DRUSEN SIZE AND AREA
gives the number and percentage of right eyes of participants free of advanced AMD in both eyes at baseline that developed advanced AMD within 5 years, by drusen area and maximum drusen size at baseline. The association between drusen size and area is apparent. Among 401 eyes with very large drusen, 309 (77%) had drusen area of 0.5 standard disc area (DA) or greater, while among 1249 eyes with only small drusen, 1096 (88%) had area less than C-1. The P values at the bottom of each column are from a test for trend in risk of advanced AMD with increasing drusen area within each drusen size category, while those at the end of each row are for this trend across drusen size within area. Within drusen size categories, the risk of developing advanced AMD generally increases with increasing drusen area, although there is little or no increase between the 2 largest area categories (≥0.5 DA, <1.0 DA; and ≥ 1.0 DA). The increase in risk of advanced AMD with increasing drusen size is less consistent. Because drusen area appeared to be the stronger and more consistent risk factor and because the drusen size grade indicates only the largest druse present, whereas drusen area provides a measure of total drusen, subsequent development of the severity scale focused on drusen area rather than size.
Five-Year Rates of Advanced AMD,* by Drusen Area and Maximum Drusen Size at Baseline
SOFT INDISTINCT DRUSEN
A similar analysis comparing drusen area and predominance of soft indistinct drusen demonstrated the association between these characteristics (). Among 467 eyes with drusen area of 0.5 DA or greater, in 211 (45%) soft indistinct drusen were predominant in all 3 zones and in 410 (88%) they were present to some degree. The predictive power of drusen area was stronger and more consistent than that of predominance of soft indistinct drusen. In view of the complexity that would be added to the scale by inclusion of a second drusen characteristic, and the limited additional predictive power to be gained, further scale building used only drusen area.
Five-Year Rates of Advanced AMD,* by Drusen Area and Predominance of Soft Indistinct Drusen At Baseline
gives 5-year rates of advanced AMD by baseline gradings for area of increased pigmentation and for area of depigmentation or presence of noncentral GA (the combined depigmentation-GA scale; see the “Methods” section). Of the 3212 eyes, 2412 (75%) had no pigmentary abnormalities (column 1, row 1); among them, 38 (1.6%) developed neovascular AMD and none developed CGA. Among the remaining 381 eyes in column 1, which had any degree of increased pigmentation but no depigmentation, 67 (18%) developed advanced AMD. This rate appeared to change little with increasing amounts of pigment except for an increase in the 2 highest categories. Only 52 eyes had depigmentation without accompanying increased pigment (row 1, columns 2–7). Although the numbers in each cell of columns 2 through 7 are small, the rates shown in the column totals show a steady increase from 8.5% when depigmentation was questionable to about 50% when depigmentation was 0.5 DA or greater or noncentral GA was present.
Five-Year Rate of Advanced AMD,* by Area of Increased Pigmentation and by Area of Depigmentation–Presence of Geographic Atrophy at Baseline
gives a pigment abnormality scale created by collapsing . Step 1 represents the upper left cell of . Step 2 combines the remainder of column 1 with columns 2 and 3. Step 3 combines columns 4 and 5. Steps 4 and 5 represent columns 5 and 6, respectively. For both neovascular AMD and CGA, risk increased progressively except for the decrease in risk of neovascular AMD in eyes that had previously developed noncentral GA (step 5).
Five-Year Rates of Advanced AMD,* by Severity of Pigmentary Abnormalities at Baseline
TREE-STRUCTURED REGRESSION ANALYSES
shows the results of tree-structured regression analyses of progression to neovascular AMD or CGA within 5 years. In , baseline variables were limited to drusen area, increased pigmentation, and depigmentation-GA in the subfields chosen a priori (see the “Methods” section). The branchings helped in the selection of cutoff points for collapsing to create and in collapsing the drusen area axis of to that used in . In , baseline variables included drusen size and predominance of soft indistinct drusen, as well as assessments of drusen area, increased pigment, and depigmentation in each of 3 nested zones (see the “Methods” section). The principal differences between parts A and B of are (1) selection of drusen size, rather than area, at the second branching of the drusen area less than O-2 limb, and (2) selection of drusen area in the central subfield, rather than depigmentation, at the pigment present branching of the limb for drusen area greater than or equal to O-2. These differences were not considered substantial enough to warrant increasing the complexity of the scale.
