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1.  Longitudinal Trends in Resource Utilization in an Incident Cohort of Open Angle Glaucoma Patients 
American journal of ophthalmology  2012;154(3):452-459.e2.
To characterize the costs of caring for patients with open-angle glaucoma (OAG) in the United States (US) over time and to identify factors that influence these costs.
Longitudinal cohort study.
Claims data from 19,927 newly-diagnosed OAG patients enrolled in a large US managed care network were reviewed to identify glaucoma-related charges for all incident OAG patients from 2001–2009. Average glaucoma-related charges for enrollees with OAG were characterized in six month blocks from the date of initial OAG diagnosis through the following 5 years. Factors associated with being an enrollee in the costliest 5% for glaucoma-related charges (accruing ≥$5810 in charges in the first 2 years) were identified using logistic regression.
The costliest 5% of enrollees were responsible for $10,202,871 (24%) of all glaucoma-related charges. By comparison, those whose costs fell within the lower 50% of the cost distribution collectively amassed only $7,986,582 (19%) of all glaucoma-related charges. A spike in glaucoma-related charges occurred in the 6 month period around the time of OAG diagnosis, stabilized by 1 year following diagnosis, and remained relatively constant over time. Risk factors associated with being in the costliest 5% for glaucoma-related care included younger age, Northeastern US state residence, undergoing cataract surgery, and possessing ocular co-morbidities.(p<0.006 for all comparisons).
A small subset of enrollees account for a large proportion of all glaucoma-related charges. Understanding the characteristics of these individuals and finding ways to reduce disease burden and costs associated with their care can result in substantial cost savings.
PMCID: PMC3422396  PMID: 22789564
2.  Factors Associated with Intraocular Pressure Prior to and during Nine Years of Treatment in the Collaborative Initial Glaucoma Treatment Study 
Ophthalmology  2007;115(6):927-933.
To evaluate, both at initial glaucoma diagnosis and during treatment, the role of demographic and clinical factors on intraocular pressure (IOP).
Cohort study of patients enrolled in a randomized clinical trial.
607 patients with newly diagnosed, open-angle glaucoma (OAG) were enrolled at 14 U.S. centers.
After randomization to initial surgery or medications, patients were followed at six-month intervals. IOP was measured by Goldmann applanation tonometry. Predictive factors for IOP at baseline and during follow-up were analyzed using linear mixed models.
Main Outcome Measure
IOP at baseline and during follow-up.
The mean baseline IOP was 27.5 mmHg (standard deviation, 5.6 mmHg). Predictive factors for higher baseline IOP included younger age (0.7 mmHg per 10 years), male sex (2.4 mmHg higher than females), pseudoexfoliative glaucoma (5.4 mmHg higher than primary OAG), and pupillary defect (2.2 mmHg higher than those without a defect). During nine years of follow-up, both surgery and medications dramatically reduced IOP from baseline levels, but the extent of IOP reduction was consistently greater in the surgery group. Over follow-up years 2–9, mean IOP was 15.0 vs. 17.2 mmHg for surgery vs. medicine, respectively. Predictive associations with higher IOP during follow-up included higher baseline IOP (P<0.0001), worse baseline visual field (mean deviation; P<0.0001), and lower level of education (P=0.0019). Treatment effect was modified by smoking status: non-smokers treated surgically had lower IOP than smokers treated surgically (14.6 vs. 16.7 mmHg, respectively; P=0.0013). Clinical center effects were significant (P<0.0001) in both the baseline and follow-up models.
In this large cohort of newly diagnosed glaucoma patients, predictors of pre-treatment IOP and IOP measurements over nine years of follow-up were identified. Our findings lend credence to the postulate that sociodemographic, economic, compliance, or other environmental influences play a role in IOP control during treatment.
PMCID: PMC2758572  PMID: 17964655
3.  Comparison of Newly Diagnosed Ocular Hypertension and Open-Angle Glaucoma: Ocular Variables, Risk Factors, and Disease Severity 
Journal of Ophthalmology  2011;2012:757106.
Purpose. To describe the distribution of ocular variables, risk factors, and disease severity in newly diagnosed ocular hypertension (OH) or open-angle glaucoma (OAG). Methods. Eligible subjects underwent a complete history and examination. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) obtained from multiple logistic regression models were used to compare OAG to OH and advanced to early/moderate OAG. Results. 405 subjects were enrolled: 292 (72.1%) with OAG and 113 (27.9%) with OH. 51.7% had early, 27.1% moderate, and 20.9% advanced OAG. The OR for OAG versus OH was 8.19 (P < 0.0001) for disc notch, 5.36 (P < 0.0001) for abnormal visual field, 1.45 (P = 0.001) for worsening mean deviation, 1.91 (P < 0.0001) for increased cupping, 1.03 for increased age (P = 0.030), and 0.36 (P = 0.010) for smoking. Conclusions. Increased age was a risk for OAG, and smoking decreased the risk of OAG compared to OH. Almost half of the OAG subjects had moderate/advanced disease at diagnosis.
PMCID: PMC3159007  PMID: 21869921
4.  The Relationship Between Statin Use and Open-Angle Glaucoma 
Ophthalmology  2012;119(10):2074-2081.
To determine whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) affect the risk of developing open-angle glaucoma (OAG) in persons with hyperlipidemia.
Retrospective longitudinal cohort analysis.
Individuals age ≥60 with hyperlipidemia enrolled in a national United States managed care network between 2001 and 2009.
