Central Corneal Thickness in the Ocular Hypertension Treatment Study (OHTS).

OBJECTIVE: Central corneal thickness influences intraocular pressure (IOP) measurement. We examined the central corneal thickness of subjects in the Ocular Hypertension Treatment Study (OHTS) and determined if central corneal thickness is related to race. DESIGN: Cross-sectional study. PARTICIPANTS: One thousand three hundred one OHTS subjects with central corneal thickness measurements. INTERVENTION: Central corneal thickness was determined with ultrasonic pachymeters of the same make and model at all clinical sites of the OHTS. MAIN OUTCOME MEASURES: Correlation of mean central corneal thickness with race, baseline IOP, refraction, age, gender, systemic hypertension, and diabetes. RESULTS: Mean central corneal thickness was 573.0 ± 39.0 µm. Twenty-four percent of the OHTS subjects had central corneal thickness > 600 µm. Mean central corneal thickness for African American subjects (555.7 ± 40.0 µm; n = 318) was 23 µm thinner than for white subjects (579.0 ± 37.0 µm; P < 0.0001). Other factors associated with greater mean central corneal thickness were younger age, female gender, and diabetes. CONCLUSIONS: OHTS subjects have thicker corneas than the general population. African American subjects have thinner corneas than white subjects in the study. The effect of central corneal thickness may influence the accuracy of applanation tonometry in the diagnosis, screening, and management of patients with glaucoma and ocular hypertension.

Glaucoma Risk Alleles in the Ocular Hypertension Treatment Study.

PURPOSE: Primary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Comparative series. PARTICIPANTS: One thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study. METHODS: Samples of DNA were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using analyses of variance. The 2 largest subgroups, non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%), also were analyzed separately. The probability of glaucoma developing over the course of the OHTS was compared between participants stratified for transmembrane and coiled-coil domains 1 (TMCO1) risk alleles using Kaplan-Meier and Cox proportional hazards analyses. MAIN OUTCOME MEASURES: Association of POAG with known genetic factors. RESULTS: No association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls (P = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of glaucoma developing than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increased relative risk comparable with that of some previously analyzed clinical measures (i.e., intraocular pressure). CONCLUSIONS: The size of the OHTS cohort and its composition of 2 large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that long have been associated with glaucoma.

Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits.

This study evaluated in vivo imaging capabilities and safety of qualitative monitoring of oxygen saturation of hemoglobin (sO2) of rabbit ciliary body tissues obtained with acoustic resolution (AR) photoacoustic tomography (PAT). AR PAT was used to collect trans-scleral images from ciliary body vasculature of seven New Zealand White rabbits. The PAT sO2 measurements were obtained under the following conditions: when systemic sO2 as measured by pulse oximetry was between 100% and 99% (level 1); systemic sO2 as measured by pulse oximetry was between 98% and 90% (level 2); and systemic sO2 as measured by pulse oximetry was less than 90% (level 3). Following imaging, histological analysis of ocular tissue was conducted to evaluate for possible structural damage caused by the AR PAT imaging. AR PAT was able to resolve anatomical structures of the anterior segment of the eye, viewed through the cornea or anterior sclera. Histological studies revealed no ocular damage. On average, sO2 values (%) obtained with AR PAT were lower than sO2 values obtained with pulse oximetry (all p < 0.001): 86.28 ± 4.16 versus 99.25 ± 0.28, 84.09 ± 1.81 vs. 95.3 ± 2.6, and 64.49 ± 7.27 vs. 71.15 ± 10.21 for levels 1, 2 and 3 respectively. AR PAT imaging modality is capable of qualitative monitoring for deep tissue sO2 in rabbits. Further studies are needed to validate and modify the AR PAT modality specifically for use in human eyes. Having a safe, non-invasive method of in vivo imaging of sO2 in the anterior segment is important to studies evaluating the role of oxidative damage, hypoxia and ischemia in pathogenesis of ocular diseases.

Visual field progression patterns in the ocular hypertension treatment study correspond to vulnerability regions of the disc.

