Factors Influencing the Development of Visual Loss in Advanced Diabetic Retinopathy

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1 Factors Influencing the Development of Visual Loss in Advanced Diabetic Retinopathy Diabetic Retinopathy Study (DRS) Report No. 10 Lawrence I. Rand, Gerard J. Prud'homme, Fred Ederer, Paul L. Conner, and the Diabetic Rerinoparhy Study Research Group Natural history data from the Diabetic Retinopathy Study were examined by multivariate methods to determine which baseline characteristics could predict the occurrence of severe visual loss (SVL) in eyes originally assigned to no treatment. The presence and extent of new blood vessels on the optic disc (NVD) had the strongest association with SVL. Several other ocular characteristics also were strongly associated with visual outcome. In the absence of NVD at baseline, the degree of intraretinal hemorrhages and microaneurysms (HMA) had the strongest association with development of SVL. Macular edema was a factor in determining visual loss to 20/200 but not SVL (less than 5/200). Among systemic characteristics, urinary protein was the best predictor of visual outcome, but none were as good as the major ocular variables. Invest Ophthalmol Vis Sci 26: , 1985 The Diabetic Retinopathy Study (DRS) found photocoagulation treatment effective in reducing the risk of severe visual loss in patients with advanced diabetic retinopathy. 1 ' 2 After a lengthy and thorough informed consent procedure, one eye of each of 1,742 patients enrolled in the Study between 1972 and 1975 was randomly assigned to an untreated control group, while the other was randomly assigned to one of two treatments, xenon arc or argon laser photocoagulation. 3 ' 4 Although the Study was primarily designed to test treatment efficacy, the existence Of an untreated control eye provides a unique opportunity for describing the clinical course of advanced diabetic retinopathy uninfluenced by treatment. The DRS protocol was changed in 1976 to allow treatment of the untreated control eyes. The DRS has previously reported that four characteristics of diabetic retinopathy increased risk of From the DRS Coordinating Center, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, Maryland. Supported by the Diabetic Retinopathy Study contracts 1EY , 1EY-32119, 1EY-32121, 1EY-32122, 1EY-32123, 1EY , 1EY-32125, 1EY-32126, 1EY-32127, 1EY-32129, 1EY , 1EY-42128, 1EY-42142, 1EY-42170, 1EY-42171, 1EY , and 1EY from the National Eye Institute, National Institutes of Health, US Department of Health, Education, and Welfare; and by Grant EY-02636, and the Joslin Diabetes Center (Dr. Rand). Submitted for publication: January 18, Reprint requests: Lawrence I. Rand, MD, Wm. P. Beetham Eye Unit, Joslin Diabetes Center, One Joslin Place, Boston, MA severe visual loss in untreated eyes: presence of vitreous and/or preretinal hemorrhage, presence of new vessels, location of new vessels at or near the optic disc, and severity of new vessels. 5 These retinal factors were chosen for initial investigation because they seemed clinically important rather than because they were necessarily the most important ones. Risk was found to increase progressively as the number of characteristics present increased. It was for eyes with three or more of these risk factors that the study protocol was changed in April 1976 to allow consideration of treatment of control eyes. The present report describes a comprehensive, systematic search for risk factors for visual loss in untreated eyes. More than 200 baseline ocular and nonocular measurements are evaluated for their prognostic importance. This exhaustive search does not substantially improve on the total predictive power of the original clinically derived variables; it does, however, appreciably increase the number of variables on which an outcome prediction can be made. Baseline Characteristics Materials and Methods Two hundred patient and eye characteristics at study entry are evaluated for their importance in predicting visual loss in the eye assigned to the untreated control group of all 1,742 DRS patients; for many of these characteristics, the percentage of patients with the characteristics and correlations be- 983

