Original Article
Sickle Cell Disease as a Cause of Osteonecrosis of the Femoral Head
N Engl J Med 1991; 325:1476-1481November 21, 1991
- Abstract
- Abstract
Background and Methods.
Osteonecrosis of the femoral head is an important complication of sickle cell disease. We studied 2590 patients who were over 5 years of age at entry and followed them for an average of 5.6 years. Patients were examined twice a year, and radiographs of the hips were taken at least twice: at study entry and approximately three years later.
Results.
At study entry, 9.8 percent of patients were found to have osteonecrosis of one or both femoral heads. On follow-up, patients with the hemoglobin SS genotype and α-thalassemia were at the greatest risk for osteonecrosis (age-adjusted incidence rate, 4.5 cases per 100 patient-years, as compared with 2.4 in patients with the hemoglobin SS genotype without α-thalassemia and 1.9 in those with the hemoglobin SC genotype). Although the rate of osteonecrosis in patients with the hemoglobin SC genotype did not differ significantly from that in patients with the hemoglobin SS genotype without α-thalassemia, osteonecrosis tended to develop in these patients later in life. Intermediate rates of osteonecrosis were observed among patients with the hemoglobin S—β0-thalassemia and the hemoglobin S—β+-thalassemia genotypes (3.6 and 3.3 cases per 100 patient-years, respectively). Osteonecrosis was found in patients as young as five years old (1.8 cases per 100 patient-years for all genotypes).
The frequency of painful crises and the hematocrit were positively associated with osteonecrosis. The mean corpuscular volume and serum aspartate aminotransferase level were negatively associated. Twenty-seven patients had hip arthroplasty during the study; 10 were under 25 years of age. Five of the 27 required reoperation 11 to 53 months after the initial operation.
Conclusions.
Osteonecrosis of the femoral head is common in patients with sickle cell disease, with an incidence ranging from about 2 to 4.5 cases per 100 patient-years. Patients with the hemoglobin SS genotype and α-thalassemia and those with frequent painful crises are at highest risk. The overall prevalence is about 10 percent. The results of hip arthroplasty are poor. (N Engl J Med 1991;325:1476–81.)
Media in This Article
Figure 1
Probability That Osteonecrosis of the Femoral Head Will Not Develop in Patients with the Hemoglobin SC Genotype, Patients with the Hemoglobin SS Genotype with α-Thalassemia, and Patients with the Hemoglobin SS Genotype without α-Thalassemia.Figure 2
Probability That a Hip Prosthesis Will Not Require Revision.Article Activity
- Article
IN the 1930s Diggs, Pulliam, and King1 drew attention to the pathologic effects of sickle cell disease on the skeleton, and Grinnan2 described the roentgenographic appearance of the bone lesions. There followed many reports in the radiologic and orthopedic literature describing the effects of these lesions, which led to a 1969 review of the literature on necrosis of the femoral head by Chung and Ralston.3 Sickle cell disease is now known to be an important cause of osteonecrosis, affecting persons from the Mediterranean, the Persian Gulf, and the Indian subcontinent as well as those of African descent.4 Lee et al.5 have described the radiologic features of femoral-head necrosis in 52 patients participating in a survey of 1031 Jamaicans with sickle cell anemia. Although large, this retrospective study focused only on patients with the hemoglobin SS genotype (sickle cell anemia). Osteonecrosis of the femoral head affects not only patients with sickle cell anemia, but also those with the double heterozygous hemoglobinopathies: hemoglobin SC disease (hemoglobin SC genotype), hemoglobin S—β0-thalassemia (Sβ0 genotype), and hemoglobin S—β+-thalassemia (Sβ+ genotype). Concomitant α-thalassemia, which affects about 30 percent of patients with sickle cell anemia,6 7 8 can play an important part in modifying the course of disease.9 , 10
There is a need for prospective data on osteonecrosis in patients with sickle cell disease to determine not only the rates of disease, but also clinical outcomes. Although some patients remain asymptomatic, many experience pain and ultimately undergo hip arthroplasty. The identification of factors indicative of high risk before the onset of osteonecrosis may help prevent debilitating clinical outcomes.