OBJECTIVES: To determine the locations on the 24-2 visual field (VF) testing grid that are most likely to progress in patients with ocular hypertension (OHTN). Based on a structural model of superior and inferior areas of relative vulnerability at the optic disc, we hypothesized that the nasal and paracentral regions are more prone to show a reduction in sensitivity. METHODS: Posthoc analysis of data collected in phases 1 and 2 of the Ocular Hypertension Treatment Study (OHTS). A pointwise analysis was applied to determine the progression patterns in the early and delayed treatment groups. Each group's progression rate and frequency were calculated for each of the 52 locations corresponding to the 24-2 VF strategy, using trend- and event-based analyses, respectively. RESULTS: For the event-based analysis, the events were most commonly found in the nasal and paracentral regions. The same regions, with some modest variation, were found to have the fastest rates of progression (ROP) measured with trend analysis. A similar pattern of progression was observed in both the early and delayed treatment groups. The difference in event rates and ROP between the early and delayed treatment groups was also greatest in the nasal and paracentral regions. CONCLUSIONS: Development of VF loss in ocular hypertensive eyes appears to be consistent with the vulnerability zones previously described in glaucomatous eyes with established VF loss. Ocular hypotensive treatment likely helps to slow the rate of progression in these regions. This suggests that careful monitoring of these locations may be useful.

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study.

Importance: Primary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification. Objective: To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension. Design, Setting, and Participants: This was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023. Exposures: From February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models. Results: Of 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset. Conclusions and Relevance: Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.

Seasonal changes in visual field sensitivity and intraocular pressure in the ocular hypertension treatment study.

PURPOSE: Longitudinal testing plays a key role in glaucoma management. Variability between visits hampers the ability to monitor progression. It has previously been shown that average intraocular pressure (IOP) exhibits seasonal fluctuations. This study examines whether visual field sensitivity also exhibits seasonal fluctuations and seeks to determine whether such fluctuations are correlated to seasonal IOP effects. DESIGN: Comparative case series. PARTICIPANTS: A total of 33 873 visits by 1636 participants enrolled in the Ocular Hypertension Treatment Study. Participants were split into 6 geographic zones according to the prevailing climate in their location. TESTING: At each visit, standard automated perimetry was conducted on each eye, and IOP was measured. MAIN OUTCOME MEASURES: Mixed effects regression models were formed to look for sinusoidal periodic effects on the change in perimetric mean deviation since the last visit (ΔMD) and on IOP, both overall and within each zone. RESULTS: When all the data were included, a significant seasonal effect on ΔMD was found with magnitude 0.06 dB, peaking in February (P < 0.001). Five of the 6 geographic zones exhibited significant seasonal effects on ΔMD, peaking between January and April, with magnitudes ranging from 0.04 dB (P = 0.049) to 0.21 dB (P < 0.001). Zones with greater climactic variation showed larger seasonal effects on ΔMD. All 6 zones exhibited a seasonal effect on IOP, peaking in January or February, with magnitudes ranging from 0.14 to 0.39 mmHg (P ≤ 0.02 in all cases). However, there was no evidence of a significant association between the magnitudes or dates of peaks of the 2 seasonal effects. CONCLUSIONS: The mean deviation was significantly higher in winter than in summer. There is no evidence of an association with seasonal IOP fluctuations. The cause of the seasonal effect on visual field sensitivity is unknown. These findings may help shed light on the glaucomatous disease process and aid efforts to reduce test-retest variability.

What is the Optimal Frequency of Visual Field Testing to Detect Rapid Progression Among Hypertensive Eyes?

PRCIS: We evaluated 16,351 visual field (VF) tests from Ocular Hypertension Treatment Study (OHTS) database and showed that more frequent testing resulted in a shorter time to detect glaucoma progression, with the best trade-off being the 6-month intervals for high-risk and 12 months for low-risk patients. PURPOSE: To investigate the effect of different testing intervals on time to detect visual field progression in eyes with ocular hypertension. METHODS: A total of 16,351 reliable 30-2 VF tests from 1575 eyes of the OHTS-1 observation arm with a mean (95% CI) follow-up of 4.8 (4.7-4.8) years were analyzed. Computer simulations (n = 10,000 eyes) based on mean deviation values and the residuals of risk groups (according to their baseline 5 y risk of developing primary open angle glaucoma: low, medium, and high risk) were performed to estimate time to detect progression with testing intervals of 4, 6, 12, and 24 months using linear regression. The time to detect VF progression ( P < 5%) at 80% power was calculated based on the mean deviation slope of -0.42 dB/year. We assessed the time to detect a -3 dB loss as an estimate of clinically meaningful perimetric loss. RESULTS: At 80% power, based on the progression of -0.42 dB/year, the best trade-off to detect significant rates of VF change to clinically meaningful perimetric loss in high, medium, and low-risk patients was 6, 6, and 12-month intervals, respectively. CONCLUSION: Given the importance of not missing the conversion to glaucoma, the frequency of testing used in OHTS (6 mo) was optimal for the detection of progression in high-risk patients. Low-risk patients could potentially be tested every 12 months to optimize resource utilization.

