There is a high and ever-increasing global prevalence of diabetic retinopathy (DR). |
The practice of fluorescein angiography to confirm proliferative disease when the clinical examination is not conclusive is invasive and time-consuming. |
We explored the ability of ultra-widefield (OCT-A) to differentiate severe from proliferative DR using both clinical and bespoke image analysis, automated measures. |
We recruited 75 patients and analyzed 4 × 4 and 10 × 10 mm (widefield) and mosaic (ultra-widefield) OCT-As. |
Results demonstrate clinical utility of particularly the ultra-widefield OCT-A to detect proliferative disease and significant differences in capillary density and ischemic areas, demonstrating potential for future image analysis. |
Introduction
Methods
Ethical Approval
Study Design
Patient Recruitment and Imaging
Presence of Definitive Proliferative Vessels
Image Analysis
Single-Shot Central and Widefield Images (4 × 4 and 10 × 10 mm)
Mosaic Ultra-Widefield Images (17.5 × 17.5 mm)
-
FAZ area; Foveal avascular zone area
-
FAZ circularity; Foveal avascular zone circularity
-
Mean vessel density; segmented vessel area/ total area of tissue
-
Mean vessel intensity; mean pixel intensity of areas defined as capillaries.
-
Mean vessel density;
-
Mean vessel intensity;
-
Total area of ischemia; combined area in pixels of all regions defined as ischemic
-
Number of ischemic areas; number of discrete regions identified as representing ischemic zones.
Statistical Analysis
4 × 4 and 10 × 10-mm Widefield Images
17.7 × 17.5-mm Ultra-Widefield Images
Results
Baseline Patient Clinical Characteristics
4 × 4 and 10 × 10-mm Single-Shot Widefield Images (Tables 1 and 2)
Type | N | Mean | Median | SD | Minimum | Maximum | Shapiro–Wilk | Statistical tests | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
W | p | Test | Statistic | df | p value | ||||||||
Age | Proliferative | 28 | 55.9 | 60.5 | 17.1 | 23 | 83 | 0.954 | 0.243 | Student’s t | 0.343 | 73 | 0.732 |
Severe | 47 | 54.7 | 56 | 14.0 | 21 | 87 | 0.976 | 0.452 | |||||
Duration of diabetes | Proliferative | 20 | 17.8 | 18.5 | 5.7 | 5 | 25 | 0.931 | 0.163 | Student’s t | 0.129 | 58 | 0.898 |
Severe | 40 | 17.5 | 17 | 8.6 | 1 | 43 | 0.958 | 0.145 | |||||
HbA1c (last 4 months) | Proliferative | 13 | 79.4 | 81 | 18.4 | 46 | 110 | 0.982 | 0.986 | Student’s t | 0.29 | 30 | 0.774 |
Severe | 19 | 77.2 | 73 | 23.1 | 44 | 140 | 0.921 | 0.118 | |||||
Best-corrected visual acuity | Proliferative | 27 | 0.3 | 0.2 | 0.2 | − 0.2 | 0.7 | 0.967 | 0.524 | Mann–Whitney U | 339 | < 0.001 | |
Severe | 47 | 0.2 | 0.1 | 0.2 | − 0.2 | 0.8 | 0.903 | < 0.001 | |||||
4 × 4-mm scan quality | Proliferative | 28 | 6.0 | 6 | 1.0 | 3 | 8 | 0.887 | 0.006 | Mann–Whitney U | 569 | 0.304 | |
