Submitted:
09 April 2025
Posted:
10 April 2025
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Abstract
Keywords:
1. Introduction
2. Materials and Methods
2.1. Definition of Definite OAG
2.2. Definition of Endpoints
2.3. Statistical Methods and Model Development
2.4. Machine Learning Algorithms, Training and Testing
2.5. Feature Selection
2.6. Reject Option
3. Results
3.1. Overview of Demographic Data at Baseline
| Mean | SD | -95% CI | +95% CI | |
|---|---|---|---|---|
| Age (y) | 58.9 | 8.1 | 58.8 | 59.6 |
| Follow-up (years) | 11.1 | 1.1 | 10.99 | 11.2 |
| IOP (mmHg) | 15.3 | 3.2 | 15.1 | 15.6 |
| Total Contour Area (mm2) | 2.23 | 0.44 | 2.20 | 2.27 |
| Effective Area (mm2) | 0.96 | 0.39 | 0.93 | 0.99 |
| Neuroretinal Rim Area (mm2) | 1.28 | 0.33 | 1.25 | 1.31 |
| Half Depth Area (mm2) | 0.38 | 0.21 | 0.36 | 0.40 |
| Half Depth Volume (mm3) | -0.06 | 0.057 | -0.066 | -0.057 |
| Volume Below (mm3) | -0.26 | 0.19 | -0.27 | -0.24 |
| Cup-To-Disc Ratio | 0.42 | 0.14 | 0.41 | 0.43 |
| N | Percentage -95% CI 95% CI | |||
| Endpoint E1: OAG2 at 10 year FU |
21/585 | 3.6% 2.23% 5.43% | ||
| Endpoint E2: OAG2 at 10 year FU or IOP lowering therapy within 10 yrs |
41/585 | 7% 5.1% 9.4% | ||
3.2. Overview of Demographic Data at 10 Year FU
| Free of OAG and no IOP lowering therapy 10 yr FU (n=544) |
OAG or IOP lowering therapy at 10 yr FU (n=41) |
|||||
|---|---|---|---|---|---|---|
| Mean | Std | Mean | Std | Odds ratio | p-value | |
| Age (yrs) | 58.84 | 7.96 | 60.7 | 7.29 | 1.02 (0.99-1.08) | 0.161 |
| IOP (mmHg) | 15.1 | 2.83 | 18.5 | 4.27 | 1.33 (1.21-1.46) | < 0.00011* |
| PEX | 12/532 | 2.2% | 3/38 | 7.3% | 3.5 (0.6-13.7) | 0.0272* |
| Effective Area (mm2) | 0.95 | 0.40 | 1.08 | 0.32 | 2.37 (1.02-5.5) | 0.0421* |
| Neuroretinal Rim Area (mm2) | 1.29 | 0.32 | 1.19 | 0.18 | 0.38 (0.13-1.09) | 0.071 |
| Half Depth Area (mm2) | 0.37 | 0.21 | 0.44 | 0.20 | 4.0 (1.01-15.8) | 0.0471* |
| Half Depth Volume (mm3) | -0.06 | 0.06 | -0.07 | 0.05 | 0.08 (0.008-7.09) | 0.261 |
| Volume Below (mm3) | -0.25 | 0.18 | -0.31 | 0.20 | 0.23 (0.05-0.996) | 0.0471* |
| Cup-To-Disc Ratio/0.1 unit change | 0.42 | 0.14 | 0.48 | 0.12 | 1.46 (1.11-1.92) | 0.0061* |
3.3. Illustration of the Models with Real Data
3.4. Illustration for the Need of Reject Option
4. Discussion
4.1. Discussion of Model M1
4.2. Discussion of Model M2
4.3. PEX as Risk Factor and how it Was Handled by the Models
4.4. Implication for Practical Purposes
4.5. Outlook and Further Developments
4.6. Strengths and Limitations of This Study
4.6.1. Strengths
4.6.2. Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
- Kashiwagi K., Kogure S., Mabuchi F., et al. Change in visual acuity and associated risk factors after trabeculectomy with adjunctive mitomycin C. Acta Ophthalmol 2016;94:561-570.
