. Williams, H. A. Junkins, W. R. Harlan, E. M. Ramos, and J. Haines. 2011. The PhenX toolkit: Get the most from your measures. American Journal of Epidemiology 174(3):253–260.
Harmon, K. G., J. A. Drezner, D. Klossner, and I. M. Asif. 2012. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: A database with 2 million athlete-years as the denominator. British Journal of Sports Medicine 46(5):325–330.
Harrison, S. E., C. M. Walcott, and T. D. Warner. 2017. Knowledge and awareness of sickle cell trait among young African American adults. Western Journal of Nursing Research 39(9):1222–1239.
Hassell, K., B. Pace, W. Wang, R. Kulkarni, N. Luban, C. S. Johnson, J. Eckman, P. Lane, and W. G. Woods. 2009. Sickle Cell Disease Summit: From clinical and research disparity to action. American Journal of Hematology and Oncology 84(1):39–45.
Hinton, C. F., C. T. Mai, S. K Nabukera, L. D. Botto, L. Feuchtbaum, P. A. Romitti, Y. Wang, K. N. Piper, and R. S. Olney. 2014. Developing a public health-tracking system for follow-up of newborn screening metabolic conditions: A four-state pilot project structure and initial findings. Genetic Medicine 16(6):484–490.
Hinton, C. F., C. J. Homer, A. A. Thompson, A. Williams, K. L. Hassell, L. Feuchtbaum, S. A. Berry, A. Comeau, B. L.Therrell, A. Brower, K. B. Harris, C. Brown, J. Monaco, R. J. Ostrander, A.E. Zuckerman, C. Kaye, D. Dougherty, C. Greene, N. S. Green, and the Follow-up and Treatment Sub-Committee of the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). 2016. A framework for assessing outcomes from newborn screening: On the road to measuring its promise. Molecular Genetics and Metabolism 118(4):221–229.
Hoff, T., and A. Hoyt. 2006. Practices and perceptions of long-term follow-up among state newborn screening programs. Pediatrics 117(6):1922–1929.
Hoffman, K. M., S. Trawalter, J. R. Axt, and M. N. Oliver. 2016. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proceedings of the National Academy of Sciences 113(16):4296–4301.
Hoots, W. K. 2010. The registry and surveillance in hemoglobinopathies: Improving the lives of individuals with hemoglobinopathies. American Journal of Preventive Medicine 38(4 Suppl):S510–S511.
Housten, A. J., R. A. Abel, T. Lindsey, and A. A. King. 2016. Feasibility of a community-based sickle cell trait testing and counseling program. Journal of Health Disparities Research and Practice 9(3):1.
Hulihan, M. M., L. Feuchtbaum, L. Jordan, R. S. Kirby, A. Snyder, W. Young, Y. Greene, J. Telfair, Y. Wang, W. Cramer, E. M. Werner, K. Kenney, M. Creary, and A. M. Grant. 2015. State-based surveillance for selected hemoglobinopathies. Genetics in Medicine 17(2):125–130.
IOM (Institute of Medicine). 2009. Beyond the HIPAA privacy rule: Enhancing privacy, improving health through research. Washington, DC: The National Academies Press.
Jones, S. R., R. A. Binder, and E. M. Donowho, Jr. 1970. Sudden death in sickle-cell trait. New England Journal of Medicine 282(6):323–325.
Jordan, L. B., K. Smith-Whitley, M. J. Treadwell, J. Telfair, A. M. Grant, and K. Ohene-Frempong. 2011. Screening U.S. college athletes for their sickle cell disease carrier status. American Journal of Preventive Medicine 41(6 Suppl 4):S406–S412.
Kark, J. A., D. M. Posey, H. R. Schumacher, and C. J. Ruehle. 1987. Sickle-cell trait as a risk factor for sudden death in physical training. New England Journal of Medicine 317(13):781–787.
Kark, J. A., R. J. Labotka, J. W. Gardner, and F. T. Ward. 2010. Prevention of exercise-related death unexplained by preexisting disease (EDU) associated with sickle cell trait (SCT) without hemoglobin (Hb) screening or Hb specific management. Blood 116(21):945.
