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Cerebral White Matter Lesions, Retinopathy, and Incident Clinical Stroke
Tien Yin Wong, MD, MPH;
Ronald Klein, MD, MPH;
A. Richey Sharrett, MD, DrPH;
David J. Couper, PhD;
Barbara E. K. Klein, MD, MPH;
Duan-Ping Liao, MD, PhD;
Larry D. Hubbard, MAT;
Thomas H. Mosley, PhD;
for the ARIC Investigators
JAMA. 2002;288:67-74.
ABSTRACT
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Context White matter lesions (WMLs) detected on cerebral imaging scans have
been hypothesized to have a microvascular etiology and to precede the development
of clinical stroke. However, few clinical data are available to support these
hypotheses.
Objective To examine the relationship of WMLs, retinal microvascular abnormalities,
and incident clinical stroke in healthy, middle-aged men and women.
Design and Setting The Atherosclerosis Risk in Communities Study (ARIC), a prospective,
population-based cohort study conducted in 4 US communities and initiated
in 1987-1989.
Participants A total of 1684 persons aged 51 to 72 years who had cerebral magnetic
resonance imaging (MRI) and retinal photography at the third examination (1993-1995).
Main Outcome Measures Odds of WMLs, defined by standardized methods from MRI, by presence
or absence of specific retinal microvascular abnormality (eg, microaneurysm,
retinal hemorrhage) on retinal photograph; incident clinical stroke, ascertained
after a median follow-up of 4.7 years, according to presence or absence of
WMLs and retinopathy.
Results Persons with retinopathy were more likely to have WMLs than those without
retinopathy (22.9% vs 9.9%; odds ratio, 2.5; 95% confidence interval [CI],
1.5-4.0, adjusted for age, sex, race, and vascular risk factors). The 5-year
cumulative incidence of clinical stroke was higher in persons with vs without
WMLs (6.8% vs 1.4%; adjusted relative risk [RR], 3.4; 95% CI, 1.5-7.7) and
in persons with vs without retinopathy (8.0% vs 1.4%; adjusted RR, 4.9; 95%
CI, 2.0-11.9). Persons with both WMLs and retinopathy had a significantly
higher 5-year cumulative incidence of stroke than those without either WMLs
or retinopathy (20.0% vs 1.4%; adjusted RR, 18.1; 95% CI, 5.9-55.4).
Conclusions In this cohort, middle-aged persons with cerebral WMLs detected on MRI
were more likely to have retinal microvascular abnormalities and to have an
increased risk of clinical stroke than people without WMLs. The risk of stroke
was higher when retinopathy was simultaneously present in persons with WMLs.
INTRODUCTION
With the increasing use of magnetic resonance imaging (MRI) to scan
the brain, changes in the cerebral white matter are commonly detected in elderly
people.1-3 These
white matter lesions (WMLs) are found in 27% to 87% of populations aged 65
years and older.4-5 Despite recent
research, the pathogenesis and clinical significance of WMLs are obscure.6-9 These
lesions have been hypothesized to be ischemic complications of cerebral microvascular
disease,6 based on histopathological studies
that demonstrate small-vessel changes in brains with WMLs10-12
and on clinical studies that show associations between WMLs and microvascular
risk factors, such as hypertension13-16
and diabetes.17-19
In people with a history of stroke, WMLs have been suggested to increase the
risk of recurrent stroke and cognitive decline.20-21
However, existing studies are limited by their small sample sizes and
highly selected populations, and it remains uncertain whether WMLs have a
microvascular etiology6 and are associated
with development of clinical stroke in the general population.8
Retinal arterioles share similar anatomy, physiology, and embryology with
the cerebral arterioles.22 Retinal microvascular
changes (eg, microaneurysms, retinal hemorrhages) due to aging, hypertension,
and other processes appear to reflect cerebral microvascular disease23 and are associated with stroke.24
Thus, the retinal arterioles provide a unique opportunity to study the correlates
and consequences of cerebral small-vessel diseases.
The purposes of our current study were to examine the association of
cerebral WMLs and retinal microvascular abnormalities and the association
of WMLs and incident clinical stroke.