Multivariable Cox regression analyses were performed to assess the relationship between statin use and the development of OAG (from no prior OAG diagnosis), progression from a prior diagnosis of suspected glaucoma to a diagnosis of OAG, and need for medical or surgical interventions for OAG. Regression models were adjusted for sociodemographic factors, medical and ocular comorbidities.
Main Outcome Measures
Hazard ratios (HR) with 95% confidence intervals (CI).
Of the 524,109 individuals with hyperlipidemia, 316,182 (60%) had at least 1 outpatient prescription for statins. The hazard of developing OAG decreased 0.3% (adjusted HR = 0.997, CI (0.994–0.999)) for every additional month of statin consumption. Individuals with hyperlipidemia who took statins continuously for 2 years had an 8% (adjusted HR = 0.922, CI (0.870–0.976) decreased OAG risk relative to those who received no statin therapy. The hazard of progressing from a diagnosis of suspected glaucoma to OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.999)) for every additional month of statin exposure. Individuals who took statins continuously for 2 years had a 9% (adjusted HR = 0.907, CI (0.846–0.973) decreased risk of progressing from suspected glaucoma to OAG relative to those who received no statin therapy. The hazard of requiring medical treatment for OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.998)) for every additional month of statin exposure. No significant differences in need for glaucoma surgery were noted among those with OAG who were and were not taking statins (adjusted HR = 1.002, CI (0.994–1.010)).
Statin use was associated with a significant reduction in the risk of OAG in persons with hyperlipidemia. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG.
PMCID: PMC3459293  PMID: 22727176
5.  Selective laser trabeculoplasty 
The introduction of selective laser trabeculoplasty (SLT) provided a new choice for the reduction of intraocular pressure (IOP) in eyes with open angle glaucoma (OAG) and ocular hypertension (OHT). SLT was demonstrated equally as effective as topical medical therapy and argon laser trabeculoplasty (ALT) to lower IOP. It is a potentially repeatable procedure because of the lack of coagulation damage to the trabecular meshwork (TM) and also effect in patients with previously failed ALT. SLT can be used to treat patients with OAG, pseudoexfoliation glaucoma, pigmentary glaucoma, normal-tension glaucoma, OHT, juvenile glaucoma, pseudophakic and aphakic glaucoma. Furthermore, SLT can be considered as a primary treatment option in patients who cannot tolerate or are noncompliant with medications, while not interfering with the success of future surgery. Its safety profiles include mild and transient inflammation, ocular pain and a small risk of moderate IOP elevations after the procedure. SLT is a safe and effective means of IOP reduction in eyes with OAG and OHT.
PMCID: PMC3530819  PMID: 23275911
open angle glaucoma; intraocular pressure; selective laser trabeculoplasty
6.  Baseline Risk Factors that Predict the Development of Open-angle Glaucoma in a Population: The Los Angeles Latino Eye Study 
Ophthalmology  2012;119(11):2245-2253.
To determine which baseline socio-demographic, lifestyle, anthropometric, clinical, and ocular risk factors predict the development of open-angle glaucoma (OAG) in an adult population.
A population-based, prospective cohort study.
A total of 3,772 self-identified Latinos aged 40 years and older from Los Angeles, California who were free of OAG at baseline.
Participants from the Los Angeles Latino Eye Study had standardized study visits at baseline and 4-year follow-up with structured interviews and a comprehensive ophthalmologic examination. OAG was defined as the presence of an open angle and a glaucomatous visual field abnormality and/or evidence of glaucomatous optic nerve damage in at least one eye. Multivariate logistic regression with stepwise selection was performed to determine which potential baseline risk factors independently predict the development of OAG.
Main Outcome Measure
Odds ratios for various risk factors.
Over the 4-year follow-up, 87 participants developed OAG. The baseline risk factors that predict the development of OAG include: older age (odds ratio [OR] per decade, 2.19; 95% confidence intervals [CI], 1.74-2.75; P<0.001), higher intraocular pressure (OR per mmHg, 1.18; 95% CI, 1.10-1.26; P<0.001), longer axial length (OR per mm, 1.48; 95% CI, 1.22-1.80; P<0.001), thinner central cornea (OR per 40 μm thinner, 1.30; 95% CI, 1.00-1.70; P=0.050) higher waist to hip ratio (OR per 0.05 higher, 1.21; 95% CI, 1.05-1.39; P=0.007) and lack of vision insurance (OR, 2.08; 95% CI, 1.26-3.41; P=0.004).
Despite a mean baseline IOP of 14 mmHg in Latinos, higher intraocular pressure is an important risk factor for developing OAG. Biometric measures suggestive of less structural support such as longer axial length and thin CCT were identified as important risk factors. Lack of health insurance reduces access to eye care and increases the burden of OAG by reducing the likelihood of early detection and treatment of OAG.
PMCID: PMC3474872  PMID: 22796305
7.  Predictors of additional intraocular pressure reduction in patients changed to latanoprost/timolol fixed combination 
BMC Ophthalmology  2010;10:10.
Given the growing number of ocular hypotensive medications available, it is important to be able to predict a positive response to therapy. The purpose of the present study was to identify predictors of an additional 10% intraocular pressure (IOP) reduction after 12 weeks of treatment with latanoprost/timolol fixed combination (FC) in patients requiring a change in their previous ocular hypotensive medication.
This multicenter, open-label, prospective, phase IIIb study included subjects ≥18 years of age with open-angle glaucoma (OAG) or ocular hypertension (OHT). Eligible subjects had baseline IOP ≥21 mmHg and insufficient response to current beta-blocker monotherapy. The primary efficacy analysis (logistic regression) identified predictors of a positive response after 12 weeks of latanoprost/timolol FC.
