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Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 288-294
Cerebrovascular Accidents in Sickle Cell Disease: Rates and Risk
Factors
By
Kwaku Ohene-Frempong,
Steven J. Weiner,
Lynn A. Sleeper,
Scott T. Miller,
Stephen Embury,
John W. Moohr,
Doris L. Wethers,
Charles H. Pegelow,
Frances M. Gill, and
the Cooperative Study of Sickle Cell
Disease
From The University of Pennsylvania School of Medicine and the
Division of Hematology, The Children's Hospital of Philadelphia,
Philadelphia, PA; the New England Research Institutes, Watertown, MA;
the Department of Pediatrics, State University of New York Health
Science Center at Brooklyn, Brooklyn, NY; the San Francisco General
Hospital and the University of California, San Francisco, San
Francisco, CA; the Department of Pediatrics, Woodhull Medical and
Mental Health Center, Brooklyn, NY; the Department of Pediatrics,
Columbia University School of Medicine and St Luke's/Roosevelt
Hospital, New York, NY; the Department of Pediatrics, University of
Miami, Miami, FL; and the Department of Pediatrics, The University of
Pennsylvania School of Medicine, Philadelphia, PA.
 |
ABSTRACT |
Cerebrovascular accident (CVA) is a major complication of sickle
cell disease. The incidence and mortality of and risk factors for CVA
in sickle cell disease patients in the United States have been reported
only in small patient samples. The Cooperative Study of Sickle Cell
Disease collected clinical data on 4,082 sickle cell disease patients
enrolled from 1978 to 1988. Patients were followed for an average of
5.2 ± 2.0 years. Age-specific prevalence and incidence rates of CVA
in patients with the common genotypes of sickle cell disease were
determined, and the effects of hematologic and clinical events on the
risk of CVA were analyzed. The highest rates of prevalence of CVA
(4.01%) and incidence (0.61 per 100 patient-years) were in sickle cell
anemia (SS) patients, but CVA occurred in all common genotypes. The
incidence of infarctive CVA was lowest in SS patients 20 to 29 years of
age and higher in children and older patients. Conversely, the
incidence of hemorrhagic stroke in SS patients was highest among
patients aged 20 to 29 years. Across all ages the mortality rate was
26% in the 2 weeks after hemorrhagic stroke. No deaths occurred after
infarctive stroke. Risk factors for infarctive stroke included prior
transient ischemic attack, low steady-state hemoglobin concentration
and rate of and recent episode of acute chest syndrome, and elevated
systolic blood pressure. Hemorrhagic stroke was associated with low
steady-state hemoglobin and high leukocyte count.
| |
INTRODUCTION |
CEREBROVASCULAR accident (CVA) is a
catastrophic complication of sickle cell disease (SCD) and a leading
cause of death in both children1 and adults.2
The reported risk of first CVA in the first 20 years of life is 0.761
per 100 patient-years.3 A cohort study in Jamaica estimated
the prevalence of CVA to be 7.8% among 310 patients of all genotypes
aged 9 to 17 years who were observed since birth.4
Among patients with the common genotypes of SCD, CVA is most frequent
in those with sickle cell anemia (SS).5 The rate of CVA for
patients with other genotypes (SC, S- + thalassemia, and
S-0 thalassemia) has not been reported. The influence of
age, clinical events, and hematologic and genetic factors on the risk
of CVA needs to be clarified so that accurate counseling can be
provided to patients, their families, and couples at risk for producing
children with these genotypes.
To address these and other questions related to CVA, the Cooperative
Study of Sickle Cell Disease (CSSCD) prospectively collected data on
CVA in a large cohort of patients.6,7 These data comprise
the largest series of CVAs in a group of SCD patients. The younger
patients in this cohort were observed since birth and provide the most
accurate rates of CVA in children with SCD living in the United States.
