**Purpose.**:
To assess the relative risk of an eye's conversion to wet age-related macular degeneration (AMD) based primarily on drusen measurements obtained from analysis of digitized images.

**Methods.**:
Four hundred forty-four subjects (820 eyes) enrolled in the Age-Related Eye Disease Study (AREDS I) and 78 subjects (129 eyes) from the Prophylactic Treatment of AMD trial (PTAMD) were studied retrospectively. Drusen size, distribution, drusen area, and hyperpigmentation in two central macular regions on baseline fundus images were determined using an image analysis algorithm. The relative risk for choroidal neovascularization (CNV) based on drusen area, presence of one or five large drusen, hyperpigmentation, and fellow eye status was calculated.

**Results.**:
Odds ratios (ORs) for measured drusen area within the 1000- and 3000-μm regions were 1.644* (1.251–2.162) and 1.278 (0.927–1.762) for AREDS eyes and 0.832 (0.345–2.005) and 1.094 (0.524–2.283) for PTAMD eyes (**P* < 0.05). In the 1000-μm region, respective ORs for the presence of a large druse, hyperpigmentation, and fellow eye affected were 2.60, 1.71, and 6.44* for AREDS eyes and 8.24, 1.37, and 17.56* for PTAMD eyes; for the 3000-μm region, ORs were 3.45*, 3.40*, and 4.59* for AREDS and nonsignificant, 6.58, and 11.62* for PTAMD eyes, respectively.

**Conclusions.**:
Total drusen area, presence of large drusen, and the presence of hyperpigmentation were not consistent risk factors for an eye's development of CNV. Risk depended on study cohort as well as location. Having an affected fellow eye was the strongest and most consistent risk factor across all models. A larger drusen area does not necessarily increase an eye's risk of conversion to CNV.

^{ 1,2 }and genetic

^{ 3–7 }risk factors continue to be identified, the results of a fundus examination allow a clinician to approximate risk immediately.

^{ 8–13 }It has been stated that the number of large drusen is closely related to the total area of drusen and that total drusen area is an important reported risk factor for the development of late AMD.

^{ 14,15 }Unfortunately, the actual measurement of the area covered by drusen in a specific region of regard is not a simple task. The drusen area in eyes of subjects enrolled in large trials has been measured using fixed circular templates, requiring that some estimates be made by the reader.

^{ 10 }We carefully investigated the association between drusen size and drusen area using a computer algorithm and found that the number of intermediate drusen, as measured rigorously in a large cohort of AMD patient eyes, was more highly correlated to drusen area than was the number of large drusen.

^{ 16 }

^{ 17 }Advanced AMD was defined as the presence of neovascular AMD, a history of photocoagulation for AMD, or geographic atrophy involving the central macula. Trained readers made morphological assessments of baseline photos, grading each image for drusen characteristics (size, type, and area), pigment abnormalities (increased pigment, decreased pigment, geographic atrophy), and the presence or absence of abnormalities characteristic of wet AMD such as hemorrhage, fibrosis, and fluid. Large drusen were defined as those being at least 125 microns in size, measured along the smallest dimension. Intermediate drusen were 63 to 124 microns in diameter, while small drusen were less than 62 microns. A detailed and comprehensive severity scale was subsequently derived from these image data, allowing the risk of developing end-stage or advanced AMD to be estimated from morphological criteria as assessed at baseline.

^{ 14 }

^{ 15 }With the simplified scale, pigment abnormalities and the presence or absence of a large druse are key to the risk assessment, and if present, 1 point is given for each of these features. The points for each eye are summed then converted to a probability. If a patient has no late AMD in either eye, the scale gives the chance of that patient progressing to late AMD in either one of their two eyes. If a patient already has late AMD in one eye, the risk of progression is estimated for the remaining eye.

^{ 14 }large drusen located within two disc diameters from the foveola were counted (inside a 6000-micron diameter circle). Pigmentary abnormalities, however, were tallied when they were found within 1500 microns from the fovea. This disparity is not mentioned in the simplified scale descriptions,

^{ 15 }and the effect that such ambiguity has on risk assessment is not clear.

^{ 10 }Computer analysis has been shown to facilitate reproducible assessment of satellite and surveillance images, and the technique is valuable in drusen detection and characterization.

^{ 18,19 }

^{ 19 }We also assessed these and other features in specific regions of regard to investigate whether the location of the pathology had a substantial influence on the risk profiles. We are unaware of other reports wherein computerized methods were applied to thousands of digital images from large cohorts of subjects to study drusen.

