THE EPIDEMIOLOGY AND CONTROL OF OPEN ANGLE GLAUCOMA: A Population-B ased Perspective

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1 Annu Rev. Public Health 19%. 17: Copyright 8 I595 by Annual Reviews Inc. AN righrs resewed THE EPIDEMIOLOGY AND CONTROL OF OPEN ANGLE GLAUCOMA: A Population-B ased Perspective James M. Tielsch Department of International Health, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland KEY WORDS: prevalence, risk factors, screening, cost ABSTRACT Chronic open angle glaucoma is an etiologically heterogeneous group of diseases characterized by damage to the optic nerve, resulting in peripheral visual loss that can progress to involve the fovea and central vision. Open angle glaucoma can be divided into primary conditions and conditions which are secondary to another ocular or systemic disease. Causes of secondary glaucoma include uveitis, cataract, trauma, and disorders affecting the developmental structure of the angle. This review focuses on primary open angle glaucoma (POAG), since it accounts for the vast majority of the disease burden in the US population and its etiology remains unknown. INTRODUCTION Chronic open angle glaucoma is an etiologically heterogeneous group of diseases characterized by damage to the optic nerve, resulting in peripheral visual loss that can progress to involve the fovea and central vision. Open angle glaucoma can be divided into primary conditions and conditions which are secondary to another ocular or systemic disease. Causes of secondary glaucoma include uveitis, cataract, trauma, and disorders affecting the developmental structure of the angle. This review focuses on primary open angle glaucoma (POAG), since it accounts for the vast majority of the disease burden in the US population and its etiology remains unknown. The pathophysiologic mechanism by which damage occurs in POAG is the subject of much debate. Two major hypotheses have been proposed to account for the observed optic nerve damage. The first focuses on reductions in vascular /96/ $08.OO

2 122 TIELSCH perfusion of the optic nerve and nerve fiber layer; the second centers on mechanical damage occurring at the level of the lamina cribrosa. For both, the damage to the optic nerve is thought to be mediated through a combination of inherent susceptibility of the optic nerve head and elevation in the intraocular pressure (IOP) beyond what the susceptible eye can tolerate. It is likely that both mechanisms operate to produce damage and that their relative importance may depend on a variety of factors, including the level of the IOP. Unfortunately, whatever mechanism plays the leading role in producing glaucomatous optic nerve damage, there is little good information about what initiates this process or about the subgroups of the population who are at high risk for the onset of such damage. ISSUES OF MEASUREMENT AND DEFINITION Prior to reviewing the literature on the epidemiology of POAG, it is critical to understand the evolution of diagnostic methods and definitions used for this disorder. It is widely accepted now that POAG is fundamentally an optic neuropathy with the defining clinical sign being damage to the axons of retinal ganglion cells. This damage is evidenced clinically by abnormalities in the visual field, excavation of the optic nerve, or thinning of the nerve fiber layer (78). A major issue in the epidemiology of POAG continues to be the definition of the disease. For many years, the definition of glaucoma was synonymous with elevated intraocular pressure. As a result, early studies often included groups of cases dominated by patients who had elevated IOP only and neither optic nerve excavation nor visual field loss (25, 81). This confusion was reinforced by a statistical classification of the distribution of IOP that equated infrequent observations with abnormality [personal communication from W Leydhecker to FC Hollows & PA Graham (25)]. In response, two different conditions are now described, glaucoma and ocular hypertension, separating those with optic nerve damage from those with only statistically defined elevated IOP. There remain, however, large differences in the definitions used for glaucoma. Differences exist in the criteria for glaucomatous optic nerve damage, the techniques used to measure such damage, who is qualified to make such assessments, and whether elevated IOP is a necessary component of the disease definition. Dilated examinations of the optic nerve head are critical to making full use of the dimensional clues to the status of the optic nerve. Despite the relative safety of pupillary dilation [risk of dilating a potentially occludable angle using appropriate screening criteria is less than 3/1000 (51)], few nonophthalmologists are able to adequately examine the optic nerve for signs of glaucomatous optic nerve damage. The last issue, regarding the role of elevated