In 1978, 23 clinical centers began a cooperative study of the clinical course of sickle cell disease, which was organized by the Sickle Cell Branch of the Heart, Lung, and Blood Institute of the National Institutes of Health. This report presents the prevalence, incidence, risk factors, and outcomes of osteonecrosis of the femoral head in a large prospective study of patients over the age of five years who had sickle cell disease.
Methods
Patients
The design of the Cooperative Study of Sickle Cell Disease has been described elsewhere.11 , 12 A total of 2804 patients over five years of age were enrolled in the study from March 1979 through May 1981. All patients who had visited their clinic for any reason in the previous three years were candidates for the study. Patients were followed for an average (±SD) of 5.6±1.7 years. A diagnosis based on hemoglobin analysis by the Centers for Disease Control was missing for 23 patients (0.8 percent), and orthopedic data on the femoral head were incomplete for 191 patients (6.8 percent). Our prevalence analysis was based on the remaining 2590 patients, whose ages and genotypes are shown in Table 1Table 1
Hemoglobin Genotype of Patient Population and Age at Entry.. Analyses of the incidence of osteonecrosis, which required prospective data, were based on 1712 patients. We excluded 289 patients who had osteonecrosis (at any site) at study entry, 66 patients who died, 302 patients who were lost to follow-up, and 221 patients for whom no radiologic data were available during follow-up.Laboratory Diagnosis
A blood sample was sent to the Centers for Disease Control for genotyping by cellulose acetate electrophoresis and quantitation of fetal hemoglobin and hemoglobin A2. To establish the presence of α-thalassemia in patients with the hemoglobin SS genotype, mapping of the α-globin gene was performed by one investigator on DNA extracted from EDTA-anticoagulated whole blood with a 32P-labeled α-globin—specific probe for blot hybridization.13 14 15
Of the 1785 patients with the hemoglobin SS genotype, 1356 were tested for the presence of an α-thalassemia gene, and 429 patients were not tested, because gene mapping was not available until five years after the start of the study, and most of this group died or were lost to follow-up during that period. Thus, of the 1356 tested, 33 (2.4 percent) were homozygous (—α/—α) for α-thalassemia, and 383 (28.2 percent) were heterozygous (αα/—α).
Radiographic Diagnosis
Seventy-six percent of radiographs considered to show osteonecrosis at the clinical centers were reviewed by one investigator to confirm the diagnosis, ensure uniformity of interpretation, and assign disease stage.16 For the remaining 24 percent, clinical-center diagnoses were used for classification. As a control measure, radiographs considered to show normal joints in randomly selected patients from each center were requested for central review. Only 2 of 127 such radiographs were considered to show evidence of osteonecrosis. Therefore, the rate of false negative classification at the clinical center was estimated to be 1.6 percent. Application of this rate to a sample of 2590 patients suggests that an average of 42 radiographs (upper 95 percent confidence limit, 98, or 3.8 percent) may have been incorrectly classified as normal by the clinical centers.
Statistical Analysis
Crude and age-specific prevalence rates were calculated as the number of cases of osteonecrosis observed at study entry divided by the total number of patients in the relevant subgroup. The direct method of standardization17 was used for age-adjusted rates (with the overall age distribution used as the standard), and a normal approximation was used to construct confidence intervals.