METHODS
Study Population
The study population consisted of 1684 persons who participated in cerebral
MRI and retinal photography in the Atherosclerosis Risk in Communities (ARIC)
study.25 Initiated in 1987 through 1989, the
ARIC study is a cohort study of cardiovascular disease among 15 792 persons
45 to 64 years of age, selected from 4 US communities.25
Participants in the study herein underwent a second examination 3 years later
in 1990 through 1992 (93% return rate) and a third examination 3 years after
the second in 1993 through 1995 (86% return rate).
Cerebral MRI and retinal photography were performed at the third examination,
when participants were 51 to 72 years of age.26-27
Retinal photography was offered to all participants.27
Of the 12 884 participants at the third examination, 12 553 (97.4%)
had retinal photography performed. Cerebral MRI was only offered to participants
at 2 study sites (Forsyth County, North Carolina; Jackson, Miss) in 1993 and
1994 in the third examination.26 The MRI examinees
could be considered a random sample of the full cohort because examination
dates were allocated at baseline through randomly selected induction cycles
and, to the degree possible, reexamination visits were scheduled according
to the anniversary date. Among individuals screened for eligibility for cerebral
MRI (n = 2887), we excluded 8 whose race was neither black nor white, 106
who were ineligible, 649 who declined to participate in the MRI study, and
204 with ungradeable MRI. In general, persons who were examined were similar
to those who were ineligible or who declined to participate in the MRI examination.26 Additionally, 50 persons with a history of stroke,
49 with no retinal photographs, and 137 with ungradeable photographs were
also excluded, leaving 1684 (58.3%) for the current study.
Institutional review boards at each study site, the MRI reading center,
and the retinal reading centers approved the study. Informed consent was obtained
from all participants.
Cerebral MRI
Cerebral MRI scanning and image interpretation have been previously
described.15, 26 In brief, T1-
and T2-weighted magnetic resonance images were obtained. Axial images were
angled to be parallel to the anterior commissure–posterior commissure
line. Trained and certified MRI readers, who were masked to participants'
clinical condition and retinal photography findings, evaluated the digitized
scan data on a personal display workstation at the MRI reading center. When
evaluating for WMLs, focal abnormalities were ignored. Thus, if one or both
sides of the brain were focally abnormal, estimates were based on the uninvolved
or unaffected areas. The spin-density images (repetition time, 3000 milliseconds;
echo time, 30 seconds) were used to estimate the overall volume of periventricular
and subcortical white matter signal abnormality. These were coded on a scale
from 0 to 9, based on "pattern matching" of a scan to a set of reference standards,
which are described in detail elsewhere.15, 26
The reference standards are: no white matter signal abnormalities (grade 0);
discontinuous periventricular rim or minimal "dots" of subcortical white matter
(grade 1); thin continuous periventricular rim or few patches of subcortical
WMLs (grade 2); thicker continuous periventricular rim with scattered patches
of subcortical WMLs (grade 3); thicker, shaggier periventricular rim with
mild subcortical WMLs—may have minimal confluent periventricular lesions
(grade 4); mild periventricular confluence surrounding the frontal and occipital
horns (grade 5); moderate periventricular confluence surrounding the frontal
and occipital horns (grade 6); periventricular confluence with moderate involvement
of the centrum semiovale (grade 7); periventricular confluence involving most
of the centrum semiovale (grade 8); and all white matter involved (grade 9).
The ARIC MRI standard images were graded 1 through 8: anything less than grade
1 was considered grade 0 and anything more than grade 8 was considered grade
9 (Figure 1). Quality control procedures,
described elsewhere,26 showed that interreader
and intrareader intraclass correlation coefficients were 0.68 and 0.71, respectively.
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Figure. Reference Magnetic Resonance Images
for Classifying White Matter Lesions (Grades 1-8)
Grading of white matter lesions (WMLs) was based on the total volume
of periventricular and subcortical white matter signal abnormalities on spin
density–weighted axial images. The reference images above are example
slices derived from complete scans showing successively increasing WMLs ranging
from barely detectable, discontinuous lesions located along the periventricular
rim (grade 1), progressing to thick, continuous, shaggy lesions along the
periventricular rim with mild subcortical involvement (grade 4), and finally
to confluent periventricular lesions and involvement of most of the centrum
semiovale (grade 8). Studies with no WMLs were graded 0; those with WMLs worse
than grade 8 were graded 9. The worm-shaped shadows, most apparent in the
grade 8 image, are artifact.
