Collaborative Initial Glaucoma Treatment Study Research Articles

Performance of perimetric glaucoma staging systems and their preference patterns among the Indian eye care practitioners.

Various systems are available to stage glaucomatous field defects into different severity grades. Still, the preference for such systems among Indian eye care practitioners (ECPs) and the consensus between them are not explored. To compare the clinical performance of perimetric glaucoma staging systems and to assess their preference patterns among Indian ECPs. Retro-prospective cross-sectional study. Three investigators stratified 400 perimetry reports using four systems: Hodapp Anderson Parrish (HAP), enhanced Glaucoma Severity Staging (eGSS), Advanced Glaucoma Intervention Study (AGIS), and Collaborative Initial Glaucoma Treatment Study (CIGTS). Their performance was compared in terms of agreement and association. Following this, 30 ECPs from across the country segregated a subset of reports (n = 20) into different stages based on their system of choice, and their preferences/perceptions about the available perimetry staging systems were enquired and documented. Descriptive statistics, Kruskal-Wallis, Cohen's kappa, and Spearman's correlation. For the consolidated severity stages, substantial agreements (K ranging from 0.61 to 0.75) were found between all the systems, except for HAP-CIGTS (K = 0.58) and AGIS-CIGTS (K = 0.51). All ECPs were aware of perimetry staging systems, and a high preference was reported for HAP (97%) due to ease of implementation and interpretation. Among the four staging systems, the highest agreement was found between HAP and eGSS. A majority of ECPs proposed the need for a uniform classification system across the practices for clinical comparisons and patient education.

Predicting Visual Field Worsening with Longitudinal OCT Data Using a Gated Transformer Network

To identify visual field (VF) worsening from longitudinal OCT data using a gated transformer network (GTN) and to examine how GTN performance varies for different definitions of VF worsening and different stages of glaucoma severity at baseline. Retrospective longitudinal cohort study. A total of 4211 eyes (2666 patients) followed up at the Johns Hopkins Wilmer Eye Institute with at least 5 reliable VF results and 1 reliable OCT scan within 1 year of each reliable VF test. For each eye, we used 3 trend-based methods (mean deviation [MD] slope, VF index slope, and pointwise linear regression) and 3 event-based methods (Guided Progression Analysis, Collaborative Initial Glaucoma Treatment Study scoring system, and Advanced Glaucoma Intervention Study [AGIS] scoring system) to define VF worsening. Additionally, we developed a "majority of 6" algorithm (M6) that classifies an eye as worsening if 4 or more of the 6 aforementioned methods classified the eye as worsening. Using these 7 reference standards for VF worsening, we trained 7 GTNs that accept a series of at least 5 as input OCT scans and provide as output a probability of VF worsening. Gated transformer network performance was compared with non-deep learning models with the same serial OCT input from previous studies-linear mixed-effects models (MEMs) and naive Bayes classifiers (NBCs)-using the same training sets and reference standards as for the GTN. Area under the receiver operating characteristic curve (AUC). The M6 labeled 63 eyes (1.50%) as worsening. The GTN achieved an AUC of 0.97 (95% confidence interval, 0.88-1.00) when trained with M6. Gated transformer networks trained and optimized with the other 6 reference standards showed an AUC ranging from 0.78 (MD slope) to 0.89 (AGIS). The 7 GTNs outperformed all 7 MEMs and all 7 NBCs accordingly. Gated transformer network performance was worse for eyes with more severe glaucoma at baseline. Gated transformer network models trained with OCT data may be used to identify VF worsening. After further validation, implementing such models in clinical practice may allow us to track functional worsening of glaucoma with less onerous structural testing. Proprietary or commercial disclosure may be found after the references.

Commentary: Decoding the intraocular pressure conundrum surrounding the core of COR.