We estimated incidence rates and survival curves using data on 1712 patients. However, 157 patients with the hemoglobin SS genotype for whom mapping of the α-globin gene was not done were excluded from the calculation of incidence rates involving genotype. It should be noted that the incidence rates reflect the diagnosis of osteonecrosis and not necessarily its onset because some patients were asymptomatic — that is, osteonecrosis was not documented until radiographic evidence was found on the second screening visit (approximately three years after study entry). Patients with negative radiographs were followed until June 1986, unless they died or were lost to follow-up before that date. Incidence rates were compared with the normal approximation to a test of binomial proportions. A Bonferroni adjustment18 was used to provide conservative estimates of pairwise differences between groups. Disease-free (according to the date of diagnosis) survival curves were estimated for patients with the hemoglobin SS and SC genotypes by the Kaplan–Meier method, with adjustment of the risk set to account for the wide range of ages at entry typically seen in a natural-history study.19
A multivariate risk factor model for osteonecrosis of the femoral head was developed with a Weibull survival regression model for interval-censored data.20 The final model included all variables with a P value of 0.01 or less. The following variables were examined as potential predictors of osteonecrosis: hematocrit; mean corpuscular volume; white-cell count; red-cell count; hemoglobin level; fetal hemoglobin level; sex; age at entry; frequency of painful crises; occurrence of leg ulcers, proteinuria, and urinary tract infections; bilirubin level; creatinine level; uric acid level; aspartate aminotransferase level; alanine aminotransferase level; blood urea nitrogen level; and alkaline phosphatase level. When appropriate, covariate values in the regression model were expressed as steady-state averages of measurements from study entry to diagnosis of the disease (for cases of osteonecrosis) or to the end of follow-up (for cases not involving osteonecrosis).
Patients given a diagnosis of osteonecrosis during the study were questioned during twice-yearly visits about pain and limited motion in their left and right hip joints. Such data regarding bilateral disease and symptoms were adequate for 131 of 152 patients in whom osteonecrosis developed during the study.
A Kaplan–Meier survival curve was estimated for the life expectancy of the hip prosthesis in 27 patients who had one or more arthroplastic operations on the same hip during follow-up.
Results
Prevalence of Osteonecrosis
Of 2590 patients, 253 (9.8 percent) were found to have osteonecrosis at study entry. We examined differences in the prevalence of osteonecrosis according to genotype using the age-adjusted rates shown in Table 2Table 2
Prevalence of Osteonecrosis of the Hip in Sickle Cell Disease., since the distribution of ages at entry was not uniform across genotypes (P = 0.001). The prevalence of osteonecrosis was greatest in the group with the Sβ0 genotype (13.1 percent), followed by those with the hemoglobin SS genotype (10.2 percent), those with the hemoglobin SC genotype (8.8 percent), and patients with the Sβ+ genotype (5.8 percent). Although the high prevalence of osteonecrosis among patients with the Sβ0 genotype is notable, this group was small, resulting in a wide 95 percent confidence interval for the age-adjusted rate, which overlapped with the confidence intervals of the other genotypes. However, these data do suggest that the prevalence of osteonecrosis in patients with the hemoglobin SS genotype was significantly different from that in patients with the Sβ+ genotype (P<0.10).Among patients with the hemoglobin SS genotype, we found a clear relation between the prevalence of osteonecrosis and the number of α-thalassemia genes. The crude prevalence of osteonecrosis of the hip was 21.2 percent among homozygotes, 11.5 percent among heterozygotes, and 8.7 percent among patients with the hemoglobin SS genotype who did not have an α-thalassemia gene (MantelHaenszel chi-square test statistic for linear trend, 6.01; P = 0.014).
Osteonecrosis was present in young patients with all genotypes except Sβ+. The prevalence of osteonecrosis was approximately 6 percent in patients with the hemoglobin SS and Sβ0 genotypes who were under 25 years of age. Notably, there were no cases of osteonecrosis among patients with the Sβ+ genotype in this age group. Osteonecrosis appeared to develop later in life in patients with the hemoglobin SC or Sβ+ genotype.
