In its early stages, glaucoma is predominantly asymptomatic, making early diagnosis difficult. Consequently, the majority of cases are identified in later stages after considerable damage has taken place, thus rendering future interventions ineffective at preserving functional vision. If glaucoma is detected early enough, interventions such as pressure lowering medications or surgery can be used to slow or halt the progression of disease. Thus, a key strategy to addressing glaucoma worldwide is detecting the disease at its earlier stages and predicting when individuals are at high risk for glaucomatous progression.

Advances in artificial intelligence (AI) and, more specifically, deep learning (DL) provide hope for an earlier and more accurate diagnosis of glaucoma in patients. AI uses computer systems (algorithms) to perform tasks that normally require human intelligence, such as visual perception and natural language processing. Deep learning, a branch of AI, is largely inspired by the structure of the human brain and functions by processing data and creating patterns for use in decision making. There are several methods through which such systems learn. One method, known as supervised learning, occurs when a machine is given a set of input–output pairs and the machine learns characteristics that define the specified output. This is useful in situations where there is a predicted output (ie, mild, moderate, severe glaucoma) for a given input (ie, optic nerve head [ONH] images) and where a labeled dataset is available to train the AI algorithms. In terms of glaucoma diagnosis, this would mean feeding the machine data from both healthy eyes and eyes suffering from glaucoma. The AI algorithm learns from a process known as backpropagation to optimize its ability to identify the presence or absence of disease indicators.

Unsupervised learning is another branch within DL where the machine is given unlabeled data and categorizes the input into groups that may not necessarily match traditional output classes. For example, the algorithm might cluster optic nerve images that exhibit a characteristic loss of the neuroretinal rim, such as notching, with other similar images and optic nerves with intact neuroretinal rims in another group without labeling them as diseased or healthy. This can be particularly useful to unveil novel patterns or trends that are relevant to glaucoma.

In both unsupervised and supervised learning, a training phase is necessary where the machine is fed the data set (labeled in supervised, unlabeled in unsupervised). Once the algorithm is optimized, the accuracy of the algorithm is defined by how well it predicts a validation data set. Only then is the algorithm allowed to analyze an independent “test” data set. This independent data set must be comprised of images that are different from the initial data set to ensure the results are not biased. In ophthalmology, and more specifically in glaucoma, DL has accurately detected complicated patterns from images and has been shown to have accuracy levels that rival the results from expert human graders.¹ This article will focus on how DL algorithms can facilitate the diagnosis of early-stage glaucoma and identify individuals at high risk for glaucomatous progression.

Detecting Glaucomatous Damage Using Optical Coherence Tomography Images

Optical coherence tomography (OCT) has become widely used in the clinical setting to detect structural changes of the optic nerve and macula, which have been shown to be highly correlated with the diagnosis and monitoring of glaucoma and detecting pathologic glaucomatous changes prior to vision loss.² Identifying retinal nerve fiber layer (RNFL) thinning is one of the first signs of glaucoma and often precedes functional loss.³ As a result, detecting RNFL damage is critical in identifying glaucoma in its early stages. Spectral-domain (SD)-OCT has become the gold standard for objectively quantifying structural damage in glaucoma, because it allows for both a single time point measurement and longitudinal quantifications of tissue thickness. This imaging technique is widely used in the clinical setting;⁴ however, the equipment is expensive and not portable, and the images require segmentation so that essential measurements can be extracted. Although various components are automatically segmented by the machine, this process is associated with a high rate of errors; one study found that the percentage of artifacts found in SD-OCT imaging for RNFL thickness was 46.3%,⁵ and another study found that segmentation failure for RNFL thickness was 21%.⁶ These errors can often lead to inaccurate diagnoses and adversely affect management. Manually reviewing each image for potential errors and artifacts can be time consuming and burdensome. To avoid these errors, several studies have attempted to use DL to predict RNFL damage from OCT images without using segmentation and found significantly better results than determining RNFL through conventional methods.^7,8 Marionetti et al found that their DL algorithm that analyzed raw OCT images performed similarly to the conventional method in good-quality images and better than conventional methods in images with artifacts.⁷

Another important structural parameter in determining glaucoma involves changes in the ONH. Because SD-OCT often is used to quantify ONH damage, it is associated with the same drawbacks listed above regarding segmentation. Several studies have revealed success in applying DL algorithms to the detection of important parameters of ONH damage.^9,10

Detecting Glaucoma Through Fundus Photography

Obtaining quality OCT images requires expensive hardware, as well as skilled personnel, which is not always possible in resource-strained areas. In contrast, fundus photography is a universally available diagnostic modality that is more suitable for screening because the technology is more cost effective and easier to use. Studies have attempted to determine the utility of this approach in diagnosing and monitoring the progression of glaucoma in various clinical settings.¹¹ Within the past decade, several technologies utilizing smartphones to create portable nonmydriatic fundus cameras have been validated in the clinical setting for use in low-resource areas.¹²

Fundus photography is useful in detecting glaucoma because it allows the clinician to appreciate structural characteristics, such as the optic nerve, peripapillary atrophy, and vessel characteristics. More specifically, the components of interest include assessing disc size, cup-to-disc ratio, and neuroretinal rim integrity, all of which are centered around the optic disc. Just as it was important to segment the components of interest in OCT imaging, localization of the essential features of the optic disc from fundus photos is the focus of DL algorithms used in diagnosing glaucoma.