Severe | 47 | 6.3 | 6 | 0.9 | 5 | 8 | 0.865 | < 0.001 | |||||
10 × 10-mm scan quality | Proliferative | 28 | 6.5 | 7 | 1.0 | 4 | 8 | 0.89 | 0.007 | Mann–Whitney U | 527 | 0.128 | |
Severe | 47 | 6.9 | 7 | 0.9 | 5 | 8 | 0.867 | < 0.001 |
Type | χ2 tests | ||||||
---|---|---|---|---|---|---|---|
Proliferative | Severe | Total | N | Value | df | p value | |
Gender | |||||||
Male | 15 (53.6%) | 35 (74.5%) | 50 (66.7%) | 75 | 3.45 | 1 | 0.063 |
Female | 13 (46.4%) | 12 (25.5%) | 25 (33.3%) | ||||
Total | 28 (100%) | 47 (100%) | 75 (100%) | ||||
Type of diabetes (1/2) | |||||||
1 | 7 (25.9%) | 12 (25.5%) | 19 (25.7%) | 74 | 0.0014 | 1 | 0.97 |
2 | 20 (74.1%) | 35 (74.5%) | 55 (74.3%) | ||||
Total | 27 (100%) | 47 (100%) | 74 (100%) | ||||
Associated cardiovascular disease | |||||||
No | 8 (28.6%) | 10 (21.3%) | 18 (24.0%) | 75 | 0.512 | 2 | 0.774 |
Yes | 13 (46.4%) | 24 (51.1%) | 37 (49.3%) | ||||
Unknown | 7 (25.0%) | 13 (27.7%) | 20 (26.7%) | ||||
Total | 28 (100%) | 47 (100%) | 75 (100%) | ||||
Confounders (cataract, media opacity…) | |||||||
No | 19 (68%) | 39 (83%) | 58 (77%) | 75 | 2.29 | 1 | 0.130 |
Yes | 9 (32%) | 8 (17%) | 17 (23%) | ||||
Total | 28 (100%) | 47 (100%) | 75 (100%) |
17.5 × 17.5-mm Mosaic Ultra-Widefield Images (Tables 3 and 4)
Type | N | Mean | Median | SD | Minimum | Maximum | Shapiro–Wilk | Statistical tests | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
W | p | Test | Statistic | df | p value | ||||||||
Age | Proliferative | 16 | 55.7 | 62.0 | 18.4 | 23 | 80 | 80 | 0.169 | Student's t | 0.0112 | 38 | 0.991 |
Severe | 24 | 55.6 | 55.5 | 16.4 | 21 | 87 | 87 | 0.347 | |||||
Duration of diabetes | Proliferative | 11 | 18.7 | 18 | 5.5 | 10 | 25 | 25 | 0.180 | Student’s t | 0.5320 | 32 | 0.598 |
Severe | 23 | 17.1 | 15 | 9.5 | 1 | 43 | 43 | 0.260 | |||||
HbA1c (last 4 months) | Proliferative | 7 | 85.7 | 86 | 15.0 | 64 | 110 | 110 | 0.969 | Student’s t | 0.4378 | 16 | 0.667 |
Severe | 11 | 80.6 | 73 | 28.6 | 44 | 140 | 140 | 0.314 | |||||
Best-corrected visual acuity | Proliferative | 15 | 0.4 | 0.2 | 0.2 | 0.02 | 0.72 | 0.720 | 0.051 | Mann–Whitney U | 86.0 | 0.007 | |
Severe | 24 | 0.2 | 0.1 | 0.3 | − 0.1 | 0.8 | 0.800 | 0.001 | |||||
4 × 4-mm scan quality | Proliferative | 16 | 5.8 | 6.0 | 1.2 | 3 | 8 | 8 | 0.191 | Mann–Whitney U | 141.0 | 0.142 | |
Severe | 24 | 6.4 | 6.0 | 0.9 | 5 | 8 | 8 | 0.008 | |||||
10 × 10-mm scan quality | Proliferative | 16 | 6.3 | 6.5 | 1.1 | 4 | 8 | 8 | 0.161 | Mann–Whitney U | 136.0 | 0.107 | |
Severe | 24 | 6.9 | 7.0 | 0.8 | 6 | 8 | 8 | < .001 |
Type | χ2 tests | |||||
---|---|---|---|---|---|---|
Proliferative | Severe | Total | Value | df | p | |
Gender | ||||||
Male | 7 (43.8%) | 20 (83.3%) | 27 (67.5%) | 6.86 | 1 | 0.009 |