2 984 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / July 1985 Vol. 26 tween pairs of characteristics were previously published. 2 For convenience of reference, the eyes assigned at entry to the untreated control group will simply be referred to as the index eyes, and those assigned to photocoagulation treatment as the fellow eyes. The baseline variables are of three types: (1) presence and severity of retinal lesions as graded from stereoscopic fundus photographs of seven standard fields; (2) information from the clinical eye examination; and (3) nonocular variables. The fundus photograph variables and the eye exam variables are further subdivided into (a) index eye variables, and (b) fellow eye variables. Retinal variables from both the photographic evaluation and the clinic examination are included here because, although the two methods have the same goal, they do not always achieve the same results. From the baseline fundus photographs, 34 retinal lesions, divided into 47 variables, were independently graded for each eye by two readers. 6 Some characteristics were graded in only one field (disc or macula), and others in more than one field. Numerical scaling and data reduction were necessary before the data could be used in the multivariate (multiple regression) analysis. The absence and presence of characteristics were scaled 0, 1; and characteristics graded according to severity were typically scaled 1, 2, 3, etc. The score used for single-field lesions was the average of the two gradings and for multiple-field lesions the score was the average maximum grade in any field. Variables from the eye examination include visual acuity measurement, history of visual impairment, and information from slit-lamp and indirect ophthalmoscopic examinations of both the control and treated eyes. Some 60 baseline nonocular characteristics determined by clinical history, physical examination, and laboratory tests are included as predictor variables. Outcome Measures and Length of Follow-up All patients entering the Diabetic Retinopathy Study had to have visual acuity of >20/100 in each eye. In the present analysis, two outcome measures of visual loss (in index eyes) are used: (1) development of visual acuity <5/200 (also referred to here as severe visual loss, or SVL) at anytime during follow-up before implementation of the 1976 change of protocol; and (2) development of visual acuity <20/200 at any time during the first 2 yr of follow-up. The first 2 yr of follow-up included observations subsequent to the implementation of the 1976 protocol change for those patients with less than 2 yr of follow-up under the original protocol. Visual acuity information prior to death is included for all patients who died during follow-up. Endpoint of<5/200: A total of 339 (19.5%) of the 1,742 patients developed this endpoint in the index eye, and 125 patients died before the protocol change was implemented. Follow-up ranged from 4 to 28 mo and averaged about 2 yr. Endpoint of <20/200: Of the 1,742 patients, 524 patients (30.1%) developed this endpoint in the index eye, and 144 patients died during the 2-yr follow-up period. Statistical Methods Simple and multiple linear regression methods were used. 7 Multiple linear, rather than logistic, regression was used because it entails substantially lower computer costs and because the results of logistic regression do not appear to differ much from those of linear regression in analyses of this type. 8 It should be noted, however, that risk predicted from linear risk functions, unlike logistic risk functions, is not limited to a range of zero to one. A stepwise forward procedure was used for selecting predictor variables to be included in the multivariate risk equations. Separate equations were obtained for each of the three types (sets) of baseline variables, including separate equations for index and fellow eyes for the fundus photograph and eye exam variables. Variables selected early from each of the three sets were then pooled to obtain a prediction equation from all sources, combined. The measure commonly used to assess the strength of the relationship between a set of independent variables and a dependent variable is the multiple correlation coefficient, R. Because visual acuity, the dependent variable in this analysis, is dichotomous, all of its variation cannot be explained by the regression, and hence the maximum value of R is less than one. Therefore caution is required for interpreting R 2, the coefficient of determination, as the proportion of variation in visual loss explained by the regression. Nevertheless, the relative size of R 2 is a relevant measure for comparing the strengths of association of different combinations of independent variables. Endpoint of <5/200 Results Of the 1,742 index eyes, 339 (19.5%) developed a decrease in visual acuity to worse than 5/200. Fundus photograph variables: Of the 47 index eye variables, 20 were found by simple regression to have absolute t-values (for the slope of the regression line)

