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of the risk of development and progression of glaucoma. The purpose of this chapter is to review the motivations and steps involved in the construction and validation of predictive models for the development and progression of glaucoma.

Risk assessment in ocular hypertension and glaucoma

Glaucoma is a neurodegenerative disease of the optic nerve that presents to the practitioner at various stages of a continuum and is characterized by accelerated retinal ganglion cell death, subsequent axonal loss and optic-nerve damage, and eventual visual-field loss (Fig. 1). These initial changes in the retina and optic nerve are often asymptomatic and undetectable with existing diagnostic tests. Also, there is no agreement on the criteria for the diagnosis of early damage that precedes standard achromatic visual-field loss. This suggests that awaiting overt signs of disease involves accepting some irreversible damage and probable progression. As optic-nerve damage progresses, severe visual dysfunction and blindness may ensue in a small group of patients. Since many patients present in the early stages of the disease, the goal of treatment is to arrest or delay the progression of early optic-nerve damage to significant visual impairment.

It is estimated that approximately 8% of adults over the age of 40 years in the United States have ocular hypertension (Tielsch et al., 1991). While ocular hypertension is a common finding, eye-care providers do not know which patients to treat or which patients to monitor without treatment. In 2002, the publication of the results of the Ocular Hypertension Treatment Study (OHTS) stimulated a reassessment of the ways in which to evaluate and manage patients with ocular hypertension (Gordon et al., 2002; Kass et al., 2002). Since the OHTS publication, several strategies for risk assessment in ocular hypertension have been proposed and some have been successfully implemented in clinical practice. Several predictive models (or risk calculators) have been proposed and their use in clinical practice is likely to provide a more objective and evidence-based approach to the management of patients with ocular hypertension.

Risk factors for glaucoma development

The development of predictive models requires a series of complex steps which initially involve the acquisition and analysis of data from one or multiple longitudinal studies that have carefully followed patients over time. A critical step is the identification of the risk factors associated with the

outcome one wants to predict. A few large, prospective, longitudinal studies have provided evidence with regard to the risk factors for conversion from ocular hypertension to glaucoma. From these studies, two were randomized clinical trials, the OHTS (Gordon et al., 2002) and the European Glaucoma Prevention Study (EGPS) (Miglior et al., 2007). These two studies have provided the basis for development and validation of the prediction models for glaucoma development available today. Both studies have evaluated a large number of predictive factors for their potential association with the risk of converting to glaucoma. When pooled analyses of the OHTS and EGPS data were conducted, only five baseline factors were identified as significantly associated with the risk of converting to glaucoma: age, intraocular pressure (IOP), central corneal thickness, the measurement of the vertical cup/disc ratio of the optic nerve, and the visual-field index pattern standard deviation (PSD) (Gordon et al., 2007). Table 1 shows relative risks for the baseline predictive factors found to be significantly associated with the risk of developing glaucoma in these two studies. These predictive factors have been incorporated into predictive models to estimate the risk of converting from ocular hypertension to glaucoma.

Several other factors were not found to be statistically significantly related to the risk of conversion to glaucoma in the OHTS/EGPS pooled dataset, such as diabetes mellitus, history of heart disease, and race, among others. It is important to emphasize, however, that even for the OHTS/EGPS combined dataset, the power of the study was probably not enough to detect a significant predictive value for many of the

Table 1. OHTS vs. EGPS — risk factors

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evaluated risk factors. Also, methodological weaknesses precluded a better investigation of the real value of potential risk factors, such as positive family history of glaucoma. As no relatives of the study subjects were examined, investigators had to rely on self-reported family history with its potential inaccuracy. It is likely that this contributed to the lack of association between family history and risk of glaucoma development as reported by these investigations.

Below, we review some of the evidence with regard to the predictive value of risk factors reported to be associated with glaucoma development.

