Novel Anatomic Endpoints For The Study Of Geographic Atrophy Secondary To Non-Exudative Age-Related Macular Degeneration

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 \u3c 0.001), lesion number (r2 = 0.10, P \u3c 0.001), and circularity index (r2 = 0.28, P \u3c 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 \u3c 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

A hierarchical Bayesian entry time realignment method to study the long-term natural history of diseases

A major question in clinical science is how to study the natural course of a chronic disease from inception to end, which is challenging because it is impractical to follow patients over decades. Here, we developed BETR (Bayesian entry time realignment), a hierarchical Bayesian method for investigating the long-term natural history of diseases using data from patients followed over short durations. A simulation study shows that BETR outperforms an existing method that ignores patient-level variation in progression rates. BETR, when combined with a common Bayesian model comparison tool, can identify the correct disease progression function nearly 100% of the time, with high accuracy in estimating the individual disease durations and progression rates. Application of BETR in patients with geographic atrophy, a disease with a known natural history model, shows that it can identify the correct disease progression model. Applying BETR in patients with Huntington's disease demonstrates that the progression of motor symptoms follows a second order function over approximately 20 years

An In Silica Model for RPE Loss Patterns in Choroideremia

PurposeTo use empirical data to develop a model of cell loss in choroideremia that predicts the known exponential rate of RPE loss and central, scalloped preservation pattern seen in this disease.MethodsA computational model of RPE loss was created in Python 3.7, which constructed an array of RPE cells clusters, binarized as either live or atrophic. Two rules were applied to this model: the background effect gave each cell a chance of dying defined by a background function, and the neighbor effect increased the chance of RPE cell death if a neighbor were dead. The known anatomic distribution of rods, RPE, choriocapillaris density, amacrine, ganglion, and cone cells were derived from the literature and applied to this model. Atrophy growth rates were measured over arbitrary time units and fit to the known exponential decay model. The main outcome measures: included topography of atrophy over time and fit of simulated residual RPE area to exponential decay.ResultsA background effect alone can simulate exponential decay, but does not simulate the central island preservation seen in choroideremia. An additive neighbor effect alone does not simulate exponential decay. When the neighbor effect multiplies the background effect using the rod density function, our model follows an exponential decay, similar to previous observations. Also, our model predicts a residual island of RPE that resembles the topographic distribution of residual RPE seen in choroideremia.ConclusionsThe pattern of RPE loss in choroideremia can be predicted by applying simple rules. The RPE preservation pattern typically seen in choroideremia may be related to the underlying pattern of rod density. Further studies are needed to validate these findings

Subretinal Drusenoid Deposit Formation: Insights From Turing Patterns

PurposeThe purpose of this study was to demonstrate that the organized formation of subretinal drusenoid deposits (SDDs) may be a Turing pattern.MethodsA Java-based computational model of an inferred reaction-diffusion system using paired partial differential equations was used to create topographic images. Reaction kinetics were varied to illustrate a spectrum of pattern development, which were then compared to dot-like, reticular, and confluent SDD patterns observed clinically.ResultsA reaction-diffusion system using two agents, one an "activator" that increases its own production, and the other an "inhibitor" that decreases the activator's production, can create patterns that match the spectrum of topographic appearance of organized SDD. By varying a single parameter, the strength of the activator, the full spectrum of clinically observed SDD patterns can be generated. A new pattern, confluence with holes, is predicted and identified in one case example.ConclusionsThe formation of clinically significant SDD and its different patterns can be explained using Turing patterns obtained by simulating a two-component reaction-diffusion system.Translational relevanceThis model may be able to guide future risk stratification for patients with SDD, and provide mechanistic insights into the cause of the disease

Topographic Variation of Retinal Vascular Density in Normal Eyes Using Optical Coherence Tomography Angiography

PurposeTo establish a continuous topography of retinal vessel density in normal eyes using optical coherence tomography angiography (OCTA).MethodsA retrospective chart review was performed, and 8-mm × 8-mm OCTA images from 22 normal eyes were analyzed. Vessel density was plotted as a continuous function of distance from the foveal center (radial vessel density) and directional meridians (directional vessel density) for the superficial capillary plexus and deep capillary plexus.ResultsContinuous radial and directional vessel density plots for the superficial and deep capillary plexus were generated. Radial vessel density analysis revealed transition points at 657 microns (95% confidence interval [CI], 619-696) and 950 microns (95% CI, 903-997) from the foveal center for the superficial plexus and deep plexus, respectively. Directional vessel density analysis demonstrated significant vessel density variations in these vascular layers and provided greater detail compared to traditional quadrant analysis.ConclusionsThere are significant topographic variations of retinal vessel density in normal eyes. Continuous vessel density analysis offers greater sensitivity in detecting topographic vessel density changes compared to traditional methods of analysis.Translational relevanceThis study establishes a normative continuous vessel density topography that may help elucidate the role of the vascular bed in different chorioretinal diseases

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location

PurposeTo assess the influence of lesion morphology and location on geographic atrophy (GA) growth rate.MethodsWe manually delineated GA on color fundus photographs of 237 eyes in the Age-Related Eye Disease Study. We calculated local border expansion rate (BER) as the linear distance that a point on the GA border traveled over 1 year based on a Euclidean distance map. Eye-specific BER was defined as the mean local BER of all points on the GA border in an eye. The percentage area affected by GA was defined as the GA area divided by the total retinal area in the region.ResultsGA enlarged 1.51 ± 1.96 mm2 in area and 0.13 ± 0.11 mm in distance over 1 year. The GA area growth rate (mm2/y) was associated with the baseline GA area (P < 0.001), perimeter (P < 0.001), lesion number (P < 0.001), and circularity index (P < 0.001); in contrast, eye-specific BER (mm/y) was not significantly associated with any of these factors. As the retinal eccentricity increased from 0 to 3.5 mm, the local BER increased from 0.10 to 0.24 mm/y (P < 0.001); in contrast, the percentage of area affected by GA decreased from 49.3% to 2.3%.ConclusionsUsing distance-based measurements allows GA progression evaluation without significant confounding effects from baseline GA morphology. Local GA progression rates increased as a function of retinal eccentricity within the macula which is opposite of the trend for GA distribution, suggesting that GA initiation and enlargement may be mediated by different biological processes