^{ 17 }and the Prophylactic Treatment of Age-Related Macular Degeneration study (PTAMD).

^{ 20,21 }The images were digitized and read by masked readers. Institutional review board approval was obtained, and the Declaration of Helsinki was followed. To be eligible for AREDS, subjects had to have had good visual acuity of at least 20/32 in both eyes (categories 1–3) or in one eye with a specific AMD morphological profile in the fellow eye (category 4). The amount of AMD varied from virtually none in both eyes (category 1), mild or borderline AMD in one or both eyes (category 2), or large drusen or extensive intermediate drusen in one or both eyes (category 3), to advanced AMD in one eye and good visual acuity ≥20/32 in the fellow eye. We studied 376 AREDS subjects who had both eyes eligible and 68 who had only one eligible eye (total 444 AREDS subjects, 820 eyes). We also analyzed the images of 78 subjects in the PTAMD study, 51 of whom had both eyes eligible and 27 of whom had only one eye eligible.

^{ 15 }was used to measure the features of drusen. An advantage of the software that helps make the data more reproducible is the requirement that the measurements made on each digital image be indexed to the diameter of the optic nerve on that image. In this way, any noise in the measurements resulting from variable magnification or from the influence of the refractive status of each eye is minimized. The drusen area measurement provided by the analytical software results in the form of a continuous variable, in increments of one hundredth of a square millimeter.

^{ 19 }The drusen distribution, that is, the number of drusen of various sizes, is also generated.

*x*in years divided by the odds at age

*x*− 1. For these statistical models, the measured drusen area in the eyes of cohorts was transformed to have a mean of 0 and a standard deviation of 1. Thus, the OR is based on the effect of a 1-standard deviation increase of drusen area. The level of statistical significance was set at 0.05.

**Table 1.**

**Table 1.**

Parameter | Odds Ratio Point Estimates (Except as Noted) | ||||

Model 1 | Model 2 AREDS Only | Model 3 PTAMD Only* | Model 4 AREDS + PTAMD Assumes No Influence of Study Group | ||

AREDS as Reference | PTAMD as Reference | ||||

No. of subjects | 506 | 506 | 444 | 62 | 506 |

Intercept (age = 0, pigment = N, fellow eye affected = N, Drusen area = 0) | 0.128 | 0.385 | 0.026 | 0.894 | 0.359 |

Age, y | 0.975 | 0.975 | 0.994 | 0.955 | 0.963 |

Pigment = Y | 1.836 | 1.836 | 1.634 | 3.050 | 1.850 |

Fellow eye affected = Y | 7.202 | 7.202 | 6.177 | 13.100 | 7.769 |

Drusen area (scaled) | 1.685 | 0.862 | 1.644 | 0.832 | 1.540 |

Study = AREDS | NA | 0.331 | NA | NA | NA |

Drusen area × (study = AREDS) | NA | 1.956 | NA | NA | NA |

Study = PTAMD | 3.022 | NA | NA | NA | NA |

Drusen area × (study = PTAMD) | 0.511 | NA | NA | NA | NA |

**Table 1A.**

**Table 1A.**

Model 1: AREDS as Base | ||||

1000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.128 | 0.002 | 9.636 | |

Age, y | 0.975 | 0.924 | 1.029 | |

Pigment = Y | 1.836 | 0.739 | 4.559 | |

Fellow eye affected = Y | 7.202 | 3.201 | 16.205 | * |

Drusen area (scaled) | 1.685 | 1.248 | 2.276 | * |

Study = PTAMD | 3.022 | 1.160 | 7.871 | |

Drusen area × (study = PTAMD) | 0.511 | 0.280 | 0.934 | * |

Model 1: PTAMD as Base | ||||

1000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.385 | 0.006 | 25.579 | |

Age, y | 0.975 | 0.924 | 1.029 | |

Pigment = Y | 1.836 | 0.739 | 4.559 | |

Fellow eye affected = Y | 7.202 | 3.201 | 16.205 | * |

Drusen area (scaled) | 0.862 | 0.494 | 1.502 | |

Study = PTAMD | 0.331 | 0.127 | 0.862 | |

Drusen area × (study = AREDS) | 1.956 | 1.071 | 3.571 | * |

Model 2: AREDS Only | ||||

1000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.026 | 0.000 | 23.387 | |