The intent-to-treat (ITT) population included 383 subjects treated with ≥1 drop of FC and having ≥1 follow-up IOP assessment. Mean IOP was 22.19 ± 2.16 mmHg at baseline and was reduced by 5.42 ± 2.71 mmHg at study end. In all, 325 (84.9%) subjects had a positive response to latanoprost/timolol FC; the response rate was similar across groups: OAG (n = 208; 82.7%); OHT (n = 161; 87.6%); OAG+OHT (n = 14; 85.7%). Higher baseline IOP (odds ratio: 1.284; 95% confidence interval [CI]: 1.101, 1.497; p = 0.0014) and absence of adverse events (odds ratio: 0.318; 95% CI: 0.161, 0.629; p = 0.0010) were significant predictors of positive response. Age, gender, ethnic origin, diagnosis, family history of OAG/OHT, corneal thickness, and concomitant systemic beta-blocker were not significant predictors of a positive response in the ITT analysis. The FC was well tolerated. The most common adverse events were related to the eye and were consistent with known adverse events associated with latanoprost and timolol.
These results support the use of latanoprost/timolol FC in patients whose IOP is insufficiently controlled on beta-blocker monotherapy. Patients with higher baseline IOP levels and who do not experience adverse events while on therapy are most likely to achieve a positive response to latanoprost/timolol FC.
Trial Registration
Study registration number: NCT00230763
PMCID: PMC2861019  PMID: 20346127
8.  Mathematical modeling approaches in the study of glaucoma disparities among people of African and European descents 
Open angle glaucoma (OAG) is a severe ocular disease characterized by progressive and irreversible vision loss. While elevated intraocular pressure (IOP) is a well-established risk factor for OAG, the progression of OAG in many cases, despite IOP treatment, suggests that other risk factors must play significant roles in the development of the disease. For example, various structural properties of the eye, ocular blood flow properties, and systemic conditions have been identified as risk factors for OAG. Ethnicity has also been indicated as a relevant factor that affects the incidence and prevalence of OAG; in fact, OAG is the leading cause of blindness among people of African descent. Numerous clinical studies have been designed to examine the possible correlation and causation between OAG and these factors; however, these studies are met with the challenge of isolating the individual role of multiple interconnected factors. Over the last decade, various mathematical modeling approaches have been implemented in combination with clinical studies in order to provide a mechanical and hemodynamical description of the eye in relation to the entire human body and to assess the contribution of single risk factors to the development of OAG. This review provides a summary of the clinical evidence of ocular structural differences, ocular vascular differences and systemic vascular differences among people of African and European descent, describes the mathematical approaches that have been proposed to study ocular mechanics and hemodynamics while discussing how they could be used to investigate the relevance to OAG of racial disparities, and outlines possible new directions of research.
PMCID: PMC3912249  PMID: 24501718
Mathematical Modeling; Glaucoma; Blood Flow; Ocular Mechanics; Ocular Hemodynamics
9.  The Relationship Between Components of Metabolic Syndrome and Open-Angle Glaucoma 
Ophthalmology  2011;118(7):1318-1326.
To determine whether an association exists between various components of metabolic syndrome (diabetes mellitus (DM), systemic arterial hypertension (HTN), hyperlipidemia, and obesity) and open-angle glaucoma (OAG) in a large, diverse group of individuals throughout the United States.
Longitudinal cohort study.
All beneficiaries age ≥40 years continuously enrolled in a managed care network who had ≥1 visit to an eye care provider were identified from 2001–2007.
Billing codes were used to identify individuals with OAG and those with components of metabolic syndrome. Cox regression was used to determine the hazard of developing OAG in enrollees with individual components or combinations of components of metabolic syndrome, with adjustment for sociodemographic factors, systemic medical conditions, and other ocular diseases.
Main Outcome Measures
Hazard of developing OAG.
Of the 2,182,315 enrollees who met inclusion criteria, 54,558 (2.5%) had OAG. After adjustment for confounding factors, those with DM (hazard ratio (HR)=1.35 [95% confidence interval (CI): 1.21–1.50]) or HTN (HR=1.17 [95% CI: 1.13–1.22]) alone, or in combination, (HR=1.48 [95% CI: 1.39–1.58]) had an increased hazard of developing OAG relative to persons with neither of these conditions. By contrast, persons with hyperlipidemia alone had a 5% decreased hazard of OAG (HR=0.95 [95% CI: 0.91–0.98]). Comorbid hyperlipidemia attenuated the increased hazard between HTN (HR=1.09 [95% CI 1.05–1.12]) or DM (HR=1.13 [95% CI 1.05–1.21]) and OAG.
Given the increasing prevalence of metabolic disorders in the United States, this study furthers our understanding of risk factors associated with OAG and helps identify persons who may be at risk for this condition.
PMCID: PMC3129406  PMID: 21481477
10.  Anterior Chamber Configuration Changes after Cataract Surgery in Eyes with Glaucoma 
To evaluate changes in anterior chamber depth (ACD) and angle width induced by phacoemulsification and intraocular lens (IOL) implantation in eyes with glaucoma, using anterior segment optical coherence tomography (AS-OCT).
Eleven eyes of 11 patients with angle-closure glaucoma (ACG) and 12 eyes of 12 patients with open-angle glaucoma (OAG) underwent phacoemulsification and IOL implantation. Using AS-OCT, ACD and angle parameters were measured before and 2 days after surgery. Change in intraocular pressure (IOP) and number of ocular hypotensive drugs were evaluated.
