We would like to thank Dr. Chua and Dr. Schmetterer for their interest and relevant comment on our cross-sectional exploratory analysis of the value of optical coherence tomography angiography (OCTA) parameters to predict the clinical stage of non-proliferative diabetic retinopathy (NPDR) [1]. Indeed, several studies have raised awareness to the fact that individual differences in axial length (AL) affect the lateral magnification of OCTA scans and, hence, hamper the accuracy of quantitative measurements made on these images [2]. Dr. Chua and Dr. Schmetterer propose two ways of correcting for this: either (1) computing the vessel density (VD) of the deep capillary plexus (DCP) within an annular region of interest (ROI) that excludes the foveal avascular zone (FAZ) or (2) rescaling of the OCT scans, based on individual AL values. It is relevant to highlight that what is described in the first suggestion is already implemented in our analysis. As described in the “Methods” section, the DCP parafoveal density was defined as “the vessel density (...) within the annular zone of 1to 3-mm dimeter around the foveal centre (parafoveal density)”, which should exclude all (or, at least, most) of the FAZ (as also illustrated in Fig. 2). Unfortunately, image rescaling of the scans in our study (second suggestion) is not possible, because rescaling formulas require the AL value (e.g., refs. [3, 4]) and measurement of AL was not included in our study protocol. Indeed, the consequence of a larger AL (i.e., of a larger optical path) is that the scanning beam of the OCT effectively scans a larger area of retina and thus, in the OCTA scan, both vessels, and areas without vessels are more compactly displayed. However, the VD, typically calculated as the percentage of pixels above a given grey value threshold (“white” pixels, corresponding to vessels), should not change significantly, as long as the FAZ is not included in the ROI. Accordingly, it was reported that the change in VD calculation after image rescaling is greatest for the area of the scan including the FAZ [5]. Furthermore, within the parafoveal annulus (not including the FAZ), the averaged difference in VD density after rescaling was found to be null, with a 95% confidence interval of ±1% [5]. In our study, the maximal averaged effect size of parafoveal VD in the DCP between ETDRS Level groups is 7.8%; hence, well above the effect magnitude that would be expected purely due to the scaling effect. Nevertheless, we opted to explore this issue further at the level of the statistical analysis. The distribution of refractive error in the cohort reported in our study is left-skewed, with five statistically outlier observations, pertaining to highly myopic eyes. ETDRS grading of these eyes is as follows: n= 3 for Level 20 ETDRS and n= 2 for Level 35C ETDRS. The effect of OCT scaling on VD calculation is non-linear and its magnitude was shown to be higher in highly myopic eyes [5]. It * Tiago M. Rodrigues tiago.fm.rod@gmail.com

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对“评论：预测非增殖性糖尿病视网膜病变临床分期的黄斑OCT-血管造影参数：探索性分析”的回应

我们要感谢 Chua 博士和 Schmetterer 博士对我们对光学相干断层扫描血管造影 (OCTA) 参数的价值预测非增殖性糖尿病视网膜病变 (NPDR) 临床分期的横断面探索性分析的兴趣和相关评论) [1]。事实上，几项研究已经提高了人们对轴向长度 (AL) 的个体差异影响 OCTA 扫描的横向放大倍数的事实的认识，因此阻碍了对这些图像进行定量测量的准确性 [2]。Chua 博士和 Schmetterer 博士提出了两种纠正方法：(1) 在不包括中央凹无血管区的环形感兴趣区域 (ROI) 内计算深毛细血管丛 (DCP) 的血管密度 (VD)（ FAZ) 或 (2) 基于单个 AL 值的 OCT 扫描的重新缩放。需要强调的是，在我们的分析中已经实施了第一个建议中描述的内容。如“方法”部分所述，DCP 中心凹旁密度被定义为“中心凹中心周围 1 至 3 毫米直径的环形区域内的血管密度（...）（旁中心凹密度）”，应排除所有（或者，至少，大部分）FAZ（也如图 2 所示）。不幸的是，我们研究中扫描的图像重新缩放（第二个建议）是不可能的，因为重新缩放公式需要 AL 值（例如，参考文献 [3, 4]）并且我们的研究协议中不包括 AL 的测量。事实上，更大的 AL（即更大的光路）的结果是 OCT 的扫描光束有效地扫描了更大的视网膜区域，因此，在 OCTA 扫描中，两条血管，没有船只的区域显示得更紧凑。然而，VD 通常计算为高于给定灰度值阈值的像素百分比（“白色”像素，对应于血管），只要 FAZ 不包含在 ROI 中，就不应该发生显着变化。因此，据报道，对于包括 FAZ 在内的扫描区域，图像重新缩放后 VD 计算的变化最大 [5]。此外，在旁中心凹环（不包括 FAZ）内，发现重新缩放后 VD 密度的平均差异为零，95% 的置信区间为 ±1% [5]。在我们的研究中，ETDRS 水平组之间 DCP 中旁中心凹 VD 的最大平均效应大小为 7.8%；因此，远高于纯粹由于缩放效应而预期的影响幅度。尽管如此，我们选择在统计分析层面进一步探讨这个问题。在我们的研究中报告的队列中屈光不正的分布是左偏的，有五个统计异常观察值，与高度近视眼有关。这些眼睛的 ETDRS 分级如下：对于 20 级 ETDRS，n= 3，对于 35C ETDRS，n= 2。OCT 缩放对 VD 计算的影响是非线性的，其幅度在高度近视眼中更高 [5]。它 * Tiago M. Rodrigues tiago.fm.rod@gmail.com OCT 缩放对 VD 计算的影响是非线性的，其幅度在高度近视眼中更高 [5]。它 * Tiago M. Rodrigues tiago.fm.rod@gmail.com OCT 缩放对 VD 计算的影响是非线性的，其幅度在高度近视眼中更高 [5]。它 * Tiago M. Rodrigues tiago.fm.rod@gmail.com