Age, y | 0.994 | 0.914 | 1.082 | |

Pigment = Y | 1.634 | 0.573 | 4.661 | |

Fellow eye affected = Y | 6.177 | 2.406 | 15.857 | * |

Drusen area (scaled) | 1.644 | 1.251 | 2.162 | * |

Model 3: PTAMD Only† | ||||

1000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.894 | 0.001 | 704.18 | |

Age, y | 0.955 | 0.886 | 1.029 | |

Pigment = Y | 3.050 | 0.370 | 25.113 | |

Fellow eye affected = Y | 13.100 | 1.878 | 91.380 | * |

Drusen area (scaled) | 0.832 | 0.345 | 2.005 |

^{2}, with a mean and standard deviation of 0.043 ± 0.060 for AREDS, 0.123 ± 0.076 for PTAMD, and 0.049 ± 0.065 for AREDS and PTAMD combined. To put these results into perspective, the area covered by 5 large drusen is 0.06136 mm

^{2}.

^{ 19 }The estimated ORs for the presence of a large druse were not consistent across study and region, and they differed from the results generated when drusen area was treated as a continuous variable (as in Tables 1 and 2). This could very well be due to confounding effects often seen when quantitative variables are artificially categorized, and especially when they are dichotomized. For the central 3000-micron region in the AREDS model, the following risk factors were statistically significant: the presence or absence of pigment, the presence or absence of a large druse, and whether or not the fellow eye was affected (Table 3A).

**Table 2.**

**Table 2.**

Parameter | Odds Ratio Point Estimates (except as noted) | ||||

Model 1 | Model 2 AREDS Only | Model 3 PTAMD Only* | Model 4 AREDS + PTAMD Assumes No Influence of Study Group | ||

AREDS as Reference | PTAMD as Reference | ||||

No. of subjects | 506 | 506 | 444 | 62 | 506 |

Intercept (age = 0, pigment = N, Fellow eye affected = N, drusen area = 0) | 0.094 | 0.169 | 0.043 | 0.128 | 0.173 |

Age, y | 0.976 | 0.976 | 0.986 | 0.970 | 0.969 |

Pigment = Y | 4.542 | 4.542 | 4.250 | 7.399 | 4.591 |

Fellow eye affected = 1 | 5.925 | 5.925 | 5.070 | 12.718 | 6.217 |

Drusen area (scaled) | 1.296 | 1.029 | 1.278 | 1.094 | 1.273 |

Study = AREDS | NA | 0.559 | NA | NA | NA |

Drusen area × (study = AREDS) | NA | 1.260 | NA | NA | NA |

Study = PTAMD | 1.790 | NA | NA | NA | NA |

Drusen area × (study = PTAMD) | 0.794 | NA | NA | NA | NA |

^{2}(the area of one large druse) or at least 0.06136 mm

^{2}(the area of five large drusen), respectively, our results again changed (Table 4). In the central 1000-micron region and using the threshold drusen area as >0.06136 mm

^{2}, the OR for AREDS subjects was 3.299 and significant. In the 3000-micron region of regard, only pigment and fellow eye affected were significant risk factors when the drusen area threshold was ≥0.01227 microns

^{ 2 }(one large druse–equivalent area). At a threshold drusen area equivalent to at least five large drusen, all factors were significant (pigment present, fellow eye affected, and drusen area >0.06136). Note that there were no PTAMD observations in the lowest one druse area grouping for either the 1000- or 3000-micron regions of regard because the eligibility requirements for the PTAMD study required the presence of multiple macular drusen centrally. A side-by-side comparison of the data in Table 4 is made in Tables 4A and 4B, which summarize the results for the 1000 and 3000 micron regions, respectively.

**Table 2A.**

**Table 2A.**

Model 1: AREDS as Base | ||||

95% Confidence Interval | ||||

3000 | Point Estimate | Lower Bound | Upper Bound | SS Slope |

Intercept | 0.094 | 0.001 | 8.542 | |

Age, y | 0.976 | 0.923 | 1.031 | |

Pigment = Y | 4.542 | 1.718 | 12.006 | * |

Fellow eye affected = Y | 5.925 | 2.424 | 14.483 | * |

Drusen area (scaled) | 1.296 | 0.916 | 1.833 | |

Study = PTAMD | 1.790 | 0.594 | 5.396 | |

Drusen area × (study = PTAMD) | 0.794 | 0.471 | 1.338 | |

Model 1: PTAMD as Base | ||||

3000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.169 | 0.002 | 13.755 | |