Incidence of Osteonecrosis
Of 1712 patients followed for 5274 patient-years, 152 (8.9 percent) had osteonecrosis of the femoral head during the study. The estimated time to diagnosis according to age among patients with the hemoglobin SS and SC genotypes is shown in Figure 1Figure 1
Probability That Osteonecrosis of the Femoral Head Will Not Develop in Patients with the Hemoglobin SC Genotype, Patients with the Hemoglobin SS Genotype with α-Thalassemia, and Patients with the Hemoglobin SS Genotype without α-Thalassemia.. The estimated median age at diagnosis was 28 years for the patients with the hemoglobin SS genotype and α-thalassemia, 36 years for those with the hemoglobin SS genotype without α-thalassemia, and 40 years for those with the hemoglobin SC genotype.We found the highest incidence of osteonecrosis (Table 3Table 3
Incidence of Osteonecrosis of the Femoral Head per 100 Patient-Years.) among patients with the hemoglobin SS genotype and α-thalassemia (age-adjusted rate, 4.47 cases per 100 patient-years). Pairwise tests of the incidence of osteonecrosis according to genotype revealed that the age-adjusted rates in patients with the hemoglobin SS genotype (2.35 cases per 100 patient-years) and in patients with the hemoglobin SC genotype (1.91 cases per 100 patient-years) differed from that in patients with the SS genotype and α-thalassemia (P = 0.001 and P = 0.002, respectively). No other comparisons between genotypes were statistically significant, but this may have been due to the small number of patients with the Sβ+ and Sβ0 genotypes who were available for follow-up.To determine whether there were age-specific differences in the incidence of osteonecrosis according to genotype, we studied two age groups of interest: patients who were 5 to 14 years old and those who were 35 or older. We found that the incidence of osteonecrosis in the older age group was highest among patients with the Sβ+ genotype (13.83 cases per 100 patient-years). This rate differed significantly from that for patients with the hemoglobin SS genotype (P = 0.0002). The incidence of osteonecrosis in the younger age group was highest among patients with the hemoglobin SS genotype and α-thalassemia and patients with the Sβ0 genotype. However, we found no significant differences in incidence with respect to genotype in this age group.
Bilateral Disease
Bilateral disease developed in 54.2 percent of the patients. There was little variation among genotypes. However, 51 percent of the cases of bilateral disease occurred in patients under 25 years of age.
Symptoms and Stage of Disease
Almost half the patients (47.3 percent) in whom osteonecrosis developed during the study had no pain or limitation of motion at the time of diagnosis. However, one fifth of these patients (21 percent) reported symptoms or had limitation of motion in the affected joint at a later date.
The degree of osteonecrosis on radiography was staged according to the classification of Ficat16: findings of sclerosis and radiolucent areas were considered to represent Stage II disease; findings of subepiphyseal radiolucency and widening of the joint space, Stage III disease; and late radiographic changes of flattening of the epiphysis with sclerosis, fragmentation, or both, Stage IV disease. A subgroup of 135 films of the hip in patients in whom osteonecrosis developed during the study were classified by one reader. Almost half the films (47.4 percent) showed Stage II disease, 29.6 percent showed Stage III, and 23.0 percent showed Stage IV at the time of the diagnosis of osteonecrosis. We were surprised by the large proportion of asymptomatic patients in view of the fact that many patients had later stages of osteonecrosis at the time of the diagnosis.
Risk Factors
To identify characteristics of patients with the hemoglobin SS genotype that were predictive of osteonecrosis of the femoral head, multivariate modeling of the time to diagnosis was used. The final model contained four variables significant at a level of 0.01. Patients with more frequent vasoocclusive crises were found to be at higher risk for osteonecrosis (P = 0.0013). Similarly, a higher hematocrit (P = 0.0049), lower mean corpuscular volume (P = 0.0097), and lower aspartate aminotransferase level (P = 0.0014) were also identified as risk factors.