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Objective or Purpose: Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension. Design: A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data. Setting Participants and/or Controls: 1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank. Methods Interventions or Testing: Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models. Results: Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset. Conclusions: Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.

Adjusting intraocular pressure for central corneal thickness does not improve prediction models for primary open-angle glaucoma.

PURPOSE: To determine if the accuracy of the baseline prediction model for the development of primary open-angle glaucoma (POAG) in patients with ocular hypertension can be improved by correcting intraocular pressure (IOP) for central corneal thickness (CCT). DESIGN: Reanalysis of the baseline prediction model for the development of POAG from the Ocular Hypertension Treatment Study (OHTS) substituting IOP adjusted for CCT using 5 different correction formulae for unadjusted IOP. PARTICIPANTS: A total of 1433 of 1636 participants randomized to OHTS who had complete baseline data for factors in the prediction model: age, IOP, CCT, vertical cup-to-disc ratio (VCDR), and pattern standard deviation (PSD). METHODS: Reanalysis of the prediction model for the risk of developing POAG using the same baseline variables (age, IOP, CCT, VCDR, and PSD) except that IOP was adjusted for CCT using correction formulae. A separate Cox proportional hazards model was run using IOP adjusted for CCT by each of the 5 formulae published to date. Models were run including and excluding CCT. MAIN OUTCOME MEASURES: Predictive accuracy of each Cox proportional hazards model was assessed using the c-statistic and calibration chi-square. RESULTS: C-statistics for prediction models that used IOP adjusted for CCT by various formulas ranged from 0.75 to 0.77, no better than the original prediction model (0.77) that did not adjust IOP for CCT. Calibration chi-square was acceptable for all models. Baseline IOP, whether adjusted for CCT or not, was statistically significant in all models including those with CCT in the same model. The CCT was statistically significant in all models including those with IOP adjusted for CCT in the same model. CONCLUSIONS: The calculation of individual risk for developing POAG in ocular hypertensive individuals is simpler and equally accurate using IOP and CCT as measured, rather than applying an adjustment formula to correct IOP for CCT.

Reduction in intraocular pressure after cataract extraction: the Ocular Hypertension Treatment Study.

PURPOSE: To determine the change in intraocular pressure (IOP) after cataract extraction in the observation group of the Ocular Hypertension Treatment Study. DESIGN: Comparative case series. PARTICIPANTS: Forty-two participants (63 eyes) who underwent cataract surgery in at least 1 eye during the study and a control group of 743 participants (743 eyes) who did not undergo cataract surgery. METHODS: We defined the "split date" as the study visit date at which cataract surgery was reported in the cataract surgery group and a corresponding date in the control group. Preoperative IOP was defined as the mean IOP of up to 3 visits before the split date. Postoperative IOP was the mean IOP of up to 3 visits including the split date (0, 6, and 12 months' with "0 months" equaling the split date). In both groups, we censored data after initiation of ocular hypotensive medication or glaucoma surgery of any kind. MAIN OUTCOME MEASURES: Difference in preoperative and postoperative IOP. RESULTS: In the cataract group, postoperative IOP was significantly lower than the preoperative IOP (19.8 ± 3.2 mmHg vs. 23.9 ± 3.2 mmHg; P<0.001). The postoperative IOP remained lower than the preoperative IOP for at least 36 months. The average decrease in postoperative IOP from preoperative IOP was 16.5%, and 39.7% of eyes had postoperative IOP ≥ 20% below preoperative IOP. A greater reduction in postoperative IOP occurred in the eyes with the highest preoperative IOP. In the control group, the corresponding mean IOPs were 23.8 ± 3.6 before the split date and 23.4 ± 3.9 after the split date. CONCLUSIONS: Cataract surgery decreases IOP in patients with ocular hypertension over a long period of time.