The concept of intraocular pressure (IOP) gained popularity around the 19th century. It was during that time when Albrecht von Graefe developed the first IOP measuring instrument, the Maklakoff applanation tonometer, in 1865. Somewhere around the 10th century, it started off as an assessment of the firmness of the eyeball.[1] Currently, we possess cutting-edge technology like dynamic contour tonometry to provide in vivo IOP measurements. IOP control is an important component of glaucoma management, and therein lies the importance of accurate IOP measurement and documentation. Consensual Ophthalmotonic Reaction The concept of consensual ophthalmotonic reaction (COR) has been a point of debate for several decades now.[2] There have always been claims for and against this phenomenon. Though inconclusive, this theory needs to be taken into account in view of the sensitive nature of the disease. The accompanying article represents the largest evaluation to date of the untreated fellow eye response after unilateral trabeculectomy. The author’s suggestion raises the possibility of a real risk of IOP increase in the fellow eye following ipsilateral glaucoma surgery.[3] Nearly a third of patients needed an intervention to control IOP in the entire study population. COR – The Gray Area Surrounding the How and Why The authors of the accompanying article report that contralateral eye IOP was increased following ipsilateral glaucoma surgery. However, some works of literature have reported conflicting results and noted a drop in IOP, while some agreed.[4–7] The pathophysiology for this increase or decrease of IOP following ipsilateral glaucoma surgery is unclear and not well known. Possible Hypothesis and Postulations Surrounding COR Several hypotheses have been made to explain COR, but all are not entirely accepted. Some suggest that topical medication either works on the fellow eye via the bloodstream or acts centrally on IOP control mechanisms after systemic absorption. Smith et al. disproved it with the use of pindolol and stated that the IOP falls after topical and intravenous administration of pindolol.[8] Pindolol treatment is used to help decrease IOP in the contralateral untreated eye, which is unlikely to have resulted from systemic absorption of the drug. This theory can also not explain the COR seen in mechanical alteration of IOP, such as following laser trabeculoplasty and tonography. Leplat hypothesized the existence of a nervous mechanism that causes changes in IOP in one eye to provoke a reflex alteration in pressure in the contralateral eye.[9] Moreover, the Collaborative Initial Glaucoma Treatment Study (CIGTS) showed a moderate drop in IOP in the contralateral eye, but the findings were not statistically significant and were found to be transient. Hence, it is inferred that this COR does not warrant any clinical management.[10] It is postulated that post-trabeculectomy, the increased IOP in the fellow eye could be due to a reflex increase in aqueous humor production, an effort of the eyes to compensate for the low IOP of the operated eye. The ocular central nervous system (CNS) reflex mechanism would trigger an increase in aqueous production both in the ipsilateral and the contralateral eyes, resulting in a buildup of IOP in the contralateral eye. It is also possible that the IOP fluctuations in the nonsurgical eye are due to changes in the blood flow or circulation to the eye or due to the body’s overall response to the surgery.[4] COR and Minimally Invasive Glaucoma Surgery Though trabeculectomy has been the gold standard for the past few decades, minimally invasive glaucoma surgery (MIGS) is now taking up space in the world of glaucoma. Currently, there is a paucity of data regarding the efficacy of MIGS, but it is a sought-after mode of treatment. So, studies also need to focus on COR in MIGS patients to see if any similar responses are seen in that category. Conclusion Changes in IOP are possible after glaucoma surgery due to a multitude of factors coming into play, suggesting that the fellow eye needs to be carefully monitored after glaucoma surgery in one eye. In many instances, the fellow eye is often the one with useful vision. Failure to recognize and monitor IOP changes carefully may unnecessarily delay treatment and appropriate management of these eyes. In addition, fellow eyes already damaged by glaucomatous processes may be at significant risk of glaucoma progression due to higher IOP levels. Although the evidence for the existence of COR is strengthened, larger studies with more patients in each glaucoma category may shed light on its exact biological role.

Follow-up studies of the classical landmark studies in Glaucoma.

It was not until the nineteen nineties that there was scientific evidence for the primary treatment concept of glaucoma, lowering intraocular pressure. The treatment concept of lowering intraocular pressure is now proven by randomized controlled clinical trials (landmark studies). This review provides an overview of the follow-up studies to these landmark studies from the last 18 months. The 20-year data of the ocular hypertension treatment study showed a 49% incidence of primary open-angle glaucoma. The data of this landmark study was used for developing different machine learning algorithms. Bilateral disease, disc hemorrhages, and higher intraocular pressure (IOP) were risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study. The Advanced Glaucoma Intervention Trial and the Collaborative Initial Glaucoma Treatment Study identified demographic factors, comorbidity, and clinical variables associated with visual field damage. Analysis was performed on Chinese subsets from the Laser in Glaucoma and Ocular Hypertension Study (LiGHT). Looking at all the follow-up studies to the tube shunt landmark studies, preoperative IOP, neovascular glaucoma, Ahmed implantation, and younger age were predictors of failure. A follow-up study to the Effectiveness in Angle-Closure Glaucoma in Lens Extraction Study showed that patients were ten times more likely to maintain a drop-free target IOP after lens extraction than after laser iridotomy. A superior location for iridotomy results in significantly more significant angle widening than temporal or nasal locations, as shown by a follow-up study to the Zhongshan Angle Closure Prevention Trial using OCT and gonioscopy. The number of published follow-up studies to the landmark studies in glaucoma show the ongoing development of clinical questions in management of glaucoma.

Clinical and Visual Field Outcomes Following Minimally Invasive Glaucoma Surgery Combined with Cataract Surgery.