We found that the presence of α-thalassemia was not a significant risk factor (P = 0.28), after accounting for the four variables in the final model. However, separate analyses revealed that α-thalassemia was not merely a surrogate for the hematocrit. Among the patients with the hemoglobin SS genotype who had a below-average (<0.25) hematocrit, the rates of osteonecrosis were significantly different among those with α-thalassemia and those without the disease (12.4 percent vs. 5.5 percent, P = 0.0105). The rates of osteonecrosis among patients with the hemoglobin SS genotype who had an above-average hematocrit were not significantly different between those with and those without α-thalassemia.
Surgical Intervention
Of the 253 patients with osteonecrosis of the hip at entry into the study, 44 (17.4 percent) had had arthroplasty. Almost one third (14 of 44) had had both hip joints replaced. During the study period, 27 patients required hip surgery. Twenty-two of these patients (81.5 percent) were under 35 years of age at the time of surgery, and 10 (37.0 percent) were under 25 years. Nine of the 27 patients had surgery for osteonecrosis that developed during the study, so that the time from diagnosis to surgery was known: it ranged from 1.8 to 11.3 months (mean [±SD], 6.4±3.3).
We estimated the life expectancy of a hip prosthesis for the 27 patients who had their first arthroplasty performed during follow-up (Fig. 2Figure 2
Probability That a Hip Prosthesis Will Not Require Revision.). Five of the 27 patients required further hip operations. The curve in Figure 2 reveals that there was an 8 percent chance of requiring revision within 1 year (95 percent confidence interval, 2 percent to 13 percent), a 20 percent chance within 3 years (95 percent confidence interval, 10 percent to 29 percent), and a 30 percent chance within 4.5 years (95 percent confidence interval, 17 percent to 42 percent). The mean interval between the first operation and reoperation was 27 months (range, 11.3 to 53.4). One patient required arthroplasty twice after the initial operation.Information regarding symptoms was available for 59 of the 71 patients (83 percent) known to have had hip arthroplasty. Even after surgery, almost two thirds (64.4 percent) continued to experience pain and three quarters (76.3 percent) had limited range of movement.
Discussion
All patients in the Cooperative Study of Sickle Cell Disease were identified from clinic rosters maintained during three years of visits. Thus, with the possible exception of patients with the Sβ+ genotype (many of whom remain asymptomatic throughout life), we consider this sample of 2590 subjects to be representative of the population of patients with sickle cell disease. Variability in osteonecrosis diagnoses was minimized by a central review of most of the radiographs considered abnormal at the various clinics (the review was conducted after the false negative rate of clinic diagnoses was found to be sufficiently small). For these reasons, we believe that the data presented in this report provide a valid description of osteonecrosis of the hip in a representative sample of patients with sickle cell disease.
It appears that patients with the hemoglobin SS genotype and α-thalassemia (and possibly those with the Sβ0 genotype) are at highest risk for osteonecrosis. The effect of α-thalassemia depends on the number of α-globin genes present. The prevalence of osteonecrosis among patients with the hemoglobin SS genotype was highest in those homozygous for α-thalassemia (21 percent) and lower in those heterozygous for α-thalassemia (12 percent) and those without α-thalassemia (9 percent). This relation is similar to that found by Bailas et al.9 in a study of 52 selected adults with the hemoglobin SS genotype. Thus, mapping of the α-globin gene, if available, may be useful for identifying potentially high-risk patients with the hemoglobin SS genotype. We did not look for α-thalassemia in other genotypes, but Steinberg et al.21 did not find any clinical effect of the presence or absence of α-thalassemia in patients with the hemoglobin SC genotype.