The effect of changes in intraocular pressure on the risk of primary open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis.

BACKGROUND: Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. While lowering intraocular pressure (IOP) has been proven to be effective in delaying or preventing the onset of POAG in many large-scale prospective studies, one of the recent hot topics in glaucoma research is the effect of IOP fluctuation (IOP lability) on the risk of developing POAG in treated and untreated subjects. METHOD: In this paper, we analyzed data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) for subjects who had at least 2 IOP measurements after randomization prior to POAG diagnosis. We assessed the interrelationships among the baseline covariates, the changes of post-randomization IOP over time, and the risk of developing POAG, using a latent class analysis (LCA) which allows us to identify distinct patterns (latent classes) of IOP trajectories. RESULT: The IOP change in OHTS was best described by 6 latent classes differentiated primarily by the mean IOP levels during follow-up. Subjects with high post-randomization mean IOP level and/or large variability were more likely to develop POAG. Five baseline factors were found to be significantly predictive of the IOP classification in OHTS: treatment assignment, baseline IOP, gender, race, and history of hypertension. In separate analyses of EGPS, LCA identified different patterns of IOP change from those in OHTS, but confirmed that subjects with high mean level and large variability were at high risk to develop POAG. CONCLUSION: LCA provides a useful tool to assess the impact of post-randomization IOP level and fluctuation on the risk of developing POAG in patients with ocular hypertension. The incorporation of post-randomization IOP can improve the overall predictive ability of the original model that included only baseline risk factors.

Detecting Glaucoma in the Ocular Hypertension Study Using Deep Learning.

Importance: Automated deep learning (DL) analyses of fundus photographs potentially can reduce the cost and improve the efficiency of reading center assessment of end points in clinical trials. Objective: To investigate the diagnostic accuracy of DL algorithms trained on fundus photographs from the Ocular Hypertension Treatment Study (OHTS) to detect primary open-angle glaucoma (POAG). Design, Setting, and Participants: In this diagnostic study, 1636 OHTS participants from 22 sites with a mean (range) follow-up of 10.7 (0-14.3) years. A total of 66 715 photographs from 3272 eyes were used to train and test a ResNet-50 model to detect the OHTS Endpoint Committee POAG determination based on optic disc (287 eyes, 3502 photographs) and/or visual field (198 eyes, 2300 visual fields) changes. Three independent test sets were used to evaluate the generalizability of the model. Main Outcomes and Measures: Areas under the receiver operating characteristic curve (AUROC) and sensitivities at fixed specificities were calculated to compare model performance. Evaluation of false-positive rates was used to determine whether the DL model detected POAG before the OHTS Endpoint Committee POAG determination. Results: A total of 1147 participants were included in the training set (661 [57.6%] female; mean age, 57.2 years; 95% CI, 56.6-57.8), 167 in the validation set (97 [58.1%] female; mean age, 57.1 years; 95% CI, 55.6-58.7), and 322 in the test set (173 [53.7%] female; mean age, 57.2 years; 95% CI, 56.1-58.2). The DL model achieved an AUROC of 0.88 (95% CI, 0.82-0.92) for the OHTS Endpoint Committee determination of optic disc or VF changes. For the OHTS end points based on optic disc changes or visual field changes, AUROCs were 0.91 (95% CI, 0.88-0.94) and 0.86 (95% CI, 0.76-0.93), respectively. False-positive rates (at 90% specificity) were higher in photographs of eyes that later developed POAG by disc or visual field (27.5% [56 of 204]) compared with eyes that did not develop POAG (11.4% [50 of 440]) during follow-up. The diagnostic accuracy of the DL model developed on the optic disc end point applied to 3 independent data sets was lower, with AUROCs ranging from 0.74 (95% CI, 0.70-0.77) to 0.79 (95% CI, 0.78-0.81). Conclusions and Relevance: The model's high diagnostic accuracy using OHTS photographs suggests that DL has the potential to standardize and automate POAG determination for clinical trials and management. In addition, the higher false-positive rate in early photographs of eyes that later developed POAG suggests that DL models detected POAG in some eyes earlier than the OHTS Endpoint Committee, reflecting the OHTS design that emphasized a high specificity for POAG determination by requiring a clinically significant change from baseline.