Figure 2 Tree-structured analyses of progression to neovascular age-related macular degeneration or central geographic atrophy (CGA) within 5 years. A, Drusen area, increased pigment, and depigmentation–geographic atrophy (GA) as used in and (more ...)
Five-Year Rates of Advanced AMD and (for Eyes That Did Not Progress to Advanced AMD) Rates of Progression From Scale Steps 1 to 6 to Steps 7 to 9 for Right and Left Eyes of Participants Free of Advanced AMD in Both Eyes at Baseline
DRUSEN AREA AND PIGMENT ABNORMALITIES CROSS-CLASSIFIED
The 2 smallest steps on the drusen area scale () were combined, as were the 2 largest, and eyes were cross-classified by this collapsed drusen area scale and by the pigment abnormality scale shown in to produce the entries shown in the cells of for right eyes. This table also provides comparable information for the left eyes of the same participants, ie, participants in whom both eyes were free of advanced AMD at baseline. Development of the scale was based on results for right eyes; left eyes are shown for comparison. The cells in were combined to create a 9-step overall severity scale (the cells assigned to each of the 9 steps are indicated by shading). For each drusen area category in , the number at risk and the percentage of eyes (right and left separately) that developed advanced AMD within 5 years are provided. The cells that make up parts of steps 1 to 6 of the overall severity scale also provide percentages of eyes progressing to steps 7, 8, or 9, but not to advanced AMD. The assignment of cells to steps in the scale was based primarily on similarity of these 2 outcomes between cells. Secondarily, preference was given to the diagonal connection between cells that would be expected when 2 predictive characteristics are cross-classified.
Results for right and left eyes were similar, but if the grouping of cells into the 9 steps of the scale had been based on left eyes, there could have been several differences, for example: (1) step 3 might have been combined with 2; (2) the smallest cell in step 5 (11 left eyes) might have been combined with the cell below it in step 6 (16 left eyes); and (3) pooling all eyes with depigmentation of 0.5 DA or greater as step 8 might have seemed less appropriate.
The data for the first and last drusen area categories of demonstrate the close association of pigmentary abnormalities with large drusen area; 6% of eyes with drusen area less than C-1 had pigmentary abnormalities, compared with 67% of eyes with drusen area of 0.5 DA or greater.
combines the same-step cells of for right and left eyes combined, and presents the proportions of eyes progressing to the specified outcomes. These findings are summarized in . Progression to advanced AMD increased across all 9 steps of the scale, although there was little change between steps 4 and 5, and progression to steps 7 to 9 increased across steps 1 to 6, although there was little difference between steps 2 and 3 (). The risk of neovascular AMD increased from steps 1 through 8 and then decreased in step 9 (). The risk of CGA was low in steps 1 to 5 and then increased across the remaining steps (). The bar representing step 9 is offset to emphasize that the increase in outcome in this step is due exclusively to CGA. This step can be included in or excluded from the scale depending on the goals of the study in which it is used. Inclusion would seem appropriate when CGA alone or the AREDS definition of advanced AMD is the outcome of interest, but would be problematic for neovascular AMD. defines the steps in the scale.
Table 7 Five-Year Rates of Advanced AMD and (for Eyes That Did Not Progress to Advanced AMD) Rates of Progression From Scale Steps 1 to 6 to Step 7 or 8 or to Step 9, for Right and Left Eyes Combined, of Participants Free of Advanced AMD in Both Eyes at Baseline (more ...)
Figure 3 Five-year progression rates in 6426 eyes of 3214 patients free of advanced age-related macular degeneration (AMD) in both eyes at baseline. The width of the bars is proportional to the number of eyes in the Age-Related Eye Disease Study (AREDS) scale (more ...)
EYES FREE OF ADVANCED AMD IN PARTICIPANTS WITH NEOVASCULAR AMD IN ONE EYE AT BASELINE
corresponds to but considers the eye with nonadvanced AMD of the 543 participants whose other eye had neovascular AMD at baseline, and provides information for these eyes comparable to that in . Comparison of with () shows that presence of neovascular AMD in one eye of an individual increases the risk of its development in the fellow eye by a factor that ranges from 2 for eyes in step 8 to about 20 for eyes in steps 1 and 2, as compared with an eye in an individual free of neovascular AMD in both eyes.