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Retinal Photography
Retinal photography procedures are described elsewhere.27
Briefly, photographs of the retina were taken of 1 randomly selected eye after
5 minutes of dark adaptation. Trained graders at the retinal reading center
who were masked to participant characteristics evaluated the photographic
slides for presence of microvascular abnormalities using a standardized protocol.27 Retinopathy was defined as present if any of the
following lesions were detected: microaneurysms, retinal hemorrhages, soft
exudates, and other less-common lesions (eg, hard exudates, macular edema,
optic disc swelling).27 Arteriovenous nicking
and focal arteriolar narrowing were separately defined as present if graded
definite or probable.27 To estimate the severity
of generalized retinal arteriolar narrowing, photographs were digitized and
diameters of individual retinal vessels coursing through a specified area
were measured on the computer and summarized as the arteriole-to-venule ratio
(AVR).27 A smaller AVR represents narrower
arterioles (since venular diameters vary little), with generalized arteriolar
narrowing defined as the lowest 20th percentile of the sample AVR distribution.24 As previously reported, intragrader and intergrader 
statistics for retinopathy, arteriovenous nicking, and focal narrowing ranged
from 0.61 to 1.00.27 For AVR, intragrader and
intergrader reliability coefficients were 0.84 and 0.79, respectively.
Ascertainment of Incident Stroke
Incident stroke was defined to include strokes occurring between the
time of a participant's MRI scan (1993 to 1994) and December 31, 1998, using
previously described methods of ascertainment and diagnosis.28
Strokes were identified by contacting participants and their families annually
to identify hospitalizations and deaths from stroke during the previous year,
and by surveying discharge lists from local hospitals and death certificates
from state vital statistics offices. When a potential stroke was identified,
a trained nurse sent hospital records for abstraction. A computer algorithm
classified each case according to standardized criteria. A physician independently
classified cases and a second physician-reviewer adjudicated disagreements
between the first physician and computer classification. Details on quality
assurance are presented elsewhere.28 For analysis,
strokes were further categorized as ischemic (thrombotic or embolic brain
infarction), hemorrhagic (subarachnoid or intracerebral hemorrhage), or combined.28
Definition of Risk Factors
Participants had a standardized interview, clinical examination, and
laboratory investigations.29 Cigarette smoking
was ascertained from interview. Blood pressure was determined using a random-zero
sphygmomanometer and the mean of the last 2 measurements was used. Mean arterial
blood pressure was computed as two thirds of the diastolic plus one third
of the systolic value and the average of this over the first 3 examinations
(ie, 6-year mean arterial blood pressure) was used as a covariate for adjustment
of blood pressure. Hypertension was defined as systolic blood pressure of
140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or
use of antihypertensive medication during the previous 2 weeks. Diabetes mellitus
was defined as a fasting glucose level of at least 126 mg/dL (7.0 mmol/L),
a nonfasting glucose level of at least 200 mg/dL (11.1 mmol/L), or a self-reported
history of physician-diagnosed diabetes or treatment for diabetes. Average
internal carotid intima-media wall thickness (IMT) was measured using B-mode
ultrasonograms.29 Collection of fasting blood
samples and assays of total cholesterol, high-density lipoprotein cholesterol,
and glucose levels are described elsewhere.29
All data were from the third examination (considered baseline in this study),
except for 6-year mean arterial blood pressure.
Statistical Analysis
We classified persons with WMLs of grade 3 or higher as having "WML"
and of grade 2 or lower as having "little or no WML" (cutoff corresponds to
the 90th percentile of WML scores in the sample).15, 26
We used logistic regression to determine the odds ratios (ORs) and their 95%
confidence intervals (CIs) for WMLs in the presence vs absence of a specific
retinal abnormality. Polytomous logistic regression models were also used
to determine a possible graded effect by treating WML grade as a nominal outcome
(ie, grades 0-1 [reference], grade 2, grade 3, and grades 4-9).30
To examine prospectively the association of WMLs to incident clinical
stroke, we used the Kaplan-Meier method to estimate the 5-year cumulative
incidence of stroke (defined as 100 x [1 - Kaplan-Meier estimators])
according to presence vs absence of WMLs. Follow-up time was defined as the
number of days from the MRI examination to the hospital admission date of
the first stroke, death, last contact, or December 31, 1998, whichever occurred
first. We used Cox regression to estimate the relative risk (RR) of stroke
associated with WMLs. To determine the separate and joint effects of WMLs
and retinopathy on the risk of stroke, we stratified the population into 4
groups (ie, people with neither lesion, WMLs only, retinopathy only, and both
WMLs and retinopathy) and calculated the stroke incidence for each group and
the RR of stroke of a particular group vs the group with neither lesion.