3 EPIDEMIOLOGY OF GLAUCOMA 123 IOP in the definition of POAG, has resulted in the further categorization of POAG into classical POAG, which has elevated IOP as well as optic nerve damage, and low-tension glaucoma, which has IOP in the normal range, but damage to the optic nerve. While a number of investigators have claimed to demonstrate differences in the clinical presentation of low tension glaucoma as compared with classical POAG (14, 16), a growing body of evidence suggests that most cases are part of the expected distribution of POAG (2,43, 60, 64). Nevertheless, it is likely that there is heterogeneity in the etiology of POAG in both the classical form as well as those with normal IOP. An extremely important problem regarding the definition of POAG from an epidemiologic perspective is the realization that objective structural criteria such as cup:disc ratio or other characteristics of the optic nerve are poorly sensitive to detecting glaucomatous optic nerve damage (28, 73). Examination of the visual field is necessary, as up to one third of cases will be missed when using structural criteria alone. MAGNITUDE AND SEVERITY OF THE PROBLEM There is a significant amount of recent data on the prevalence of POAG in the United States and around the world. As can be seen in Table 1, estimates range from 0.42% in Wales to over 14% among blacks on St. Lucia. Two main factors account for the observed variation in rates (excluding sampling error): race of the study population and the definition of glaucoma used. Persons of African heritage have higher rates than whites (see section below on Race). In whites, studies that conducted visual field testing on all subjects and did not require elevated IOP as a criterion for diagnosis suggest that the prevalence is between 1.5% and 2.0% for those 40 years or older. While good data on the prevalence of glaucoma are now available, adequate information on the incidence of POAG is not. Statistical models that incorporate age-specific cross-sectional prevalence data and general population survival rates (41) as well as longitudinal studies that were not population-based (5, 6, 52) have been used to estimate incidence rates for various populations, primarily white residents of the United States. Such studies indicate that, even in study populations enriched with subjects who are considered high risk for the development of glaucomatous optic nerve damage, the incidence of new cases is quite low, in the range of 1/1000 to 1/100 per year (5, 6, 52). Results from statistical modeling of incidence indicate that, for a general population of whites, rates are even lower, ranging from 0.08/1000 per year for those in their early forties to 1.46/1000 per year for persons in their eighties (41). Direct estimates of incidence will be available over the next few years from longitudinal studies currently under way in Baltimore, Beaver Dam (Wisconsin), and Barbados.

4 Table 1 Prevalence of open angle glaucoma in various populations Criteria for defining Prevalence Source POAG N Age range estimate Ethnicity Europe Wales, 1966 (25) Dalby, Sweden, 1981 (10) Iceland, 1986 (80) Sweden, 1982 (45) Rotterdam, The Netherlands, 1994 (20) Ireland, 1993 (17) United States Framingham, U.S (28) Baltimore, U.S., 1991 (75) Beaver Dam, Wisconsin, U.S (38) Concurrent cupping % White Welsh of the optic disc years and visual field loss (visual fields were only done on 113 of the sample) Concurrent visual % White Swedish field loss and optic nerve cupping years Pharmacy and phy years 1.91% White Icelandic sician dispensary records indicating treatment for glaucoma or hospital records indicating surgery for glaucoma Diagnoses of optic Entire 250 years 1.4% White Swedish disc cupping and population visual field loss as of Sweden recorded in clinical records Visual field loss plus years 1.1% White Dutch either optic disk cupping or elevated intrao- cular pressure At least two of the following: visual field loss, cupping of the optic disc, elevated intraocular pressure years 1.9% White Irish Visual field loss % White Americans years Visual field loss years 1.7% White Americans, andor severe optic disc cupping 5.6% Black Americans At least two of the % White Americans following: visual years field loss, cupping of the optic disc, elevated intraocular pressure