Five-Year Rates of Advanced AMD and (for Eyes That Did Not Progress to Advanced AMD) Rates of Progression From Scale Steps 1 to 6 to Steps 7 to 9 for the Eyes at Risk of Participants With Neovascular AMD in the Fellow Eye at Baseline
Five-Year Rates of Advanced AMD and (for Eyes That Did Not Progress to Advanced AMD) Rates of Progression From Scale Steps 1 to 6 to Step 7 or 8 or to Step 9, for Eyes at Risk of Participants With NeoAMD in the Fellow Eye at Baseline
Figure 4 Five-year rates of neovascular age-related macular degeneration (AMD) (with or without central geographic atrophy) in eyes with and without neovascular AMD in the fellow eye at baseline. The width of the bars is proportional to the number of eyes in the (more ...)
EYES FREE OF ADVANCED AMD IN PARTICIPANTS WITH CGA IN ONE EYE AT BASELINE
There were only 57 participants who had CGA in one eye at baseline; in 16 of them the fellow eye was in steps 1 to 6 combined at baseline and in 41 it was in steps 7 to 9. In the former group, 1 eye developed neovascular AMD and 1 developed CGA (total, 12.5%), while in the latter group, 7 developed neovascular AMD, 13 developed CGA, and 2 developed both (total, 53.7%).
TRANSITIONS ALONG THE SCALE
classifies the 334 right eyes of participants free of advanced AMD in both eyes at baseline that progressed (and 32 right eyes that improved) by 3 or more steps on the scale between the baseline and 5-year visits by the course followed at the 2- and 4-year visits. Progression was “abrupt” in 31% of the 334 eyes (the steps at 2 and 4 years were the same as those at baseline and/or 5 years and never had a reversal of direction) and was “stepwise” in 47% (at least 1 of the steps at 2 and 4 years was intermediate between baseline and 5 years and there was never a reversal). The remainder had reversals of some degree. For example, progressions in the sequence 3-3-3-6 or 3-6-6-6 would be classified as abrupt, 2-4-4-5 or 2-3-4-5 as stepwise, and 2-4-3-4 as “variable 1” (because changing 1 visit 1 step would be sufficient to move the eye to either the stepwise category, 2-3-3-4, or the abrupt category, 2-4-4-4). Variable 2 and variable 3 have corresponding definitions of the number of steps of change required in the 2- and/or 4-year gradings to remove reversals. Similar tables for each baseline severity level showed similar results (data not shown).
Transitions From Baseline to Years 2, 4, and 5 for Eyes With 3-Step or Greater Change Between Baseline and 5-Year Visit
REPRODUCIBILITY OF THE SCALE
examines the reproducibility of the scale, expanded to include CGA and neovascular AMD as additional steps, by comparing the original grading with a replicate grading (see the “Methods” section). There was complete agreement in 63.4% of eyes, agreement within 1 step in 86.6%, and agreement within 2 steps in 93.6%. An unweighted κ statistic (SE) was 0.58 (0.015), and κ weighted to give 75% credit for 1-step disagreement was 0.73(0.013).
Intergrader Reproducibility of Scale: Original Grade by Regrading*
INFLUENCE OF AREDS TREATMENT
The scale-building data set was selected before publication of AREDS results, and analyses were carried out without knowledge of treatment assignment. After completion of all analyses, 5-year rates of advanced AMD in the placebo group were compared with those in the antioxidants plus zinc group and in the 3 active treatment groups combined (). Events were few, and there was no suggestion of a treatment effect through step 4. As events and rates increased thereafter, trends consistent with the beneficial treatment effect previously reported were seen in steps 5 through 9 and when steps 2 through 9 were pooled. Inspection of , and of the underlying cross-tabulations of drusen area by pigment abnormalities from which individual cells were combined to create (data not shown), does not suggest any change in the definitions of scale steps. Although based on small numbers, comparison of the placebo and all groups combined columns for scale steps 8 and 9 suggests that 5-year risks of advanced AMD for untreated eyes in these steps are somewhat higher than those given by the scale.
Five-Year Rates of Advanced AMD (or Right and Left Eyes Combined of Participants Free of Advanced AMD in Both Eyes at Baseline, by Treatment Assignment
A similar analysis for the eye at risk in participants with neovascular AMD in the fellow eye at baseline demonstrated treatment effect more clearly and suggested that risks for untreated eyes in steps 1 to 7 were somewhat higher than those given by the scale ().
Five-Year Rates of Advanced AMD for the Eye at Risk in Participants With Neovascular AMD in the Fellow Eye at Baseline, by Treatment Assignment