Age, y | 0.976 | 0.923 | 1.031 | |

Pigment = Y | 4.542 | 1.718 | 12.006 | * |

Fellow eye affected = Y | 5.925 | 2.424 | 14.483 | * |

Drusen area (scaled) | 1.029 | 0.646 | 1.637 | |

Study = AREDS | 0.559 | 0.185 | 1.683 | |

Drusen area × (study = AREDS) | 1.260 | 0.748 | 2.124 | |

Model 2: AREDS Only | ||||

3000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.043 | 0.000 | 30.22 | |

Age, y | 0.986 | 0.909 | 1.069 | |

Pigment = Y | 4.250 | 1.412 | 12.791 | * |

Fellow eye affected = Y | 5.070 | 1.804 | 14.253 | * |

Drusen area (scaled) | 1.278 | 0.927 | 1.762 | |

Model 3: PTAMD Only† | ||||

3000 | 95% Confidence Interval | |||

Point Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.128 | 0.000 | 222.994 | |

Age, y | 0.970 | 0.881 | 1.068 | |

Pigment = Y | 7.399 | 1.507 | 36.332 | * |

Fellow eye affected = Y | 12.718 | 1.567 | 103.197 | * |

Drusen area (scaled) | 1.094 | 0.524 | 2.283 |

**Figure 1.**

**Figure 1.**

^{ 14,15 }This may be one reason why our results differ from those described in previous reports. In our cohort of AREDS participants, we did find that the presence of a single large druse located within the central 3000-micron region of regard was a significant risk factor, but when the druse was found within the central 1000-micron zone alone, it was not (Table 3A).

^{ 15 }In this way, the relative importance of each risk factor for an eye can be seen more clearly.

^{ 22,23 }The OCT provides a geometric profile of larger drusen, allowing the volume to be calculated from the cross-sectional, z-axis information. Germane to these calculations, however, is the necessity that accurate measurements of drusen area in the x-y plane must be made. Since we found that drusen area, when measured as a continuous variable, was not a consistent and compelling risk factor for the development of CNV, we are skeptical that drusen volume itself will be particularly relevant. Furthermore, as part of a recent report, we longitudinally assessed morphological features in thousands of images from hundreds of subjects with AMD followed over several years.

^{ 24 }In that study, measurements of drusen were conducted at baseline and at each annual visit up to 8.1 years thereafter (median, 3.8 years). We found that sequential changes in drusen area over time did not signal an increased risk of conversion to neovascular AMD. We did find, however, that ETDRS protocol–measured visual acuity decreased in subjects well before the neovascular event occurred, and this reduction in acuity appeared to signal the eventual conversion of dry AMD to the wet form of the disease.

^{ 24 }

^{ 1,2,25 }We did control for vitamin and mineral assignment in the AREDS cohort. In PTAMD, vitamin usage was not documented. Failure to control for these parameters is an admitted weakness in our investigation, but we doubt that adjusted ORs for our drusen parameters would be substantially different.

^{2}was reached (an area equivalent to approximately 60 large drusen).