5 EPIDEMIOLOGY OF GLAUCOMA 125 Table 1 (continued) Criteria for defining Prevalence Source POAG N Age range estimate Ethnicity Caribbean Jamaica, Concurrent cupping years 1.4% Black Jamaicans 1969 (81) of the optic disc and visual field loss St. Lucia, Visual field loss years 8.8% Black St. Lucians 1989 (48) and/or severe -14.7% optic disc cupping Barbados, Visual field loss and % Black Barbadians 1994 (40) cupping of the years optic nerve The degree of functional loss associated with glaucoma is not well understood but is thought to be relatively low except in far advanced disease. Recently, a variety of patient-oriented measures of visual functional status have been developed and applied to patients with cataract (1 1,46,66). Whether such instruments will be useful for a disease like glaucoma, where central vision is spared until the latest stages, is not clear, but modifications will likely be needed in these instruments in order to detect functional loss associated with peripheral vision deficits. Data are limited on the prevalence of the most severe form of visual functional impairment, blindness due to glaucoma. Most data come from blindness registration systems which are usually incomplete in their ascertainment of blind persons. The Model Reporting Area Study, which last reported results from 1970, used data from 16 states in the U.S. that agreed to a common reporting format and criteria for the definition of blindness (30). Standardization of diagnostic criteria for defining the cause of blindness was not possible, however, nor was there any assurance that ascertainment was equivalent across all participating states. Despite these problems, the Model Reporting Area Study remains a heavily used source of data on the cause-specific rates of blindness in the U.S. In 1970, glaucoma was the third leading cause of blindness (after cataract and age-related macular degeneration) with a prevalence of 16.2/100,000 and an incidence of new blindness registrations of 1.5/100,000 per year (30). Data from other sources suggest that these rates are serious underestimates. The Baltimore Eye Survey estimated the prevalence of glaucomatous blindness at 1.7/1000 in a population with equal numbers of blacks and whites, of which more than 75% was due to POAG (63, 76). Global estimates of prevalence are particularly difficult, since adequate

6 126 TIELSCH information is missing from large parts of the world. Thylefors & Negrel used available prevalence data and population models to estimate that there are 13.5 million persons 40 years or older affected with POAG, of whom 3 million are blind (68). Better systems are needed for measuring the burden of disability caused by glaucoma in the population, especially as such data begin to play a major role in evaluating the effectiveness of health care delivery systems. Another perspective on the size of the glaucoma problem is economic. While cost-of-illness studies often suffer from lack of adequate data, reasonable assumptions can be used to develop a more comprehensive picture of the impact of disease on society than prevalence alone can provide. Such efforts divide total costs into those associated with the direct medical care of persons with illness (direct costs), indirect costs such as lost wages, and income transfer. In 1991, the best estimate of total direct costs for glaucoma in the U.S. was approximately $1.6 billion (69). This estimate reflects the costs of treating one half the total number of persons with glaucoma, as only 50% of those who have POAG have been diagnosed (17,38,75). Treating the additional 50% of cases would more than double this estimate, since costly efforts would be required to identify the undiagnosed group. Another $1.1 billion was paid by the government to support individuals blind from glaucoma, and indirect costs were estimated very conservatively at $235 million (69). DEMOGRAPHIC RISK FACTORS Age Glaucoma is strongly associated with age (Figure 1). An increased prevalence with older age has been found in every population-based study. The magnitude s9 Z $ 6 ' 5 g 4 p I I I I I I I I I Age Figure 1 Prevalence of primary open angle glaucoma in whites and blacks based on data from the Baltimore Eye Survey (72).

7 EPIDEMIOLOGY OF GLAUCOMA 127 of this association is large, with prevalence rates between four and ten times higher in the oldest age groups as compared persons in their forties (25, 38, 39, 75). Similarly, the 13-year incidence of glaucomatous visual field defects rose from 0.7% among those less than 40 years of age at baseline to 4.8% among those 60 years or older at baseline in the Collaborative Glaucoma Study (6). Leske et al s statistical projections for white populations show a rise from O.O8/10oO per year to 1.46/1000 per year with increasing age (41), as noted above. Gender The relationship of gender to risk of POAG is inconsistent. The Framingham and Barbados Eye Studies found that men had a significantly higher prevalence of POAG than women (39, 40), whereas the opposite was found in Sweden (9, lo), and no association was found in Wales (25), Baltimore (56,75), Beaver Dam (38), or the Collaborative Glaucoma Study (6). Thus, gender is unlikely to be a major risk factor for POAG. Race Racial variations in the risk of POAG are an important part of the epidemiology of this disease. Persons of West African ancestry, including black populations in the Caribbean and the U.S., have significantly higher prevalence of POAG than do Caucasians. The evidence for this excess risk in blacks comes from a wide variety of sources. Clinic-based studies have shown that blacks comprise a higher proportion of glaucoma clinic attendees than among general eye clinic populations (47, 83). Blacks also have glaucoma surgery at higher rates than whites (18), and among those who self present to glaucoma screening programs, blacks are more likely to be diagnosed as having glaucoma (23). Prevalence surveys conducted in primarily black populations have shown higher rates of glaucoma than those using similar methods in white populations. Using similar diagnostic criteria, Jamaican blacks had a rate three times higher than that found among the Welsh (25, 81). More recent studies in St. Lucia and Barbados have found extremely high rates, 7% to 16% among those 40 or older, among the black populations of these islands (40,48). In the United States, the only direct comparison of prevalence between blacks and whites comes from the Baltimore Eye Survey, which found an age-adjusted 4.3-fold excess prevalence of POAG in blacks as compared with their white neighbors (75). POAG also may be a more severe disease among blacks as they have a younger onset, have more advanced disease at the time of first diagnosis, and are more often refractory to medical therapy (24,75, 85). It is unclear whether this reflects a more rapid progression of disease or whether it is a combination

