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Address correspondence and reprint requests to: Kathryn L. Hassell, MD, Colorado Sickle Cell Treatment and Research Center, 13121 East 17th Avenue, Mail Stop C-222, P.O. Box 6511, Building L28 Room 351, Aurora CO 80045
The number of individuals with sickle cell disease (SCD) in the U.S. is unknown. Determination of burden of disease, healthcare issues, and policies is best served by representative estimations of the SCD population.
To update SCD population estimates by using recent U.S. Census and birth-cohort SCD prevalence for at-risk populations as available through the centralized reporting of universal newborn screening for hemoglobinopathies, with an effort to demonstrate the potential effect of early mortality.
National and state SCD populations were estimated based on the 2008 U.S. Census, using total, African-American, and Hispanic birth-cohort disease prevalence derived from the National Newborn Screening Information System. Estimates were corrected for early mortality for sickle cell anemia using data from the CDC's Compressed Mortality Report and published patient-cohort survival information.
National SCD population estimates ranged from 104,000 to 138,900, based on birth-cohort disease prevalence, but from 72,000 to 98,000 when corrected for early mortality. Several limitations were noted in the available data, particularly for SCD mortality in adults.
The number of individuals with SCD in the U.S. may approach 100,000, even when accounting for the effect of early mortality on estimations. A paucity of high-quality data limits appropriate estimation. State-to-state variability may preclude application of state-specific information to other states or to the nation as a whole. Standardized collection and centralized reporting, a surveillance system, will be necessary to assess the size and composition of the U.S. SCD population.
The number of individuals with sickle cell disease (SCD) in the U.S. is unknown. Thirty years ago, the U.S. sickle cell anemia population was estimated to be 32,000–50,000, based on reported gene frequencies derived from testing of African-American neonates.
Subsequent population estimates of over 50,000–80,000 for both SCD and sickle cell anemia (a common form of SCD) are noted in a variety of publications, usually without a specific reference. When a source is documented, information reported by the Agency for Health Care Policy and Research (AHCPR),
is most often cited. Specific methods used to obtain these figures are not provided but are usually discussed in the context of the frequency of sickle cell anemia in the U.S. African-American population as determined by newborn screening data. Although some authors note a potential effect of early mortality,
corrects California SCD population estimates for early mortality, utilizing data from state administrative data sets, but this correction has not been applied to national estimates.
To date, there are no published national population estimates that use contemporary birth cohort-disease prevalence data that clearly delineate specific types of SCD or that incorporate the emergent Hispanic community, a growing segment of the U.S. population that is also affected. Yet the availability of more-representative population estimates is critical when anticipating public health and healthcare service needs, conducting health economics analysis, and developing policy. In the absence of current available information, examples of extrapolation based on old population estimates continue into 2009,
which may underestimate the total burden and need.
This article seeks to update SCD population estimates by using recent U.S. Census and birth cohort-SCD prevalence for at-risk populations, as made available through the expansion and voluntary centralized reporting of universal newborn screening for hemoglobinopathies. An effort to demonstrate the potential effect of early mortality on such estimates is also undertaken.
Birth Cohort–Based Population Estimate
The number of individuals with SCD was estimated by multiplying population estimates determined by the 2008 U.S. Census
by reported or derived birth cohort-SCD prevalence. For this analysis, the birth cohort-disease prevalence was assumed to represent the prevalence of SCD in the broader resident population in which the births occurred. Several sources were used for estimation of SCD prevalence based on birth cohort information.
Agency for Health Care Policy and Research
Figures for the prevalence of SCD in the African-American and Hispanic populations by AHCPR were published in 1993.
That report combined all forms of SCD into a single estimate of prevalence for African-American and Hispanic populations, distinguishing Hispanic populations from Eastern and Western states, as noted in Table 1. The estimates were based on a review of the literature at the time and available newborn screening data from at least six states (Wisconsin, Louisiana, Texas, California, Michigan, and Virginia) as collected by the Council of Regional Networks for Genetic Services. Hispanic population disease prevalence for the Eastern states was based primarily on data from New York and Florida, reported to reflect Caribbean rather than Mexican background.
The Eastern Hispanic prevalence estimate reported by AHCPR was applied to states in the Northeast region as defined by the U.S. Census (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont, New Jersey, New York, and Pennsylvania) and Florida. The Western Hispanic estimates were applied to all other states.
Subsequent data voluntarily reported to a national data set by state newborn screening programs from 1990 to 1999 were analyzed by Therrell and Hannon.