Kavanagh, P. L., C. J. Wang, B. L. Therrell, P. G. Sprinz, and H. Bauchner. 2008. Communication of positive newborn screening results for sickle cell disease and sickle cell trait: Variation across states. American Journal of Medical Genetics. Part C: Seminars in Medical Genetics 148C(1):15–22.
Key, N. S., P. Connes, and V. K. Derebail. 2015. Negative health implications of sickle cell trait in high income countries: From the football field to the laboratory. British Journal of Haematology 170(1):5–14.
Kunz, J. B., H. Cario, R. Grosse, A. Jarisch, S. Lobitz, and A. E. Kulozik. 2017. The epidemiology of sickle cell disease in Germany following recent large-scale immigration. Pediatric Blood & Cancer 64(7).
Lang, C. W., A. P. Stark, K. Acharya, and L. F. Ross. 2009. Maternal knowledge and attitudes about newborn screening for sickle cell disease and cystic fibrosis. American Journal of Medical Genetics, Part A 149A(11):2424–2429.
Lee, L. M., and P. Marks. 2014. When a blood donor has sickle cell trait: Incidental findings and public health. Hastings Center Report 44(4):17–21.
Lin, K. W. 2009. Screening for sickle cell disease in newborns. American Family Physician 79(6):507–508.
Lussier, M.-T., C. Richard, T.-L. Bennett, T. Williamson, and A. Nagpurkar. 2012. Surveillance or research: What’s in a name? Canadian Family Physician/Medecin de Famille Canadien 58(1):117.
Manco-Johnson, M. J., V. R. Byams, M. Recht, B. Dudley, B. Dupervil, D. J. Aschman, M. Oakley, S. Kapica, M. Voutsis, S. Humes, R. Kulkarni, A. M. Grant, and U.S. Haemophilia Treatment Center Network. 2018. Community counts: Evolution of a national surveillance system for bleeding disorders. American Journal of Hematology 93(6):E137–E140.
Maryland Department of Health. n.d. Newborn screening—Frequently asked questions. https://health.maryland.gov/laboratories/Pages/nbs-faq.aspx (accessed March 10, 2020).
Mayo-Gamble, T. L., S. E. Middlestadt, H. C. Lin, J. Cunningham-Erves, P. Barnes, and P. B. Jackson. 2018. Identifying factors underlying the decision for sickle cell carrier screening among African Americans within middle reproductive age. Journal of Genetic Counseling 27(5):1302–1311.
McGann, P. T., and C. Hoppe. 2017. The pressing need for point-of-care diagnostics for sickle cell disease: A review of current and future technologies. Blood Cells, Molecules, and Diseases 67:104–113.
Minkovitz, C. S., H. Grason, M. Ruderman, and J. F. Casella. 2016. Newborn screening programs and sickle cell disease: A public health services and systems approach. American Journal of Preventive Medicine 51(1 Suppl 1):S39–S47.
Mitchell, B. L. 2018. Sickle cell trait and sudden death. Sports Medicine—Open 4(1):19.
Morales, A., A. Wierenga, C. Cuthbert, S. Sacharow, P. Jayakar, D. Velazquez, J. Loring, and D. Barbouth. 2009. Expanded newborn screening in Puerto Rico and the U.S. Virgin Islands: Education and barriers assessment. Genetics in Medicine 11(3):169–175.
Moseley, K. L., S. Z. Nasr, J. L. Schuette, and A. D. Campbell. 2013. Who counsels parents of newborns who are carriers of sickle cell anemia or cystic fibrosis? Journal of Genetic Counseling 22(2):218–225.
Mukherjee, M. B., R. B. Colah, P. R. Mehta, N. Shinde, D. Jain, S. Desai, K. Dave, Y. Italia, B. Raicha, and E. Serrao. 2019. Multicenter evaluation of HemoTypeSC as a point-of-care sickle cell disease rapid diagnostic test for newborns and adults across India. American Journal of Clinical Pathology 153(1):82–87.
Naik, R. P., and C. Haywood, Jr. 2015. Sickle cell trait diagnosis: Clinical and social implications. Hematology 2015:160–167.