Intraocular pressure

In the OHTS, 1636 ocular hypertensive patients were randomized to either observation or treatment and followed for a median time of 72 months. Ocular hypertension was defined based on the presence of qualifying IOP between 24 and 32 mmHg in one eye and 21 and 32 mmHg in the other eye, gonioscopically open angles, normal visual fields, and normal optic discs (Gordon and Kass, 1999). Participants randomized to medication began treatment to achieve a target IOP of 24 mmHg or less and a minimum of 20% reduction in IOP from the average of the qualifying IOP and IOP at the baseline randomization visit. At baseline, mean IOP was 24.972.6 and 24.972.7 mmHg in the treated and observation groups, respectively. The average IOP reduction in the treated group was 22.579.9% compared to 4.0711.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group compared to 9.5% in the observation group, which

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translates into a 54% relative reduction in the risk of developing POAG with treatment. In the analysis of baseline predictive factors for development of POAG, 1 mmHg higher baseline IOP was associated with a 10% higher risk of developing POAG during follow-up, after adjustment for other predictive factors in a multivariate model (Gordon et al., 2002). For this calculation, baseline IOP was calculated from four to six baseline IOP measurements per eye.

The EGPS (Miglior et al., 2005) was also designed to investigate whether the onset of POAG can be prevented or delayed in ocular hypertensive patients by medical hypotensive therapy. Inclusion criteria for the EGPS were similar to the OHTS, requiring participants to have normal visual fields and normal optic discs at baseline. However, qualifying IOP had to be between 22 and 29 mmHg in at least one eye on two consecutive measurements taken at least 2 h apart. There was no mention with regard to the IOP in the other eye in the study protocol (Miglior et al., 2002). The EGPS randomized 1081 patients to treatment with Dorzolamide or placebo, with a planned follow-up of 5 years. However, only 64% of patients randomized to Dorzolamide and 75% of the patients randomized to placebo completed the

groups, respectively. Mean IOP reduction at 5 years was 22.1% in the Dorzolamide group and 18.7% in the placebo group. At the completion of the study, there was no statistically significant difference in the cumulative probability of developing POAG between patients randomized to Dorzolamide versus placebo (13.4 vs. 14.1%, respectively; HR ¼ 0.86; 95% CI: 0.58–1.26).

Several reasons have been proposed to explain the conflicting results between the OHTS and EGPS including regression to the mean effects, lack of target IOP, and selective loss to follow-up (Quigley, 2005; Parrish, 2006). However, despite the fact that the EGPS could not find significant differences between Dorzolamide and placebo groups on the rate of POAG development, its results are compatible with higher IOP being a risk factor for POAG incidence. A 1 mmHg higher baseline IOP was associated with 18% higher

risk of developing POAG (HR ¼ 1.18; 95% CI: 1.06–1.31; P ¼ 0.002) in a multivariable model containing age, presence of cardiovascular disease, CCT, and presence of pseudoexfoliation (Miglior et al., 2007).

In the pooled analysis of the OHTS and EGPS control groups (1319 patients followed without treatment), 1 mmHg higher baseline IOP was associated with 9% higher risk of developing POAG (HR ¼ 1.09; 95% CI: 1.03–1.17), after adjustment for other predictive factors (Gordon et al., 2007). It is important to note that even for this pooled analysis, the 95% confidence interval was still relatively large, ranging from 1.03 to 1.17. That is, each 1 mmHg increased IOP could be associated with 3%–17% increased risk.

Corneal thickness

Corneal thickness is another factor that has been associated with the risk of conversion from OHT to glaucoma. IOP as assessed by applanation tonometry may be overestimated or underestimated in thick or thin corneas, respectively (Ehlers et al., 1975; Whitacre et al., 1993; Herndon et al., 1997; Copt et al., 1999; Doughty and Zaman, 2000; Brandt, 2001). A considerable subset of patients classified as having ocular hypertension may simply have thicker than average corneas that result in an overestimation of what is likely a normal, true IOP. As a consequence, OHT patients with thicker corneas may be at a lower risk for glaucoma development. In fact, the OHTS showed that CCT was a powerful predictor of development of primary open-angle glaucoma among ocular hypertensive eyes (Gordon et al., 2002). Eyes with CCT of 555 mm or less had a threefold greater risk of developing glaucoma compared with participants who had CCT of more than 588 mm. A 40 mm thinner cornea was associated with a 71% increase in the risk of converting to glaucoma among OHTS patients in a multivariate model adjusting for other risk factors. Similar results were found by the EGPS, with a 40 mm thinner cornea being associated with a 32% increase in the risk of converting to glaucoma in the multivariate model. Recent results from the Barbados Eye Study, a population-based cohort