All models were adjusted for age, sex, and race. In multivariable models,
we further adjusted for 6-year mean arterial blood pressure, antihypertensive
medication use (yes, no), diabetes (yes, no), levels of fasting glucose and
total cholesterol, carotid IMT, and cigarette smoking (ever, never).
RESULTS
In the study population, 186 (11.0%) persons had cerebral WMLs (grade
3 or more) and 153 (9.1%) persons had retinopathy. Table 1 shows the baseline characteristics comparing the presence
vs absence of cerebral WMLs and retinopathy. In general, cerebral WMLs were
significantly associated with increasing age, black race, and—after
adjusting for age, sex, and race—with higher blood pressure and increased
carotid IMT. Retinopathy was significantly associated with black race and,
after similar adjustment, with higher systolic blood pressure and fasting
glucose level, diabetes, and increased carotid IMT.
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Table 1. Baseline Characteristics of Participants,
by Cerebral WMLs and Retinopathy*
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Table 2 shows the distribution
of WML grades by presence vs absence of retinopathy and other microvascular
abnormalities. Persons with each of the retinal abnormalities were significantly
more likely to have higher grades of WML than persons without retinal abnormalities.
Logistic regression models of the association between cerebral WML (grade
3 or higher) and specific retinal abnormalities are shown in Table 3. After controlling for age, sex, and race, persons with
retinal abnormalities were 1.5 to 3.6 times more likely to have cerebral WMLs
than persons without these retinal abnormalities. These associations were
not substantially altered with further adjustment for blood pressure and other
risk factors, with the exception of generalized retinal arteriolar narrowing
(which was no longer significant).
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Table 2. Distribution of Different Grades
of Cerebral WMLs, by Retinal Microvascular Characteristics*
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Table 3. Odds Ratio of Cerebral WMLs, by Retinal
Microvascular Characteristics*
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Analyses repeated using polytomous logistic regression with WML categorized
as a nominal outcome (grades 0-1 [reference], 2, 3, and 4-9) indicated a stronger
association between the presence of retinal abnormalities and higher grades
of WML (data not shown). For example, the multivariable-adjusted OR (95% CI)
for WML grade 4 through 9 vs grade 0 through 1 was 5.0 (2.6-9.5) for retinopathy,
4.4 (2.4-8.0) for arteriovenous nicking, and 3.6 (1.9-6.7) for focal arteriolar
narrowing.
Over a median follow-up of 4.7 years (maximum, 5.8 years), 32 persons
developed a clinical stroke. The 5-year cumulative incidence of stroke was
6.8% in persons with WMLs compared with 1.4% in those without. After adjustment
for age, sex, race, and vascular risk factors, persons with WMLs were 3.4
times as likely to develop a stroke than persons without WMLs (Table 4). Retinopathy, as previously reported,24
was also an independent predictor of stroke.
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Table 4. Cumulative Incidence and Relative
Risk of Clinical Stroke Associated With Cerebral WMLs*
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We performed the following supplementary analyses. First, analysis repeated
with WMLs categorized into grades 0 through 1, 2, 3, and 4 through 9 showed
higher risk of stroke with increasing grades of WML. Compared with grades
0 through 1, the multivariable-adjusted RR (95% CI) of stroke was 2.0 (0.7-5.6)
for grade 2, 5.7 (2.0-16.2) for grade 3, and 4.9 (1.2-13.9) for grades 4 through
9 (P<.001 for trend). Second, of the 32 incident
strokes, 25 were ischemic, 5 were hemorrhagic, and 2 were combined ischemic
and hemorrhagic. In general, the association between WMLs and risk of ischemic
stroke was similar to the association for all strokes (multivariable-adjusted
RR, 3.2; 95% CI, 1.2-8.3).
