 |
|
How Many Steps of Progression of Diabetic Retinopathy Are Meaningful?
The Wisconsin Epidemiologic Study of Diabetic Retinopathy
Arch Ophthalmol. 2001;119:547-553.
ABSTRACT
| |
Objective To determine whether a 1-step or more or 2-step or more progression
on the Early Treatment Diabetic Retinopathy Study retinopathy severity scale
over a 4-year period is meaningful in predicting the subsequent incidence
of proliferative diabetic retinopathy (PDR) and clinically significant macular
edema (CSME) over the following 6 years.
Design Population-based study of diabetic persons with 10 years of follow-up.
Setting and Patients Eleven-county area in southern Wisconsin. There were 1025 persons with
diabetes who had fundus photographs at baseline and at 4- and 10-year follow-up
examinations.
Main Outcome Measures Incidence of PDR or CSME between the 4- and 10-year follow-up examinations
as determined by masked grading of color stereoscopic fundus photographs of
7 standard fields.
Results In a univariate analysis, those with 1 or more steps of progression
(n = 551) over the first 4 years of the study were significantly (P<.0001) more likely to develop PDR over the next 6 years than those
with no progression (n = 474) (26% vs 4%) (relative risk, 5.85; 95% confidence
interval, 4.05-8.47). Similarly, those with 2 or more (n = 364) (33%) or 3
or more (n = 231) (41%) steps of progression over the first 4 years of the
study were significantly (P<.0001) more likely
to develop PDR over the next 6 years than those with lesser progression (n
= 661 [7%] and n = 794 [9%], respectively) (relative risk, 5.10; 95% confidence
interval, 3.83-6.80; and relative risk, 4.61; 95% confidence interval, 3.57-5.99,
respectively). Similar associations were apparent at every level of retinopathy,
duration of diabetes, and glycosylated hemoglobin, and by type of diabetes
at baseline. There were also associations between retinopathy progression
and incidence of CSME.
Conclusions It seems that 1 or more or 2 or more steps of progression of retinopathy
over a 4-year period strongly predict the development of PDR over the next
6 years. Therefore, using these end points of progression would result in
the need for fewer subjects or shorter follow-up in some clinical trials.
INTRODUCTION
REDUCTION IN the incidence of proliferative diabetic retinopathy (PDR),
clinically significant macular edema (CSME), and substantial loss of vision
have served as primary end points in randomized clinical trials of treatment
for diabetic retinopathy.1-3
Data from epidemiologic studies show that over a 10-year period these end
points have a low incidence in people with no or minimal diabetic retinopathy
at the beginning of the observation interval.4
For this reason, other clinically meaningful measures of progression of retinopathy,
such as 2- or 3-step progression on the Early Treatment Diabetic Retinopathy
Study (ETDRS) severity scale, have been used as primary end points in clinical
trials testing the efficacy of intensive hypoglycemic treatment in patients
with no or minimal diabetic retinopathy.5-6
These trials required large numbers of subjects followed up for many years.
Trials designed to test the efficacy of new treatments for primary prevention
may not always be feasible because of the length of time required and the
large number of subjects needed. For this reason, other end points that are
associated with development of severe disease outcomes in the future, such
as change in retinal microaneurysm counts, have been suggested for use in
these trials.7-10
There are few studies that actually examined the relationship of only 1 or
more steps of progression as important predictors of the incidence of PDR
and macular edema. It is the purpose of this report to describe an investigation
in our data as to whether 1 step or more or 2 steps or more of progression
on the ETDRS retinopathy severity scale is associated with the subsequent
incidence of PDR and CSME.
PATIENTS AND METHODS
A population-based sample of 2990 persons was selected for examination.4, 11-14
The sample was composed of 2 groups. The first group consisted of all patients
diagnosed as having diabetes before the age of 30 years and taking insulin
(n = 1210); this group will be referred to as "younger onset." The second
group consisted of a probability sample of patients whose conditions were
diagnosed when they were 30 years or older. Their diagnosis had been confirmed
by a random or postprandial serum glucose level of at least 11.1 mmol/L, or
a fasting serum glucose level of at least 7.8 mmol/L on at least 2 occasions
(n = 1780); this group will be referred to as "older onset." Of the older-onset
group, 824 were taking insulin and 956 were not. Participants from both the
younger- and older-onset groups contribute data to subsequent analyses.