3 No. 7 VISUAL LOSS IN ADVANCED DIABETIC RETINOPATHY / Rand er ol. 985 Table 1. Relationship between entry characteristics and development in index eyes of VA < 5/200 during follow-up; stepwise linear regression analysis Simple /- Values for slope Adjusted R 2 (at each step) A. Fundus photograph lesions, index eye 1. Neovascularization of disc (NVD) 2. Hemorrhages and microaneurysms (HMA) 3. Plane of proliferation of disc (PPD) 4. Vitreous hemorrhage (VH) 5. Arteriolar abnormalities (AA) 6. Venous caliber abnormalities (VCAB) 7. Perivenous exudates (PE) 8. Hemorrhages and microaneurysms, Field 2 (HMA2) 9. Fibrous proliferation involving the macula (FP2) 10. Retinal distortion from tension lines involving macula (RDTL) 11. Cystoid changes (CC) 12. A-V nicking (AVN) All fundus photograph variables for index eye, R 2 = B. Eye exam characteristics, index eye 1. Neovascularization of disc (NVD) and/or fibrous proliferation of disc (FPD) 2. Visual acuity at Initial Visit 2 3. Sudden vision loss before Initial Visit 2 4. Preretinal or vitreous hemorrhage 5. Spherical equivalent at Initial Visit 2 6. Sudden vision loss before Initial Visit 1 7. Posterior vitreous detachment (PVD) 8. Neovascularization elsewhere (NVE) and/or fibrous proliferation elsewhere (FPE) All eye exam variables for index eye, R 2 = C. Nonocular patient characteristics 1. Urine protein 2. Hematocrit 3. Maternal diabetes history 4. Age at entry 5. Paternal diabetes history 6. Amputation, leti lower limb All nonocular variable, R 2 = D. Variables from all sources (including fellow eye fundus photograph variables) 1. Neovascularization of disc (NVD) (A) 2. Visual acuity at Initial Visit 2 (B) 3. Hemorrhages and microaneurysms (HMA) (A) 4. Plane of proliferation of NVD (A) 5. Arteriolar abnormalities (AA) (A) 6. Sudden vision loss before Initial Visit 2 (B) 7. Venous caliber abnormalities, fellow eye (VCAB) (F) 8. Preretinal or vitreous hemorrhage (B) 9. Urine protein (C) 10. Perivenous exudates (PE) (A) 11. Amputation of left lower limb (C) 12. Preretinal hemorrhage, fellow eye (PRH) (F) Top variables from each of the following sources: fundus photograph variables index and fellow eyes, and nonocular patient characteristics. R 2 = from index and fellow eyes, eye exam variables from Note. The sources of the variables in panel D are identified as A (panel A), B (panel B), C (panel C), or F (fellow eye fundus photograph variables). of 2.00 or greater. New vessels at or near the optic disc (NVD) was the variable most highly correlated with visual loss, t = 12.32; next highest were plane of proliferation of NVD (PPD), t = 10.88, and fibrous proliferation on disc (FPD), t = Panel A of Table 1 shows the results of the stepwise regression of visual loss on lesions in the index eye. Only variables with adjusted absolute t-values of 2.00 or greater are included in the table (adjusted t-values take into account the effect of all selected variables). The top 12 variables yielded a multiple correlation coefficient of R = 0.40 (R 2 = 0.159), ie, they accounted for about 16% of the observed variance. When the remaining 35 fundus photograph variables for the index eye were added to the regression model, R 2 increased from to only 0.177, so that 90% of

4 986 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / July 1985 Vol. 26 the R 2 from all 47 variables was accounted for by the first 12. Fundus photograph variables from the fellow eye, as a group, had only half the power (R 2 = 0.088) of index eye photographic variables (R 2 = 0.177) to predict severe visual loss in the index eye (data not shown). When the photographic data from the fellow eye were added to those from the index eye, no appreciable increase in predictive ability resulted. Ophthalmic examination variables: Baseline retinal and nonretinal ocular characteristics in both eyes were assessed by clinical examination at two baseline visits, Initial Visits 1 and 2. Eight index eye exam variables were found to have absolute adjusted t-values of 2.00 or more (panel B, Table 1). The variable combining presence and elevation of NVD/FPD was selected first, as it has the highest simple t-value. After adjustment for the other seven variables, the t-value still remains high, though reduced to Visual acuity, episodes of sudden vision loss, and preretinal or vitreous hemorrhage are also strongly related to visual loss after taking into account the other variables. The coefficient of determination, R 2, for the top eight variables is 0.114, and increases negligibly to when the remaining 13 eye exam variables are added. As a group, the eye examination variables are markedly less predictive of visual loss (R 2 = 0.119) than the fundus photograph variables (R 2 = 0.177). Here again, when data from the fellow eyes were added to those of the index eyes, they increased overall predictive power, R 2, only negligibly, from to (data not shown). Nonocular variables: Three laboratory measures had the strongest univariate correlation with the endpoint: urine protein had a positive association (t = 3.70), while hematocrit (t = -3.21) and hemoglobin (t = 2.86) had negative associations (a negative association signifies an inverse relationship). Fortyseven percent of patients had some evidence of urinary protein, and this variable had a major association with death during the study. 