In this report, the prevalence and incidence of CVA and the effects of
age, genotype, and other risk factors are described.
| |
MATERIALS AND METHODS |
The CSSCD, a longitudinal clinical study, observed in its first phase
4,082 patients from 23 clinical centers across the United States
between October 1978 and September 1988. The study was approved by the
Institutional Review Boards of the participating centers. The study
design, recruitment process, and characteristics of patients enrolled
are described in detail elsewhere.6-8 In addition to
newborns, all patients who had visited a participating clinic for any
medical reason between 1975 and 1978 were eligible subjects. Enrollment
was closed in May 1981, except for newborns who were enrolled
throughout the study period. Patients were observed for an average of
5.2 ± 2.0 years. A hemoglobin (Hb) diagnosis was not confirmed for
139 of the 4,082 patients because they were on transfusion therapy; 31
of the 139 and 122 other patients had had at least one CVA before study
entry. An additional 174 patients were observed for routine visits but
not clinical events. Estimates of the incidence of CVA were based on
the remaining 3,647 patients. The genotype distribution of the patient
sample at entry is shown in Table 1.
Laboratory diagnosis.
The Centers for Disease Control (CDC) determined the Hb phenotype by
cellulose acetate and citrate agar electrophoresis methods9
and the presence of -thalassemia by quantification of Hb
A2 levels using column chromatography.10 The
percentage of fetal Hb (Hb F) was measured using the
method of alkali denaturation11 by the CDC for patients
entered at 2 years of age and older and by local centers for younger
patients. Steady-state complete blood counts were performed at local
centers from samples taken during routine clinic visits.  -Globin
gene mapping to determine the presence of a thalassemia was performed
on samples from 2,002 of the 2,675 SS patients (75%) by one of us
(S.E.) using the blot hybridization method.12,13
Definition of clinical syndromes.
CVA was defined as an acute neurologic syndrome secondary to occlusion
of an artery or hemorrhage with resultant ischemia and neurologic
symptoms and signs. In this study, CVA included transient ischemic
attack (TIA), completed infarctive stroke (neurologic deficits lasting
more than 24 hours), and hemorrhagic stroke. TIA was defined as
neurologic signs with vascular distribution that resolve within 24
hours (or 48 hours if basilar system is involved). Strokes were
classified by the investigator at the center as hemorrhagic or
infarctive based on the available clinical and imaging studies.
Ninety-five percent of the patients classified as having infarctive
stroke underwent computer tomography (CT) scan, brain
scan, and/or magnetic resonance imaging (MRI; 1 patient) at the
time of the event. Ninety-three percent of the patients classified as
having hemorrhagic stroke underwent CT scan, brain scan, arteriogram,
and/or autopsy after the event. MRI information was not
collected during the first 8 years of the CSSCD (ie, before December
1986). Studies were performed uniformly across all ages.
The CSSCD definitions of acute anemic episode, acute chest syndrome,
meningitis, and painful event are presented elsewhere.14
Seizure included major or minor motor seizures or psychomotor seizures
that were not secondary to central nervous system infection, tumor, or
stroke. Priapism was defined as a painful erection of the penis lasting
more than 1 hour. Only events severe enough to bring the patient to
seek medical care were recorded.
Statistical analyses.
Crude and age-specific prevalence rates were calculated as the number
of patients with at least one CVA before study entry divided by the
total number of patients in the relevant subgroup. Crude incidence
rates of the first CVA on study were calculated as the number of first
CVAs occurring during the specified time interval divided by the number
of person-years of observation in the relevant subgroup. The direct
method of standardization was used for all age-adjusted rates, with the
age distribution of the entire study sample used as the standard.
Incidence rates were compared using a test of binomial
proportions.15 The SAS macro SMOOTH (Paul
Allison, University of Pennsylvania) was used to obtain kernel-smoothed
hazard estimates for CVA as a function of age.16 Event-free
survival curves were estimated using the Kaplan-Meier method, with
adjustment of the risk sets to account for differing entry
ages,17 and age at CVA used as the time measure. The
proportional hazards model score function test was used to compare
survival curves.