Sickle cell disease is the most common cause of osteonecrosis of the femoral head in children. Indeed, we found that 3 percent of the patients under 15 years of age had osteonecrosis at study entry. The incidence was 2.1 cases per 100 patient-years in this age group. Other studies have also found evidence of osteonecrosis in young patients with the hemoglobin SS genotype.5 , 22 Some of these early lesions lead to deformities in later life,23 seen radiologically as epiphyseal—metaphyseal overlap, mushroom-head deformity with intact cortex, and metaphyseal radiolucency with sclerotic borders.4 , 24
It appears that femoral-head osteonecrosis is almost nonexistent in patients with the Sβ+ or hemoglobin SC genotype who are under the age of 15 years. However, osteonecrosis is found in patients with these genotypes during adulthood. Patients with hemoglobin S—β+-thalassemia (which is characterized by less severe anemia and sickling than sickle cell anemia) had the highest incidence of osteonecrosis in the oldest age groups (≥35 years), as compared with all other genotypes. The rates of osteonecrosis in older patients with the hemoglobin SC genotype were remarkable, although slightly lower than those reported by River et al.25 and Serjeant et al.26
The strong positive correlation between the hematocrit and the incidence of osteonecrosis is to some extent accounted for by the fact that patients with the hemoglobin SS genotype and α-thalassemia tend to have high hematocrits.9 Nevertheless, the presence of α-thalassemia in patients with below-average hematocrits was related to an increased incidence of osteonecrosis. Perhaps the patients with the hemoglobin SS genotype and α-thalassemia who had relatively low hematocrits possessed one or more of the other risk factors that we identified: low mean corpuscular volume, low aspartate aminotransferase level, or a high frequency of painful crises. Since it has been shown that patients with the hemoglobin SS genotype and α-thalassemia who have higher-than-average hematocrits have more frequent vaso-occlusive pain crises,27 we were not surprised to find that the frequency of painful crises was significantly correlated with the development of osteonecrosis.
Vaso-occlusive crises are not the only cause of osteonecrosis, however, and do not account for the increasing rates of osteonecrosis with respect to age in patients with the hemoglobin SC and Sβ+ genotypes, since these groups had a low incidence of such crises. However, with increasing age such patients are also at high risk for proliferative retinopathy, a silent lesion produced by obstruction of fine peripheral vessels of the retinal artery.23 It is tempting to suggest that a similar silent but progressive occlusion of the micro-circulation within the femoral head kills osteoblasts and increases intraosseous pressure, the factors responsible for necrosis in these patients.
Arthroplasty has been the main treatment for osteonecrosis of the femoral head, but the prognosis is not as favorable as that of arthroplasty performed for an arthritic hip.28 The placement of internal prostheses for osteonecrosis caused by sickle cell disease has been complicated by several factors, including the presence of hard sclerotic bone (making placement of the femoral component more difficult) and a high morbidity due to loosening of both cemented and uncemented prostheses.29 An increased incidence of infection is also troublesome,29 , 30 and a failure rate of 50 percent has been reported.30 The experience of patients in this study was somewhat better: 18.5 percent of the patients who had their first operation during the study required reoperation. Because 81.5 percent of these patients were under 35 years of age and many now have an average life expectancy of 50 years, additional operations may someday be required. However, the hip prostheses in our series were of the various types, and more recent techniques may have improved the life expectancy of hip prostheses.
In this study, the diagnosis of osteonecrosis was made on the basis of radiographs that showed bone changes of Ficat Stage II or greater.16 The presence of Stage I osteonecrosis can now be detected by magnetic resonance imaging31; thus, some cases in which the initial bone insult indicative of Stage I was present at study entry may have escaped diagnosis. However, most such cases probably progressed sufficiently to be detected two or three years later, when the second radiograph was taken.
The pathophysiology of nontraumatic osteonecrosis is poorly understood.32 The initial event is probably necrosis of bone marrow and associated bone-forming cells, brought about by localized sludging of sickled cells in the marrow sinusoids. Subsequent repair processes may lead to healing of this lesion, especially in younger patients, but may also produce increased intramedullary pressure,33 , 34 ultimately leading to bone resorption and collapse of the structure of the femoral head.35 In the future, it should be possible to detect these lesions at an early stage and prevent progression. Recently, core decompression of Stage I and early Stage II lesions has shown some promise in the treatment of osteonecrosis.16 , 34 , 36 , 37 Few reports of this procedure, however, have included patients with sickle cell disease, and none have examined the outcome in these patients separately. It is possible that the relatively young age of patients with sickle cell disease who have osteonecrosis, coupled with the greater vascularity of the cancellous bone (due to erythropoietic hyperplasia), may make them better candidates for early intervention with core decompression than patients with osteonecrosis from other causes. Formal clinical trials would be required for an answer to this question.
