time is at least as important as estimating the risk of unaffected patients developing glaucoma. The development of predictive models for glaucoma progression could use the same principles as those used to develop and validate models for glaucoma development. Initially, longitudinal studies that followed patients with glaucoma would have to be reviewed to identify risk factors associated with progressive disease.

Several studies have investigated the risk factors for progression in patients with established glaucomatous damage. The Early Manifest Glaucoma Trial (EMGT) (Heijl et al., 2002) was designed specifically to evaluate the effect of IOP-lowering treatment on progression of glaucoma. The EMGT enrolled 255 newly diagnosed, previously untreated, open-angle glaucoma patients who had reproducible visual-field defects at baseline. Patients with advanced visual-field loss or IOP greater than 30 mmHg at baseline were excluded. Patients were randomized to 3601 trabeculoplasty plus betaxolol versus no treatment. Eyes stayed in their allocation arms unless significant progression

35 mmHg in control eyes, latanoprost was added. Patients were followed for a median of 6 years, with excellent retention. Baseline IOP in treated and untreated groups were 20.674.1 and 20.974.1 mmHg, respectively. Mean IOP reduction was 25% in the treated group, with no changes in the control group. At study closure, the proportion of patients who developed progression was significantly larger in the control versus the treatment group (62% vs. 45%, respectively; HR ¼ 0.60; 95% CI: 0.42–0.84; P ¼ 0.003). Differences between treated and untreated patients remained when results were stratified by baseline IOP level (o21 mmHg or Z21 mmHg), degree of visual-field damage, age, or presence of exfoliation.

Besides IOP, several other risk factors were identified by the EMGT as significantly associated with the risk of glaucoma progression: older age, exfoliation, presence of bilateral disease, and worse mean deviation on the baseline visual fields. Recently, the EMGT also published results on the long-term follow-up of the original cohort and

23

concluded that thinner central corneal thickness and decreased ocular perfusion pressure were also associated with higher risk of visual-field progression over time.

A predictive model could theoretically be developed based on the results from the EMGT incorporating all the risk factors found to be significantly associated with progressive disease. Such a model would be helpful in estimating which glaucoma patients are at higher risk for developing progressive loss of visual function. It is important to emphasize that any predictive model developed on the basis of the EMGT or other studies evaluating risk factors for glaucoma progression would have to be validated on an independent population of patients, as described above for the risk calculators in ocular hypertension.

Limitations of predictive models

The use of predictive models in clinical practice has several limitations. Predictive models are based on restricted populations of patients that were selected based on strict inclusion and exclusion criteria and that may not be representative of all patients seen at everyday clinical settings. Use of these models should be restricted to those patients who are similar to the ones included in the studies used to develop and/or validate it. It is also important to emphasize that although predictive models can provide a more objective evaluation of risk, their use does not replace the judgment of a clinician when making management decisions. For example, current risk calculators to estimate risk of glaucoma development do not include important information to guide treatment such as medical health status and life expectancy, patient’s willingness to treatment, costs of medications, and overall effect of treatment on quality of life. Also, it is important to emphasize that current risk calculators for glaucoma have been designed to estimate the risk of development of the earliest signs of disease, which do not necessarily have an impact on the quality of vision of the patient. Finally, as more evidence regarding risk factors for disease development and progression accumulates, newer and better refined

24

predictive models will be developed that should replace current existing ones.

References

Brandt, J.D. (2001) The influence of corneal thickness on the diagnosis and management of glaucoma. J. Glaucoma, 10(5 (Suppl 1)): S65–S67.

Coleman, A.L., Gordon, M.O., et al. (2004) Baseline risk factors for the development of primary open-angle glaucoma in the ocular hypertension treatment study. Am. J. Ophthalmol., 138(4): 684–685.

Copt, R.P., Thomas, R., et al. (1999) Corneal thickness in ocular hypertension, primary open-angle glaucoma, and normal tension glaucoma. Arch. Ophthalmol., 117(1): 14–16.

D’Agostino, R.B. and Nam, B.H. (2004). Evaluation of the performance of survival analysis models: discrimination and calibration measures. In: N. Balakrishnan and C.R. Rao (Eds.). Handbook of Statistics, Vol. 23. Elsevier, Amsterdam.