9 Neither blood pressure nor smoking history were important predictors of severe visual loss. The multivariate analysis (panel C, Table 1) showed that nonocular variables, as a group, had only about one-fourth the predictive power (R 2 = 0.051) as the fundus photograph variables and less than NVD alone. Maternal and paternal diabetes history were among six variables with adjusted absolute t-values greater than 2.00, but their correlations with the endpoint were in opposite directions. Variables from all sources: The top variables from each data source, 12 fundus photograph variables (index eye and fellow eye), nine eye exam variables (index eye and fellow eye), and six nonocular variables, all with adjusted t-values greater than 2.00, were combined in another multivariate analysis (panel D, Table 1). Index eye NVD as measured on the fundus photographs was the first variable selected. The nonphotographic variables pretreatment visual acuity, history of recent visual loss and urinary protein were among the first ten variables selected, as were the index eye variables hemorrhages and microaneurysms, plane of proliferation, arteriolar abnormalities, vitreous hemorrhage, and perivenous exudates. The R 2 for the 27 variables from all sources (for only 19 was t > 2.00) incorporated into the analysis was 0.197, only a modest improvement over R 2 = for the top 12 variables alone and over R 2 = for the top 12 index eye fundus photograph variables. Endpoint of <20/200 The univariate and multivariate regression of the fundus photograph variables on reduction of visual acuity in the index eye to <20/200 within 2 yr is summarized in panel A of Table 2. The three variables with the highest simple t-values are the same as for visual acuity <5/200. In the multivariate analysis, NVD, its plane of proliferation (PPD), vitreous hemorrhage (VH), and preretinal hemorrhage (PRH), HMA, and macular edema have the greatest independent contributions to explaining loss in vision to <20/200. These variables closely parallel those chosen for the first endpoint, except that the presence of macular edema appears to be more important in explaining this less severe loss of visual acuity. The R 2 for the first eight selected fundus photograph variables was 0.172, somewhat greater than for the endpoint visual acuity less than 5/200 (R 2 = 0.148). The analysis of eye exam characteristics (panel B, Table 2) shows that macular edema on exam is an important predictor, selected fifth in the stepwise regression. The R 2 for all the eye exam variables is somewhat less (0.162) than for the fundus photograph variables (0.187). Nonocular variables (panel C, Table 2) showed about as little predictive power for this endpoint (R 2 = 0.057) as for the primary endpoint (R 2 = 0.051). Diastolic blood pressure was most highly correlated with development of visual acuity <20/200, though not much more so than six others. This variable did not appear as an important predictor for the more severe visual acuity loss. Urine protein, hematocrit, and hemoglobin were also correlated with this endpoint. When variables from all sources are combined (panel D), overall prediction from 13 variables (R 2 = 0.219) was better here than for the endpoint <5/200(R 2 = 0.174).

5 No. 7 VISUAL LOSS IN ADVANCED DIABETIC RETINOPATHY / Rand er ol. 987 Table 2. Relationship between baseline entry characteristics and development in index eyes of VA <, 20/200 during follow-up; stepwise multiple regression analysis /- Values for slope A. Fundus photograph lesions, index eye 1. Neovascularization of disc (NVD) 2. Hemorrhages and microaneurysms (HMA) 3. Vitreous hemorrhage (VH) 4. Plane of proliferation disc (PPD) 5. Macular edema (ME) 6. Arteriolar abnormalities (AA) 7. Preretinal hemorrhage (PRH) 8. Vitreous hemorrhage disc Top 8 fundus photograph variables for index eye, R 2 = All fundus photograph variables for index eye, R 2 = B. Eye exam characteristics, index eye 1. Visual acuity at Initial Visit 2 2. Neovascularization of disc (NVD) and/or fibrous proliferation of disc (FPD) 3. Preretinal or vitreous hemorrhage 4. Sudden vision loss before Initial Visit 2 5. Macular edema 6. Spherical equivalent at Initial Visit 2 7. Iris abnormalities 8. Neovascularization elsewhere (NVE) and/or fibrous proliferation elsewhere (FPE) Top 8 eye exam variables for index eye, R 2 = All eye exam variables for index eye, R 2 = C. Nonocular patient characteristics 1. Diastolic blood pressure 2. Hemoglobin 3. Liver disease 4. Kidney disease 5. Urine protein 6. Hospitalization in last 12 months 7. Amputation, right lower limb Top 7 nonocular variables, R 2 = All nonocular variables, R 2 = D. Variables from all sources (including fellow eye variables) 1. Neovascularization of disc (NVD) (A) 2. Visual acuity at Initial Visit 2 (B) 3. Hemorrhages and microaneurysms (HMA) (A) 4. Preretinal or vitreous hemorrhage (B) 5. Plane of proliferation of disc (PPD) (A) 6. Diastolic blood pressure (C) 7. Hemorrhages and microaneurysms, Field 2 (HMA2) (A) 8. Preretinal hemorrhage, fellow eye (PRH) (F) 9. Amputation of right lower limb (C) 10. Arterior abnormalities (AA) (A) 11. Sudden vision loss prior