Assessment of Cumulative Incidence and Severity of Primary Open-Angle Glaucoma Among Participants in the Ocular Hypertension Treatment Study After 20 Years of Follow-up.

Importance: Ocular hypertension is an important risk factor for the development of primary open-angle glaucoma (POAG). Data from long-term follow-up can be used to inform the management of patients with ocular hypertension. Objective: To determine the cumulative incidence and severity of POAG after 20 years of follow-up among participants in the Ocular Hypertension Treatment Study. Design, Setting, and Participants: Participants in the Ocular Hypertension Treatment Study were followed up from February 1994 to December 2008 in 22 clinics. Data were collected after 20 years of follow-up (from January 2016 to April 2019) or within 2 years of death. Analyses were performed from July 2019 to December 2020. Interventions: From February 28, 1994, to June 2, 2002 (phase 1), participants were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). From June 3, 2002, to December 30, 2008 (phase 2), both randomization groups received medication. Beginning in 2009, treatment was no longer determined by study protocol. From January 7, 2016, to April 15, 2019 (phase 3), participants received ophthalmic examinations and visual function assessments. Main Outcomes and Measures: Twenty-year cumulative incidence and severity of POAG in 1 or both eyes after adjustment for exposure time. Results: A total of 1636 individuals (mean [SD] age, 55.4 [9.6] years; 931 women [56.9%]; 1138 White participants [69.6%]; 407 Black/African American participants [24.9%]) were randomized in phase 1 of the clinical trial. Of those, 483 participants (29.5%) developed POAG in 1 or both eyes (unadjusted incidence). After adjusting for exposure time, the 20-year cumulative incidence of POAG in 1 or both eyes was 45.6% (95% CI, 42.3%-48.8%) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The 20-year cumulative incidence of POAG was 55.2% (95% CI, 47.9%-61.5%) among Black/African American participants and 42.7% (95% CI, 38.9%-46.3%) among participants of other races. The 20-year cumulative incidence for visual field loss was 25.2% (95% CI, 22.5%-27.8%). Using a 5-factor baseline model, the cumulative incidence of POAG among participants in the low-, medium-, and high-risk tertiles was 31.7% (95% CI, 26.4%-36.6%), 47.6% (95% CI, 41.6%-53.0%), and 59.8% (95% CI, 53.1%-65.5%), respectively. Conclusions and Relevance: In this study, only one-fourth of participants in the Ocular Hypertension Treatment Study developed visual field loss in either eye over long-term follow-up. This information, together with a prediction model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.

The incidence of retinal vein occlusion in the ocular hypertension treatment study.

OBJECTIVE: To determine the incidence of retinal vein occlusion (RVO) in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Retrospective analysis of data from a randomized clinical trial. PARTICIPANTS: We included 1636 ocular hypertensive participants with a mean follow-up of 9.1 years. Participants in the medication and observation groups were managed according to their original randomization assignment until June 1, 2002. At that time, the observation participants were offered ocular hypotensive treatment. Data to July 1, 2005, are included in this report. METHODS: Occurrences of RVO in study participants, categorized as branch, central or hemicentral vein occlusion, were documented. Potential RVO events were identified by a keyword search of Adverse Event Reports, the Optic Disc Reading Center database, Endpoint Committee reviews, and by response to a written request for information sent to each clinical site. To confirm a potential RVO, the complete OHTS chart was reviewed. Statistical analyses included t tests, chi-square tests and Cox proportional hazards models. MAIN OUTCOME MEASURES: Incidence of RVO. RESULTS: Twenty-six RVOs-5 branch, 14 central, and 7 hemicentral RVOs-were confirmed in 23 participants (15 observation and 8 medication). The 10-year cumulative incidence of RVO was 2.1% in the observation group and 1.4% in the medication group (P = 0.14; log-rank test). At baseline, participants who later developed a RVO were significantly older (65.1 vs 55.3 years; P = 0.01), and had greater horizontal cup-to-disc ratios (P = 0.0004). CONCLUSIONS: Although the incidence of RVO was higher in the observation group than the medication group, this difference did not attain significance. Consistent with some previous studies, older age and greater cup-to-disc ratio were associated with the development of RVO.