Finally, we examined the separate and joint effects of WMLs and retinopathy
on risk of stroke. The 5-year cumulative incidence of stroke was 1.4% in persons
without WMLs or retinopathy, 4.0% in those with WMLs only, 4.7% in those with
retinopathy only, and 20.0% in those with both WMLs and retinopathy. Compared
with their absence, the multivariable-adjusted RR for stroke was 2.6 for WMLs
only, 3.7 for retinopathy only, and 18.1 for both WMLs and retinopathy (Table 5). The results were similar for
an alternate model that included only age, sex, race, and covariates that
were independently associated with stroke at the P
= .10 level (6-year mean arterial blood pressure, carotid IMT, and diabetes)
(Table 5). Although the pattern
was consistent with a multiplicative effect of WMLs and retinopathy on the
risk of stroke, due to the infrequency of events the formal test for interaction
was not statistically significant (P = .45).
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Table 5. Independent and Joint Effects of
Cerebral WMLs and Retinopathy on Risk of Stroke*
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Using different cutoffs to define WML did not alter the general pattern
shown. For example, using a cutoff of grade 2 or more as the definition of
WML, the multivariable-adjusted RR of stroke was 2.1 for WMLs alone, 2.5 for
retinopathy alone, and 11.5 for both WMLs and retinopathy. Similarly, the
risk of stroke associated with WMLs was increased in the presence of other
retinal microvascular lesions (multivariable-adjusted RR of 6.3 for focal
arteriolar narrowing, 9.0 for arteriovenous nicking, and 7.0 for generalized
arteriolar narrowing).
COMMENT
Each year, approximately 2.5 million computed tomography and MRI scans
of the brain are performed in persons 65 years and older in the United States.31 Although population-based data indicate that up to
80% of these people may have changes in their cerebral white matter,1-5
the pathogenesis and clinical consequences of these cerebral changes are uncertain.
The current study provides key insights into the underlying pathogenic
mechanisms and clinical significance of WMLs in a community-based cohort of
middle-aged persons who were initially free of stroke. First, we demonstrate
a strong independent association between retinal microvascular abnormalities,
as detected on retinal photographs, and WMLs, as defined from cerebral MRI.
Persons with retinopathy and other arteriolar abnormalities (arteriovenous
nicking and focal arteriolar narrowing) were 2.1 to 4.0 times as likely to
have WMLs than persons without these retinal signs, independent of age and
vascular risk factors. Second, we show that WMLs were independently associated
with risk of clinical stroke. After controlling for blood pressure, diabetes,
cigarette smoking, and other stroke risk factors, persons with WMLs were 3.4
times as likely to develop a clinical stroke than those without WMLs in the
ensuing 5 years. In addition, we found a multiplicative interaction between
retinopathy and WMLs on the risk of stroke. In the presence of retinopathy,
persons with WMLs were 18.1 times as likely to develop stroke than those without
either WMLs or retinopathy.
Retinal microvascular abnormalities result from small-vessel damage
from aging, elevated blood pressure, and other microvascular processes.32 Studies have shown that retinal microvascular flow
is reduced in persons with WMLs and lacunar infarction33-34
and that retinal and cerebral arterioles share similar histopathology in stroke
decedents.23 In the ARIC study, these retinal
abnormalities, as detected from photographs, were related to concurrent blood
pressure27 and independently to past blood
pressure35 and markers of inflammation,36 but not to measures of atherosclerosis.36
Thus, the strong independent association between these retinal abnormalities
and WMLs provides further evidence that microvascular processes (due to hypertension,
inflammation, and other factors) may contribute to the occurrence of WMLs,
supporting previous pathological studies that have reported small-vessel abnormalities
in brains with WMLs,10-12
and clinical studies that show associations of WMLs with hypertension13-16 and
diabetes,17-19
but not consistently with atherosclerosis.37-38
Our finding that WMLs predict incident stroke may have important clinical
implications. In persons with previous stroke or vascular dementia, these
lesions have been reported to predict future episodes of stroke.8-9,20-21
Fewer data are available regarding stroke risk associated with WMLs in healthy
people.39-40 In the Cardiovascular
Health Study,40 11.1% of participants aged
65 years and older with MRI-defined WMLs developed a stroke as compared with
3.5% of participants with normal MRI results. The current data offer additional
evidence that asymptomatic persons with WMLs appear to be at increased risk
of stroke, independent of other risk factors. Additionally, the risk of stroke
associated with WMLs appears to be substantially elevated in the presence
of retinopathy. The multiplicative interaction between WMLs and retinopathy
on the risk of stroke suggests that cerebral microvascular pathology is more
severe in persons with both WMLs and retinopathy. Another possible explanation
is that WMLs reflect heterogeneous entities,6-8
and the presence or absence of retinopathy distinguishes "pathological" WMLs
(with much higher risk of stroke) from those more "benign" in nature.