PurposeTo determine the change in Humphrey visual field and clinical parameters after minimally invasive glaucoma surgery combined with cataract surgery.Patients and MethodsPatients undergoing minimally invasive glaucoma surgery combined with cataract surgery in a multicenter retrospective case series between 2013 and 2021 with reliable preoperative and 12 to 18 month postoperative visual field measurements were included. Devices included iStent, XEN, and Hydrus. Clinical parameters were compared with a generalized linear model with generalized estimating equations between preoperative and postoperative visits including best corrected visual acuity, intraocular pressure, number of glaucoma medications and visual fields. Visual field metrics included mean deviation (MD), pattern standard deviation (PSD), visual field index (VFI), and Collaborative Initial Glaucoma Treatment Study (CIGTS) score of total deviation probability and pattern deviation probability.ResultsForty-four eyes from 39 patients were included. During the follow up period, visual acuity improved from 0.23±0.17 to 0.10±0.14 logMAR (mean ± standard deviation, p<0.001), number of glaucoma medications was reduced from 2.68±1.06 to 1.46±1.32 (p<0.001), and intraocular pressure decreased from 17.08±4.23 mmHg to 14.92±3.13 mmHg (p=0.003). Differences across devices were negligible. The only significant difference was a greater reduction in number of glaucoma medications in the XEN group (p<0.001). There were no significant changes in the global parameters of VFI, MD, PSD, or CIGTS.ConclusionOverall, minimally invasive glaucoma surgery combined with cataract surgery appears to be effective at stabilizing visual field function, reducing intraocular pressure, reducing number of glaucoma medications, and improving visual acuity over a 12 to 18 month follow-up period across MIGS devices.

Development and Comparison of Machine Learning Algorithms to Determine Visual Field Progression.

PurposeTo develop and test machine learning classifiers (MLCs) for determining visual field progression.MethodsIn total, 90,713 visual fields from 13,156 eyes were included. Six different progression algorithms (linear regression of mean deviation, linear regression of the visual field index, Advanced Glaucoma Intervention Study algorithm, Collaborative Initial Glaucoma Treatment Study algorithm, pointwise linear regression [PLR], and permutation of PLR) were applied to classify each eye as progressing or stable. Six MLCs were applied (logistic regression, random forest, extreme gradient boosting, support vector classifier, convolutional neural network, fully connected neural network) using a training and testing set. For MLC input, visual fields for a given eye were divided into the first and second half and each location averaged over time within each half. Each algorithm was tested for accuracy, sensitivity, positive predictive value, and class bias with a subset of visual fields labeled by a panel of three experts from 161 eyes.ResultsMLCs had similar performance metrics as some of the conventional algorithms and ranged from 87% to 91% accurate with sensitivity ranging from 0.83 to 0.88 and specificity from 0.92 to 0.96. All conventional algorithms showed significant class bias, meaning each individual algorithm was more likely to grade uncertain cases as either progressing or stable (P ≤ 0.01). Conversely, all MLCs were balanced, meaning they were equally likely to grade uncertain cases as either progressing or stable (P ≥ 0.08).ConclusionsMLCs showed a moderate to high level of accuracy, sensitivity, and specificity and were more balanced than conventional algorithms.Translational RelevanceMLCs may help to determine visual field progression.

Sympathetic context of the disease - a new era in glaucoma management.

Primary open angle glaucoma (POAG) is a multifactorial optic neuropathy, which progresses in a chronic manner. Several etiological factors are involved, including genetic factors, race, age, IOP or vascular, systemic factors. IOP has an established role in the initiation and evolution of glaucoma, but its interactions with additional risk factors are complex. We propose the notion of the Glaucoma Etiological Area (GEA), as a representation of all the elements acting in collaboration in the physiopathology of each glaucoma case. When combined in different proportions, these elements may trigger the typical glaucomatous optic neuropathy (GON). We know that the statistical values of IOP are valid for normal eyes, but the glaucoma eye is not a normal eye. The notion of GEA can open a new perspective to interpret IOP values and to assess the true value of IOP control as a treatment for glaucoma. Applying the GEA theory allows us to tune the role of IOP. Additional factors, such as ocular properties (RGCL status, CCT, IOP fluctuation curve), ocular comorbidities (PEX, PDS), systemic comorbidities (arterial hypertension, vasospastic diseases such as migraines or Reynaud’s syndrome) or patient’s attitude towards glaucoma management (treatment compliance, access to follow-up and treatment) may greatly influence the evolution of GON and should be viewed holistically when developing a management plan for each patient. Applying the notion of GEA in clinical practice allows a more realistic approach of the pathophysiology of the disease and for a glaucoma treatment that is tailored to each patient.Abbreviations: AG = advanced glaucoma, BP = blood pressure, CCT = central corneal thickness, CIGTS = Collaborative Initial Glaucoma Treatment Study, CNTGS = Collaborative Normal-Tension Glaucoma Study, EMGT = Early Manifest Glaucoma Trial, GEA = glaucoma etiological area, GON = glaucomatous optic neuropathy, IOP = intraocular pressure, NTG = Normal Tension Glaucoma, OHTS = Ocular Hypertension Study, PDS = Pigmentary dispersion syndrome, PEX = Pseudoexfoliation syndrome, POAG - primary open-angle glaucoma, RGCL = retinal ganglion cell layer, VFL = visual field loss

Infographic: Collaborative Initial Glaucoma Treatment Study (CIGTS).