They reported incidences for sickle cell anemia (Hb SS, 1:3044); hemoglobin SC disease (Hb SC, 1:7386); and Hb SS+SC (1:2474) in the overall U.S. population. For this analysis, these prevalence estimates were applied to the total U.S. population in 2008.
California Newborn Screening Program
Several publications used data from the California newborn screening program to estimate the prevalence of SCD. Using data from 1990–1996, disease prevalence estimates for three major forms of SCD—Hb SS, Hb SC, and Hb Sβthalassemia (HbSβthal)—for both African-American and Hispanic populations were calculated by Lorey et al.
and are listed in Table 1. No distinction was made between Hb Sβ+thalassemia (Hb Sβ+thal) and Hb Sβ°thalassemia (HbSβ°thal). Updated incidences of specific types of SCD per 100,000 total infants screened in California from 1998 through 2006 were recently published, without designation of race/ethnicity.
The authors reported an incidence of 8.5 per 100,000 (1:11,764) for Hb SS and 4.4 per 100,000 (1:22,727) for Hb SC; 1.4 per 100,000 (1:71,428) for Hb Sβ+thalassemia; and 0.8 per 100,000 (1:250,000) for Hb Sβ°thalassemia. For this analysis, these estimates were applied to the 2008 California population and used for comparison to figures obtained for California from pooled national data (e.g., AHCPR).
The National Newborn Screening Information System–Based Estimates
The National Newborn Screening Information System (NNSIS) was established in 2005 to sustain timely and meaningful centralized national newborn screening data.
Each state newborn screening program is asked to voluntarily report and distinguish suspected from confirmed cases of hemoglobinopathies using their own case definition and sources of race/ethnicity information; national standardization of submitted data has not been adopted.
State-specific information was accessed from this resource for the years 2005–2007, and it included the number and type of confirmed cases of hemoglobinopathies, including Hb SS, Hb SC, and Hb Sβthal, and race/ethnicity of some identified cases.
No distinction was made between Hb Sβ+thal and Hb Sβ°thal in the database. Other types of SCDs were not included in this analysis.
The NNSIS data set was found to be incomplete, as some states did not report information and others began universal newborn screening for hemoglobinopathies after 2005. State-specific birth cohort-prevalence estimates were generated only for states that reported data from 2005–2007. Data from these reporting states were pooled to derive a birth cohort-prevalence estimate that was applied to states without NNSIS information to permit state-specific birth-cohort estimates.
Information from NNSIS was used to calculate the birth cohort-SCD prevalence as follows: Total birth cohort-prevalence was calculated for SCD (HbSS+HbSC+HbSβthal) for each state by dividing the number of total confirmed cases into the total birth cohort using combined data from 2005 to 2007. As noted, this calculation was performed only for states with 3 years of data. Variation in individual state population demographics precluded pooling data to derive a representative total birth-cohort prevalence.
Specific African-American and Hispanic birth-cohort prevalence figures were calculated in a similar fashion for Hb SS, Hb SC and Hb Sβthal, and SCD (HbSS+HbSC+HbSβthal), but in this case for the African-American and non-white Hispanic birth cohorts in each state using combined data from 2005 to 2007. Only states that reported race and ethnicity information for at least 75% of the identified cases were included in this part of the analysis. This threshold for inclusion in the analysis was used to permit data from states with only a few cases of SCD, for example, when three of four cases (75%) were assigned race and ethnicity. Data from states with sufficient information were also pooled to calculate birth-cohort prevalence estimates for African-American and Hispanic populations. These figures were then applied to the specific at-risk populations in states that had not reported data for 2005–2007 or that reported race/ethnicity for <75% of identified cases.
It was recognized that this approach potentially resulted in an underestimate of the birth cohort-disease prevalence, as up to 25% of a cohort may not have been designated as African-American or Hispanic as a result of missing data. Additionally, those assigned to different race categories (e.g., Caucasian) were not captured. To assess for this effect, population estimates based on the total birth cohort-disease prevalence, as described above, were compared to those based on estimates using African-American and Hispanic population birth cohorts.
Mortality-Adjusted Population Estimates
Population estimates using birth cohort-disease prevalence and census data did not consider the effect of early mortality. There were no available national mortality data or contemporary life expectancy figures for individuals with SCD. Three different sources of information were used.
Cooperative Study of Sickle Cell Disease
Published figures for life expectancy (median of 45 years for Hb SS, 65 years for Hb SC) from the Cooperative Study of Sickle Cell Disease (CSSCD) were derived from subjects followed between 1978 and 1988.
