Date of Award
Medical Doctor (MD)
Lucian V. Del Priore
Geographic atrophy (GA) is the end stage of nonexudative age-related macular degeneration, affecting more than 5 million patients worldwide. The enlargement rate of GA area is the most common primary endpoint in clinical trials aiming to slow GA progression. However, this endpoint varies widely across patients with different GA morphology and is also poorly associated with patients’ visual acuity (VA). We aimed to develop an anatomic endpoint that is independent of GA morphology, and that correlates with VA in eyes with GA.We manually delineated GA on 1654 fundus photographs of 365 eyes from the Age-Related Eye Disease Study (median follow-up duration = 4 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate (mm/year) was defined as the ratio between GA area growth rate (mm2/year) and mean GA perimeter (mm) between the first and last visit for each eye. We measured GA areas in 9 macular subfields and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We measured the residual area in the optimal central zone and calculated central residual effective radius as square root of (residual area/π). GA area growth rate was strongly correlated with mean GA perimeter (r2 = 0.66). GA area growth rate was associated with baseline GA area (r2 = 0.39, P < 0.001), lesion number (r2 = 0.10, P < 0.001), and circularity index (r2 = 0.28, P < 0.001). In comparison, GA perimeter-adjusted growth rate (0.098 ± 0.062 mm/year) was uncorrelated with baseline GA area (r2 = 0.005, P = 0.20), lesion number (r2 = 0.00009, P = 0.86), and circularity index (r2 = 0.007, P = 0.14). Total GA area correlated poorly with VA (r2 = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was independently associated with VA (P < 0.001). GA area in the central 1-mm-diameter zone correlated best with VA (r2 = 0.45). On average, full GA coverage of the central zone corresponded to 34.8 letters decline in VA. The decline rate of central residual area was associated with baseline residual area (P = 0.008), but a transformation from central residual area to central residual effective radius eliminated this relationship (P = 0.51). After the introduction of horizontal translation factors to each dataset, central residual effective radius declined linearly over approximately 13 years (r2 = 0.80) at a mean rate of 0.038 mm/year. In conclusion, GA perimeter-adjusted growth rate is uncorrelated with GA morphology (i.e., lesion size, number, and circularity) and may serve as a sensitive and reliable anatomic endpoint in future clinical trials. GA area in the central 1-mm-diameter zone was significantly correlated with VA. The residual effective radius in this central zone declined consistently over time and may serve as another endpoint for future trials.
Shen, Liangbo L., "Novel Anatomic Endpoints For The Study Of Geographic Atrophy Secondary To Non-Exudative Age-Related Macular Degeneration" (2021). Yale Medicine Thesis Digital Library. 4030.