Female | 9 (56.3%) | 4 (16.7%) | 13 (32.5%) | |||
Total | 16 (100%) | 24 (100%) | 40 (100%) | |||
Type of diabetes (1/2) | ||||||
1 | 5 (33.3%) | 7 (29.2%) | 12 (30.8%) | 0.0752 | 1 | 0.784 |
2 | 10 (66.7%) | 17 (70.8%) | 27 (69.2%) | |||
Total | 15 (100%) | 24 (100%) | 39 (100%) | |||
Associated cardiovascular disease | ||||||
No | 5 (31.3%) | 5 (20.8%) | 10 (25%) | 2.87 | 2 | 0.238 |
Yes | 5 (31.3%) | 14 (58.3%) | 19 (47.5%) | |||
Unknown | 6 (37.5%) | 5 (20.8%) | 11 (27.5%) | |||
Total | 16 (100%) | 24 (100%) | 40 (100%) | |||
Confounders (cataract, media opacity…) | ||||||
No | 12 (75%) | 22 (91.7%) | 34 (85%) | 2.09 | 1 | 0.148 |
Yes | 4 (25%) | 2 (8.3%) | 6 (15%) | |||
Total | 16 (100%) | 24 (100%) | 40 (100%) |
Outcome Measures
Presence of Definitive Proliferative Vessels
Image Analysis Comparison Between Proliferative and Severe Groups
Group descriptives | Shapiro–Wilk | Statistical tests | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Type | N | Mean | Median | SD | W | p | Test | Ha | Statistic | df | p value | |
Mean vessel intensity | Proliferative | 27 | 223.1 | 222.8 | 3.7 | 0.955 | 0.276 | Student’s t | μ P < μ S | − 1.6607 | 71 | 0.051 |
Severe | 46 | 224.4 | 224.1 | 2.8 | 0.979 | 0.58 | ||||||
Mean capillaries intensity | Proliferative | 26 | 131.4 | 130.7 | 5.4 | 0.979 | 0.847 | Student’s t | μ P < μ S | 0.547 | 66 | 0.707 |
Severe | 42 | 130.7 | 130.5 | 5.0 | 0.973 | 0.4 | ||||||
Density of capillaries | Proliferative | 28 | 42.5 | 42.7 | 2.6 | 0.947 | 0.168 | Student’s t | μ P < μ S | − 0.1347 | 73 | 0.447 |
Severe | 47 | 42.6 | 43.0 | 2.3 | 0.973 | 0.337 | ||||||
Density of capillaries in the 4 × 4-mm image | Proliferative | 28 | 39.2 | 39.5 | 1.8 | 0.952 | 0.219 | Student’s t | μ P < μ S | − 0.4573 | 71 | 0.324 |
Severe | 45 | 39.4 | 39.6 | 1.8 | 0.984 | 0.791 | ||||||
Intensity of capillaries in the 4 × 4-mm image | Proliferative | 26 | 134.7 | 136.2 | 7.4 | 0.655 | < 0.001 | Mann–Whitney U | μ P < μ S | 593 | 0.479 | |
Severe | 46 | 135.6 | 135.9 | 4.8 | 0.976 | 0.437 | ||||||
Total areas of ischemia | Proliferative | 26 | 810.4 | 391.5 | 1497.4 | 0.555 | < 0.001 | Mann–Whitney U | μ P > μ S | 596 | 0.512 | |
Severe | 46 | 1467.0 | 332.5 | 3250.5 | 0.492 | < 0.001 | ||||||
Number of ischemic areas | Proliferative | 28 | 2.7 | 1 | 5.0 | 0.544 | < 0.001 | Mann–Whitney U | μ P > μ S | 642 | 0.428 | |
Severe | 47 | 2.6 | 1 | 4.0 | 0.699 | < 0.001 | ||||||
Area of FAZ | Proliferative | 28 | 1847.3 | 1713 | 342.0 | 0.48 | < 0.001 | Mann–Whitney U | μ P > μ S | 510 | 0.94 | |
Severe | 46 | 1931.9 | 1749.5 | 479.1 | 0.506 | < 0.001 | ||||||
Perimeter of FAZ | Proliferative | 28 | 0.92 | 1.02 | 0.18 | 0.637 | < 0.001 | Mann–Whitney U | μ P > μ S | 524 | 0.084 | |