Baseline (1980-1982) and follow-up (1984-1986 and 1990-1992) examinations
were conducted using standardized protocols. Pertinent parts of the ocular
and physical examination included measuring blood pressure,15
dilating the pupils, administering a medical history questionnaire, taking
stereoscopic color fundus photographs of 7 standard fields and a nonstereoscopic
red reflex photograph of each eye, and determining glycosylated hemoglobin
values.16
To determine retinopathy status at both the baseline and follow-up examinations,
all fundus photographs were graded using a modification of the Airlie House
classification scheme that specified the following levels of retinopathy for
each eye4: (1) level 10: no retinopathy; (2)
level 21: microaneurysms only or retinal hemorrhages of soft exudates in the
absence of microaneurysms; (3) level 31: microaneurysms plus 1 or more of
the following: venous loops of 31 µm or larger, questionable soft exudate,
intraretinal microvascular abnormalities or venous beading, and retinal hemorrhage;
(4) level 37: microaneurysms plus hard exudate and/or soft exudate; (5) level
43: microaneurysms plus 1 or more of the following: retinal hemorrhages/microaneurysms
greater than or equal to standard photograph 1 in 4 to 5 fields, retinal hemorrhages/microaneurysms/microaneurysms
greater than or equal to standard photograph 2A in 1 field, intraretinal microvascular
abnormalities in 1 to 3 fields; (6) level 47: microaneurysms and retinal hemorrhages/microaneurysms
characteristics from level 43, intraretinal microvascular abnormalities in
4 to 5 fields, retinal hemorrhages/microaneurysms greater than or equal to
standard photograph 2A in 2 to 3 fields, and venous beading in 1 field; (7)
level 53: microaneurysms plus 1 or more of the following: any 2 or 3 of level
47 characteristics, retinal hemorrhages/microaneurysms greater than or equal
to standard photograph 2A in 4 to 5 fields, intraretinal microvascular abnormalities
greater than or equal to standard photograph 8A, and venous beading in 2 or
more fields; (8) level 60 and higher: any of several levels of severity of
proliferative retinopathy, including eyes with neovascularization, fibrous
proliferations, vitreous hemorrhages and preretinal hemorrhage, scars of scatter
panretinal photocoagulation and/or retinopathy ungradable because of vitreous
hemorrhage obscuring the retina, phthisis bulbi, or enucleation secondary
to a complication of diabetic retinopathy.
In the analyses, eyes that could not be graded for retinopathy because
of opacities in the media or enucleation not related to diabetic retinopathy
were defined as "cannot grade." For purposes of classification, if the retinopathy
severity could not be graded in an eye, it was considered to have a score
equivalent to that in the other eye. Individuals in whom retinopathy severity
could not be graded in either eye (n = 5) were excluded from the analyses.
Levels of retinopathy for a participant were derived by combining the
severity levels for each eye but giving greater weight to the eye with the
higher level. In this scheme, participants in a given level were divided into
2 groups: those with the same level in each eye and those with a lesser level
in 1 eye. For example, a participant with level 31 retinopathy in each eye
is classified by the notation "level 31/31," whereas a subject with level
31 in 1 eye and either 10 or 21 in the other is classified as "level 31/<31."
This procedure results in a 15-step scale (10/10, 21/<21, 21/21, 31/<31,
31/31, 37/<37, 37/37, 43/<43, 43/43, 47/<47, 47/47, 53/<53, 53/53,  60/<60,
and 60/60). One-step or more progression for a person was defined
as an increase in 1 level or more (eg, from 10/10 to 21/<21 or greater,
or from 31/<31 to 31/31 or greater). Two-steps or more progression for
a person was defined as an increase in 2 levels or more (eg, from 10/10 to
21/21 or greater, or from 31/<31 to 37/<37 or greater). Three-steps
or more progression for a person was defined as an increase in 3 steps or
more (eg, from 10/10 to 31/<31 or greater, or from 31/<31 to 37/37 or
greater). Incidence of PDR was estimated from all persons who were free of
this complication at the baseline and 4-year follow-up examinations.