- Heijl A., Leske M.A.C. et al. Reduction of Intraocular Pressure and Glaucoma Progression. Results From the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268-1279.
- Quigley, H.A. Glaucoma. The Lancet 2011; 1367-1377.
- Tonti E, Tonti S, Mancini F, Bonini C, Spadea L, D’Esposito F, Gagliano C, Musa M, Zeppieri M. Artificial Intelligence and Advanced Technology in Glaucoma: A Review. J Pers Med. 2024 Oct 16;14(10):1062. [CrossRef] [PubMed] [PubMed Central]
- Wu JH, Lin S, Moghimi S. Application of artificial intelligence in glaucoma care: An updated review. Taiwan J Ophthalmol. 2024 Sep 13;14(3):340-351. [4] Gordon M.O., Beiser J.A. Brandt J.D., Heuer D.K., Higginbotham E.J., Johnson C.A., Keltner J.L., Miller J.P., Parrish R.K. 2nd, Wilson MR, Kass MA. The Ocular Hypertension Treatment Study. Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714-720. [CrossRef] [PubMed] [PubMed Central]
- Ravindranath R, Stein JD, Hernandez-Boussard T, Fisher AC, Wang SY; SOURCE Consortium. The Impact of Race, Ethnicity, and Sex on Fairness in Artificial Intelligence for Glaucoma Prediction Models. Ophthalmol Sci. 2024 Aug 14;5(1):100596. [CrossRef] [PubMed] [PubMed Central]
- de Voogd S., Ikram M.K., Wolfs R.C., Jansonius N.M., Hofman A., de Jong P.T. Incidence of open-angle glaucoma in a general elderly population: the Rotterdam Study. Ophthalmology. 2005;112(9):1487-1493.
- Mukesh B.N., McCarty C.A., Rait J.L., Taylor H.R. Five-year incidence of open-angle glaucoma: the visual impairment project. Ophthalmology. 2002; 109(6):1047-1051.
- Leske M.C., Wu S.Y., Honkanen R., et al. Nine-year incidence of open-angle glaucoma in the Barbados Eye Studies. Ophthalmology. 2007;114(6):1058-1064.
- Bengtsson, B.O. Incidence of manifest glaucoma. Br J Ophthalmol. 1989;73(7):483-487.
- Kroese M., Burton H., Vardy S., Rimmer T., McCarter D. Prevalence of primary open angle glaucoma in general ophthalmic practice in the United Kingdom. Br J Ophthalmol. 2002;86(9):978-980.
- Hitzl W., Hornykewycz K., Grabner G., Reitsamer H.A. On the relationship between age and prevalence and/or incidence of primary open-angle glaucoma in the „Salzburg-Moorfields Collaborative Glaucoma Study. Klin Monatsbl Augenheilkd. 2007;224(2):115-9.
- Coleman A.L. and Miglor S. Risk factors for glaucoma oneset and progression. Surv Ophthalmol 2008 Nov;53 Suppl1:S3-10.
- European Glaucoma Society. Terminology and Guidelines for Glaucoma. IInd Edition, Editrice DOGMA S.r.l, 2003.
- Oskarsdottir S.E., Heijl A., Bengtsson B. Predicting undetected glaucoma according to age and IOP: a prediction model developed from a primarily European-derived population. Acta Ophthalmol. 2019;97(4):422-426.
- Ekstrom, C. Elevated intraocular pressure and pseudoexfoliation of the lens capsule as risk factors for chronic open-angle glaucoma. A population-based five-year follow-up study. Acta Ophthalmol (Copenh) 1993;71:189–195.
- Ekström C., Alm A. Pseudoexfoliation as a risk factor for prevalent open-angle glaucoma.Acta Ophthalmol. 2008 Jun 19.
- Bishop C. M., Neural networks for pattern recognition (1995), Oxford university press Inc., United States.
- Hill, T. & Lewicki, P. (2007). STATISTICS Methods and Applications. StatSoft, Tulsa, OK.
- Wolfram Research, Inc., Mathematica, Version 13, Champaign, IL (2022).
- Li Z., He Y., Keel S., Meng W., Chang R.T., He M. Efficacy of a Deep Learning System for Detecting Glaucomatous Optic Neuropathy Based on Color Fundus Photographs Ophthalmology. 2018;125(8):1199-1206.