However, long-term survival estimates and the proportion of individuals alive after age 18 were not addressed. A report from Jamaica documented an estimated median survival of 53 years for men and 58 years for women with Hb SS,
Information describing the proportion of individuals alive at different ages was available from these publications, estimated in most cases from a specific group of individuals; this information was used as discussed below to estimate the effect of early mortality on population estimates.
Compressed Mortality Report from the CDC
The CDC collects national mortality data from death certificates in the CDC Wonder online database and provides compressed mortality reports.
For this analysis, the ages at death for individuals with SCD (indicated on the death certificate as sickle cell anemia with and without crisis, double heterozygote sickling disorders, or other sickle cell disorders) were tabulated and used to extrapolate the relative proportion of individuals still alive in each 5-year age bracket. Separate analysis of individuals with sickle cell anemia and those with other types of sickle cell disorders, including double heterozygous sickling disorders, was planned as life expectancies differed by 20 years in the CSSCD.
Unfortunately, the small number of deaths (<5%) reported in conditions other than sickle cell anemia precluded meaningful analysis, so all types of SCD were grouped together for this analysis. Similarly, there were only a small number of reported deaths in individuals identified as Hispanic, precluding separate analysis based on race/ethnicity. Because >95% deaths were associated with sickle cell anemia, the correction for early mortality was applied only to the population estimates for sickle cell anemia. The CSSCD reported that the life expectancy for HbSC (age 65) was nearly that of the African-American population at the time (68 years),
so a strong early mortality effect for HbS disorders other than sickle cell anemia was not anticipated. In contrast to the other sources used, these data reflected a cross-sectional view of age at death, rather than a longitudinal assessment of survival for a given cohort.
Using the 2008 U.S. Census population estimates, as divided into 5-year age brackets, the number of individuals with sickle cell anemia in each bracket was estimated using total, African-American, and Hispanic birth cohort-disease prevalence data. This number was then adjusted for the proportion of individuals who would be expected to still be alive in that age bracket as derived from the pediatric and Jamaican cohorts, the CSCCD, and the CDC Compressed Mortality Report. This permitted assessment of the impact of the variability of survival on population estimates. National population figures were derived using sickle cell anemia prevalence estimates for the African-American (1:601) and Hispanic populations (1:18642) and summed for a total national population estimate of sickle cell anemia. This correction was also applied to individual states for which a state-specific total birth-cohort disease prevalence had been calculated using NNSIS data. The mortality-adjusted sickle cell anemia population was added to the birth cohort-disease prevalence–based population estimates for HbSC and HbSβthal to obtain total population estimates for each state.
Table 1 lists the birth-cohort prevalence estimates of SCD for African-American and Hispanic populations as reported by AHCPR,
and as derived from the NNSIS as described in the Methods section. Race and ethnicity data were available from 30 states in the NNSIS for the years 2005–2007 to calculate state-specific birth-cohort disease prevalence estimates for African-American and Hispanic populations, which were pooled to calculate birth cohort-disease prevalence figures listed under NNSIS in Table 1.
Total birth cohort-SCD prevalence estimation, without regard to race/ethnicity, was possible from 37 states using data reported to the NNSIS. These data varied significantly by state; SCD occurred in 1:400–600 of all births in some states/areas with large at-risk populations (e.g., Mississippi, District of Columbia) but in only 1:20,00–30,000 of all births in states with small at-risk populations (e.g., Utah, South Dakota). Because of this wide variability and incomplete information from 13 states, a national total (as distinct from African-American or Hispanic) birth cohort-disease prevalence estimate was not made from the 2005–2007 NNSIS data.
The total U.S. SCD population estimates based on disease prevalence as reported by AHCPR
were used, the total U.S. sickle cell population was estimated to be 122,900, of which 99,888 (81%) had HbSS. Of the 104,487 individuals with SCD as estimated using NNSIS-derived prevalence data from 2005 to 2007, there were 66,070 (63%; 64,131 African-American and 1946 Hispanic) individuals with HbSS.
Table 2U.S. SCD population estimates based on total U.S. population (2008 census data)
Population estimate based on
AHCPR, Agency for Health Care Policy and Research; NNSIS, National Newborn Screening Information System; SCD, sickle cell disease
Individual state SCD population estimates were performed using state-specific birth-cohort disease prevalence for total, African-American, and Hispanic birth cohorts and are provided in Table 3. Analysis using total birth cohort-prevalence resulted in an average increase of 37% (range=25%–70%) in population estimates when compared to the sum based on African-American and Hispanic cohorts. For those states without 2005–2007 data to calculate the total birth cohort-disease prevalence, the figure based on African-American and Hispanic cohorts was carried over to permit national population estimation. These data are shown in the third and fourth columns of Table 3. The distribution of SCD types was fairly consistent across states, with HbSS representing 60%, HbSC representing 30%, and HbSβthal representing 10% of the population. Combining figures derived from these various sources, without correction for early mortality, the average estimate for number of people with SCD in the U.S. is 119,100±11,915.