Infographic: Collaborative Initial Glaucoma Treatment Study (CIGTS).

Evaluation of the relationship between glaucomatous disc subtypes and occurrence of disc hemorrhage and glaucoma progression in open angle glaucoma

To compare the occurrence of disc hemorrhages (DH) and glaucoma progression in open-angle glaucoma (OAG) patients with different glaucomatous disc types. Prospective, hospital-based, observational cohort study. OAG patients examined between 2000 and 2005, whose discs were classified as typical myopic glaucomatous (MG), generalized enlargement of cup (GE), or focal glaucomatous (FG) disc type were included and followed for 5 years. The first occurrence of DH during follow-up was analyzed using Kaplan–Meier analysis and difference in DH occurrence based on glaucomatous disc type using the Cox proportional-hazards model to adjust for effects of confounding factors. For inter-group comparison of glaucoma progression, the change rate of the mean deviation, Collaborative Initial Glaucoma Treatment Study scores, and fundus photographs were used. Thirty-nine patients with MG-, 18 with FG-, and 17 with GE-disc types were included. No significant inter-group difference was seen in the rate of glaucoma progression. The five-year probability of DH occurrence was much lower with MG- than with FG- or GE-disc types (P < 0.0220). The central corneal thickness (P = 0.0024) and mean intraocular pressure and its variations (P = 0.0450, 0.0219) contributed to DH occurrence. The MG-disc type demonstrated a much lower DH occurrence during follow-up than other disc types.

Comparing Perimetric Loss at Different Target Intraocular Pressures for Patients with High-Tension and Normal-Tension Glaucoma

To compare forecasted changes in mean deviation (MD) for patients with normal-tension glaucoma (NTG) and high-tension open-angle glaucoma (HTG) at different target intraocular pressures (IOPs) using Kalman filtering, a machine learning technique. Retrospective cohort study. From the Collaborative Initial Glaucoma Treatment Study or Advanced Glaucoma Intervention Study, 496 patients with HTG; from Japan, 262 patients with NTG. Using the first 5 sets of tonometry and perimetry measurements, each patient was classified as a fast progressor, slow progressor, or nonprogressor. Using Kalman filtering, personalized forecasts of MD changes over 2.5 years' follow-up were generated for fast and slow progressors with HTG and NTG with IOPs maintained at hypothetical IOP targets of 9 to 21 mmHg. Future MD loss with different percentage IOP reductions from baseline (0%-50%) were also assessed for the groups. Mean forecasted MD change at different target IOPs. The mean (± standard deviation) patient age was 63.5 ± 10.5 years for NTG and 66.5 ± 10.9 years for HTG. Over the 2.5-year follow-up, at target IOPs of 9, 15, and 21 mmHg, respectively, the mean forecasted MD losses for fast progressors with NTG were 2.3 ± 0.2, 4.0 ± 0.2, and 5.7 ± 0.2 dB; for slow progressors withNTG, losses were 0.63 ± 0.02, 1.02 ± 0.03, and 1.49 ± 0.07 dB; for fast progressors with HTG, losses were 1.8 ± 0.1, 3.4 ± 0.1, and 5.1 ± 0.1 dB; and for slow progressors with HTG, losses were 0.55 ± 0.06, 1.04±0.08, and 1.59 ± 0.10 dB. Fast progressors with NTG had greater MD decline than fast progressors with HTG at each target IOP (P≤0.007 for all). The MD decline for slow progressors with HTG and NTG were similar (P≥0.24 for all target IOPs). Fast progressors with HTG had greater MD loss than those with NTG with 0%-10% IOP reduction since baseline (P ≤ 0.01 for all), but not 25% (P= 0.07) or 50% (P= 0.76) reduction since baseline. Machine learning algorithms using Kalman filtering techniques demonstrate promise at forecasting future MD values at different target IOPs for patients with NTG and HTG.

Evaluation of Long-Term Visual Field Function in Patients Undergoing Glaucoma Drainage Device Implantation

