Multicenter, Head-to-Head, Real-World Validation Study of Seven Automated Artificial Intelligence Diabetic Retinopathy Screening Systems. Diabetes Care 2021;44:XXXX-XXXX.

We thank Dr. Soliz for his expedient comments (1) regarding our work evaluating seven artificial intelligence (AI) algorithms in a head-to-head fashion (2). We welcome the opportunity to clarify these points of concern.

We agree that the two U.S. Food and Drug Administration–approved diabetic retinopathy (DR) systems, one of which was tested in our study, use a threshold of moderate nonproliferative DR (NPDR) or higher for referral. We set the threshold to any DR versus no DR because that represents the clinical practice at the Veterans Affairs (VA) teleretinal system, as stated in our methods. All participating companies were aware of the study threshold prior to submitting their algorithms and were allowed to adjust their algorithms accordingly. As the VA manages one of the largest teleretinal screening systems in the U.S., we believe this threshold constitutes a reasonable real-world cut point for DR detection. Algorithm performance at this threshold is important to investigate because this threshold would most likely be used for referral decisions if these AI systems were to be used in the VA.

Diabetic macular edema (DME) represents an important trigger for referrals in teleretinal systems and is always accompanied by retinopathy of any degree including less than moderate NPDR. Had we used the recommended referral threshold of moderate NPDR or higher, omitting DME as a referral criterion would have constituted a serious error. However, it is not possible to have DME without having some level of retinopathy, and thus referral of all cases of DR (including mild DR) would encompass all patients with DME in the reference standard grading.

We also agree that most studies report metrics at the case level. In our study, we report all metrics at the case level for each encounter level. As we stated in our methods, we asked the companies to use all images available per patient encounter to reach a referral decision, including ungradable images, which resulted in one referral decision for each time a patient underwent screening. If one patient had a few ungradable images but multiple acceptable-quality images sufficient to determine whether referral was needed, then the overall encounter was still graded appropriately as per clinical standards. Therefore, the performance we reported in our article was based on each case and not each image. This was true both for the human VA teleretinal grader and for the AI algorithm output.

As stated in our discussion, the primary difference between the two sites was the use of routine dilation in Atlanta versus nonmydriatic imaging in Seattle. We also note that we performed stratified analyses by location in Fig. 1, and this provides a valuable opportunity to understand the impact of mydriasis on AI algorithms. We believe that this difference and other differences in real-world imaging protocols between screening locations represent important variations for understanding the performance of AI algorthms.

We again thank Dr. Soliz for his comments.