After surgery, central ACD and angle parameters increased significantly in eyes with glaucoma (p < 0.05). Prior to surgery, mean central ACD in the ACG group was approximately 1.0 mm smaller than that in the OAG group (p < 0.001). Post surgery, mean ACD of the ACG group was still significantly smaller than that of the OAG group. No significant differences were found in angle parameters between the ACG and OAG groups. In the ACG group, postoperative IOP at the final visit was significantly lower than preoperative IOP (p = 0.018) and there was no significant change in the number of ocular hypotensive medications used, although clinically, patients required fewer medications. In the OAG group, the IOP and number of ocular hypotensive drugs were almost unchanged after surgery.
The ACD and angle width in eyes with glaucoma increased significantly after phacoemulsification and IOL implantation. Postoperative ACD significantly differed between the ACG and OAG groups, whereas angle parameters did not differ.
PMCID: PMC3325628  PMID: 22511835
Angle-closure glaucoma; Anterior chamber; Anterior eye segment; Cataract extraction; Open-angle glaucoma
11.  Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy. 
Journal of Medical Genetics  1997;34(7):546-552.
The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too.
PMCID: PMC1050993  PMID: 9222961
12.  Trends in Utilization of Ancillary Glaucoma Tests for Patients with Open-Angle Glaucoma from 2001 to 2009 
Ophthalmology  2012;119(4):748-758.
To assess trends in the use of ancillary diagnostic tests in the evaluation of patients with open-angle glaucoma (OAG) and glaucoma suspects over the past decade.
Retrospective longitudinal cohort analysis.
169,917 individuals with OAG and 395,721 with suspected glaucoma age ≥40 enrolled in a national United States managed care network between 2001–2009.
Claims data were analyzed to assess trends in visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) testing for patients with OAG or suspected glaucoma in 2001–2009. Repeated measures logistic regression was performed to identify differences in the odds of undergoing these procedures in 2001, 2005, and 2009 and whether differences exist for patients under the exclusive care of optometrists versus ophthalmologists.
Main Outcome Measures
Odds and annual probabilities of undergoing VF testing, FP, and OOI for OAG from 2001–2009.
For patients with OAG, the odds of undergoing VF testing decreased by 36% from 2001 to 2005, 12% from 2005 to 2009, and 44% from 2001 to 2009. By comparison, the odds of having OOI increased by 100% from 2001 to 2005, 24% from 2005 to 2009, and 147% from 2001 to 2009. Probabilities of undergoing FP were relatively low (13–25%) for both provider types and remained fairly steady over the decade. For patients cared for exclusively by optometrists, the probability of VF testing decreased from 66% in 2001 to 44% in 2009. Among those seen exclusively by ophthalmologists, the probability of VF testing decreased from 65% in 2001 to 51% in 2009. The probability of undergoing OOI increased from 26% in 2001 to 47% in 2009 for patients of optometrists and from 30% in 2001 to 46% in 2009 for patients of ophthalmologists. By 2008, patients with OAG receiving care exclusively by optometrists had a higher probability of undergoing OOI than VF testing.
During 2001–2009 OOI rose dramatically whereas VF testing declined considerably. Since OOI has not been shown to be as effective at detecting OAG or disease progression compared to VF testing, increased reliance upon OOI technology, in lieu of VF testing, may be detrimental to patient care.
PMCID: PMC3319788  PMID: 22218146
13.  Differences in Rates of Glaucoma Among Asian Americans Compared With Other Races and Among Individuals of Different Asian Ethnicities 
Ophthalmology  2011;118(6):1031-1037.
To determine the incidence and prevalence rates of different glaucoma types among Asian Americans, contrast glaucoma incidence and prevalence rates for Asian Americans with other races, and evaluate the hazard of developing glaucoma among different Asian ethnicities and other races.
Retrospective longitudinal cohort study
2,259,061 beneficiaries aged ≥40 enrolled in a large, national managed-care network in the United States (US) in 2001–2007
Incidence and prevalence rates of open-angle glaucoma (OAG), narrow-angle glaucoma (NAG), and normal-tension glaucoma (NTG) were determined for the beneficiaries and stratified by race and Asian ethnicity. Cox regression analyses determined the hazard of developing OAG, NAG, and NTG for Asian Americans compared with other races and among different Asian ethnicities, with adjustment for confounding factors.
Main Outcome Measures
Multivariable hazard of OAG, NAG, and NTG among different races and Asian ethnicities.
The OAG prevalence rate for Asian Americans of 6.52% was similar to that of Latinos (6.40%) and higher than that of non-Hispanic whites (5.59%). The NAG and NTG prevalence rates (3.01% and 0.73%, respectively) were considerably higher among Asian Americans compared with each of the other races. After adjustment for confounding factors, Asian Americans had a 51% increased hazard of OAG (Hazard ratio (HR)=1.51 (95% confidence interval (CI) 1.42–1.60), a 123% increased hazard of NAG (HR=2.23 (95% CI 2.07–2.41), and a 159% increased hazard of NTG (HR=2.59 (95% CI 2.22–3.02) compared with non-Hispanic whites. Vietnamese Americans (HR=3.78, (95% CI 3.19–4.48), Pakistani Americans (HR=2.45, 95% CI 1.50–4.01) and Chinese Americans (HR=2.31, 95% CI 2.06–2.59) had considerably higher hazards of NAG while Japanese Americans (HR=4.37, 95% CI 3.24–5.89) had a substantially higher hazard of NTG, compared with non–Asian Americans.