To determine the change in global and regional Humphrey visual fields (VF) after glaucoma drainage device (GDD) implantation over a 3-year follow-up period. Retrospective interventional case series. Patients undergoing GDD placement from between 2010 and 2015 with reliable preoperative and yearly postoperative VF measurements were included. Clinical parameters were compared between preoperative and follow-up visits, including visual acuity, intraocular pressure (IOP), number of glaucoma medications, global VF metrics (mean deviation [MD]), pattern standard deviation (PSD), CIGTS (Collaborative Initial Glaucoma Treatment Study) score of total deviation probability (CIGTS_TDP) and pattern deviation probability (CIGTS_PDP), and regional metrics (regional total deviation (TD), regional pattern deviation (PD), and regional CIGTS_TDP and CIGTS_PDP). Multivariate regression analyses were performed to determine risk factors for VF worsening after GDD surgery. A total of 106 eyes from 95 patients were included. Mean IOP ± SD was reduced from 23.1 ± 8.5mm Hg to 12.7 ± 3.1mm Hg at 3-year follow-up (P < .001). MD, PSD, and global CIGTS_PDP showed no significant changes in follow-up, whereas global CIGTS_TDP showed mild progression from 10.7 to 12.8 at 3-year follow-up (P= .01). No regional metrics showed worsening at follow-up examinations. Defects in the superior hemifield were more common than in the inferior hemifield at baseline and follow-up examinations for all regional metrics. Pre-operative number of glaucoma medications was associated with worsening on CIGTS_TDP. Overall, GDD surgery is effective at stabilizing VF function over 3 years of follow-up. The superior hemifield is affected more than other regions. The number of pre-operative glaucoma medications is associated with mild VF progression, measured by CIGTS_TDP.

The Association between Medication Adherence and Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study

To evaluate the relationship between medication adherence and visual field progression in participants randomized to the medication arm of the Collaborative Initial Glaucoma Treatment Study (CIGTS). The CIGTS was a randomized, multicenter clinical trial comparing initial treatment with topical medications to trabeculectomy for 607 participants with newly diagnosed glaucoma. Three hundred seven participants randomized to the medication arm of the CIGTS. Participants were followed up at 6-month intervals for up to 10 years. Self-reported medication adherence and visual fields were measured. Medication adherence was assessed by telephone from responses to the question, "Did you happen to miss any dose of your medication yesterday?" The impact of medication adherence on mean deviation (MD) over time was assessed with a linear mixed regression model adjusting for the effects of baseline MD and age, cataract extraction, interactions, and time (through year 8, excluding time after crossover to surgery). Medication adherence was modeled as a cumulative sum of the number of prior visits where a missed dose of medication was reported. Mean deviation over time. Three hundred seven subjects (306 with adherence data) were randomized to treatment with topical medications and followed up for an average of 7.3 years (standard deviation, 2.3 years). One hundred forty-two subjects (46%) reported never missing a dose of medication over all available follow-up, 112 patients (37%) reported missing medication at up to one third of visits, 31 patients (10%) reported missing medication at one third to two thirds of visits, and 21 patients (7%) reported missing medication at more than two thirds of visits. Worse medication adherence was associated with loss of MD over time (P= 0.005). For subjects who reported never missing a dose of medication, the average predicted MD loss over 8 years was 0.62 dB, consistent with age-related loss (95% confidence interval [CI], 0.17-1.06; P= 0.007); subjects who reported missing medication doses at one third of visits had a loss of 1.42 dB (95% CI, 0.86-1.98; P < 0.0001); and subjects who reported missing medication doses at two thirds of visits showed a loss of 2.23 dB (95% CI, 1.19-3.26; P < 0.0001). This longitudinal assessment demonstrated a statistically and clinically significant association between medication nonadherence and glaucomatous vision loss.

Comparison of Methods to Detect and Measure Glaucomatous Visual Field Progression.

PurposeTo compare methods to assess visual field (VF) progression in glaucoma.Methods4,950 VFs of 253 primary open angle-glaucoma patients were evaluated for progression with the following methods: clinical evaluation, guided progression analysis (GPA), mean deviation (MD), and visual field index (VFI) rates, Advanced Glaucoma Intervention Study (AGIS) and Collaborative Initial Glaucoma Treatment Study (CIGTS) scores, pointwise linear regression (PLR), permutation of PLR (PoPLR), and glaucoma rate index (GRI). A separate simulated series of longitudinal VFs was assessed with all methods except for GPA and clinical evaluation.ResultsThe average (±SD) age of the patients at baseline was 65.4 (±11.5) years. The average (±SD) follow-up was 11.8 (±4.6) years, and the mean (±SD) number of VFs was 16.8 (±7.0). Proportion of series detected as progressing was 65% for PoPLR, 58% for GRI, 41% for GPA, 40% for PLR, 36% for CIGTS, 35% for clinicians, 31% for MD rate, 29% for AGIS, and 22% for VFI rate. Median times to detection of progression were 7.3 years for PoPLR, 7.5 years for GRI, 11 years for clinicians, 14 years for GPA, 16 years for PLR, 17 years for CIGTS, 19 years for AGIS, and more than 20 years for MD and VFI rates. In simulated VF series, GRI had the highest partial area under the receiver operator characteristic curve (0.040) to distinguish between glaucoma progression and aging/cataract decay, followed by VFI rate (0.028), MD rate (0.024), and PoPLR (0.006).ConclusionsGRI and PoPLR showed the highest proportion of series detected as progressing and shortest times to progression detection. GRI exhibited the best ability to detect progression in the simulated VF series.Translational RelevanceKnowledge of the properties of every method would allow tailoring application in both clinical and research settings.