Cox proportional hazards regression with risk set adjustment was used
to determine the risk factors for an initial CVA. Separate models were
fit for hemorrhagic and completed infarctive CVA. For all patients who
did not experience a CVA, observation time was truncated at the
earliest of the following: the end of the study, the time of loss to
follow-up, or the date of death from any cause. Potential covariates
were gender, systolic blood pressure, Hb F level, mean Hb level, mean
leukocyte count, mean platelet count, -thalassemia; history of
meningitis; presentation for seizure, surgery, priapism, acute anemia,
acute chest syndrome, and transfusion within 2 weeks before CVA; and
rates of painful episodes and acute chest syndrome. Mean
values were calculated using all values collected during regular clinic
visits after 1 year of age and before the CVA. Blood pressure was not
averaged; rather, the values were collected over all annual visits
after 2 years of age were incorporated into the model. TIA was examined
also as a risk factor for completed stroke, because, in practice, many
physicians may not consider TIA as a CVA event. Of the 2,436 SS
patients who had no history of CVA before study entry, 36 were excluded
because they were not observed past 1 year of age, leaving 2,400 in the
analysis. A stepwise procedure was used to arrive at a final
multivariate model. -Thalassemia was examined individually but not
included in the stepwise regression due to unknown -globin gene
number for 25% of SS patients.
Descriptive statistics are presented as percentages and means ± 1
standard deviation. All P values are two-sided, and a P
value of .05 is considered significant.
| |
RESULTS |
Prevalence and incidence of CVA.
At entry into the study 153 of 4,082 patients had a history of CVA
resulting in an overall crude prevalence rate of 3.75%. The highest
age-adjusted prevalence estimate, 4.01%, was in patients with SS,
followed in decreasing order by the rates of 2.43% for
S-0 thalassemia, 1.29% for S-+
thalassemia, and 0.84% for SC. One hundred thirty-nine patients had
unknown genotype due to chronic transfusion. Assuming that those
patients are SS results in an age-adjusted prevalence of 4.96% in that
group. The age-specific prevalence rates for each genotype, separating
those with unconfirmed genotype ("unknown"), are shown in Table
2. There was no difference in prevalence
between male and female patients.
During the study, 87 of the 3,647 patients with no history of CVA at
entry had a CVA, yielding an overall incidence rate of 0.46 per 100
patient-years. Age-specific incidence rates for each genotype are shown
in Table 3. The highest incidence of first
CVA was in the SS group, with an age-adjusted rate of 0.61 per 100
patient-years. We compared the incidence rates in broader age groups,
isolating those less than 1 year of age, none of whom had a CVA.
Incidence rates of CVA in SS patients less than 1 year of age, 1 to 9
years of age, 10 to 19 years of age, and 20+ years of age were 0.00,
0.84, 0.41, and 0.59, respectively. When compared with each other, only
the difference in incidence between the 1 to 9 years of age and 10 to
19 years of age groups was statistically significant (P =
.026). The 2 youngest of the 7 SC patients who had first CVA on study
were 5 years of age; they both had TIA. There was no significant
difference in incidence of first CVA between male and female patients
at any age.
Age at first CVA.
Data from the 3,647 patients used to calculate incidence rates were
used to determine CVA-free survival curves. The estimated age at first
CVA was significantly different for SS and SC patients (P <
.001; Fig 1). The chances of having a first
CVA by 20 years of age, 30 years of age, and 45 years of age were
estimated at 11%, 15%, and 24%, respectively, for SS patients and
2%, 4%, and 10%, respectively, for those with SC.
Age and type of CVA in SS patients.