to Initial Visit 2 (B) 12. Iris abnormalities (B) 13. Preretinal hemorrhage (PRH) (A) Top 13 variables from all sources, R 2 = Simple Adjusted Note. Field 2 is a photographic view of the macula. The sources of the variables in panel D are identified as A (panel A), B (panel B), C (panel C), or F (fellow eye fundus photograph variables). Technique Validation A multiple linear regression function from the 10 best predictors of visual acuity <5/200 in index eyes was used to predict risk in individual index eyes. The eyes were then ranked from high to low according to risk score and divided into deciles. The observed rate of SVL for eyes in the highest decile of risk score, 56.3%, was more than 16 times that in the lowest decile, 3.4%. Of the 339 eyes with visual acuity less than 5/200 in this analysis, 168 (49.7%) were in the upper two deciles of risk score. For each decile, the percentage of eyes expected to lose vision based on the risk function closely approximates the percent actually observed to have lost vision. To further validate our technique, a linear risk function was derived from baseline information in all right fellow eyes. The first 10 variables selected in the stepwise procedure were used to compute risk scores in left fellow eyes. Because each patient con-

6 988 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / July 1985 Vol. 26 Table 3. Number and percent of index eyes developing visual acuity < 5/200 according to number of selected index eye baseline characteristics present Number of characteristics present Total Number of eyes Percent event Selected characteristics: Neovascularization of disc (A), neovascularization elsewhere (A), preretinal hemorrhage (A), vitreous hemorrhage (A), visual acuity at Initial Visit 2 (B), hemorrhages and microaneurysms (A), plane of proliferation on the disc (A), venous caliber abnormalities (A), episodes of sudden vision loss before Initial Visit 2 (B). The letters in parentheses are the sources of the variables (see footnote, Table 1). tributed only one fellow eye, right and left eyes were from different patients. For left eyes in the highest decile of risk score, the observed rate of visual loss was 55.3%, which was more than 11 times the rate of 4.8% in the lowest decile. Of the 162 left eyes developing visual acuity <5/200 during follow-up, 79 (49%) were in the highest two deciles, thus confirming the ability of the multiple regression method to predict risk in one group of patients from a function developed in another. Lastly, the nine entry characteristics first selected in the stepwise procedures were transformed into dichotomous variables to indicate presence or absence of a characteristic or of a specified level of that characteristic. The number of these characteristics, here called "risk characteristics," were determined for each control eye. Table 3 shows the percentage of eyes which developed SVL according to each number (0 to 9) of baseline risk characteristics present. A large progressive increase in the percentage of the eyes developing the event is apparent, from 1.3% of 80 eyes with none of the characteristics to 54.5% of the 143 eyes with seven or more characteristics. This "risk characteristics" approach, though not easily applied clinically, demonstrates that variables chosen early by stepwise regression procedures strongly correlate with visual acuity loss during follow-up. Eyes without New Vessels on the Optic Disc For DRS patients, disc new vessels (NVD), as documented by the fundus photographs, is the most important factor in predicting moderate or severe visual acuity loss. To identify risk factors for severe visual loss in eyes with less severe retinopathy, a regression analysis was conducted with the 895 index eyes without definite NVD at entry. Table 4 summarizes the results of this analysis for the endpoint visual acuity <5/200 in index eyes. Hemorrhages and microaneurysms (HMA) in the index eye was the first fundus photograph lesion selected. Since nearly all eyes in the DRS had HMA at baseline, it must be the severity of this lesion, rather than its presence, which is prognostically important. The overall power of fundus photograph and eye exam variables of the index eye to predict development of severe visual loss was reduced by about one-third when eyes without NVD were excluded from the analysis; on the other hand, the predictive power for nonocular characteristics, though still low, increased by about the same proportion when eyes with NVD were excluded. A regression analysis for the endpoint visual acuity <20/200 within 2 yr of follow-up (not shown) obtained results similar to those in Table 4, except that macular edema was also an important predictor. Discussion The DRS previously examined four retinopathy factors in patients with advanced diabetic retinopathy and found that they were predictive of the risk of severe visual loss. 5 In the present study, a large number of