D’Agostino, R.B., Sr., Grundy, S., et al. (2001) Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA, 286(2): 180–187.

D’Agostino, R.B., Russell, M.W., et al. (2000) Primary and subsequent coronary risk appraisal: new results from the Framingham study. Am. Heart J., 139(2 (Pt 1)): 272–281.

Doughty, M.J. and Zaman, M.L. (2000) Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv. Ophthalmol., 44(5): 367–408.

Ehlers, N., Bramsen, T., et al. (1975) Applanation tonometry and central corneal thickness. Acta Ophthalmol. (Copenh.), 53(1): 34–43.

Gordon, M.O., Beiser, J.A., et al. (2002) The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucomaArch. Ophthalmol., 120(6): 714–720; discussion 829–830.

Gordon, M.O. and Kass, M.A. (1999) The ocular hypertension treatment study: design and baseline description of the participants. Arch. Ophthalmol., 117(5): 573–583.

Gordon, M.O., Torri, V., et al. (2007) Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology, 114(1): 10–19.

Heijl, A., Leske, M.C., et al. (2002) Reduction of intraocular pressure and glaucoma progression: results from the early manifest glaucoma trial. Arch. Ophthalmol., 120(10): 1268–1279.

Herndon, L.W., Choudhri, S.A., et al. (1997) Central corneal thickness in normal, glaucomatous, and ocular hypertensive eyes. Arch. Ophthalmol., 115(9): 1137–1141.

Kass, M.A., Heuer, D.K., et al. (2002) The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucomaArch. Ophthalmol., 120(6): 701–713; discussion 829–830.

Liu, J., Hong, Y., et al. (2004) Predictive value for the Chinese population of the Framingham CHD risk assessment tool compared with the Chinese multi-provincial cohort study. JAMA, 291(21): 2591–2599.

Mansberger, S.L. and Cioffi, G.A. (2006) The probability of glaucoma from ocular hypertension determined by ophthalmologists in comparison to a risk calculator. J. Glaucoma, 15(5): 426–431.

Medeiros, F.A., Sample, P.A., et al. (2003a) Corneal thickness measurements and frequency doubling technology perimetry abnormalities in ocular hypertensive eyes. Ophthalmology, 110(10): 1903–1908.

Medeiros, F.A., Sample, P.A., et al. (2003b) Corneal thickness measurements and visual function abnormalities in ocular hypertensive patients. Am. J. Ophthalmol., 135(2): 131–137.

Medeiros, F.A., Weinreb, R.N., et al. (2005) Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch. Ophthalmol., 123(10): 1351–1360.

Miglior, S., Pfeiffer, N., et al. (2007) Predictive factors for openangle glaucoma among patients with ocular hypertension in the European glaucoma prevention study. Ophthalmology, 114(1): 3–9.

Miglior, S., Zeyen, T., et al. (2002) The European glaucoma prevention study design and baseline description of the participants. Ophthalmology, 109(9): 1612–1621.

Miglior, S., Zeyen, T., et al. (2005) Results of the European glaucoma prevention study. Ophthalmology, 112(3): 366–375.

Parrish, R.K., 2nd (2006) The European glaucoma prevention study and the ocular hypertension treatment study: why do two studies have different results? Curr. Opin. Ophthalmol., 17(2): 138–141.

Quigley, H.A. (2005) European glaucoma prevention studyOphthalmology, 112(9): 1642–1643; author reply 1643–1645.

Tielsch, J.M., Katz, J., et al. (1991) A population-based evaluation of glaucoma screening: the Baltimore eye survey. Am. J. Epidemiol., 134(10): 1102–1110.

Weinreb, R.N., Friedman, D.S., Fechtner, R.D., Cioffi, G.A., Coleman, A.L., Girkin, C.A., Liebmann, J.M., Singh, K., Wilson, M.R., Wilson, R. and Kannel, W.B. (2004) Risk assessment in the management of patients with ocular hypertension. Am. J. Ophthalmol., 138(3): 458–467.

Whitacre, M.M., Stein, R.A., et al. (2004) The effect of corneal thickness on applanation tonometry. Am. J. Ophthalmol., 115(5): 592–596.