Macular edema was defined as thickening of the retina, with or without
partial loss of transparency, within 1 disc diameter (about 1.5 mm) from the
center of the macula.3 Clinically significant
macular edema was defined as the presence of any one of the following: (1)
thickening of the retina within 500 µm of the center of the macula;
(2) hard exudates with thickening of the adjacent retina within 500 µm
of the center of the macula; or (3) retinal thickening 1 disc area or larger
in size, some of which was located within 1 disc diameter of the center of
the macula.3 The incidence of CSME was estimated
from data for all persons who had no macular edema and had not been treated
with photocoagulation at the baseline or 4-year follow-up examinations. For
the purposes of this study, only participants with retinopathy severity level
43 or less in each eye at baseline were included. Of the 1862 subjects who
participated in the baseline and 4-year examinations, and who had gradable
retinopathy at both examinations, 336 had retinopathy greater than 43/43 at
baseline. The current age was defined as the age at the time of the baseline
examination. Duration of diabetes was the time interval between diagnosis
of diabetes and the baseline examination.
SAS was used for tabulating the data and for developing logistic regression
models.17-18 Estimates of relative
risks across strata were obtained using methods described by Mantel.19 Sample size estimates were obtained from nQuery Advisor,20 and were based on the  2 test of proportions
with correction for continuity.
RESULTS
Of the 1526 persons who had retinopathy severity at level 43 or less
in both eyes at baseline, and who had gradable fundus photographs at both
baseline and the 4-year follow-up visit, 1075 participated in the 10-year
follow-up and had gradable fundus photographs. Fifty subjects who had developed
PDR and 31 subjects who had developed CSME by the 4-year follow-up visit were
excluded from the analysis. Inclusion of these subjects in a separate analysis
yielded similar results (data not shown). Participants with gradable retinopathy
at the 10-year follow-up were younger, had shorter duration of diabetes, had
higher glycosylated hemoglobin levels, had lower systolic blood pressure,
had lower body mass, had less proteinuria at baseline, and were more likely
to be in the younger-onset group than people who did not participate at the
10-year follow-up (Table 1).
|
|
|
|
Table 1. Selected Baseline Characteristics of Participants and Nonparticipants
|
|
|
The relationship between steps of progression of retinopathy over the
first 4 years of the study and subsequent incidence of PDR and CSME by the
time of the 10-year follow-up is presented in Table 2. Persons with 1 or more steps of progression of retinopathy
over the first 4 years of the study were 5.8 times as likely to develop PDR
and 3.8 times as likely to develop CSME over the subsequent 6 years of follow-up
as those with no progression of retinopathy. This relationship was independent
of retinopathy severity level (Table 3),
glycosylated hemoglobin level (Table 4),
duration of diabetes (Figure 1 and
Figure 2), or type of diabetes (data not
shown).
|
|
|
|
Table 2. The Relationship of Step-Change in Retinopathy Severity Between
Baseline and 4-Year Follow-up and Progression to Proliferative Retinopathy
or Clinically Significant Macular Edema by 10-Year Follow-up
|
|
|
|
|
|
|
Table 3. The Relationship of Step-Change in Retinopathy Severity Between
Baseline and 4-Year Follow-up and Progression to Proliferative Retinopathy
or Clinically Significant Macular Edema by Retinopathy Severity Level at Baseline*
|
|
|
|
|
|
|
Table 4. The Relationship of Step-Change in Retinopathy Severity Between
Baseline and 4-Year Follow-up and Progression to Proliferative Retinopathy
or Clinically Significant Macular Edema by Glycosylated Hemoglobin Level*
|
|
|
|
|
|
|
Figure 1. The association of the number
of steps of progression of retinopathy over a 4-year period and the incidence
of proliferative diabetic retinopathy in the subsequent 6-year interval by
duration of diabetes at baseline in persons in the Wisconsin Epidemiologic
Study of Diabetic Retinopathy.