Naik, R. P., K. Smith-Whitley, K. L. Hassell, N. I. Umeh, M. de Montalembert, P. Sahota, C. Haywood, Jr., J. Jenkins, M. A. Lloyd-Puryear, C. H. Joiner, V. L. Bonham, and G. J. Kato. 2018. Clinical outcomes associated with sickle cell trait: A systematic review. Annals of Internal Medicine 169(9):619–627.
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1979. The Belmont report: Ethical principles and guidelines for the protection of human subjects of research. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html (accessed January 9, 2020).
NCSL (National Conference of State Legislatures). 2019. State laws related to insurance coverage for infertility treatment. https://www.ncsl.org/research/health/insurance-coverage-forinfertility-laws.aspx (accesssed January 9, 2020).
Nelson, D. A., P. A. Deuster, R. Carter, 3rd, O. T. Hill, V. L. Wolcott, and L. M. Kurina. 2016. Sickle cell trait, rhabdomyolysis, and mortality among U.S. Army soldiers. New England Journal of Medicine 375(5):435–442.
NewSTEPs. 2020. Data visualizations: State profiles. Silver Spring, MD: Association of Public Health Laboratories. https://www.newsteps.org/data-visualizations (accessed January 9, 2020).
NHLBI (National Heart, Lung, and Blood Institute). 2007. Establishing a database of people with sickle cell disease (Comprehensive Sickle Cell Centers Collaborative Data Project, C-Data). https://ClinicalTrials.gov/show/NCT00529061 (accessed January 9, 2020).
Nnodu, O., H. Isa, M. Nwegbu, C. Ohiaeri, S. Adegoke, R. Chianumba, N. Ugwu, B. Brown, J. Olaniyi, E. Okocha, J. Lawson, A. A. Hassan, I. Diaku-Akinwumi, A. Madu, O. Ezenwosu, Y. Tanko, U. Kangiwa, A. Girei, Y. Israel-Aina, A. Ladu, P. Egbuzu, U. Abjah, A. Okolo, N. Akbulut-Jeradi, M. Fernandez, F. B. Piel, and A. Adekile. 2019. HemoTypeSC, a low-cost point-of-care testing device for sickle cell disease: Promises and challenges. Blood Cells, Molecules, and Diseases 78:22–28.
NRC (National Research Council). 1975. Genetic screening: Programs, principles, and research. Washington, DC: National Academy of Sciences.
OCR (Office for Civil Rights). 2013. Summary of the HIPAA security rule. https://www.hhs.gov/hipaa/for-professionals/security/laws-regulations/index.html (accessed March 11, 2020).
Okwi, A. L., W. Byarugaba, C. M. Ndugwa, A. Parkes, M. Ocaido, and J. K. Tumwine. 2009. Knowledge gaps, attitude and beliefs of the communities about sickle cell disease in eastern and western Uganda. East African Medical Journal 86(9):442–449.
Paulukonis, S. T., W. T. Harris, T. D. Coates, L. Neumayr, M. Treadwell, E. Vichinsky, and L. B. Feuchtbaum. 2014. Population based surveillance in sickle cell disease: Methods, findings and implications from the California Registry and Surveillance System in Hemoglobinopathies project (RuSH). Pediatric Blood & Cancer 61(12):2271–2276.
Paulukonis, S., F. Raider, and M. Hulihan. 2015. Longitudinal data collection for sickle cell disease in California: History, goals and challenges. https://trackingcalifornia.org/cms/file/sickle-cell-disease/scd-in-cali (accessed March 11, 2020).
Pecker, L. H., and R. P. Naik. 2018. The current state of sickle-cell trait: Implications for reproductive and genetic counseling. Blood 132(22):2331–2338.
Pena, A. 2018. Sickle cell disease association launches first patient-powered registry. Sickle Cell Disease News, June 21. https://sicklecellanemianews.com/2018/06/21/sickle-cell-disease-association-launches-first-patient-powered-registry (accessed April 1, 2020).
Peters, M., K. Fijnvandraat, X. W. van den Tweel, F. G. Garre, P. C. Giordano, J. P. van Wouwe, R. R. Pereira, and P. H. Verkerk. 2010. One-third of the new paediatric patients with sickle cell disease in the Netherlands are immigrants and do not benefit from neonatal screening. Archives of Disease in Childhood 95(10):822–825.