8 128 TIELSCH of a higher age-specific incidence and poor access to or utilization of appropriate eye care services. Clinical trials and longitudinal population studies of POAG in blacks and whites are currently under way and should provide the information necessary to determine if progression and treatment efficacy vary by race. The reason for the excess risk among blacks is not well understood, but is likely related to an underlying predisposition (75). The association of other conditions such as sickle cell disease, systemic hypertension, and diabetes with race led to suggestions that the racial variation in POAG risk may be a function of this excess comorbidity. However, this hypothesis has not been supported for sickle cell trait, systemic hypertension, or diabetes (67,70,71); these factors act independently, if at all, on the risk of POAG. OCULAR RISK FACTORS Intraocular Pressure The relationship between IOP and POAG is strong and consistent even when elevated IOP is excluded as a diagnostic criterion (5,6,38, 39,40,56,60,64). Especially convincing evidence for an etiologic role of increased IOP in development of glaucomatous optic nerve damage comes from the monotonic increase in risk of POAG with increasing IOP (Figure 2), from studies that show asymmetric optic nerve damage in persons with ipsilateral asymmetric elevations in intraocular pressure (15, 19), and from studies that demonstrate a reduction in risk of optic nerve damage among high-risk populations in whom the IOP was lowered (31). While elevated IOP is one of the strongest predictors of who will develop glaucomatous optic neuropathy, even at levels considered - White Intraocular Pressure (mm Hg) Figure 2 Prevalence of primary open angle glaucoma by intraocular pressure based on data from the Baltimore Eye Survey. Taken from Sommer et al, Arch. Ophthalmol : (62). Copyright 1991/95, American Medical Association

9 EPIDEMIOLOGY OF GLAUCOMA 129 dangerously high a significant proportion of persons will never be affected (5). In addition, because of the dramatic overlap of intraocular pressure distributions between those with and without POAG, a large proportion of cases have IOP well within the normal range (25, 39, 60, 64). The sensitivity of the classical cut-off for IOP of greater than 21mm Hg is less than 50%, and there is no level at which a reasonable balance of sensitivity and specificity is achieved (39, 60, 64, 73). The implications of these results for the use of tonometry in glaucoma screening are well known; this approach is now generally discouraged (22.73). Optic Disc Parameters Characteristics of the optic nerve head have been used over the years both to identify groups of the population with high risk for glaucomatous optic nerve damage and as criteria for the definition of disease. Such parameters include the cup:disc ratio, the narrowest neuroretinal rim width, rim area, cup volume, and a variety of others, often based on sophisticated three-dimensional imaging of the optic disc. As these parameters are often used to define POAG or determine whether progression has occurred, they are not risk factors in an etiologic sense, but actual markers of damage. In spite of this direct measurement of optic nerve status, the ability of these parameters to accurately classify people into diseased and nondiseased states is poor. As with tonometry, there is no cut-off point in the distribution of cup:disc ratios that achieves adequate balance in terms of sensitivity and specificity (39,73). Similarly, the narrowest width of the neuroretinal rim, cup volume, and rim area are poor discriminators of disease status and rely on more sophisticated techniques for their measurement (72, 73; unpublished data from the Baltimore Eye Survey). The integrity of the nerve fiber layer (the axons of retinal ganglion cells) as assessed by clinical examination or fundus photography is a more direct measure of damage to the optic nerve (26) and has been shown to be both sensitive and specific in its ability to classify persons into diseased and nondiseased states (1, 62) and to predict who will develop glaucomatous visual field loss (61). Significant issues remain, however, regarding the transfer of this technology into the general practice of ophthalmology, let alone population screening. More recently, sophisticated hardware and software systems have been developed to three-dimensionally image the optic nerve head and measure the thickness of the nerve fiber layer. A variety of imaging technologies have been used for this purpose, including stereo-photography, stereo-video imaging, and scanning laser tomography and polarimetry (13,79,82). As yet, there is limited information on how these various technologies perform both for classification of persons with and without disease and for detection of progression. This