These data raise the possibility that asymptomatic people with WMLs
detected by MRI may benefit from a retinal evaluation for purposes of stroke
risk stratification. However, the MRI scans and retinal photographs in the
ARIC study were evaluated in a standardized setting, which may not be easily
translated to clinical practice. Future investigations using a more simplified
WML grading system might increase the practical utility of these data.
The strengths of our study include a population-based cohort, standardized
and masked evaluation of MRI and retinal photographs, and validated ascertainment
of incident stroke. Limitations should also be noted. First, hypertension
is a common risk factor for WMLs, retinal microvascular abnormalities, and
stroke, and the effect of blood pressure on these results may be considerable.
However, these associations remained highly significant despite controlling
for the average of 3 blood pressure measurements over a 6-year period and
for use of antihypertensive medications. Second, the small numbers of incident
stroke may reduce the precision of the RR estimates presented and may even
introduce bias in multivariable models with many covariates. Nevertheless,
the observed associations seen were strong and robust in an alternate model
with fewer covariates. A longer follow-up with more stroke events may eventually
provide a clearer picture.
In conclusion, these population-based data show that WMLs are independently
associated with retinal microvascular abnormalities, providing evidence that
small-vessel diseases are linked to the pathogenesis of WMLs. Persons with
WMLs are at increased risk of developing a clinical stroke, independent of
conventional stroke risk factors, particularly when retinopathy is also present.
AUTHOR INFORMATION
Author Contributions: Study
concept and design: Wong, R. Klein, Sharrett, B. Klein, Liao, Hubbard,
Mosley.
Acquisition of data: R. Klein, B. Klein, Liao,
Hubbard, Mosley.
Analysis and interpretation of data: Wong,
R. Klein, Sharrett, Couper, B. Klein, Liao, Hubbard, Mosley.
Drafting of the manuscript: Wong.
Critical revision of the manuscript for important
intellectual content: Wong, R. Klein, Sharrett, Couper, B. Klein, Liao,
Hubbard, Mosley.
Statistical expertise: Couper, Liao.
Obtained funding: R. Klein, B. Klein.
Administrative, technical, or material support:
Sharrett, B. Klein, Hubbard, Mosley.
Study supervision: R. Klein, B. Klein, Hubbard.
Epidemiology: Liao.
Funding/Support: This work was supported by
National Heart, Lung, and Blood Institute contracts N01-HC-35125, N01-HC-35126,
N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021,
and N01-HC-55022. Additional support provided by the American Diabetes Association
and by National Eye Institute grant EY0 13939 (Drs Wong and Klein).
Acknowledgment: We thank the staff and participants
in the ARIC study for their important contributions.
A Complete Listing of the ARIC Investigators
was published previously (Am J Epidemiol. 1989;129:687-702).
Corresponding Author and Reprints: Tien
Yin Wong, MD, MPH, Department of Ophthalmology, National University of Singapore,
10 Kent Ridge Crescent, Singapore 119260 (e-mail: ophwty{at}nus.edu.sg).
Author Affiliations: Department of Ophthalmology,
University of Wisconsin, Madison (Drs Wong, R. Klein, B. Klein, and Mr Hubbard);
Singapore National Eye Center and Department of Ophthalmology, National University
of Singapore (Dr Wong); Department of Epidemiology, Johns Hopkins University
School of Public Health, Baltimore, Md (Dr Wong); National Heart, Lung, and
Blood Institute, Bethesda, Md (Dr Sharrett); Department of Biostatistics,
University of North Carolina, Chapel Hill (Dr Couper); Department of Health
Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey
(Dr Liao); and Department of Medicine, University of Mississippi Medical Center,
Jackson (Dr Mosley).
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ABSTRACT
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