The utility of the monocular trial: data from the ocular hypertension treatment study.

OBJECTIVE: To determine whether adjusting the intraocular pressure (IOP) change of the trial eye for the IOP change of the fellow eye (i.e., monocular trial) is a better assessment of medication response than testing each eye independently. DESIGN: Analysis of data from a prospective, randomized, clinical trial. PARTICIPANTS: Two hundred six participants with ocular hypertension randomized to the observation group and later started on a topical prostaglandin analog (PGA). METHODS: Participants were started on a topical PGA in 1 eye and returned in approximately 1 month to determine medication response. The IOP response of the trial eye was determined by the IOP change between baseline and 1 month in the trial eye alone (unadjusted method) and by adjusting for the IOP change in the fellow eye between the same visits (adjusted method). Our "gold standard" for medication response was the IOP change in the trial eye between up to 3 pre- and 3 posttreatment visits on the same medication. Pearson correlation was used to compare the gold standard with the unadjusted and adjusted methods. In addition, symmetry of IOP response between trial and fellow eyes to the same medication was determined by correlating the trial eye IOP change between up to 3 pre- and 3 posttreatment visits to the fellow eye IOP change between the same visits. MAIN OUTCOME MEASURES: Correlations of IOP change of the trial eye using the gold standard to the IOP change of the trial eye using the unadjusted and adjusted methods. RESULTS: The correlations of IOP change using the gold standard to the IOP change using the unadjusted and adjusted methods were r = 0.40 and r = 0.41, respectively. The correlation of IOP change of both eyes between the same pre- and posttreatment visits was r = 0.81. CONCLUSIONS: The monocular trial (i.e., adjusted method) appears equivalent to testing each eye independently (i.e., unadjusted method); however, neither method is adequate to determine medication response to topical PGAs. Both eyes have a similar IOP response to the same PGA. Further studies to understand IOP fluctuation are necessary to improve current methods of assessing medication response. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Predicting the onset of glaucoma: the confocal scanning laser ophthalmoscopy ancillary study to theOcular Hypertension Treatment Study.

OBJECTIVE: To evaluate the predictive ability of baseline confocal scanning laser ophthalmoscopy (CSLO) Glaucoma Probability Score (GPS) for the development of primary open-angle glaucoma (POAG) and to compare it with the Moorfields regression analysis (MRA) classification, other topographic optic disc parameters, and stereophotograph-based cup-to-disc ratio. DESIGN: Longitudinal, randomized clinical trial. PARTICIPANTS: We included 857 eyes of 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) with good quality baseline CSLO images. METHODS: The ability of baseline GPS, MRA, and optic disc parameters to predict the development of POAG was evaluated in univariate and multivariable proportional hazard ratio analyses. Likelihood ratios and positive and negative predictive values were compared. MAIN OUTCOME MEASURES: The POAG end point as determined by repeatable changes in the visual field or optic disc. RESULTS: Sixty-four eyes of 50 CSLO Ancillary Study participants developed POAG. Median time to reach a POAG end point was 72.3 months. The 93 eyes of 388 participants not reaching endpoint were followed for a median of 124.9 months. Baseline GPS identified many more eyes as outside normal limits than the MRA. In multivariable analyses, all regional and global baseline GPS indices were significantly associated with the development of POAG; hazard ratios (95% confidence interval) ranged from 2.92 to 3.74 for an outside normal limits result. The MRA indices were also significantly associated with the development of POAG in multivariable analyses. In addition, the predictive ability of baseline GPS, MRA and stereometric parameters were similar to the predictive ability of models using photograph-based horizontal cup-to-disc ratio. CONCLUSIONS: These results suggest that baseline GPS, MRA, and stereoparameters alone or when combined with baseline clinical and demographic factors can be used to predict the development of POAG end points in OHTS participants and are as effective as stereophotographs for estimating the risk of developing POAG in ocular hypertensive subjects.