Severe | 46 | 0.87 | 0.97 | 0.22 | 0.721 | < 0.001 |
17.7 × 17.5-mm Ultra-Widefield Mosaic Images (Table 6)
Type | N | Descriptives | Shapiro–Wilk | Statistical tests | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mean | Median | SD | W | p | Test | Statistic | df | p value | |||
Total area of the image (in pixels) | Proliferative | 15 | 2.85E + 06 | 2,822,384 | 132,169.3 | 0.877 | 0.043 | Mann–Whitney U | 166 | 0.7 | |
Severe | 24 | 2.84E + 06 | 2.84E + 06 | 102,956.1 | 0.976 | 0.823 | |||||
Disc area (in pixels) | Proliferative | 15 | 24,704.4 | 25,702 | 4077.8 | 0.937 | 0.342 | Mann–Whitney U | 177 | 0.943 | |
Severe | 24 | 25,647.3 | 24,689 | 4846.7 | 0.901 | 0.023 | |||||
Average area of ischemic zones (in pixels) | Proliferative | 15 | 253,930.1 | 265,596 | 108,635.9 | 0.922 | 0.206 | Mann–Whitney Ua | 78 | 0.003 | |
Severe | 24 | 149,104.2 | 159,210 | 55,101.8 | 0.957 | 0.385 | |||||
Average area of ischemic zones in periphery (in pixels) | Proliferative | 15 | 174,261.7 | 165,777 | 79,799.8 | 0.961 | 0.713 | Mann–Whitney Ua | 91 | 0.009 | |
Severe | 24 | 109,643.2 | 118,663 | 44,994.7 | 0.971 | 0.688 | |||||
Density of large vessels (%) | Proliferative | 15 | 23.5 | 24.4 | 2.8 | 0.931 | 0.279 | Student’s t | 1.864 | 37 | 0.07 |
Severe | 24 | 21.7 | 22.0 | 3.0 | 0.965 | 0.557 | |||||
Density of capillaries (%) | Proliferative | 15 | 9.1 | 9.4 | 1.9 | 0.938 | 0.359 | Student’s t | -3.027 | 37 | 0.004 |
Severe | 24 | 11.0 | 11.0 | 1.9 | 0.946 | 0.223 | |||||
Density of ischemia (%) | Proliferative | 15 | 8.9 | 9.4 | 3.9 | 0.95 | 0.52 | Mann–Whitney Ua | 78 | 0.003 | |
Severe | 24 | 5.3 | 5.7 | 2.0 | 0.959 | 0.428 | |||||
Density of large vessels in periphery (%) | Proliferative | 15 | 10.5 | 10.7 | 2.5 | 0.944 | 0.441 | Student’s t | 1.282 | 37 | 0.208 |
Severe | 24 | 9.4 | 9.7 | 2.5 | 0.978 | 0.865 | |||||
Density of capillaries in periphery (%) | Proliferative | 15 | 5.2 | 5.1 | 1.5 | 0.963 | 0.74 | Student’s t | − 1.549 | 37 | 0.13 |
Severe | 24 | 6.0 | 6.0 | 1.6 | 0.963 | 0.509 | |||||
Density of ischemia in periphery (%) | Proliferative | 15 | 6.1 | 5.9 | 2.9 | 0.97 | 0.856 | Mann–Whitney Ua | 90 | 0.009 | |
Severe | 24 | 3.9 | 4.1 | 1.6 | 0.968 | 0.624 | |||||
Intensity of big vessels | Proliferative | 15 | 210.3 | 210.5 | 0.6 | 0.919 | 0.188 | Student’s t | 1.952 | 37 | 0.059 |
Severe | 24 | 209.9 | 209.9 | 0.5 | 0.951 | 0.289 | |||||
Intensity of ischemia | Proliferative | 15 | 38.7 | 36.8 | 5.1 | 0.931 | 0.285 | Student’s t | 1.691 | 37 | 0.099 |
Severe | 24 | 36.4 | 36.1 | 3.6 | 0.947 | 0.23 | |||||
Intensity of ischemia in periphery | Proliferative | 15 | 0.156 | 0.151 | 0.03 | 0.923 | 0.216 | Mann–Whitney Ua | 152 | 0.427 | |
Severe | 24 | 0.148 | 0.146 | 0.02 | 0.95 | 0.275 |