potential DRS risk factors for visual loss in advanced diabetic retinopathy, including the four described earlier, are examined for their prognostic importance. In multivariate analyses there may not be a unique set of "best," say six or 10, predictor variables, 7 ie, there may be several sets with only few predictor variables in common that have approximately equal predictive power. The consistent early appearance of a variable in the various stepwise selections may be as much an indicator of its predictive importance as its specific ranking in the stepwise process. Our analyses confirm the importance of NVD and vitreous hemorrhage as predictors of visual loss. The degree of elevation of NVD or FPD is of major importance independent of the severity of NVD. The presence and severity of NVE did not have great predictive power: this variable, which had been included in the earlier DRS analysis 5 as a risk factor, came out only 13th highest in t-value for slope in the univariate analysis of fundus photographs, and in the multivariate analysis it was not selected as one of the top 12 variables (Table 1, panel A), even when it was forced into the selection process early (data not shown). Correlations between NVE and other factors

7 No. 7 VISUAL LOSS IN ADVANCED DIABETIC RETINOPATHY / Rand er al. 989 Table 4. Relationship between baseline characteristics and development of VA < 5/200 in index eyes without NVD at entry; stepwise multiple regression analysis /- Value for slope (Adjusted) A. Fundus photograph lesions (index and fellow eyes) 1. Hemorrhages and microaneurysms, index eye (HMA) 2. Preretinal hemorrhage, index eye (PRH) 3. Plane of proliferation elsewhere, index eye (PPE) 4. Venous caliber abnormalities, fellow eye (VCAB) 5. Preretinal hemorrhage in Field 2, index eye (PRH2) 6. Retinal elevation, index eye (RELE) 7. Preretinal hemorrhage, fellow eye (PRH) 8. Hemorrhages and microaneurysms in Field 2, fellow eye (HMA2) 9. Vitreous hemorrhage of disc, index eye (VHD) Top 9 fundus photograph variables for index eye, R 2 = All fundus photograph variables for index eye, R 2 = B. Eye exam characteristics (index eye) 1. Visual acuity at Initial Visit 1 2. Sudden vision loss before Initial Visit 2 3. Sudden vision loss before Initial Visit 1 4. Anterior vitreous abnormalities Top 4 eye exam variables for index eye, R 2 = All eye exam variables for index eye, R 2 = C. Nonocular Patient Characteristics 1. Urine protein 2. Marital status Top 2 nonocular variables, R 2 = All nonocular variables, R 2 = D. Variables from all sources 1. Hemorrhages and microaneurysms, index eye (HMA) (A) 2. Urine protein (C) 3. Sudden vision loss prior to Initial Visit 2, index eye (B) 4. Preretinal hemorrhage, index eye (PRH) (A) 5. Sudden vision loss prior to Initial Visit 1, index eye (B) 6. Marital status (C) 7. Anterior vitreous abnormalities, index eye (B) 8. Venous caliber abnormalities, fellow eye (VCAB) (F) 9. Preretinal hemorrhage in Field 2, index eye (PRH2) (A) * * * Negative slope indicates greater risk for married persons. Note. The letters in parentheses in panel D identify the sources of the variables (see footnote, Table 1, panel D). selected early in the stepwise analysis, although modest, may partially explain this result. Failure of NVE to be selected in analyses of eyes free of NVD may be explained by its moderately high correlation (0.401) with plane of proliferation elsewhere (PPE), a variable which combines presence and elevation of NVE and which was selected third with the highest adjusted t- value, or with the large number of hemorrhage variables included. In the absence of NVD, preretinal or vitreous hemorrhage is likely to come from NVE. Our data suggest that NVE when not elevated and not hemorrhaging is not an important prognostic factor. They also suggest that the subsequent elevation of NVE (PPE) or development of preretinal or vitreous hemorrhage from NVE, frequently at the time of vitreous detachment, is a chance event that is not predictable from the size of the NVE, at least not as measured in the DRS. It is an impression of many experienced clinicians in the DRS that cases of flat NVE often remain unchanged for years. Even eyes with moderate to severe NVE without hemorrhage were not defined as having high risk characteristics in previous DRS reports. A new finding of particular importance is that retinopathy characteristics generally considered "nonproliferative" are also of major importance in predicting visual loss in eyes with advanced diabetic retinopathy. The extent of intraretinal hemorrhages and microaneurysms (HMA), venous caliber abnormalities (VCAB), and arteriolar abnormalities (AA) were among the top seven variables selected from all sources in the prediction of severe visual loss. Macular edema proved a strong factor in predicting the milder endpoint of vision <20/200. These factors, which were not studied in the earlier DRS reports on high risk characteristics, may provide a measure of the underlying capillary disorder which leads to the development of new vessels and may influence their rate of progression. Macular edema may be a particularly poor prognostic sign in younger individuals. 10