Evaluation of a Primary Open-Angle Glaucoma Prediction Model Using Long-term Intraocular Pressure Variability Data: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: The contribution of long-term intraocular pressure (IOP) variability to the development of primary open-angle glaucoma is still controversial. Objective: To assess whether long-term IOP variability data improve a prediction model for the development of primary open-angle glaucoma (POAG) in individuals with untreated ocular hypertension. Design, Setting, and Participants: This post hoc secondary analysis of 2 randomized clinical trials included data from 709 of 819 participants in the observation group of the Ocular Hypertension Treatment Study (OHTS) followed up from February 28, 1994, to June 1, 2002, and 397 of 500 participants in the placebo group of the European Glaucoma Prevention Study (EGPS) followed up from January 1, 1997, to September 30, 2003. Data analyses were completed between January 1, 2019, and March 15, 2020. Exposures: The original prediction model for the development of POAG included the following baseline factors: age, IOP, central corneal thickness, vertical cup-disc ratio, and pattern SD. This analysis tested whether substitution of baseline IOP with mean follow-up IOP, SD of IOP, maximum IOP, range of IOP, or coefficient of variation IOP would improve predictive accuracy. Main Outcomes and Measures: The C statistic was used to compare the predictive accuracy of multivariable landmark Cox proportional hazards regression models for the development of POAG. Results: Data from the OHTS consisted of 97 POAG end points from 709 of 819 participants (416 [58.7%] women; 177 [25.0%] African American and 490 [69.1%] white; mean [SD] age, 55.7 [9.59] years; median [range] follow-up, 6.9 [0.96-8.15] years). Data from the EGPS consisted of 44 POAG end points from 397 of 500 participants in the placebo group (201 [50.1%] women; 397 [100%] white; mean [SD] age, 57.8 [9.76] years; median [range] follow-up, 4.9 [1.45-5.76] years). The C statistic for the original prediction model was 0.741. When a measure of follow-up IOP was substituted for baseline IOP in this prediction model, the C statistics were as follows: mean follow-up IOP, 0.784; maximum IOP, 0.781; SD of IOP, 0.745; range of IOP, 0.741; and coefficient of variation IOP, 0.729. The C statistics in the EGPS were similarly ordered. No measure of IOP variability, when added to the prediction model that included mean follow-up IOP, age, central corneal thickness, vertical cup-disc ratio, and pattern SD, increased the C statistic by more than 0.007 in either cohort. Conclusions and Relevance: Evidence from the OHTS and the EGPS suggests that long-term variability does not add substantial explanatory power to the prediction model as to which individuals with untreated ocular hypertension will develop POAG.

Densitometric Profiles of Optic Disc Hemorrhages in the Ocular Hypertension Treatment Study.

PURPOSE: The origin of blood in glaucoma-related disc hemorrhages (DH) remains unknown. A prior clinic-based study of primary open-angle glaucoma (POAG)-related DH showed that they had grayscale pixel intensities more similar to blood from retinal macroaneurysms and adjacent retinal arterioles than to blood from retinal vein occlusions or adjacent retinal venules, suggesting an arterial source. Here we assessed the densitometric profile of DH from fundus photographs in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Retrospective cross-sectional study of prospectively collected images. METHODS: Stereo disc photographs of 161 DH events from 83 OHTS participants (mean age [standard deviation (SD)]: 65.6 [9.2] years; 46.6% female; 13.0% black race) were imported into ImageJ to measure densitometry differences (adjacent arterioles minus DH [ΔA] or venules minus DH [ΔV]). Their size as percentage of disc area, ratio of length to midpoint width, and location relative to the disc margin were also analyzed. We performed t tests to compare ΔA and ΔV, analysis of variance to compare ΔA and ΔV across DH recurrent events, and multivariable linear regression to identify determinants of ΔA and ΔV. RESULTS: Mean (SD) ΔA and ΔV were -2.2 (8.7) and -11.4 (9.7) pixel intensity units, respectively (P < .001). ΔA and ΔV each did not differ significantly across recurrence of DH (P ≥ .92) or between DH events with and without POAG (P ≥ .26). CONCLUSIONS: OHTS DH had densitometric measurements more similar in magnitude to adjacent arterioles than venules, supporting an arterial origin for DH. Vascular dysregulation may contribute to disc hemorrhage formation in ocular hypertension.

Variability of intraocular pressure measurements in observation participants in the ocular hypertension treatment study.