Supported by the Cooperative Study of Sickle Cell Disease, a program of the Sickle Cell Disease Branch of the National Heart, Lung, and Blood Institute.
We are indebted to Dr. Richard Entsuah and Dr. Joel Verter for preliminary statistical analysis of the data.
Source Information
From the Medical College of Georgia, Augusta (P.F.M.); the University of Tennessee, Memphis (A.P.K., J.I.S.); New England Research Institute, Watertown, Mass. (L.A.S., K.A.D.); the University of California, San Francisco (S.H.E.); Interfaith Medical Center, Brooklyn, N.Y. (R.B.); the University of Illinois, Chicago (M.K.); Woodhull-State University of New York Health Science Center at Brooklyn, (J.W.M.); and Harlem Hospital Center, Columbia University, New York (J.S.). Address reprint requests to Dr. Milner at the Adult Sickle Cell Clinic, Bldg. FR-100, Medical College of Georgia, Augusta, GA 30912.
Appendix
The following were senior investigators at the cooperating clinical centers: participating investigators: R. Johnson, Alta Bates Hospital (Oakland, Calif.); L. McMahon, Boston City Hospital (Boston); O. Platt, Children's Hospital (Boston); F. Gill and K. Ohene Frempong, Children's Hospital (Philadelphia); G. Bray, J.F. Kelleher, and S. Leikin, Children's Hospital National Medical Center (Washington, D.C.); E. Vichinsky and B. Lubin, Children's Hospital (Oakland, Calif.); A. Bank and S. Piomelli, Columbia Presbyterian Hospital (New York); W. Rosse, J. Falletta, and T.R. Kinney, Duke University (Durham, N.C.); L. Lessin, George Washington University (Washington, D.C.); J. Smith and Y. Khakoo, Harlem Hospital (New York); R.B. Scott, O. Castro, and C. Reindorf, Howard University (Washington, D.C.); H. Dosik, S. Diamond, and R. Bellevue, Interfaith Medical Center (Brooklyn); W. Wang and J. Wilimas, LeBonheur Children's Hospital (Memphis); P. Milner, Medical College of Georgia (Augusta); A. Brown, S. Miller, R. Rieder, and P. Gillette, State University of New York Downstate Medical Center (Brooklyn); W. Lande, S. Embury, and W. Mentzer, San Francisco General Hospital (San Francisco); D. Wethers and R. Grover, St. Luke's–Roosevelt Medical Center (New York); M. Koshy and N. Talishy, University of Illinois (Chicago); C. Pegelow and P. Klug, University of Miami (Miami); M. Steinberg, University of Mississippi (Jackson); A. Kraus, University of Tennessee (Memphis); H. Zarkowsky, Washington University (St. Louis); C. Dampier, Wyler Children's Hospital (Chicago); H. Pearson and A.K. Ritchey, Yale University (New Haven, Conn.); statistical coordinating centers: P. Levy, D. Gallagher, A. Koranda, Z. Flournoy-Gill, and E. Jones, University of Illinois School of Public Health (Chicago; 1979—1989); S. McKinlay, O. Platt, D. Gallagher, D. Brambilla, and L. Sleeper, New England Research Institute (Watertown, Mass.; 1989—1991); M. Espeland, Bowman—Gray School of Medicine (Chapel Hill, N.C.); program administration: M. Gaston, C. Reid, and J. Verier, National Heart, Lung, and Blood Institute (Bethesda, Md.).
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