During the study, there were 78 first CVAs in SS patients. The type of
CVA was not available for 2 patients. Forty-one (53.9%) of these CVAs
were infarctive, 26 (34.2%) were hemorrhagic, 8 (10.5%) were TIA, and
1 (1.3%) had both infarctive and hemorrhagic features (Table
4). Although the incidence of infarctive
CVA was highest in SS patients younger than 20 years of age (0.44 per
100 patient-years), adults more than 30 years of age were also found to
be at risk (Fig 2). Conversely, the rate of
hemorrhagic stroke was highest in patients 20 to 29 years of age (0.44
per 100 patient-years) and was low in children and older patients (Fig
2). Eight patients younger than 10 years of age experienced hemorrhagic
stroke (0.17 per 100 patient-years).
View larger version (12K):
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| Fig 2.
Smoothed hazard rates of infarctive and hemorrhagic
stroke in SS patients by age. ( ) Infarctive stroke; (---) hemorrhagic
stroke.
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Recurrence of CVA.
Among 72 SS patients who survived the first day of their initial CVA,
there were 10 recurrences (14%): 6.4 events per 100 patient-years in
patients with initial CVA occurring at less than 20 years of age and
1.6 events per 100 patient-years in patients with initial CVA occurring
at  20 years of age. Two events followed TIA with a mean time to
recurrence of 3.0 months, 2 events followed hemorrhagic stroke with a
mean time to recurrence of 7.2 months, and 6 events followed infarctive
stroke with a mean time to recurrence of 22.2 months. The 2 TIAs were
both followed by infarctive stroke, the 2 hemorrhagic strokes were both
followed by a second hemorrhagic stroke, and the 6 infarctive strokes
were followed by 1 TIA, 4 infarctive strokes, and 1 with mixed
infarctive/hemorrhagic stroke features. One 43-year-old SC patient with
infarctive stroke had a recurrence of unknown type 6 months later. Four
of the 10 SS patients with recurrent CVA received a blood transfusion
within 1 month before the recurrence. However, the CSSCD
did not mandate a transfusion protocol for study participants;
therefore, no definitive statement can be made regarding the
association between transfusion practices and CVA recurrence.
CVA-related mortality.
All deaths occurring less than 14 days after a CVA were considered to
be CVA related. A total of 104 patients (87 first and 17 recurrent
CVAs) had 133 episodes of CVA on study. Eleven (10.6%) of the 104
patients died, 9 after hemorrhagic stroke and 2 after strokes of
unidentified type. Seven of the 11 deaths resulted from the first CVA;
of these, 6 had a hemorrhagic stroke and 1 had stroke of unidentified
type. All 11 patients were in the SS group (11.7% of SS CVA patients)
and ranged in age from 12 to 58 years. Six died on the day of the CVA,
whereas the others died within 1 week after the CVA. The mortality rate
for hemorrhagic stroke was 24% overall and 26% for SS patients. No
deaths occurred within 14 days after 62 infarctive strokes.
-Thalassemia and CVA.
Of 2,436 SS patients with no history of CVA at study entry, 1,833 had
-globin gene mapping data: 573 (31%) had -thalassemia (48 with 2
and 525 with 3 -globin genes) and 1,260 (69%) had 4 (n = 1,242) or
5 (n = 18) -globin genes. The incidence of CVA of all types for
patients with -thalassemia (0.32 per 100 patient-years) was lower
than that for patients without -thalassemia (0.74 per 100
patient-years), yielding a relative risk of 0.44 (95% confidence
interval, 0.23 to 0.85; P = .011). There were no CVA observed
in the 48 patients with 2 -globin genes. The incidence of infarctive
stroke was 0.21 per 100 patient-years in those with -thalassemia and
0.81 per 100 patient-years in those without -thalassemia (P
= .079). The incidence of hemorrhagic stroke was 0.06 per 100
patient-years versus 0.23 per 100 patient-years in those with and
without -thalassemia (P = .076).
Risk factors for CVA.