PURPOSE: To describe variability of intraocular pressure (IOP) measurements within the same eye and between right and left eyes over a 60-month period in participants in the Ocular Hypertension Treatment Study. DESIGN: Analysis of data from a prospective, randomized clinical trial. PARTICIPANTS: Eight hundred ten participants randomized to the observation group. METHODS: Intraocular pressure measurements were obtained at the baseline visit and every 6 months thereafter. Pearson correlation coefficients were calculated for IOP measurements in the same eye between visits and for IOP measurements between right and left eyes of participants at each visit. Differences in IOP measurements between visits are reported in percent change (>15%, >20%, and >30%) and in millimeters of mercury (<3 mmHg, 3-5 mmHg, and >5 mmHg). The effects of regression to the mean, consistency in time of day, and sequence of IOP measurement of right and left eyes were examined. MAIN OUTCOME MEASURES: Correlation of IOP measurements between consecutive 6-month visits. RESULTS: The correlation of IOP measurements within the same eye between consecutive visits was r = 0.62, whereas the correlation of IOP measurements between right and left eyes at the same visit was r = 0.72. Thirteen percent of eyes had >20% change in IOP between consecutive visits. Sixty-six percent of eyes had a change in IOP within 3 mmHg, and 10% of eyes had a change in IOP >5 mmHg between visits. Eyes with a higher baseline IOP had a lower IOP at 6 months. There was a stronger correlation of IOP measured within 2 hours of the time of day between visits (r = 0.56) than >2 hours apart (r = 0.39). IOP of the right eye, which was measured first, was 0.3+/-2.8 mmHg higher than the left eye. CONCLUSIONS: The variability of IOP measurements in the same eye between consecutive visits is moderate and is greater than the variability of IOP measurements between right and left eyes at the same visit. Factors affecting the variability of IOP measurement include regression to the mean, time of day, and measurement order. Knowledge of variability in IOP and its measurements may help clinicians establish a more accurate baseline IOP, target IOP, and assessment of medication effect.

Accuracy of Kalman Filtering in Forecasting Visual Field and Intraocular Pressure Trajectory in Patients With Ocular Hypertension.

Importance: Techniques that properly identify patients in whom ocular hypertension (OHTN) is likely to progress to open-angle glaucoma can assist clinicians with deciding on the frequency of monitoring and the potential benefit of early treatment. Objective: To test whether Kalman filtering (KF), a machine learning technique, can accurately forecast mean deviation (MD), pattern standard deviation, and intraocular pressure values 5 years into the future for patients with OHTN. Design, Setting, and Participants: This cohort study was a secondary analysis of data from patients with OHTN from the Ocular Hypertension Treatment Study, performed between February 1994 and March 2009. Patients underwent tonometry and perimetry every 6 months for up to 15 years. A KF (KF-OHTN) model was trained, validated, and tested to assess how well it could forecast MD, pattern standard deviation, and intraocular pressure at up to 5 years, and the forecasts were compared with results from the actual trial. Kalman filtering for OHTN was compared with a previously developed KF for patients with high-tension glaucoma (KF-HTG) and 3 traditional forecasting algorithms. Statistical analysis for the present study was performed between May 2018 and May 2019. Main Outcomes and Measures: Prediction error and root-mean-square error at 12, 24, 36, 48, and 60 months for MD, pattern standard deviation, and intraocular pressure. Results: Among 1407 eligible patients (2806 eyes), 809 (57.5%) were female and the mean (SD) age at baseline was 57.5 (9.6) years. For 2124 eyes with sufficient measurements, KF-OHTN forecast MD values 60 months into the future within 0.5 dB of the actual value for 696 eyes (32.8%), 1.0 dB for 1295 eyes (61.0%), and 2.5 dB for 1980 eyes (93.2%). Among the 5 forecasting algorithms tested, KF-OHTN achieved the lowest root-mean-square error (1.72 vs 1.85-4.28) for MD values 60 months into the future. For the subset of eyes that progressed to open-angle glaucoma, KF-OHTN and KF-HTG forecast MD values 60 months into the future within 1 dB of the actual value for 30 eyes (68.2%; 95% CI, 54.4%-82.0%) and achieved the lowest root-mean-square error among all models. Conclusions and Relevance: These findings suggest that machine learning algorithms such as KF can accurately forecast MD, pattern standard deviation, and intraocular pressure 5 years into the future for many patients with OHTN. These algorithms may aid clinicians in managing OHTN in their patients.