Of note, the interpretation of fundus photographs for glaucoma diagnosis is vulnerable to high clinician interobserver and intraobserver variability.^13,14 Several studies have demonstrated that DL algorithms can identify the structural damage of the optic nerve from fundus photographs with results comparable to expert human graders.^15-19 Although these findings are promising, given the significant variability of human interpretation, Medeiros et al trained a DL algorithm using the objective measurements of RNFL thickness obtained by SD-OCT to classify disc photos for glaucomatous damage.¹⁶ This approach to analyzing fundus photographs may be a reasonable substitute for SD-OCT in resource-strained settings and may address variability issues noted with human graders in any clinical setting.

Detecting and Predicting Glaucomatous Progression

It is difficult to definitively detect glaucomatous progression in the clinical setting, due to the high test–retest variability seen in automated visual field testing, SD-OCT images, and fundus photographs. Another promising application for DL algorithms is predicting the rate of glaucomatous progression. Although the majority of studies have focused on detecting referable glaucoma, a few studies have focused on predicting future visual field changes,^20,21 as well as incorporating SD-OCT data to detect progression in glaucomatous patients.^22-24 These DL algorithms require validation in larger cohorts and in diverse populations to understand the true utility and predictive capacity of these findings.

Limitations

Before widespread use of AI, and more specifically DL algorithms, can be implemented in the clinical setting, several key factors need to be considered. One barrier that hinders the widespread use of DL for glaucoma is the lack of a universal, standard definition for the disease, which contributes to the high interobserver and intraobserver variability seen in glaucoma diagnosis.²⁵ At present, glaucoma is diagnosed based on a combination of patient risk factors obtained through history (age, diabetes status, ethnicity, medications), tonometry, structural characteristics (angle anatomy, optic nerve damage, RNFL thinning), and functional characteristics (visual field defects). It is difficult to combine these heterogeneous metrics to create a universal criterion for diagnosis and progression of disease.

To correctly determine the accuracy of a DL algorithm, there is a need for a gold standard, also known as the ground truth, to which to compare it. However, with the lack of an objective definition of glaucoma, this becomes difficult.

In addition, the majority of studies comparing the performance of AI in diagnosing and managing glaucoma to conventional methods have been done on patients who have been recruited from glaucoma clinics. As a result, AI algorithms may not be generalizable to patients recruited from the general population.²⁶ Therefore, special efforts need to be made to ensure that the training and testing data sets are representative of all demographics to allow the DL algorithm to be applicable to diverse populations.

Another critical concern is that the validity of the DL algorithms to detect glaucoma is reliant on learning from and analyzing quality images. Efforts are under way to ensure that quality images are obtained and used more routinely, in hopes of moving away from expert graders to investigate each data point individually.²⁷

Conclusion

AI has enormous potential for diagnosing and monitoring glaucoma. Enhanced ability to detect earlier stages of glaucoma may help maintain quality of life for patients. Given that glaucoma is diagnosed by combining medical history, physical exam, visual field tests, fundus photographs, and OCT scans, an ideal AI application will incorporate several, if not all, of these components to create a reliable prediction of disease and progression. The majority of past and current research has centered around using AI to detect referable glaucoma using visual field testing, SD-OCT, and fundus images. Although there has been less research on utilizing AI to detect anterior-chamber changes associated with glaucoma,²⁸ forecasting progression,^20,21 and monitoring for progression of glaucoma,^22,23 these areas are ripe for future research. There is little risk that the clinician will be excluded from these processes given the overall complexity of glaucoma diagnosis and monitoring, as outlined in this article. However, AI offers great hope for automating the interpretation of the various metrics we use in the clinic so that the clinician can walk the final mile more efficiently and toward enhanced patient care and improved outcomes. GP

Meghana Kalavar is a medical student at Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine in Miami, Florida.

Sabita M. Ittoop, MD, is a glaucoma specialist at the GW Medical Faculty Associates in Washington, DC.

Malik Y. Kahook, MD, is a glaucoma specialist at the Sue Anschutz-Rodgers Eye Center of The University of Colorado School of Medicine in Aurora, Colorado. The authors report no related disclosures. Reach Dr. Kahook at malik.kahook@cuanschutz.edu.

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