Agreement and Predictors of Discordance of 6 Visual Field Progression Algorithms

To determine the agreement of 6 established visual field (VF) progression algorithms in a large dataset of VFs from multiple institutions and to determine predictors of discordance among these algorithms. Retrospective longitudinal cohort study. Visual fields from 5 major eye care institutions in the United States were analyzed, including a subset of eyes with at least 5 Swedish interactive threshold algorithm standard 24-2 VFs that met our reliability criteria. Of a total of 831 240 VFs, a subset of 90 713 VFs from 13 156 eyes of 8499 patients met the inclusion criteria. Six commonly used VF progression algorithms (mean deviation [MD] slope, VF index slope, Advanced Glaucoma Intervention Study, Collaborative Initial Glaucoma Treatment Study, pointwise linear regression, and permutation of pointwise linear regression) were applied to this cohort, and each eye was determined to be stable or progressing using each measure. Agreement between individual algorithms was tested using Cohen's κ coefficient. Bivariate and multivariate analyses were used to determine predictors of discordance (3 algorithms progressing and 3 algorithms stable). Agreement and discordance between algorithms. Individual algorithms showed poor to moderate agreement with each other when compared directly (κ range, 0.12-0.52). Based on at least 4 algorithms, 11.7% of eyes progressed. Major predictors of discordance or lack of agreement among algorithms were more depressed initial MD (P < 0.01) and older age at first available VF (P < 0.01). A greater number of VFs (P < 0.01), more years of follow-up (P < 0.01), and eye care institution (P=0.03) also were associated with discordance. This extremely large comparative series demonstrated that existing algorithms have limited agreement and that agreement varies with clinical parameters, including institution. These issues underscore the challenges to the clinical use and application of progression algorithms and of applying big-data results to individual practices.

An Artificial Intelligence Approach to Detect Visual Field Progression in Glaucoma Based on Spatial Pattern Analysis.

PurposeTo detect visual field (VF) progression by analyzing spatial pattern changes.MethodsWe selected 12,217 eyes from 7360 patients with at least five reliable 24-2 VFs and 5 years of follow-up with an interval of at least 6 months. VFs were decomposed into 16 archetype patterns previously derived by artificial intelligence techniques. Linear regressions were applied to the 16 archetype weights of VF series over time. We defined progression as the decrease rate of the normal archetype or any increase rate of the 15 VF defect archetypes to be outside normal limits. The archetype method was compared with mean deviation (MD) slope, Advanced Glaucoma Intervention Study (AGIS) scoring, Collaborative Initial Glaucoma Treatment Study (CIGTS) scoring, and the permutation of pointwise linear regression (PoPLR), and was validated by a subset of VFs assessed by three glaucoma specialists.ResultsIn the method development cohort of 11,817 eyes, the archetype method agreed more with MD slope (kappa: 0.37) and PoPLR (0.33) than AGIS (0.12) and CIGTS (0.22). The most frequently progressed patterns included decreased normal pattern (63.7%), and increased nasal steps (16.4%), altitudinal loss (15.9%), superior-peripheral defect (12.1%), paracentral/central defects (10.5%), and near total loss (10.4%). In the clinical validation cohort of 397 eyes with 27.5% of confirmed progression, the agreement (kappa) and accuracy (mean of hit rate and correct rejection rate) of the archetype method (0.51 and 0.77) significantly (P < 0.001 for all) outperformed AGIS (0.06 and 0.52), CIGTS (0.24 and 0.59), MD slope (0.21 and 0.59), and PoPLR (0.26 and 0.60).ConclusionsThe archetype method can inform clinicians of VF progression patterns.

Trends in and Predictors of Depression Among Participants in the Collaborative Initial Glaucoma Treatment Study (CIGTS)

To characterize longitudinal trends and factors predictive of depressive symptoms following glaucoma diagnosis in Collaborative Initial Glaucoma Treatment Study (CIGTS) participants. Cohort study using follow-up data from a clinical trial. A total of 607 participants with newly diagnosed open-angle glaucoma were enrolled at 14 clinical centers in the United States from October 1993 through April 1997, randomized to treatment with medication or surgery, and followed every 6months through 2004. The 8-item Center for Epidemiologic Studies Depression Scale (CES-D) was administered at baseline and follow-up visits. Three outcome measures were investigated: overall CES-D depression score, presence of mild or worse depression (CES-D score ≥ 7), and number of depressive symptoms endorsed. The average baseline CES-D score was 2.4 (SD= 3.8), 12.5% of subjects reported symptoms associated with mild or worse depression, and 55.3% reported at least 1 depressive symptom. By 1 year posttreatment, depression measures decreased (1.5, 6.7%, and 38.4%, respectively), with modest decreases thereafter. Baseline factors predictive of mild or worse depression included worse vision-related quality of life (VRQOL) (odds ratio [OR]= 2.41), female sex (OR= 1.42), younger age (OR per 10 years younger= 1.24), and less than high school education (OR= 2.93); other outcomes showed similar results. Depressive symptoms decreased considerably during the first year after treatment initiation, but were elevated in those with impaired VRQOL. Given the potential of depression to reduce treatment adherence and thus increase the risk of glaucoma progression, eye care providers should ask patients about depressive symptoms, provide reassurance when appropriate, and make referrals as necessary.