Risk factors were evaluated separately for first infarctive and
hemorrhagic strokes because the two types of strokes may have different
pathophysiologies. For these analyses, TIA was considered as a risk
factor for having a subsequent completed infarctive or hemorrhagic
stroke. No patients experienced seizures, surgical procedures, or acute
anemic events within 2 weeks before CVA.
Completed infarctive stroke.
Univariate analyses of the risk of completed infarctive stroke (age at
first CVA) identified eight risk factors. Prior TIA, history of
meningitis (any type), history of bacterial meningitis, systolic blood
pressure, steady-state leukocyte count, acute chest syndrome within 2
weeks before stroke, and rate of acute chest syndrome were positively
related to infarctive stroke, whereas steady-state Hb concentration was
negatively related; ie, patients with lower steady-state Hb are at
greater risk of infarctive stroke (P < .05). The rate of
severe painful episodes (P = .671), Hb F level (P =
.106), blood transfusion within 2 weeks before stroke (P =
.077), and platelet count (P = .097) were not significantly
related to occurrence of first completed infarctive stroke.
The final multivariate model for risk of completed infarctive stroke
included five variables: prior TIA, steady-state Hb concentration,
acute chest syndrome within 2 weeks before CVA, rate of acute chest
syndrome, and systolic blood pressure (Table
5A). The most significant predictor of
completed infarctive stroke was prior TIA; however, the majority of
patients had stroke without prior TIA. In this study, 2 of 42 completed
infarctive strokes were preceded by TIA, compared with 6 TIA in 2,394
patients who did not experience any stroke. Similarly, 4 of the 42
completed infarctive strokes were preceded within 2 weeks by acute
chest syndrome. An additional 3 patients had acute chest syndrome on
the same day as the completed infarctive stroke, but these patients
were excluded from the analysis because timing of the acute chest
syndrome event relative to the onset of infarctive stroke was not
documented.
Hemorrhagic stroke.
Univariate analyses of the risk of hemorrhagic stroke (age at first
CVA) identified three significant risk factors: steady-state leukocyte
count and rate of acute chest syndrome were positively related to risk
of hemorrhagic stroke, whereas steady-state Hb concentration was
negatively related (P < .05). The presence of -thalassemia
provided a marginally significant protection against hemorrhagic stroke
in SS patients (P = .054). Unlike infarctive stroke, history of
meningitis and systolic blood pressure were not significant univariate
predictors; none of the 28 patients with first hemorrhagic stroke on
study had had meningitis.
The final multivariate model for risk of hemorrhagic stroke included
two significant variables: low steady-state Hb concentration and high
leukocyte count (Table 5B).
| |
DISCUSSION |
This report represents larger numbers of SCD patients with CVA than any
previous study. As expected, the highest incidence rate was found in SS
patients. Although SS patients are at the greatest risk of stroke,
clinicians and others counseling about SCD should note that strokes
occurred also in patients with other genotypes. Children less than 2
years of age had the lowest CVA incidence, suggesting that there may be
a protective mechanism operative in early life or that, in SCD, the
pathology responsible for CVA develops over time. However, we found the
incidence of CVA to be higher in the 1 to 9 years of age group than in
the 10 to 19 years of age group. This finding suggests that a subset of
patients may have additional risk factors for early stroke.
The type of stroke may be due to different pathophysiologic mechanisms
or to progressive cerebrovascular damage. The notion that infarctive
strokes occur more commonly in children whereas hemorrhagic strokes
occur more frequently in adults is supported partly by this study.
Infarctive stroke was more common in SS patients less than 20 years of
age than in those older, but patients more than 30 years of age were
also at risk. Interestingly, the period of lowest risk for infarctive
stroke (20 to 29 years of age) was the period of highest risk for
hemorrhagic stroke. However, it should be noted that children less than
10 years of age experienced a higher rate of hemorrhagic stroke (0.17
per 100-patient-years) than reported previously.