|
|
|
|
|
|
|
Figure 2. The association of the number
of steps of progression of retinopathy over a 4-year period and the incidence
of clinically significant macular edema in the subsequent 6-year interval
by duration of diabetes at baseline in persons in the Wisconsin Epidemiologic
Study of Diabetic Retinopathy.
|
|
|
To evaluate whether the relationship between 1 or more (or 2) steps
of progression and progression to PDR or CSME was reflecting the influence
of the " . . . more than" component, we assessed the significance of only
1 step, of only 2 steps, of only 3 steps, of only 4 steps, and of only 5 steps
of progression between the baseline and 4 years of follow-up on PDR and CSME.
Each measure of change was significantly associated with incident PDR or CSME
(Figure 3).
|
|
|
|
Figure 3. The association of specific number
of steps of progression of retinopathy over a 4-year period and the incidence
of proliferative diabetic retinopathy (PDR) or clinically significant macular
edema (CSME) in the subsequent 6-year interval in persons in the Wisconsin
Epidemiologic Study of Diabetic Retinopathy (P<.0001
for both associations based on the Mantel-Haenszel test of trend).
|
|
|
To evaluate the relative influence of several variables, including the
number of steps of progression, on incidence of PDR or incidence of macular
edema, we developed models based on logistic regression. These models are
used to test the significance of variables in predicting an outcome when the
effects of other variables are being considered. Adjusted for baseline retinopathy
severity, glycosylated hemoglobin level, and duration and type of diabetes
in all of the multivariable models, the associations between the number of
steps progressed during the first 4 years (1, 2, or 3 steps or more, or 1,
2, 3 steps only compared with fewer steps of progression in the severity of
retinopathy) remained significant antecedents of incidence of PDR over the
subsequent 6-year interval (Table 5).
Similarly, while controlling for baseline retinopathy severity, glycosylated
hemoglobin level, hypertension, and type of diabetes, the number of steps
progressed during the first 4 years was associated with the incidence of CSME
over the subsequent 6 years in most of the models (Table 5).
|
|
|
Table 5. Multivariate Models*
|
|
|
COMMENT
The findings of this study show that as few as 1 or more steps of progression
in the modified ETDRS retinopathy severity scale over a 4-year period is meaningful
in describing risk of incidence of PDR or CSME over the following 6 years.
This finding is independent of the initial level of retinopathy severity,
glycemia, blood pressure level, and duration and type of diabetes. This finding
is supplementary to and consistent with our previous report, which described
a greater likelihood of developing a progression of visual loss in those eyes
with more severe retinopathy 10 years earlier.21
In planning clinical trials of new therapeutic interventions for diabetic
retinopathy, loss of vision is not usually used as a primary end point as
this event is infrequent because photocoagulation is likely to be used to
treat macular edema or PDR before the development of loss of vision. Thus,
edema involving or threatening the center of the macula and retinopathy at
or approaching the high-risk proliferative stage, because of their strong
association with visual loss,21-22
have been accepted as primary end points in clinical trials of treatments
designed to slow the progression of diabetic retinopathy. However, these are
advanced stages of diabetic retinopathy themselves and to use these end points
one would need: a very large number of people with any level of retinopathy
evaluated for 4 years (approximate sample size would be 10 722 for high-risk
PDR as an end point and 11 290 for CSME as an end point in persons with
younger-onset diabetes and 22 384 and 15 878, respectively, for
those with older-onset diabetes [Table 6]); a smaller number of persons evaluated for a longer period; or
a study limited to persons with more advanced retinopathy. As a result, progression
of retinopathy by 3 steps or more on the ETDRS scale has been accepted as
an end point in clinical trials, but there has been a reluctance to accept
progression by fewer steps. This end point also requires relatively large
sample sizes to demonstrate a 25% reduction in retinopathy in people with
no or mild to moderate nonproliferative retinopathy at baseline (levels 10
to 43 in worse eye) (Table 6). This end point would require 1836 persons with type 1 diabetes and 2088 persons
with type 2 diabetes (assuming  = .05,  = .20, 2-tailed) to demonstrate
a 25% reduction in retinopathy in people with no retinopathy at baseline (level
10 in both eyes). Because of this, clinical trials in which subjects do not
have retinopathy in either eye at baseline require a design using another,
earlier end point. Data from the current study suggest that both 1-step or
more and 2-steps or more progression in retinopathy are possible alternative
end points in such trials and would result in a shorter duration of the trial,
smaller numbers of subjects needed, or both.