Association of Fellow Eye With Study Eye Disease Trajectories and Need for Fellow Eye Treatment in Collaborative Initial Glaucoma Treatment Study (CIGTS) Participants

Clinicians would benefit from knowing the association of glaucomatous change in 2 eyes of the same patient. To estimate the time between initial glaucoma treatment of the study eye (SE) and the need for treatment of the fellow eye (FE) and to ascertain the concordance between rates of progression in SEs and FEs. In this post hoc analysis of participants from the Collaborative Initial Glaucoma Treatment Study, 607 participants with newly diagnosed open-angle glaucoma in 1 or both eyes were followed up for up to 11 years. An SE was designated at baseline and randomized to medical or surgical treatment. By protocol, FEs were treated when eligible or at physician discretion. Survival analysis methods were used to estimate the probability of FE treatment over time and to test baseline and time-dependent predictors of treatment. Disease trajectory was calculated with linear regression as the patient eye-specific slopes of mean deviation (MD) and intraocular pressure (IOP) over time, and correlations between SE and FE trajectories were calculated. Data were collected from October 1993 to December 2004. Data were analyzed from September 2012 to May 2018. Time to FE treatment and slopes over time of MD and IOP in SEs and FEs. Of the 607 included patients, 334 (55.0%) were male and 337 (55.5%) were white, and the mean (SD) age was 58.0 (10.9) years. A total of 291 FEs (47.9%) were treated at baseline, 123 (20.3%) were eventually treated, and 193 (31.8%) never received treatment. The probability of FE treatment for open-angle glaucoma was 0.57 at 1 year and 0.68 at 7 years after randomization. Characteristics significantly associated with an increased hazard of FE treatment included older age (hazard ratio [HR], 1.33; 95% CI, 1.08-1.64; P = .007), hypertension (HR, 1.76; 95% CI, 1.16-2.67; P = .008), higher IOP (HR, 1.24; 95% CI, 1.20-1.29; P < .001), large cup-disc ratio (HR, 1.40; 95% CI, 1.23-1.58; P < .001), and worse MD. Correlations in MD slopes between SEs and FEs initially, eventually, and never treated were 0.73, 0.71, and 0.34, respectively. Comparable correlations in IOP slopes were 0.57, 0.24, and 0, respectively. Among patients with newly diagnosed open-angle glaucoma, almost half had initial treatment of both eyes. After 7 years, approximately two-thirds of patients had bilateral treatment. Of the variables predictive of FE treatment, modifiable factors included hypertension and IOP. Slopes of MD were similar between SEs and treated FEs. This implies that SE change is a harbinger of FE change and therefore warrants close surveillance.

Personalized Prediction of Glaucoma Progression Under Different Target Intraocular Pressure Levels Using Filtered Forecasting Methods

To generate personalized forecasts of how patients with open-angle glaucoma (OAG) experience disease progression at different intraocular pressure (IOP) levels to aid clinicians with setting personalized target IOPs. Secondary analyses using longitudinal data from 2 randomized controlled trials. Participants with moderate or advanced OAG from the Collaborative Initial Glaucoma Treatment Study (CIGTS) or the Advanced Glaucoma Intervention Study (AGIS). By using perimetric and tonometric data from trial participants, we developed and validated Kalman Filter (KF) models for fast-, slow-, and nonprogressing patients with OAG. The KF can generate personalized and dynamically updated forecasts of OAG progression under different target IOP levels. For each participant, we determined how mean deviation (MD) would change if the patient maintains his/her IOP at 1 of 7 levels (6, 9, 12, 15, 18, 21, or 24 mmHg) over the next 5 years. We also model and predict changes to MD over the same time horizon if IOP is increased or decreased by 3, 6, and 9 mmHg from the level attained in the trials. Personalized estimates of the change in MD under different target IOP levels. A total of 571 participants (mean age, 64.2 years; standard deviation, 10.9) were followed for a mean of 6.5 years (standard deviation, 2.8). Our models predicted that, on average, fast progressors would lose 2.1, 6.7, and 11.2 decibels (dB) MD under target IOPs of 6, 15, and 24 mmHg, respectively, over 5 years. In contrast, on average, slow progressors would lose 0.8, 2.1, and 4.1 dB MD under the same target IOPs and time frame. When using our tool to quantify the OAG progression dynamics for all 571 patients, we found no statistically significant differences over 5 years between progression for black versus white, male versus female, and CIGTS versus AGIS participants under different target IOPs (P > 0.05 for all). To our knowledge, this is the first clinical decision-making tool that generates personalized forecasts of the trajectory of OAG progression at different target IOP levels. This approach can help clinicians determine appropriate, personalized target IOPs for patients with OAG.