Some of our data may be useful in identifying patients at high risk for
completed CVA. History of TIA was a strong risk factor for completed
infarctive stroke. This fact should alert clinicians to regard TIA as a
sign of cerebrovascular disease, use definitive diagnostic studies, and
initiate aggressive management to prevent occurrence of completed
stroke. However, infarctive strokes are often not preceded by TIA, and
in young children mild TIA is likely to go unnoticed.
The temporal association of episodes of acute chest syndrome and CVA
found in this study has not been reported previously. It is possible
that in patients with damaged cerebral vessels, CVA may be precipitated
by hypoxia associated with pulmonary disease. Alternatively, these
strokes may be related to the fat embolization syndrome.18
We did not find an association between first CVA and
priapism19 or transfusion therapy occurring within 2 weeks
before the CVA.
Anemia in SCD is a reflection of overall severity of SCD. Patients with
the milder genotypes are less anemic than those with more severe
genotypes. However, within each genotype, an association between the
severity of anemia and major complications of SCD is not always
apparent. In SS patients, a high Hb level is related to increased rates
of severe pain20 and acute chest syndrome.21
Severe anemia may pose an added risk for CVA. It has been suggested
that the increased cerebral blood flow and flow velocity associated
with chronic anemia22 cause flow disturbances that may lead
to cerebrovascular damage.23
A high leukocyte count appears to be a risk factor for many severe
complications of SCD: rates of severe pain,20 acute chest
syndrome,21 and mortality.2 Association of
increased white blood cell count with CVA has been
reported4; our data show such a correlation only for
hemorrhagic CVA. The contribution of leukocytes, if any, and the
various vaso-active and cytoadhesive molecules produced by leukocytes
to vasoocclusion has not been defined.
The lack of a protective effect of increased Hb F levels on CVA was
surprising, given reports of its inhibiting effect on CVA risk in other
series.3,4 Hb F has been inversely correlated with rates of
other major vasoocclusive manifestations of sickle cell disease such as
severe pain and acute chest syndrome. It remains to be seen whether the
ameliorating effect of hydroxyurea therapy on rates of severe pain and
acute chest syndrome will be shown with CVA also.24
The effect of -thalassemia on the incidence of CVA is controversial;
whereas some studies have found that it reduces the risk of
CVA,14,25,26 others have not.4,27 This study
provides some evidence to support earlier reports that -thalassemia
protects SCD patients from CVA.14,25,26 We observed a
significant association when all types of CVA were combined, but the
effect was marginal (.05 < P < .10) when infarctive and
hemorrhagic strokes were considered separately, in part due to the
smaller number of events in each subgroup. Nevertheless, it should be
noted that the effect of -thalassemia appears to be similar for
infarctive and hemorrhagic strokes. Based on additional multivariate
analysis, we conclude that the protective effect of -thalassemia is
largely due to the improvement in Hb concentration. We did not find
-thalassemia to be a significant predictor of CVA after adjusting
for Hb.
SCD patients who suffer CVA have a high risk of recurrence that is
reduced but not abolished by chronic transfusion
therapy.28-32 We were unable to assess the impact of
chronic transfusion on CVA recurrence because the study did not mandate
any transfusion regimen for patients with CVA.
We observed no mortality after 62 infarctive strokes, but there was a
24% mortality rate after 38 hemorrhagic strokes within 2 weeks after
the event. Mortality related to hemorrhagic stroke was rapid, with 6 of
the 11 CVA-related deaths occurring on the day of the event.
For the last 2 decades, management of CVA in SCD has been directed
mainly towards prevention of recurrence. There is now strong interest
in preventing the occurrence of the first CVA. The CSSCD and others are
involved in prospective studies using magnetic resonance technology and
extensive neuropsychological testing to look for evidence of
intracranial pathology that may be predictive of CVA. Cerebral
infarcts33,34 and cerebrovascular disease35
have been demonstrated in SS patients with no history of CVA.