Table 3U.S. and individual state SCD population estimates from state-specific prevalence, corrected for early mortality
Correction of population estimates for early mortality was performed using data from pediatric cohort and Jamaican studies, the CSCCD, and CDC compressed mortality files, as described in the Methods section. The proportion of individuals still alive at age 18 years from pediatric cohorts with HbSS born after 1982 ranged from 0.85 to 0.99.
The Dallas cohort reported 85% of individuals were still alive as they entered adulthood, which was comparable with the number of deaths reported in the pediatric-aged group in 2006 (18%) obtained from the compressed mortality report. The age at death for individuals with SCD reported to the CDC database is displayed graphically in Figure 1, Figure 2, and showed a continual shift over time from 1979 to 2006. In addition to a shift toward death at older ages, deaths occurring between ages 1 and 4 years appeared to markedly diminish between 1974 and 2006, which temporally correlated with the expansion of universal newborn screening for hemoglobinopathies, implementation of penicillin prophylaxis,
and use of conjugated pneumococcal vaccination. There was less shift noted in the age at death in adults. The observation of a shift in ages at death, however, precluded the pooling of data over enough years to obtain a sufficient number of cases to perform meaningful analysis for specific SCD types or for specific at-risk populations.
The mean number of years lived (age at death) was 39 years in 2006 based on data reported to the CDC.
Of 483 reported deaths in 2006, 9% of them occurred at or before the age of 20 years, 28% between the ages of 20 and 34 years, 28% between the ages of 35 and 44 years, and 35% at ages >45 years; the proportion of individuals alive at age 45 years would be 35%. This was lower than noted by the CSSCD, in which the proportion of individuals alive at age 45 years was 50%,
Application of correction for early mortality using CDC compressed mortality data resulted in a 50% decrease in the estimated number of individuals with sickle cell anemia, with a corresponding decrease of 39% in overall SCD population estimates. The population estimates for the 37 states with an NNSIS-derived state-specific total birth cohort-disease prevalence were corrected and are displayed in Table 3. This correction resulted in a mean decrease of 39% (range=27%–54%) in state-specific SCD population estimates as shown in Table 3. The impact of early mortality was greater for states with higher percentages of individuals with HbSS as compared to HbSC and HbSβthal. Although the distribution of SCD types was not known for the states without NNSIS data, the correction (39% reduction in total birth cohort population estimates) was applied to these states to permit an adjusted national population estimate, which yielded a figure of 84,674.
Application of the same analysis using the estimates of proportions of individuals alive in each age group from the published pediatric and Jamaican cohorts in place of the CDC data resulted in a 33% decrease in the estimated number of individuals with HbSS and a 29% decrease in the total SCD population. These data represented the longest reported survival for both children and adults; the total sickle cell population estimate was 98,635, based on the adjusted state-specific population estimates as provided in Table 3.
Similar application of information from the CSCCD resulted in a 43% decrease in the sickle cell anemia population estimates, with a 36% decrease in the total sickle cell population estimate to 88,612. Application of these correction factors to the average population estimate of 119,100, without consideration of state-specific data, resulted in corrected national SCD population estimates that ranged from 72,700 to 84,561. The distribution of the estimated SCD population across the U.S., using the NNSIS-derived data for African-American and Hispanic populations, corrected for early mortality in HbSS, is depicted in the map in Figure 3.
Information for the state of California was used to assess consistency of the methods used. In the state of California, the SCD population was estimated to be approximately 7400 using birth cohort-disease prevalence derived from pooled multistate data, and 5600–6300 when using state-specific at-risk and total population birth cohort-disease prevalence estimates. When corrected for early mortality using data derived from the CDC compressed mortality figures, CSCCD, and pediatric/Jamaican cohorts, the overall sickle population estimate for California ranged from 4240 to 4707. This estimate is comparable to a population estimate of approximately 4300 calculated by Strouse et al.
In the 30 years since estimates of 50,000 were first cited, it is likely that the U.S. SCD population has increased. This would be expected given overall growth of at-risk populations, including in the African-American and Hispanic populations, and the availability of prophylactic penicillin, vaccinations, and disease-remitting therapies, including hydroxyurea, which appear to affect mortality in adults.