**Table 3.**

**Table 3.**

1000 | Confidence Intervals | |||

AREDS | Point Estimate | Lower Bound | Upper Bound | SS Slope |

Intercept | 0.032 | 0.000 | 35.273 | |

Age | 0.990 | 0.908 | 1.079 | |

Pigment = Y | 1.709 | 0.548 | 5.327 | |

Fellow eye affected = Y | 6.437 | 2.496 | 16.595 | * |

At least one large druse | 2.596 | 0.955 | 7.059 | |

1000 | Confidence Intervals | |||

PTAMD† | Point Estimate | Lower Bound | Upper Bound | SS Slope |

Intercept | 3.654 | 0.002 | 5917.327 | |

Age | 0.920 | 0.825 | 1.027 | |

Pigment = Y | 1.365 | 0.153 | 12.186 | |

Fellow eye affected = Y | 17.558 | 2.136 | 144.362 | * |

At least one large druse | 8.235 | 0.308 | 220.073 | |

3000 | Confidence Intervals | |||

AREDS | Point Estimate | Lower Bound | Upper Bound | SS Slope |

Intercept | 0.025 | 0.000 | 11.157 | |

Age | 0.986 | 0.916 | 1.062 | |

Pigment = Y | 3.398 | 1.183 | 9.76 | * |

Fellow eye affected = Y | 4.586 | 1.689 | 12.454 | * |

At least one large druse | 3.452 | 1.113 | 10.713 | * |

3000 | Confidence Intervals | |||

PTAMD† | Point Estimate | Lower Bound | Upper Bound | SS Slope |

Intercept | 0.000 | 0.000 | Infinite | |

Age | 0.978 | 0.890 | 1.075 | |

Pigment = Y | 6.579 | 0.606 | 71.389 | |

Fellow eye affected = Y | 11.624 | 1.542 | 87.646 | * |

At least one large druse | Infinite | 0.000 | Infinite |

**Table 3A.**

**Table 3A.**

Parameter | AREDS | PTAMD* | ||

1000 | 3000 | 1000 | 3000 | |

Intercept | 0.032 | 0.025 | 3.654 | 0.000 |

Age | 0.990 | 0.986 | 0.920 | 0.978 |

Pigment = Y | 1.709 | 3.398 | 1.365 | 6.579 |

Fellow eye affected = Y | 6.437 | 4.586 | 17.558 | 11.624 |

At least one large druse | 2.596 | 3.452 | 8.235 | Infinite |

**Table 4.**

**Table 4.**

AREDS One Druse Equivalent Area (EA) | ||||

1000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.012 | 0.000 | 8.816 | |

Age, y | 0.992 | 0.917 | 1.075 | |

Pigment = Y | 1.533 | 0.598 | 3.928 | |

Fellow eye affected = Y | 5.142 | 1.996 | 13.25 | * |

At least one1 large druse EA† | 5.360 | 1.482 | 19.389 | * |

AREDS Five Drusen Equivalent Area (EA) | ||||

1000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.016 | 0 | 16.168 | |

Age, y | 0.997 | 0.916 | 1.086 | |

Pigment = Yes | 1.484 | 0.548 | 4.022 | |

Fellow eye affected = Y | 5.765 | 2.241 | 14.831 | * |

At least 5 large drusen EA† | 3.299 | 1.347 | 8.08 | * |

PTAMD One Druse Equivalent Area (EA) | ||||

1000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.000 | 0.000 | Infinite | |

Age, y | 0.952 | 0.870 | 1.043 | |

Pigment = Y | 2.821 | 0.404 | 19.688 | |

Fellow eye affected = Y | 13.056 | 1.869 | 91.190 | * |

At least one large druse EA† | Infinite | 0.000 | Infinite | |

PTAMD Five Drusen Equivalent Area (EA) | ||||

1000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 1.577 | 0.001 | 2218.004 | |

Age, y | 0.951 | 0.868 | 1.043 | |

Pigment = Y | 2.920 | 0.394 | 21.619 | |

Fellow eye affected = Y | 12.62 | 1.731 | 92.012 | * |

At least five large drusen EA† | 0.728 | 0.080 | 6.632 | |

AREDS One Druse Equivalent Area (EA) | ||||

3000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.009 | 0 | 7.781 | |

Age, y | 0.993 | 0.919 | 1.072 | |

Pigment = Y | 4.690 | 1.819 | 12.097 | * |

Fellow eye affected = Y | 4.772 | 1.745 | 13.05 | * |

At least one large druse EA† | 3.296 | 0.427 | 25.464 | |

AREDS One Druse Equivalent Area (EA) | ||||

3000 | 95% Confidence Interval | |||

Estimate | Lower Bound | Upper Bound | SS Slope | |

Intercept | 0.018 | 0.000 | 8.35 | |

Age, y | 0.986 | 0.916 | 1.061 | |

Pigment = Y | 3.176 | 1.179 | 8.558 | * |

Fellow eye affected = Y | 4.048 | 1.584 | 10.346 | * |

At least five large drusen EA† | 4.904 | 1.247 | 19.282 | * |

**Table 4A.**

**Table 4A.**

AREDS | PTAMD* | |||

One Druse | Five Drusen | One Druse | Five Drusen | |

Intercept | 0.012 | 0.016 | 0.000 | 1.577 |

Age | 0.992 | 0.997 | 0.952 | 0.951 |

Pigment = Y | 1.533 | 1.484 | 2.821 | 2.920 |

Fellow eye affected = Y | 5.142 | 5.765 | 13.056 | 12.620 |

At least one (or five) large drusen EA | 5.360 | 3.299 | Infinite | 0.728 |

**Table 4B.**

**Table 4B.**

AREDS | ||

One Druse | Five Drusen | |

Intercept | 0.009 | 0.018 |

Age | 0.993 | 0.986 |

Pigment = Y | 4.690 | 3.176 |

Fellow eye affected = Y | 4.772 | 4.048 |

At least one (or five) large drusen EA | 3.296 | 4.904 |

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