Transcranial Doppler ultrasonography has been shown to be able to
select patients at high risk of stroke,36 and a national
collaborative study in which patients with abnormal flow velocities are
randomized to transfusion or observation has shown recently the risk of
first CVA can be reduced significantly with chronic transfusion
therapy. Patients with the risk factors described in this study should
be particularly evaluated for evidence of cerebrovascular disease.
Caretakers of young children with SCD should be educated about signs of
TIA and advised to report them. Furthermore, patients with clinical and
hematologic risk factors who are found to have cerebrovascular disease
should be considered seriously for intervention studies and therapy.
| |
FOOTNOTES |
Submitted January 31, 1997;
accepted August 25, 1997.
Supported by the Division of Blood Diseases and Resources of the
National Heart, Lung, and Blood Institute of the National Institutes of
Health.
Address reprint requests to Kwaku Ohene-Frempong, MD, Division of
Hematology, Children's Hospital of Philadelphia, 34th St and Civic
Center Blvd, Philadelphia, PA 19104.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Sergio Piomelli, Orah Platt, Samuel Charache, William
Mentzer, Rebecca Stellato, and Dale Usner for their thoughtful review
and helpful comments regarding this manuscript.
| |
APPENDIX |
The following were senior investigators in the CSSCD: Clinical Centers:
R. Johnson, Alta Bates Hospital (Berkeley, CA); L. McMahon, Boston City
Hospital (Boston, MA); O. Platt, Children's Hospital (Boston, MA); F.
Gill and K. Ohene-Frempong, Children's Hospital (Philadelphia, PA); G.
Bray, J. Kelleher, and S. Leikin, Children's National Medical Center
(Washington, DC); E. Vichinsky and B. Lubin, Children's Hospital
(Oakland, CA); A. Bank and S. Piomelli, Columbia Presbyterian Hospital
(New York, NY); W. Rosse, J. Falletta, and T. Kinney, Duke University
(Durham, NC); L. Lessin, George Washington University (Washington, DC);
J. Smith and Y. Khakoo, Harlem Hospital (New York, NY); R. Scott, O.
Castro, and C. Reindorf, Howard University (Washington, DC); H. Dosik,
S. Diamond, and R. Bellevue, Interfaith Medical Center (Brooklyn, NY);
W. Wang and J. Wilimas, LeBonheur Children's Hospital (Memphis, TN);
P. Milner, Medical College of Georgia (Augusta, GA); A. Brown, S.
Miller, R. Rieder, and P. Gillette, State University of New York Health
Science Center at Brooklyn (Brooklyn, NY); W. Lande, S. Embury, and W.
Mentzer, San Francisco General Hospital (San Francisco, CA); D. Wethers
and R. Grover, St Luke's-Roosevelt Medical Center (New York, NY); M.
Koshy and N. Talishy, University of Illinois (Chicago, IL); C. Pegelow,
P. Klug, and J. Temple, University of Miami (Miami, FL); M. Steinberg,
University of Mississippi (Jackson, MS); A. Kraus, University of
Tennessee (Memphis, TN); H. Zarkowsky, Washington University (St Louis,
MO); C. Dampier, Wyler Children's Hospital (Chicago, IL); H. Pearson
and A.K. Ritchey, Yale University (New Haven, CT); Statistical
Coordinating Centers: P. Levy, D. Gallagher, A. Koranda, Z.
Flournoy-Gill, and E. Jones, University of Illinois School of Public
Health (Chicago, IL; 1979-89); S. McKinlay, O. Platt, D. Gallagher, D.
Brambilla, and L. Sleeper, New England Research Institutes (Watertown,
MA; 1989-1997); M. Espeland, Bowman-Gray School of Medicine
(Winston-Salem, NC); Program Administration: M. Gaston, C. Reid, and J.
Verter, National Heart, Lung, and Blood Institute (Bethesda,
MD).
| |
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Abstract
Introduction
Abstract