Posnack, S. 2015. Connecting health and care for the nation: A shared nationwide interoperability roadmap. https://ncvhs.hhs.gov/wp-content/uploads/2015/10/Day-2-NCVHSDept-Update-POSNACK.pdf (accessed March 10, 2020).
Reeves, S. L., A. C. Tribble, B. Madden, G. L. Freed, and K. J. Dombkowski. 2018. Antibiotic prophylaxis for children with sickle cell anemia. Pediatrics 141(3):e20172182.
Ross, L. F. 2012. Newborn screening for sickle cell disease: Whose reproductive benefit? European Journal of Human Genetics 20(5):484–485.
Savage, W. J., G. R. Buchanan, B. P. Yawn, A. N. Afenyi-Annan, S. K. Ballas, J. C. Goldsmith, K. L. Hassell, A. H. James, J. John-Sowah, L. Jordan, R. Lottenberg, M. H. Murad, E. Ortiz, P. J. Tanabe, R. E. Ware, and S. M. Lanzkron. 2015. Evidence gaps in the management of sickle cell disease: A summary of needed research. American Journal of Hematology 90(4):273–275.
SCDIC (Sickle Cell Disease Implementation Consortium). n.d. Home page. https://scdic.rti.org (accessed January 9, 2020).
Schultz, C. L., T. T chume-Johnson, T. Jackson, H. Enninful-Eghan, M. Schapira, and K. Smith-Whitley. 2014. Reproductive decisions in families affected by sickle cell disease. Blood 124(21):2175.
Segbena, A. Y., A. Guindo, R. Buono, I. Kueviakoe, D. A. Diallo, G. Guernec, M. Yerima, P. Guindo, E. Lauressergues, A. Mondeilh, V. Picot, and V. Leroy. 2018. Diagnostic accuracy in field conditions of the sickle SCAN® rapid test for sickle cell disease among children and adults in two West African settings: The DREPATEST study. BMC Hematology 18:26.
Serjeant, G. R. 2013. The natural history of sickle cell disease. Cold Spring Harbor Perspectives in Medicine 3(10):a011783.
Shah, S. 2010. Henrietta Lacks’ story. The Lancet 375(9721):1154.
Shetty, A., and M. R. Matrana. 2014. Renal medullary carcinoma: A case report and brief review of the literature. Ochsner Journal 14(2):270–275.
Simopoulos, A. P., and Committee for the Study of Inborn Errors of Metabolism. 2009. Genetic screening: Programs, principles, and research-thirty years later. Reviewing the recommendations of the Committee for the Study of Inborn Errors of Metabolism (SIEM). Public Health Genomics 12(2):105–111.
Singer, D. E., C. Byrne, L. Chen, S. Shao, J. Goldsmith, and D. W. Niebuhr. 2018a. Risk of exertional heat illnesses associated with sickle cell trait in U.S. Military. Military Medicine 183(7–8):e310–e317.
Singer, D. E., L. Chen, S. Shao, J. Goldsmith, C. Byrne, and D. W. Niebuhr. 2018b. The association between sickle cell trait in U.S. service members with deployment, length of service, and mortality, 1992–2012. Military Medicine 183(3–4):e213–e218.
Smith, M., and R. T. Aguirre. 2012. Reproductive attitudes and behaviors in people with sickle cell disease or sickle cell trait: A qualitative interpretive meta-synthesis. Social Work in Health Care 51(9):757–779.
St. Jude Children’s Research Hospital. 2019. Genomic and clinical data for the sickle cell research community. https://sickle-cell.stjude.cloud (accessed January 9, 2020).
Steele, C., A. Sinski, J. Asibey, M. D. Hardy-Dessources, G. Elana, C. Brennan, I. Odame, C. Hoppe, M. Geisberg, E. Serrao, and C. T. Quinn. 2019. Point-of-care screening for sickle cell disease in low-resource settings: A multi-center evaluation of HemoTypeSC, a novel rapid test. American Journal of Hematology 94(1):39–45.