10 130 TIELSCH technology is still early in its development, especially of algorithms that can summarize the vast quantities of raw data in a meaningful fashion. Myopia Myopia has been associated with glaucoma in a number of studies. Wilson et a1 found a twofold excess prevalence of myopia among cases of POAG as compared with clinic-based controls (84). Perkins & Phelps reported an odds ratio of almost five when clinic-based cases were compared to age-specific national norms (53). The potential for selection bias when using clinic-based ascertainment for cases is strong for a variable such as myopia, because those with refractive error are more likely to seek eye care and have a higher probability of being diagnosed with glaucoma. However, a small populationbased study from Sicily showed a fivefold excess risk associated with myopia of 1.5 diopters or greater (55). NONOCULAR RISK FACTORS Diabetes While it is well known that complications of diabetes can produce secondary glaucoma, the association of diabetes with POAG has been less clear. Casecontrol studies, all of which ascertained their cases of glaucoma and controls from a clinic or private practice setting, have reported odds ratios ranging from 1.6 to 4.7 (33, 50, 57, 84). Controls were ascertained from similar sources as were cases, but selection cannot be completely ruled out as the source of the observed association in these situations. Population-based prevalence studies in Framingham, Sweden, and Baltimore, and the Collaborative Glaucoma Study have found no association between diabetes and POAG (5,6,9,27,70). In contrast, the Beaver Dam study found a twofold excess risk of diabetes in persons with POAG as compared with controls (36). This conflict with other population-based studies may be due to the lack of a direct clinical assessment by an ophthalmologist in the Beaver Dam study. Retinal complications of diabetes can produce visual field loss similar in appearance to that of POAG but without its underlying pathology. Such false positive visual field findings could account for this discrepancy. Systemic Hypertension The association of systemic hypertension with POAG is controversial and likely to be complicated. Much of the confusion is due to reports that have associated intraocular pressure with systemic blood pressure (27, 35,42, 49). However, within many of these same investigations, no association was found

11 EPIDEMIOLOGY OF GLAUCOMA 13 1 t--- i ,, 1. L A go I DIASTOLIC PIBPUSION PBESSUBI (mmh#) Figure 3 Prevalence of primary open angle glaucoma by diastolic perfusion pressure basedon data from the Baltimore Eye Survey. Taken from Tielsch et al, Arch. Ophthalmol : (68). Copyright 1991/95, American Medical Association. between POAG and systemic hypertension (27,42). Other case-control studies also have shown no association with POAG (33, SO), though one has demonstrated a strong and statistically significant association between untreated systolic hypertension and POAG (84). More recent evidence from the Baltimore Eye Survey suggests that the relationship between POAG and systemic blood pressure is complex and related to a variety of other hemo- and oculo-dynamic factors (71). Age modified the effect of systemic hypertension on risk of POAG. Those below age 60 were protected, while those older than 70 showed a positive association. Such a pattern would be expected if, early in the course of systemic hypertension, the elevated blood pressure resulted in increased perfusion, while later, after significant microvascular damage had occurred, blood flow to the optic nerve head was reduced. An additional important finding was that perfusion pressure was significantly associated with the risk of POAG in a way that would be predicted from autoregulation of blood flow. The prevalence of POAG remained constant across a wide range of perfusion pressure; when perfusion pressure was below 50mm Hg, the prevalence rose dramatically (Figure 3). Unfortunately, because of the cross-sectional nature of these data, we cannot determine the directionality of this observed association, nor do we understand the duration of low perfusion pressure necessary to produce an elevated risk of glaucomatous optic nerve damage. These data support the hypothetical role for vascular factors in the etiology of POAG. Another mechanism by which glaucomatous optic nerve damage may occur involves vascular spasm, which can result in an acute disruption in blood flow to n