|
|
|
|
Table 6. Sample Size Estimates Required to Demonstrate 25% and 50%
Reduction in Various End Points in Younger- and Older-Onset Persons With Diabetes
in a 4-Year Trial From the Wisconsin Epidemiologic Study of Diabetic Retinopathy
|
|
|
In the context of clinical trials, the Federal Food and Drug Administration
defines clinically meaningful end points as ones that measure directly how
a patient feels, functions, or survives.23
Step progression in the retinopathy severity scale would thus be considered
a surrogate end point by this definition. Acceptance of surrogate end points
in clinical trials requires that they be reliable, consistent, that they be
in the casual pathway, and that changes in the surrogate end point result
in changes in clinically important outcomes.24
Epidemiological studies, such as the Wisconsin Epidemiologic Study of Diabetic
Retinopathy (WESDR),4, 10-14
and clinical trials, such as the Diabetes Control and Complications Trial5, 25 and United Kingdom Prospective Diabetes
Study,6 have provided data demonstrating the
validity of step-changes of progression of retinopathy as being valid surrogate
end points. For example, in the Diabetes Control and Complications Trial,
better glycemic control (with less frequent 3-step progression) found in the
intensive insulin group at the end of the clinical trial was associated with
lower incidence of PDR and need for laser photocoagulation than in the conventional
treatment group, which has poorer glycemic control and a higher frequency
of 3-step progression.25 In the conventional
treatment arm of that study, there were 489 type 1 diabetic subjects who did
not develop a sustained 3-step progression of their retinopathy by year 5,
of whom 39 (8%) developed-severe nonproliferative or PDR 4 to 8 years later
compared with 43 (43%) of the 101 who had 3-step or more sustained progression
of their retinopathy. In the insulin-intensive arm of the study, comparable
numbers were 1.8% and 22.2% who developed severe nonproliferative or PDR,
respectively (personal communication, Paddy Cleary and Saul Genuth, Diabetes
Control and Complications Trial and Epidemiology of Diabetes Interventions
and Complications Research Group, May 31, 2000, unpublished data). While data
from clinical trials are necessary in demonstrating that changes in the surrogate
end point result in changes in clinically important outcomes, few have the
length or duration of the WESDR to show that even fewer steps of progression
or microaneurysm count changes10 are strongly
associated with the incidence of late clinically meaningful changes, such
as PDR or macular edema.
Choice of a specific measure as a primary end point in clinical trials
must be made with caution. Using fewer steps of progression of retinopathy
as an end point is associated with increased misclassification related to
both biological and grading variability. For example, using the ETDRS severity
scale, complete agreement of 2 independent gradings in the ETDRS is 38%, agreement
within 1-step is 71%, and agreement within 2 steps is 87%.26
In the Diabetes Control and Complications Trial, which used 2 independent
gradings and adjudication of differences that arose, complete agreement varied
from 53.3% to 67.6%, agreement within 1 step varied from 84.3% to 95.0%, and
agreement within 2 steps varied from 96.2% to 98.3%.27
The approach used in the WESDR was similar.14
The reliability of grading photographs over time to detect change would be
expected to be lower.