Given the rapid rise in the number of Asian Americans in the US population, resources need to be devoted to identifying and treating glaucoma among these individuals. Eye-care providers should be aware of the increased hazard of developing OAG, NAG, and NTG among Asian Americans relative to other races. When evaluating Asian Americans, inquiring about ethnicity can provide additional information on risk of specific glaucoma types.
Financial Disclosures
The authors have no proprietary or commercial interest in any materials discussed in this article.
PMCID: PMC3109193  PMID: 21310489
14.  Longitudinal glaucoma screening for siblings of patients with primary open angle glaucoma: the Nottingham Family Glaucoma Screening Study 
To assess the prevalence and cumulative incidence of open angle glaucoma (OAG) in a cohort group of siblings of OAG probands.
Between 1994 and 2003, a group of siblings of OAG probands underwent both initial and follow up standardised ophthalmic examinations. Siblings were classified as “definite glaucoma” (primary OAG (POAG) and normal tension glaucoma (NTG)), “glaucoma suspects” (NTG suspects or ocular hypertension (OHT)), and normal. The prevalence and cumulative incidence of OAG over the follow up interval were calculated.
At the initial study, 271 siblings (mean age 63.6 years; female to male ratio 1.2) from 156 probands were examined. 32 (11.8%) were classified as definite glaucoma and 15 (5.5%) as suspects. In the follow up study, 157 of the 224 “normal” siblings from the initial study were examined (mean interval from initial study 7.0 (SD 1.0) years). 11 (7%) were classified as definite glaucoma and 30 (19.1%) as suspects. There were significant trends of increasing prevalence and incidence of OAG with age and a lifetime risk estimated at approximately 20% by age 70.
Siblings of glaucoma patients have an increased risk of developing glaucoma and the risk increases with age. An effective and repeated screening programme should be considered for this high risk group.
PMCID: PMC1856884  PMID: 16361669
primary open angle glaucoma; siblings
15.  Cholesterol-Lowering Drugs and Incident Open-Angle Glaucoma: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e29724.
Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG.
Methodology/Principal Findings
Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31–0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81–5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41–1.94; P = 0.77] for use two years or less; 0.46 [0.23–0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP.
Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.
PMCID: PMC3251600  PMID: 22238644
16.  Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings 
Purpose of review
A possible connection between ocular perfusion pressure and open-angle glaucoma (OAG) has been hypothesized. This review summarizes the scientific rationale for the proposed relationship, presents recent data, and outlines potential implications.
Recent findings
Population-based epidemiologic studies found strong relationships between low ocular perfusion pressure and OAG prevalence, as well as OAG incidence. Clinical studies report similar associations between low perfusion pressure and OAG progression. These consistent findings suggest that altered blood flow in the optic disc increases both the risk of OAG development and the progression of established OAG. An underlying factor would be impaired vascular autoregulation, which may lead to poor perfusion in OAG. In contrast, there is conflicting evidence on the possible link of glaucoma to blood pressure/hypertension.
Current evidence supports the role of vascular factors as part of the multifactorial etiology of OAG. Since ocular perfusion pressure reflects the vascular status at the optic disc, it may be more relevant than systemic blood pressure alone. While the associations of OAG to perfusion pressure are strong, consistent and biologically plausible, they require careful interpretation. The evidence implicating a vascular etiology in OAG is mounting, but the clinical implications for patient management are still uncertain.
PMCID: PMC2662722  PMID: 19240538
Open-angle glaucoma; ocular perfusion pressure; glaucoma risk factors; blood pressure
17.  Filtering data from the collaborative initial glaucoma treatment study for improved identification of glaucoma progression 
Open-angle glaucoma (OAG) is a prevalent, degenerate ocular disease which can lead to blindness without proper clinical management. The tests used to assess disease progression are susceptible to process and measurement noise. The aim of this study was to develop a methodology which accounts for the inherent noise in the data and improve significant disease progression identification.
Longitudinal observations from the Collaborative Initial Glaucoma Treatment Study (CIGTS) were used to parameterize and validate a Kalman filter model and logistic regression function. The Kalman filter estimates the true value of biomarkers associated with OAG and forecasts future values of these variables. We develop two logistic regression models via generalized estimating equations (GEE) for calculating the probability of experiencing significant OAG progression: one model based on the raw measurements from CIGTS and another model based on the Kalman filter estimates of the CIGTS data. Receiver operating characteristic (ROC) curves and associated area under the ROC curve (AUC) estimates are calculated using cross-fold validation.
The logistic regression model developed using Kalman filter estimates as data input achieves higher sensitivity and specificity than the model developed using raw measurements. The mean AUC for the Kalman filter-based model is 0.961 while the mean AUC for the raw measurements model is 0.889. Hence, using the probability function generated via Kalman filter estimates and GEE for logistic regression, we are able to more accurately classify patients and instances as experiencing significant OAG progression.
A Kalman filter approach for estimating the true value of OAG biomarkers resulted in data input which improved the accuracy of a logistic regression classification model compared to a model using raw measurements as input. This methodology accounts for process and measurement noise to enable improved discrimination between progression and nonprogression in chronic diseases.
PMCID: PMC3878032  PMID: 24359562
18.  Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma? 