12 132 TIELSCH the retinal nerve fiber layer and optic nerve. This idea is supported by studies showing an association of migraine and Raynaud s syndrome with low tension glaucoma (21, 54), although the one population-based study which examined this matter found no association between migraine-like headache and POAG (37). Family History of Glaucoma A number of studies have suggested that between 13 and 25% of patients with glaucoma have a positive family history (8, 34). Epidemiologic studies have estimated that a positive family history of glaucoma is associated with between a two- and fivefold excess risk of POAG (5, 34,74,77). In addition, it is well accepted that a number of ocular parameters associated with POAG are influenced by heredity (3,4,7) and that certain forms of juvenile glaucoma have a genetic basis (44). The search for genetic markers associated with POAG or a common mode of inheritance, however, has not been successful. Early reports of strong associations between selected HLA antigens and glaucoma (58, 59) have not been confirmed (32) and have no value in defining high-risk groups for this disease. While there is little doubt that familial factors play an important role in the underlying susceptibility to the development of POAG through population variations in the mechanical support of the optic nerve head, methodologic weaknesses in previous studies have made it difficult to study familial associations well. Specifically, since POAG is strongly age-related, complete family studies that apply uniform criteria for diagnosis and staging are very difficult. SCREENING Glaucoma has long been regarded as a disease that fits well the criteria for screening; it has a long asymptomatic period; it is highly prevalent in the population; and treatment begun early in its course is probably more effective at preventing significant loss of vision. As a result, glaucoma screening has been a popular activity for health and community service organizations based primarily on the use of tonometry (12, 23). Over the past 20 years, however, tonometry has been discredited as an effective screening technique for glaucoma because of a poor balance between sensitivity and specificity (22, 73). Similarly, poor results are produced when classical optic nerve findings are used (73). As a result, screening with tonometry or ophthalmoscopy alone is discouraged by most agencies active in the blindness prevention field, including Prevent Blindness America, and there is general acknowledgement that visual field testing is needed. Unfortunately, even visual field testing has significant error rates, especially among those with early damage. More recently, it was suggested by Douglas Anderson, University of Miami,

13 EPIDEMIOLOGY OF GLAUCOMA 133 that screening using a modified visual field approach be limited to detecting those with moderate-to-severe optic nerve damage who needed to be treated as soon as possible to prevent further loss of vision. Using two different visual field testing strategies, the sensitivity of this approach is estimated between 92% and 97% and the specificity between 94% and 96% (65). In response to these findings, it now seems reasonable to again conduct population screening for glaucoma using trained lay personnel, especially on high-risk populations such as elderly African Americans. SUMMARY Epidemiologic studies have provided us with more accurate measures of the magnitude and severity of the disease burden caused by primary open angle glaucoma (POAG). Recent investigations that have included visual field measurements on all subjects have demonstrated that previous estimates of the prevalence of this disorder were too low, by as much as 30 to 50%. Population-based studies also have confirmed the markedly elevated risk of POAG among blacks, although the basis for this excess risk remains unclear. Age and intraocular pressure are the strongest risk factors for POAG across all population groups. There is an exponential rise in rate of POAG with increasing age and intraocular pressure. Family history of glaucoma is also a major risk factor for this disease; however, the genetic andor environmental source of this association has yet to be elucidated. Other risk factors for this disease include myopia and vascular disorders that result in lowered perfusion pressure to the optic nerve and retina. Future research on the epidemiology of primary open angle glaucoma will quantify the incidence of this disorder and evaluate the interaction of heredity and environmental factors in producing excess risk. Any Annual Review chapter, as well as any article cited in an Annuul Review chapter, may be purchased from the Annual ReGews Preprints and Reprints service ; ; arpr@class.org Literature Cited Airaksinen PJ. Drance SM, Douglas GR, Mawson DK, Nieminen H Diffuse and localized nerve fiber layer loss in glaucoma. Am. J. Ophrhalmol. 98: Anderson DR Glaucoma: the damage caused by pressure. XLVI Edward Jackson Memorial Lecture. Am. J. Ophrhalmol. 108: Armaly MF. 1%7. Genetic determination of cup/disc ratio of the optic nerve. Arch. Ophthalmol. 78:35-43 Armaly MF The genetic deter- minants of ocular pressure in the normal eye. Arch. Ophthalmol. 78: Armaly MF Lessons to be learned from the Collaborative Glaucoma Study. Sum. Ophthalmol. 25: Armaly MF, Krueger DE, Maunder L, Becker B, Hetherington J Jr, et al Biostatistical analysis of the Collaborative Glaucoma Study. 1. Summary report of the risk factors for alaucomatous visual field defects. Arch-Ophrhalmol. 98:216%71 7. Armaly MF, Monstavicius BF, Sayegh

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