Development of an 18-Item Measure of Symptom Burden in Patients With Glaucoma From the Collaborative Initial Glaucoma Treatment Study’s Symptom and Health Problem Checklist

Administration of a brief questionnaire to evaluate glaucoma symptoms would lend useful information for patient care. To develop a shortened glaucoma symptom measure based on the Collaborative Initial Glaucoma Treatment Study (CIGTS) Symptom and Health Problem Checklist (SHPC) and evaluate its psychometric properties. This measure development study evaluated the factor structure of the 43-item SHPC that was obtained from CIGTS participants at baseline and every 6 months thereafter. These 607 participants were enrolled at 14 clinical centers in the United States and had newly diagnosed open-angle glaucoma. Their mean deviation (SD) from visual field testing was −5.5 (4.3) dB. Data were collected from October 1993 through April 1997. The factor structure of the SHPC, confirmatory factor analysis of the resulting 18-item questionnaire (SHPC-18), the reliability of the SHPC-18, and associations of the 2 symptom subscales (Local Eye and Visual Function) of the SHPC-18 with visual field severity and 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ25) subscales. Among the 607 participants (mean [SD] age at enrollment, 57.5 [10.9] years), 334 (55.0%) were men and 273 (45.0%) were women; 231 (38.1%) were African American. Exploratory factor analysis and longitudinal growth modeling documented Local Eye and Visual Function symptom subscales. Cronbach α values for mean weighted internal consistency were 0.83 and 0.89 for the Local Eye and Visual Function subscales, respectively, and remained stable over time. Scores on each subscale significantly correlated with the NEI-VFQ25 total score (r = −0.41 and r = −0.59, respectively) and with all subscale scores (P < .01). Participants with more severe glaucoma had higher (worse) mean (SD) scores than those with mild glaucoma at baseline on the Local Eye (4.68 [6.62] vs 3.07 [5.60]) and Visual Function (8.44 [11.45] vs 4.42 [8.94]; P < .05) SHPC-18 subscales. Participants who underwent trabeculectomy reported a higher frequency of any Local Eye symptoms than those treated with topical medications (eg, at 12 months, 153 of 269 [56.9%] vs 11 of 276 [40.9%]; P < .001). These results suggest that the SHPC-18 is a reliable, responsive, and psychometrically sound measure of patient-reported, glaucoma-related symptoms. The measure is responsive to treatment and discriminates the severity of glaucoma. This shorter version of the original SHPC measure may be useful in clinical and research settings to better understand the influence of glaucoma symptoms on patients’ daily life.

Binocular Measures of Visual Acuity and Visual Field versus Binocular Approximations

To assess the relationship of binocular visual function tests with binocular approximations using data from the Collaborative Initial Glaucoma Treatment Study (CIGTS). Case series based on existing data from a clinical trial. Six hundred seven patients with newly diagnosed open-angle glaucoma from the CIGTS. Monocular visual field (VF) and visual acuity (VA) tests were performed at baseline and every 6 months thereafter. Binocular tests of visual function (Esterman VF score, binocular VA) were added to the CIGTS protocol 3 years into the study. The binocular approximations of binocular visual function were better or worse eye, average eye, better or worse location, and binocular summation or pointwise binocular summation. Associations between binocular tests and binocular approximations to represent binocular visual function were assessed with Pearson's correlations (r), as was the relationship between vision-related quality of life (VR QOL; Visual Activities Questionnaire [VAQ] and the 25-item National Eye Institute Visual Function Questionnaire [NEIVFQ-25]) and binocular tests or binocular approximations of visual function. Binocular visual function (VF and VA) and VR QOL. Five hundred seventy-five patients underwent at least 1 binocular visual function test. The Esterman score was correlated significantly with all binocular approximations of VF, with r values ranging from 0.31 (worse-eye mean deviation [MD]) to 0.42 (better-eye MD; P < 0.0001 for all). Binocular VA showed stronger correlations with binocular approximations, with r values ranging from 0.65 (worse-eye VA) to 0.80 (binocular summation; P<0.0001 for all). Correlations between the VAQ and Esterman score were stronger in 7 of 9 subscales (r=-0.14 to-0.25; P < 0.05 for all) than correlations with all 7 binocular approximations. In contrast, correlations between the VAQ and binocular VA (r=-0.07 to-0.21) were weaker in all subscales than those with better-eye, average-eye, and binocular summation of VA (r=-0.12 to-0.25), but not different from worse-eye values. These trends also were found in relevant subscales of the NEI VFQ-25. We found limited benefit in binocular testing of VA in the clinical setting as a means of approximating a patient's reported visual functioning. In contrast, we found some benefit in performing binocularVF testing, because the results correlated more closely with reported functioning than binocular approximations.