An improvement in mortality is also suggested by the shift in the age at death of individuals with SCD as reported to the CDC, as noted in Figure 2. However, the true number of individuals with SCD remains unknown, and in the absence of a reliable surveillance system, populations will continue to be quantified by estimation. Published estimates have not made use of the full adoption of universal national newborn screening, incorporated the Hispanic population, or attempted to assess the impact of early mortality on national population estimates.
When based solely on the use of birth cohort-disease prevalence as applied to contemporary U.S. at-risk and total populations, the number of individuals with SCD may number between 104,000 and 138,900, with a mean estimate of 119,100. However, this method overestimates the number of adults, especially older adults, as a result of the early mortality associated with SCD. When correction is made for early mortality associated with sickle cell anemia, population estimates are reduced to 72,000–98,000.
These SCD population estimates must be viewed with a great deal of caution. There are major limitations to available data and methodology used for this report. Birth cohort-disease prevalence estimates are assumed to represent the disease prevalence in the larger population, but this may not reflect immigrant or other populations with a different gene frequency. Birth cohort estimates rely on accurate, consistent, and complete reporting of confirmed cases identified by universal newborn screening using a standardized approach to data collection. The NNSIS is an excellent national resource but relies on voluntary reporting; not all states participate, and those that do are not required to use consistent case definitions; specific testing (e.g., DNA-based techniques); or standardized designation of race/ethnicity. The methods used in this report include three major types of sickle cell disease (HbSS, HbSC, HbSβthal—without separating HbSβ° from Sβ+thal) but not other, rarer sickle cell disorders. Populations other than those that are African-American and Hispanic are excluded in some analyses, as are cases without a designated race/ethnicity. Use of the total birth cohort-prevalence estimates for states with NNSIS data suggests that using only cases designated as African-American or Hispanic may result in an underestimate (perhaps up to 37%) of the total SCD population in a state.
Despite the limitations to the data and methods, however, the estimate of overall prevalence of SCD (1:365), and of sickle cell anemia (1:601) in the African-American birth cohort, is consistent with other reports, supporting some validity to the approach and data used for this report. Similarly, the consistency between state sickle cell population estimates for California using state-specific data and pooled birth-cohort prevalence estimates derived from the 2005–2007 NNSIS suggests that the use of the pooled data may be acceptable for a given state in the absence of state-specific data.
The clear challenge to SCD population estimation is the effect of early mortality. Contemporary national data regarding sickle cell disease mortality are not readily available. Published cohort data address sickle cell anemia, but not HbSC or other types of SCD. Assumption that these other forms of SCD do not cause early mortality may lead to an overestimation of the number of individuals with these disorders. Accurate information for sickle cell anemia is available from pediatric cohorts,
Interestingly, the Jamaican group suggested that their ability to carefully observe the majority of their population may have resulted in a more-accurate determination of the course of SCD as compared with other countries where limited cohort data are available.
Within the U.S., annual mortality associated with the diagnosis of SCD as reported by the CDC Compressed Mortality Report seems to vary by percentage of at-risk populations, but may be influenced by other factors.
Analysis performed in this report used information available from death certificates reported to the CDC in an effort to obtain national data, but it has a number of important major limitations. The accuracy of diagnostic coding is unknown, and there are too few individuals with forms of SCD other than HbSS and those designated as Hispanic reported to permit specific analysis. The number of individuals who died with or of SCD without documentation on the death certificate, or even the number of individuals that go unreported, is unknown. Finally, the average age of death (39 years) and the proportion of individuals surviving to age 45 years (35%) were lower in 2006 than the proportion of individuals surviving (50%) as reported by the CSSCD using data from before 1994, which seems incongruent with improved health care and disease-remitting therapy. These findings may be due to differences in estimation of survival for a specific cohort as compared to a cross-sectional sampling of age at death. It is also possible that those in the CSSCD and the pediatric and Jamaican cohorts received care within “specialized” sickle cell centers, whereas individuals reported to the CDC did not, resulting in a difference in outcomes. Unfortunately, it is not possible to sort this out without accurate national data. Application of a more-sophisticated approach to population and survival estimation should be undertaken, but it will be similarly limited by the paucity of high-quality data available at this time.
In order to accurately assess the number of individuals with SCD nationwide, a coordinated system of data collection and reporting will need to be established. Given state-to-state variability observed in this report, application of a single state's data to other states or national population estimates is not likely to yield representative information. Individual states can incorporate available information from newborn screening and administrative data sets for mortality to estimate the size and composition of their SCD population. Such state-specific information is likely to provide the best estimates for who would address healthcare needs and health policy development within a catchment area. In turn, centralized and standardized reporting of these data would possibly provide the best national assessment of the SCD population and burden of disease.
No financial disclosures were reported by the author of this paper.