Other considerations in selecting an end point in a clinical trial are
the potential adverse effects of the treatment or drug being tested. A potential
limitation of using progression in earlier stages of retinopathy is the resultant
smaller sample size and the shorter duration of the trial, permitting too
short a time for complications or adverse effects to be manifest. This would
result in little insight regarding the longer-term benefits and safety of
the treatment or drug, limiting potential cost-effectiveness analyses for
comparisons with other treatments or with different drug classes. For example,
in a primary prevention trial, one may wish to observe a sizable reduction
(more steps) in progression of retinopathy when the treatment is associated
with a high rate and severity of adverse effects (eg, severe hypoglycemic
reactions as experienced with intensive insulin treatment). The corollary
is that to justify the risk of such a severe adverse effect, a large benefit
would be needed over a longer period of observation, including phase 4 trials.
For clinical trials of treatment interventions of drugs with established minimal
adverse effects or toxicity, fewer steps of progression as the primary end
point are likely to be more appropriate.
The estimates presented in our tables and figures were based on the
WESDR data with examinations at baseline, and the 4- and 10-year follow-up
examinations. In a clinical trial, participants would be examined more frequently,
perhaps every 6 months to a year. Our relative risks and odds ratios in Table 2, Table 3, Table 4, and Table 5 are specific to the WESDR schedule
of follow-up examinations. The predictive value of a 1-, 2-, or 3-step change
in a study with annual photographs might be different from what we demonstrate,
perhaps with higher event rates as retinopathy may also regress over time,4 and persons with more rapid progression would have
an event detected sooner.
CONCLUSIONS
These data confirm the strong association of progression retinopathy
of 1 step or more or 2 steps or more with the incidence of PDR and CSME. Both
1-step or more or 2-step or more progression are meaningful outcomes in epidemiological
studies in people with diabetes, especially in studies in individuals with
no or minimal retinopathy. Using these definitions of progression increases
the potential efficiency of a trial by using the information gleaned from
those who experience meaningful real but less change than has been considered
in other trials. However, choice of fewer steps of progression or microaneurysm
counts, with the fewer numbers of subjects studied over a shorter duration,
severely limits the ability to evaluate the toxicity of the drug and its long-term
benefits, and a higher risk of variability and chance of error. Careful consideration
of different end points for different treatment trials of the same disease
is the most appropriate philosophy to adopt rather than choosing uniform end
points based on precedent.
AUTHOR INFORMATION
Accepted for publication August 22, 2000.
Supported by grants EY03083 and EY12198 (Drs R. Klein and B. E. K. Klein)
from the National Institutes of Health, Bethesda, Md, and, in part, by the
Senior Scientific Investigator Award, Research to Prevent Blindness, New York,
NY (Dr R. Klein).
We thank our collaborators, and Matthew D. Davis, MD, Larry D. Hubbard,
MAT, and Stacy M. Meuer, BA, who provided scientific advice.
Corresponding author: Ronald Klein, MD, MPH, Department of Ophthalmology
and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St,
460 WARF, Madison, WI 53705-2397.
Ronald Klein, MD;
Barbara E. K. Klein, MD;
Scot E. Moss, MA
From the Department of Ophthalmology and Visual Sciences, University
of Wisconsin Medical School, Madison.
REFERENCES
1. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs—an
extension of the modified Airlie House classification: ETDRS report number
10. Ophthalmology. 1991;98(suppl 5):786-806.
2. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy:
two-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study
report 2. Arch Ophthalmol. 1985;103:1644-1652.
ABSTRACT
3. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic
Retinopathy report number 1. Arch Ophthalmol. 1985;103:1796-1806.
ABSTRACT
4. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XIV: ten-year
incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112:1217-1228.
ABSTRACT
5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
FREE FULL TEXT
6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with type
2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
FULL TEXT
|
ISI
| PUBMED
7. Kohner EM, Sleightholm M for the Kroc Collaborative Study Group. Does microaneurysm count reflect severity of early diabetic retinopathy? Ophthalmology. 1986;93:586-589.
ISI
| PUBMED
8. The DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic
retinopathy: a multicenter randomized controlled clinical trial. Diabetes. 1989;38:491-498.
ABSTRACT
9. TIMAD Study Group. Ticlopidine treatment reduces the progression of nonproliferative retinopathy. Arch Ophthalmol. 1990;108:1577-1583.