Primary open angle glaucoma (OAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and associated visual field loss. OAG is an emerging disease with increasing costs and negative outcomes, yet its fundamental pathophysiology remains largely undetermined. A major treatable risk factor for glaucoma is elevated intraocular pressure (IOP). Despite the medical lowering of IOP, however, some glaucoma patients continue to experience disease progression and subsequent irreversible vision loss. The scientific community continues to accrue evidence suggesting that alterations in ocular blood flow play a prominent role in OAG disease processes. This article develops the thesis that dysfunctional regulation of ocular blood flow may contribute to glaucomatous optic neuropathy. Evidence suggests that impaired vascular autoregulation renders the optic nerve head susceptible to decreases in ocular perfusion pressure, increases in IOP, and/or increased local metabolic demands. Ischemic damage, which likely contributes to further impairment in autoregulation, results in changes to the optic nerve head consistent with glaucoma. Included in this review are discussions of conditions thought to contribute to vascular regulatory dysfunction in OAG, including atherosclerosis, vasospasm, and endothelial dysfunction.
PMCID: PMC2699797  PMID: 19668439
glaucoma; autoregulation; blood flow; atherosclerosis; vasospasm; endothelial dysfunction
19.  Nutrient intake and risk of open-angle glaucoma: the Rotterdam Study 
European Journal of Epidemiology  2012;27(5):385-393.
Open-angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. Apart from an increased intraocular pressure (IOP), oxidative stress and an impaired ocular blood flow are supposed to contribute to OAG. The aim of this study was to determine whether the dietary intake of nutrients that either have anti-oxidative properties (carotenoids, vitamins, and flavonoids) or influence the blood flow (omega fatty acids and magnesium) is associated with incident OAG. We investigated this in a prospective population-based cohort, the Rotterdam Study. A total of 3502 participants aged 55 years and older for whom dietary data at baseline and ophthalmic data at baseline and follow-up were available and who did not have OAG at baseline were included. The ophthalmic examinations comprised measurements of the IOP and perimetry; dietary intake of nutrients was assessed by validated questionnaires and adjusted for energy intake. Cox proportional hazard regression analysis was applied to calculate hazard ratios of associations between the baseline intake of nutrients and incident OAG, adjusted for age, gender, IOP, IOP-lowering treatment, and body mass index. During an average follow-up of 9.7 years, 91 participants (2.6%) developed OAG. The hazard ratio for retinol equivalents (highest versus lowest tertile) was 0.45 (95% confidence interval 0.23–0.90), for vitamin B1 0.50 (0.25–0.98), and for magnesium 2.25 (1.16–4.38). The effects were stronger after the exclusion of participants taking supplements. Hence, a low intake of retinol equivalents and vitamin B1 (in line with hypothesis) and a high intake of magnesium (less unambiguous to interpret) appear to be associated with an increased risk of OAG.
PMCID: PMC3374099  PMID: 22461101
Glaucoma; Nutrition; Magnesium; Vitamin A; Vitamin B1; Population-based; Dietary intake
20.  Prospective, Unmasked Evaluation of the iStent®Inject System for Open-Angle Glaucoma: Synergy Trial 
Advances in Therapy  2014;31:189-201.
Micro-invasive glaucoma surgical implantation of trabecular micro-bypass stents, previously shown to be safe and effective for open-angle glaucoma (OAG) subjects during cataract surgery, was considered for evaluation as a sole procedure. The aim of this study was to evaluate the safety and intraocular pressure (IOP)-lowering efficacy after ab interno implantation of two Glaukos Trabecular Micro-Bypass iStent inject second generation devices in subjects with OAG. This study was performed at sites in France, Germany, Italy, Republic of Armenia, and Spain.
In this pan-European, multi-center prospective, post-market, unmasked study, 99 patients with OAG on at least two topical ocular hypotensive medications who required additional IOP lowering to control glaucoma disease underwent implantation of two GTS400 stents in a stand-alone procedure. Patients were qualified if they presented with preoperative mean IOP between 22 and 38 mmHg after medication washout. Postoperatively, subjects were assessed at Day 1, Months 1, 3, 6, 7, 9, and 12. IOP, medication use and safety were assessed at each visit.
Sixty-six percent of subjects achieved IOP ≤18 mmHg at 12 months without medication, and 81% of subjects achieved Month 12 IOP ≤ 18 mmHg with either a single medication or no medication. Mean baseline washout IOP values decreased by 10.2 mmHg or 39.7% from 26.3 (SD 3.5) mmHg to 15.7 (SD 3.7) mmHg at Month 12. Mean IOP at 12 months was 14.7 (SD 3.1) mmHg in subjects not using ocular hypotensive medications. Reduction from preoperative medication burden was achieved in 86.9% of patients, including 15.2% with reduction of one medication and 71.7% with reduction of two or more medications. Postoperative complications occurred at a low rate and resolved without persistent effects.
In this series, implantation of two trabecular micro-bypass second generation stents in subjects with OAG resulted in IOP and medication reduction and favorable safety outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0095-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3930835  PMID: 24452726
Ab interno; Intraocular pressure; iStent inject; Open-angle glaucoma; Ophthalmology; Trabecular bypass
21.  Prevalence of Open-Angle Glaucoma Among Adults in the United States 
Archives of ophthalmology  2004;122(4):532-538.
To estimate the prevalence and distribution of open-angle glaucoma (OAG) in the United States by age, race/ethnicity, and gender.
Summary prevalence estimates of OAG were prepared separately for black, Hispanic, and white subjects in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US census data and to projected US population figures for 2020 to estimate the number of the US population with OAG.
The overall prevalence of OAG in the US population 40 years and older is estimated to be 1.86% (95% confidence interval, 1.75%-1.96%), with 1.57 million white and 398000 black persons affected. After applying race-, age-, and gender-specific rates to the US population as determined in the 2000 US census, we estimated that OAG affects 2.22 million US citizens. Owing to the rapidly aging population, the number with OAG will increase by 50% to 3.36 million in 2020. Black subjects had almost 3 times the age-adjusted prevalence of glaucoma than white subjects.