8 990 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / July 1985 Vol. 26 Intraretinal microvascular abnormalities (IRMA) and soft exudates (SE), characteristics that are currently considered preproliferative lesions, did not score highly as risk factors in our analysis. A modest positive correlation at baseline between these lesions and HMA 4 may contribute to this. IRMA, which are likely dilated abnormal capillaries remaining in an area where other capillaries have closed down," and soft exudates, which are focal infarcts in the nerve fiber layer, probably are earlier lesions and signs of less severe pathology than extensive hemorrhages and microaneurysms and venous caliber abnormalities which are usually seen in more severely ischemic eyes. As an eye develops arteriolar closure 12 and whole segments of retinal capillaries close down, IRMA and soft exudates could decrease as the eye becomes increasingly ischemic. This arteriolar closure leads to low flow and venous stasis with increasing venous changes and associated hemorrhages. IRMA and soft exudates may be good early predictors of development of PDR but are not predictors of progression once PDR or other more advanced preproliferative changes have developed. Even mild visual acuity reduction at baseline was important in predicting visual acuity loss to <5/200 or <20/200. Reduced vision could indicate the presence of any of several pathologic mechanisms by which more severe visual loss occurs, including vitreous hemorrhage, distortion of the macula from traction, macular edema, or extensive capillary closure. No systemic factor appeared to be as important in predicting visual loss as neovascularization of the disc, visual acuity, hemorrhages and microaneurysms, or several other retinopathy characteristics. Urine protein, an index of renal status, was the best systemic predictor. There is a long known association between severe ocular and renal disease in diabetes. In a Joslin Clinic study, almost 50% of patients with PDR had evidence of proteinuria. 13 Most mortality associated with PDR 14 occurs in patients with both PDR and proteinuria. 13 It is possible that enough eyes that would have developed SVL were withdrawn from the study by death to affect our analysis of this variable, and that in fact, its potential prognostic importance is far greater than we have been able to document, ie, in patients with proteinuria death may frequently occur before SVL. Amputation, another index of systemic vascular disease, also scored highly. Maternal and paternal history of diabetes are correlated with visual acuity loss but in opposite directions. This was at first considered chance aberration, but the lower prevalence of diabetes usually found among the offspring of diabetic women than diabetic men is not found in our study. 15 Our patients, all having moderately severe retinopathy, had a maternal history of diabetes about 25% more frequently than a paternal history. One may speculate that while diabetic women are less likely to have diabetic offspring, their diabetic children may have an increased likelihood of developing significant retinopathy and further progression towards a worse visual outcome. Why patients with a paternal history would have a reduced risk of progression is not readily discernable but both findings could be mediated through HLA DR or other genetic factors known to influence development of diabetes and currently being shown to influence development of PDR Smoking history was not demonstrated to have influence on prognosis for vision in these patients with advanced diabetic retinopathy. Blood pressure, a variable long associated with retinopathy, was not a good predictor of the development of the severe visual acuity endpoint; yet diastolic blood pressure was an important predictor of the milder visual acuity endpoint. Study of the Pima Indians 18 showed that blood pressure was an important risk factor for exudative retinopathy. Since it is not likely that exudative retinopathy alone would reduce visual acuity to less than 5/200, our data is consistent with those findings. Hypertension is also strongly associated with urine protein and most hypertension seen in diabetic patients with advanced retinopathy is secondary to renal disease. Overview The eye examination variables of the index eye are markedly less predictive of severe visual loss in that eye (R 2 = 0.119) than are the fundus photograph variables (R 2 = 0.177). This difference obtains despite the clinical examiner's capability of seeing more of the retina than the photographic grader, who sees only seven fields; and despite the fact that the eye examination variables, but not the photographic variables, include