ABSTRACT
10. Klein R, Meuer SM, Moss SE, Klein BE. The relationship of retinal microaneurysm counts to the 4-year progression
of diabetic retinopathy. Arch Ophthalmol. 1989;107:1780-1785.
ABSTRACT
11. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, II: prevalence
and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102:520-526.
ABSTRACT
12. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, III: prevalence
and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527-532.
ABSTRACT
13. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, IX: four-year
incidence and progression of diabetic retinopathy when age at diagnosis is
less than 30 years. Arch Ophthalmol. 1989;107:237-243.
ABSTRACT
14. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, X: four-year
incidence and progression of diabetic retinopathy when age at diagnosis is
30 years or more. Arch Ophthalmol. 1989;107:244-249.
ABSTRACT
15. Hypertension Detection and Follow-up Program Cooperative Group. The Hypertension Detection and Follow-up Program. Prev Med. 1976;5:207-215.
FULL TEXT
|
ISI
| PUBMED
16. Klein R, Klein BE, Moss SE, Shrago ES, Spennetta TL. Glycosylated hemoglobin in a population-based study of diabetes. Am J Epidemiol. 1987;126:415-428.
FREE FULL TEXT
17. SAS Institute Inc. SAS/STAT User's Guide. Version 6, Fourth Edition. Vols 1 and 2. Cary, NC: SAS Institute
Inc; 1989.
18. Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons Inc; 1989:1-81.
19. Mantel N. Chi-square tests with one degree of freedom: extensions of the Mantel-Haenszel
procedure. J Am Stat Assoc. 1963;58:690-700.
FULL TEXT
|
ISI
20. Elashoff JD. nQuery Advisor Version 3.0 User's Guide. Los Angeles, Calif: 1999.
21. Moss SE, Klein R, Klein BE. Ten-year incidence of visual loss in a diabetic population. Ophthalmology. 1994;101:1061-1070.
ISI
| PUBMED
22. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical
application of Diabetic Retinopathy Study (DRS) findings, DRS report number
8. Ophthalmology. 1981;88:583-600.
ISI
| PUBMED
23. Temple RJ. A regulatory authority's opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical Measurement
in Drug Evaluation. New York, NY: John Wiley & Sons Inc; 1995:57.
24. Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA for the Evidence-Based Medicine Working Group. Users' guides to the medical literature, XIX: applying clinical trial
results, A: how to use an article measuring the effect of an intervention
on surrogate end points. JAMA. 1999;282:771-778.
FREE FULL TEXT
25. The Diabetes Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years
after a trial of intensive therapy. N Engl J Med. 2000;342:381-389.
FREE FULL TEXT
26. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy:
ETDRS report number 12. Ophthalmology. 1991;98:823-833.
ISI
| PUBMED
27. The effect of intensive diabetes treatment on the progression of diabetic
retinopathy in insulin-dependent diabetes mellitus: the Diabetes Control and
Complications Trial. Arch Ophthalmol. 1995;113:36-51.
ABSTRACT
RELATED ARTICLE
Surrogate Outcomes for Clinical Trials: Use With Caution
Emily Y. Chew
Arch Ophthalmol. 2001;119(4):576-578.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Local Diabetic Retinopathy Prediction by Multifocal ERG Delays over 3 Years
Ng et al.
IOVS 2008;49:1622-1628.
ABSTRACT
| FULL TEXT
Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies
Ciulla et al.
Diabetes Care 2003;26:2653-2664.
ABSTRACT
| FULL TEXT
Longitudinal Studies of Incidence and Progression of Diabetic Retinopathy Assessed by Retinal Photography in Pima Indians
Looker et al.
Diabetes Care 2003;26:320-326.
ABSTRACT
| FULL TEXT
The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design
The DIRECT Programme Study Group and Chaturvedi
Journal of Renin-Angiotensin-Aldosterone System 2002;3:255-261.
ABSTRACT
Surrogate Outcomes for Clinical Trials: Use With Caution
Chew
Arch Ophthalmol 2001;119:576-578.
FULL TEXT
|