Open-angle glaucoma affects more than 2 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to more than 3 million by 2020.
PMCID: PMC2798086  PMID: 15078671
22.  Frequency doubling technique perimetry and spectral domain optical coherence tomography in patients with early glaucoma 
Eye  2010;25(1):17-29.
To assess the combined diagnostic power of frequency-doubling technique (FDT)-perimetry and retinal nerve fibre layer (RNFL) thickness measurements with spectral domain optical coherence tomography (SDOCT).
The study included 330 experienced participants in five age-related groups: 77 ‘preperimetric' open-angle glaucoma (OAG) patients, 52 ‘early' OAG, 50 ‘moderate' OAG, 54 ocular hypertensivepatients, and 97 healthy subjects. For glaucoma assessment in all subjects conventional perimetry, evaluation of fundus photographs, FDT-perimetry and RNFL thickness measurement with SDOCT was done. Glaucomatous visual field defects were classified using the Glaucoma Staging System. FDT evaluation used a published method with casewise calculation of an ‘FDT-score', including all missed localized probability levels. SDOCT evaluation used mean RNFL thickness and a new individual SDOCT-score considering normal confidence limits in 32 sectors of a peripapillary circular scan. To examine the joined value of both methods a combined score was introduced. Significance of the difference between Receiver-operating-characteristic (ROC) curves was calculated for a specificity of 96%.
Sensitivity in the preperimetric glaucoma group was 44% for SDOCT-score, 25% for FDT-score, and 44% for combined score, in the early glaucoma group 83, 81, and 89%, respectively, and in the moderate glaucoma group 94, 94, and 98%, respectively, all at a specificity of 96%. ROC performance of the newly developed combined score is significantly above single ROC curves of FDT-score in preperimetric and early OAG and above RNFL thickness in moderate OAG.
Combination of function and morphology by using the FDT-score and the SDOCT-score performs equal or even better than each single method alone.
PMCID: PMC3144638  PMID: 21102494
early glaucoma; frequency doubling technique; perimetry; retinal nerve fibre layer thickness; spectral domain OCT
23.  Intraocular Pressure Control and Long-term Visual Field Loss in the Collaborative Initial Glaucoma Treatment Study 
Ophthalmology  2011;118(9):1766-1773.
To evaluate the impact of measures of intraocular pressure (IOP) control on progression of visual field (VF) loss during long-term treatment for open-angle glaucoma (OAG).
Longitudinal, randomized clinical trial.
607 participants with newly-diagnosed OAG.
Study participants were randomly assigned to initial treatment with medications or trabeculectomy, and underwent examination at six-month intervals. Standardized testing included Goldmann applanation tonometry and Humphrey 24-2 full threshold VFs. Summary measures of IOP control during follow-up included the maximum, mean, standard deviation (SD), range, proportion less than 16, 18, 20, or 22 mmHg, and whether all IOP values were less than each of these four cut-points. Predictive models for VF outcomes were based on the mean deviation (MD) from VF testing, and were adjusted for age, sex, race, baseline VF loss, treatment, and time. Each summary IOP measure was included as a cumulative, time-dependent variable, and its association with subsequent VF loss was assessed from 3 to 9 years post-randomization. Both linear mixed models, to detect shifts in MD levels, and logistic models, to detect elevated odds of substantial worsening (3 dB or more), were used.
Main Outcome Measure
MD from Humphrey 24-2 full threshold VF tests.
The effect of the summary IOP measures differed between the medicine and surgery groups in models that addressed the continuous MD outcome. After adjustment for baseline risk factors, in the medicine group larger values of three IOP control measures – maximum IOP (p=0.0003), standard deviation of IOP (p=0.0056), and range of IOP (p<0.0001) – were significantly associated with lower (worse) MD in the 3 to 9 year period. No IOP summary measure was significantly associated with MD over time in the surgery group. The same three IOP summary measures were also significantly associated with substantial worsening of MD; however, the effects were similar in both treatment groups. In models predicting inadequate IOP control, consistently significant predictors of higher maximum, SD, and range of IOP included black race, higher baseline IOP, and clinical center.
These results support considering more aggressive treatment when undue elevation or variation in IOP measures is observed.
PMCID: PMC3161134  PMID: 21600658
24.  Female reproductive factors and open angle glaucoma: the Blue Mountains Eye Study 
The British Journal of Ophthalmology  2003;87(11):1324-1328.
Aims: To determine whether endogenous oestrogen exposures are associated with open angle glaucoma (OAG).
Methods: The Blue Mountains Eye Study examined 2072 women aged 49–97 years during 1992–4. Questions about female reproductive factors included age at menarche and menopause, parity, and use of hormone replacement therapy. Applanation tonometry, visual field tests, and stereo-optic disc photographs were performed. OAG was diagnosed when glaucomatous visual fields matched optic disc changes. Ocular hypertension (OH) was defined in the absence of glaucoma, but with intraocular pressure ⩾22 mm Hg.
Results: A significantly increased OAG risk with later (>13 years) compared with earlier (⩽12 years) age of menarche was found, odds ratio (OR) = 2.0; 95% confidence interval (CI) 1.0 to 3.9, p for trend = 0.01, after adjustment for multiple confounders. Non-significant increased odds for OAG were found for early natural menopause (<45 years) compared with the reference group (⩾50 years), adjusted OR = 1.7; CI: 0.7 to 3.8, and for shorter duration of endogenous oestrogen exposure (<30 years), adjusted OR = 1.8; CI: 0.6 to 5.3. Increasing parity was associated with an increased risk of OAG (p = 0.03) and decreased risk of OH (p = 0.03).