two measures of sudden visual loss during the baseline period, both of which are predictive of severe visual loss. The explanation may be that the photographic assessment of retinal lesions is more accurate than the clinical assessment because it is performed under standardized conditions in a central location and because the grader is viewing a stationary target, can take more time to observe, and his or her findings are replicated by a second grader. For the less severe visual loss endpoint (<20/200), the difference in predictive power between the two sets of variables is in the same direction, but much less marked (R 2 = vs R 2 = 0.187). Although the photographic variables are better predictors than the eye examination variables, thorough ophthalmic examination measuring ocular characteristics such as

9 No. 7 VISUAL LOSS IN ADVANCED DIABETIC RETINOPATHY / Rand er al. 991 those in panel B of Table 1 will provide a good predictive tool when gradings are not available. The fundus photographs of the index eye provided much more power than those of the fellow eye or than the systemic variables. All systemic factors combined were less predictive than NVD alone. Since the patients selected for this study had severe retinopathy, it was not to be expected that the presence or extent of a protective or predisposing systemic factor would have as important an influence on prognosis for vision as the severity of the ocular disease itself. Nevertheless, a urine dipstick for protein combined with an eye examination will help to identify high risk patients with both prolifertive retinopathy and renal disease. No attempt has been made to predict from the present multivariate functions the risk of visual loss for a group of patients outside the DRS. However, a risk function derived from all right control eyes was used to estimate risk of visual loss in left control eyes. The closeness of observed and expected numbers of eyes with visual loss supports the generalizability of our results to other similar populations of diabetics. Key words: advanced diabetic retinopathy, severe visual loss, Diabetic Retinopathy Study (DRS), regression analysis, risk factors References 1. The Diabetic Retinopathy Study Research Group: Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 81:383, The Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy: the second report of the Diabetic Retinopathy Study. Ophthalmology 85:82, Diabetic Retinopathy Study: Manual of Operations. Baltimore, Diabetic Retinopathy Study Coordinating Center, The Diabetic Retinopathy Study Research Group: Design, methods, and baseline results: Diabetic Retinopathy Study (DRS) Report Number Six. Invest Ophthalmol Vis Sci 21:149, The Diabetic Retinopathy Study Research Group: Four risk factors for severe visual loss in diabetic retinopathy: the third report from the Diabetic Retinopathy Study. Arch Ophthalmol 97:654, The Diabetic Retinopathy Study Research Group: A modification of the Airlie House Classification of Diabetic Retinopathy: DRS Report Number Seven. Invest Ophthalmol Vis Sci 21: 210, Draper NR and Smith H: Applied regression analysis. New York, Wiley and Sons, Coronary Drug Project Research Group: Factors influencing long term prognosis after recovery from myocardial infarction: three year findings of the Coronary Drug Project. J Chronic Dis 27:267, Ramsey RC, Martin MJ, Goetz FC, and Knatterud GL: Kidney function, visual acuity, and retinopathy status in the Diabetic Retinopathy Study. ARVO Abstracts. Invest Ophthalmol Vis Sci 26(Suppl):86, Aiello LM, Rand LI, Briones JC, Wafai MZ, and Sebestyen JG: Diabetic Retinopathy in Joslin Clinic patients with adultonset diabetes. Ophthalmology 88:619, Henkind P and Wise GN: Retinal neovascularization, collaterals, and vascular shunts. Br J Ophthalmol 58:422, Ashton N: Pathogenesis of diabetic retinopathy. In Diabetic Retinopathy, Little HL, Patz A, Jack RL, and Forsham PH, editors. New York, Thieme Stratton, 1983, pp Krolewski AS, Rand LI, Warram JH, and Christlieb AR: Development of proliferative retinopathy in juvenile-onset IDDM: 40 years follow-up study. ARVO Abstracts. Invest Ophthalmol Vis Sci 25(Suppl):128, Davis MD, Hiller R, Magli YL, Podgor M, Ederer F, Harris WA, Long JW, and Haug GA: Prognosis for life in patients with diabetes: relation to severity or retinopathy. Trans Am Ophthalmol Soc 77:144, Warram JH, Krolewski AS, Gottlieb MS, and Kahn CR: Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 311: 149, Dornan TL, Ting A. McPherson CK, Reckar CO, Mann JI, Turner RC, and Morris PJ: Genetic susceptibility to the development of retinopathy in insulin-dependent diabetes. Diabetes 31:166, Rand LI, Krolewski AS, and Warram J: Multiple risk factors for proliferative diabetic retinopathy (PDR). Diabetes 33(Suppl): 365, Knowler WC, Bennett PH, and Ballintine EJ: Increased incidence of diabetic retinopathy with elevated blood pressure. N Engl J Med 302:654, 1980.