Taylor, C., P. Kavanagh, and B. Zuckerman. 2014. Sickle cell trait—Neglected opportunities in the era of genomic medicine. JAMA 311(15):1495–1496.
Teach, S. J., K. A. Lillis, and M. Grossi. 1998. Compliance with penicillin prophylaxis in patients with sickle cell disease. Archives of Pediatrics and Adolescent Medicine 152(3):274–278.
Texas Department of State Health Services. 2019. Newborn screening—Use and storage of dried blood spots after NBS. Last modified March 1, 2019. https://www.dshs.texas.gov/lab/nbsbloodspots.shtm (accessed March 10, 2020).
Thacker, S. B., and R. L. Berkelman. 1988. Public health surveillance in the United States. Epidemiologic Reviews 10:164–190.
Tubman, V. N., and J. J. Field. 2015. Sickle solubility test to screen for sickle cell trait: What’s the harm? Hematology 2015(1):433–435.
Vichinsky, E., D. Hurst, A. Earles, K. Kleman, and B. Lubin. 1988. Newborn screening for sickle cell disease: Effect on mortality. Pediatrics 81(6):749–755.
Voskaridou, E., A. Kattamis, C. Fragodimitri, A. Kourakli, P. Chalkia, M. Diamantidis, E. Vlachaki, M. Drosou, S. Lafioniatis, K. Maragkos, F. Petropoulou, E. Eftihiadis, M. Economou, E. Klironomos, F. Koutsouka, K. Nestora, I. Tzoumari, O. Papageorgiou, A. Basileiadi, I. Lafiatis, E. Dimitriadou, A. Kalpaka, C. Kalkana, G. Xanthopoulidis, I. Adamopoulos, P. Kaiafas, A. Mpitzioni, A. Goula, I. Kontonis, C. Alepi, A. Anastasiadis, M. Papadopoulou, P. Maili, D. Dionisopoulou, A. Tsirka, A. Makis, S. Kostaridou, M. Politou, I. Papassotiriou, and Greek Haemoglobinopathies Study Group. 2019. National registry of hemoglobinopathies in Greece: Updated demographics, current trends in affected births, and causes of mortality. Annals of Hematology 98(1):55–66.
Vrettou, C., G. Kakourou, T. Mamas, and J. Traeger-Synodinos. 2018. Prenatal and preimplantation diagnosis of hemoglobinopathies. International Journal of Laboratory Hematology 40(Suppl 1):74–82.
Wailoo, K. 2001. Dying in the city of the blues: Sickle cell anemia and the politics of race and health. Chapel Hill, NC: University of North Carolina Press.
Wailoo, K. 2017. Sickle cell disease—A history of progress and peril. New England Journal of Medicine 376(9):805–807.
Webber, B. J., and C. T. Witkop. 2014. Screening for sickle-cell trait at accession to the United States military. Military Medicine 179(11):1184–1189.
Wilson, J. M., and Y. G. Jungner. 1968. Principles and practice of mass screening for disease. Boletín de la Oficina Sanitaria Panamericana (Pan American Sanitary Bureau) 65(4):281–393.
Wright, S. W., M. H. Zeldin, K. Wrenn, and O. Miller. 1994. Screening for sickle-cell trait in the emergency department. Journal of General Internal Medicine 9(8):421–424.
Xu, K., Z. M. Shi, L. L. Veeck, M. R. Hughes, and Z. Rosenwaks. 1999. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA 281(18):1701–1706.
Yenilmez, E. D., and A. Tuli. 2016. New perspectives in prenatal diagnosis of sickle cell anemia. In B. Inusa (ed.), Sickle cell disease: Pain and common chronic complications. London: IntechOpen.
Yusuf, H. R., M. A. Lloyd-Puryear, A. M. Grant, C. S. Parker, M. S. Creary, and H. K. Atrash. 2011. Sickle cell disease: The need for a public health agenda. American Journal of Preventive Medicine 41(6 Suppl 4):S376–S383.
Zuckerman, A. E. 2009. The role of health information technology in quality improvement in pediatrics. Pediatric Clinics of North America 56(4):965–973.
This page intentionally left blank.