Conclusion: The modest associations found in relation to late menarche and increased parity do not allow the exclusion of a possible role for endogenous female hormones in the pathogenesis of OAG.
PMCID: PMC1771896  PMID: 14609824
menarche; menopause; glaucoma; Blue Mountains Eye Study
25.  Diurnal Tension Curves for Assessing the Development or Progression of Glaucoma 
Executive Summary
Clinical Need: Condition and Target Population
There are two main types of glaucoma, primary open angle (POAG) and angle closure glaucoma, of which POAG is the more common type. POAG is diagnosed by assessing degenerative changes in the optic disc and loss of visual field (VF). Risk factors for glaucoma include an increase in intraocular pressure (IOP), a family history of glaucoma, older age and being of African descent. The prevalence of POAG ranges from 1.1% to 3.0% in Western populations and from 4.2% to 8.8% in populations of African descent.
Usually the IOP associated with POAG is elevated above the normal distribution (10-20 mmHg), but when IOP is not elevated it is often referred to as normal-tension glaucoma (NTG). In population based studies, approximately one-third to half of the patients with glaucomatous VF loss have normal IOP on initial examination.
People with elevated IOP (>21 mmHg), but with no evidence of optic disc or VF damage have ocular hypertension. It has been estimated that 3 to 6 million people in the United States including 4% to 7% of those older than 40 years have elevated IOP without detectable glaucomatous damage on standard clinical tests. An Italian study found the overall prevalence of ocular hypertension, POAG, and NTG in 4,297 people over 40 years of age to be 2.1%, 1.4% and 0.6% respectively.
Diurnal Curves for Intraocular Pressure Measurement
Diurnal Curve
In normal individuals, IOP fluctuates 2 to 6 mmHg over a 24 hour period. IOP is influenced by body position with higher readings found in the supine relative to the upright position. As most individuals sleep in the supine position and are upright during the day, IOP is higher on average in people, both with and without glaucoma, in the nocturnal period. IOP is generally higher in the morning compared to the afternoon.
Multiple IOP measurements over the course of a day can be used to generate a diurnal curve and may have clinical importance in terms of diagnosis and management of patients with IOP related conditions since a solitary reading in the office may not reveal the peak IOP and fluctuation that a patient experiences. Furthermore, because of diurnal and nocturnal variation in IOP, 24-hour monitoring may reveal higher peaks and wider fluctuations than those found during office-hours and may better determine risk of glaucoma progression than single or office-hour diurnal curve measurements.
There is discrepancy in the literature regarding which parameter of IOP measurement (e.g., mean IOP or fluctuation/range of IOP) is most important as an independent risk factor for progression or development of glaucoma. The potential for increased rates or likelihood of worsening glaucoma among those with larger IOP swings within defined time periods has received increasing attention in the literature.
According to an expert consultant:
The role of a diurnal tension curves is to assess IOP in relationship to either a risk factor for the development or progression of glaucoma or achievement of a target pressure which may direct a therapeutic change.
Candidates for a diurnal curve are usually limited to glaucoma suspects (based on optic disc changes or less commonly visual field changes) to assess the risk for development of glaucoma or in patients with progressive glaucoma despite normal single office IOP measurements.
Clinically diurnal tension curves are used to determine the peak IOP and range.
Single IOP Measurements
Intraocular pressure fluctuation as a risk factor for progression of glaucoma has also been examined without the use of diurnal curves. In these cases, single IOP measurements were made every 3-6 months over several months/years. The standard deviation (SD) of the mean IOP was used as a surrogate for fluctuation since no diurnal tension curves were obtained.
To determine whether the use of a diurnal tension curve (multiple IOP measurements over a minimum 8 hour duration) is more effective than not using a diurnal tension curve (single IOP measurements) to assess IOP fluctuation as a risk factor for the development or progression of glaucoma.
To determine whether the use of a diurnal tension curve is beneficial for glaucoma suspects or patients with progressive glaucoma despite normal single office IOP measurements and leads to a more effective disease management strategy.
Research Methods
Literature Search
Search Strategy
A literature search was performed on July 22, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2006 until July 14, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Open angle glaucoma (established or OHT high risk) in an adult population
IOP measurement by Goldmann applanation tonometry (the gold standard)
Number and timing of IOP measurements explicitly reported (e.g., 5 measurements a day for 5 visits to generate a diurnal curve or 1 measurement a day [no diurnal curve] every 3 months for 2 years)
IOP parameters include fluctuation (range [peak minus trough] or standard deviation) and mean
Outcome measure = progression or development of glaucoma
Study reports results for ≥ 20 eyes
Most recent publication if there are multiple publications based on the same study
Exclusion Criteria
Angle closure glaucoma or pediatric glaucoma
Case reports
IOP measured by a technique other than GAT (the gold standard)
Number and timing of IOP measurements not explicitly reported
Outcomes of Interest
Progression or development of glaucoma
There is very low quality evidence (retrospective studies, patients on different treatments) for the use of a diurnal tension curve or single measurements to assess short or long-term IOP fluctuation or mean as a risk factor for the development or progression of glaucoma.
There is very low quality evidence (expert opinion) whether the use of a diurnal tension curve is beneficial for glaucoma suspects or patients with progressive glaucoma, despite normal single office IOP measurements, and leads to a more effective disease management strategy.
PMCID: PMC3377558  PMID: 23074414

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