- Asaoka R., Murata H., Hirasawa K., Fujino Y., Matsuura M., Miki A., Kanamoto T., Ikeda Y., Mori K., Iwase A, Shoji N, Inoue K., Yamagami J., Araie M. Using Deep Learning and Transfer Learning to Accurately Diagnose Early-Onset Glaucoma From Macular Optical Coherence Tomography Images. Am J Ophthalmol. 2019;198:136-145.

| Endpoint | Percentage of eyes filtered out/received a prediction (%) | Performances of the models3 (n/%) |
Advantages | Disadvantages | Remarks |
|---|---|---|---|---|---|
| E11 | 53.6%/46.4% | 271/271 (100%) | 46.4% of all eyes can safely be excluded from a glaucoma screening program for up to 10 years if one wants to be certain that the eye remains free of OAG. This significantly reduces the screening amount of ophthalmologists. |
53.6% did not receive a prediction. Eyes receiving IOP lowering therapy were not filtered out. |
This model is designed for patients in a glaucoma screeing setting within a hospital, if the patient wants to remain within the screening program and IOP lowering therapy can be continued. |
| E22 | 57%/43% | 253/253 (100%) | 43% of all eyes can safely be excluded from a glaucoma screening program for up to 10 years if one wants to be certain that the eye remains free of OAG and will not have any need for a IOP lowering therapy. This also significantly reduces the screening amount. |
57% did not receive a prediction. | Eyes can safely be excluded from the OAG screening program, especially if the patient wants to leave the screening program. |
| Initial exam | Predictions of endpoint E2 made at initial exam | Observed endpoint E2 at the 10 yr FU |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age | IOP1 | EA2 | NR3 | VB4 | HDA5 | HD6 | C/D7 | PEX8 | ||
| 62 | 12 | 0.85 | 1.22 | -0.15 | 0.19 | -0.02 | 0.41 | No | No prediction | Free of OAG/no IOP low. therapy |
| 63 | 14 | 0.66 | 1.46 | -0.15 | 0.24 | -0.03 | 0.31 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 56 | 15 | 1.49 | 1.18 | -0.35 | 0.60 | -0.07 | 0.56 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 61 | 15 | 1.22 | 0.76 | -0.52 | 0.48 | -0.11 | 0.62 | No | No prediction | OAG |
| 66 | 14 | 1.41 | 1.10 | -0.34 | 0.50 | -0.09 | 0.56 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 42 | 17 | 0.51 | 1.73 | -0.10 | 0.19 | -0.03 | 0.23 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 54 | 14 | 0.85 | 0.91 | -0.13 | 0.32 | -0.02 | 0.49 | No | No prediction | OAG |
| 69 | 13 | 0.96 | 1.14 | -0.18 | 0.39 | -0.05 | 0.46 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 66 | 14 | 1.13 | 1.21 | -0.31 | 0.34 | -0.06 | 0.48 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 70 | 14 | 1.09 | 1.44 | -0.17 | 0.27 | -0.028 | 0.43 | Yes | No prediction | IOP low. therapy |
| 59 | 18 | 0.83 | 1.18 | -0.21 | 0.22 | -0.04 | 0.41 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 62 | 15 | 0.99 | 1.21 | -0.45 | 0.39 | -0.12 | 0.45 | No | No prediction | Free of OAG/no IOP low. therapy |
| 57 | 12 | 0.50 | 1.39 | -0.06 | 0.20 | -0.01 | 0.27 | No | Free of OAG/no IOP low. therapy | Free of OAG/no IOP low. therapy |
| 58 | 13 | 1.16 | 0.97 | -0.65 | 0.66 | -0.22 | 0.54 | No | No prediction | Free of OAG/no IOP low. therapy |
| 57 | 16 | 1.25 | 0.94 | -0.41 | 0.69 | -0.12 | 0.57 | No | No prediction | Free of OAG/no IOP low. therapy |
| 62 | 12 | 1.21 | 1.25 | -0.64 | 0.70 | -0.19 | 0.49 | No | No prediction | Free of OAG/no IOP low. therapy |
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