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Screening for open-angle glaucoma and its effect on blindnessJohan Aspberg, MD, PhD studentBoel Bengtsson, PhD, main supervisorDorothea Peters, MD, PhD, co-supervisorAnders Heijl, MD, PhD, co-supervisorAbstractBackground: Glaucoma is a common disease, about 2% in a European derived population older than 40 years of age are affected by its most common form, open-angle glaucoma (OAG). Open-angle glaucoma is a progressive disease leading to irreversible blindness in about 15% of those affected. The disease cannot be cured, but intraocular pressure (IOP) lowering treatment can halt or reduce the course of OAG. The most important risk factor for developing glaucoma blindness is extensive visual field loss already at the time for diagnosis. Due to the filling-in phenomena, ie completion of missing information from the surrounding visual field, patients do not perceive their visual field defects until late stages of disease, unless they are located in the center of the field close to the fovea. In developed countries, about 50% of glaucoma patients are undiagnosed. It is likely that screening for glaucoma will detect OAG at earlier stages and thereby reduce the number of individual developing glaucoma induced blindness. Our study aims at evaluating the effect of a large glaucoma screening performed in Malm?, Sweden between 1992 and 1997 on the development of glaucoma induced visual impairment until end of Dec 2017. Methods /Design: The current study is an observational study based on approximately 33,000 previously undiagnosed individuals living in the city of Malm?, that were invited to the screening. Full age cohorts of males or females born 1918-1932, and females born 1933-1939 were invited, except those with a known diagnosis of glaucoma and those who had visited the department of ophthalmology at Malm? University Hospital during the year prior to their screening date. Patient records from Jan 1, 1987 to Dec 31, 2017 for all patients with a documented diagnosis of open-angle glaucoma in the screen-invited birth cohorts 1918-1939, will be reviewed to confirm the diagnosis. For the purpose of the current evaluation only patients diagnosed at or after the screening will be included. The original purpose with the screening was to find patients with undetected glaucoma for inclusion in a randomized controlled trial, the Early Manifest Glaucoma Trial. No randomization procedure and no assignment of a control group was performed. Therefore, we decided to use the non-responders to the screening as a control group. Screened glaucoma patients will be classified as cases. Cases and controls will be matched for age and follow-up time. The use of non-responders as the control group may create selection bias, therefore we will create a separate bias control group of patients managed for glaucoma at our department, older and younger than the screening-invited cohorts, and thus not part of the screening. The bias control group will be matched to the controls by age and follow-up time and rates of glaucoma blindness will be compared to the controls. Our outcomes are: rates of visual impairment due to glaucoma, estimates of sojourn time (pre-clinical detectable phase), and the effect of screening in different age groups, and an approximation of screening intervals, if applicable.BackgroundGlaucoma is a disease affecting the optic nerve and the visual field resulting in gradual loss of vision. Typically the field defects are negative, which means that they are not perceived by the patients until they reach advanced stages. The diagnosis is therefore often set late in the course of the disease. The damage is irreversible, but treatment can halt or slow down the deterioration process. Glaucoma is the most important cause of irreversible blindness in the world (1). The prevalence of open-angle glaucoma in a white population is about 2% in the population 40 years or older in the developed world, rare in those below 50 years of age, but thereafter prevalence increases exponentially to about 6% in individuals older than 70 years of age (2,3). Several population studies have shown that approximately half of glaucoma patients are undiagnosed. These cases can probably be diagnosed by screening, which may lead to a decrease of the prevalence of visual impairment from glaucoma in the population.A large screening examination for open-angle glaucoma was performed in Malm? in 1992-1997, to recruit patients with undiagnosed glaucoma to a large randomized controlled trial, the Early Manifest Glaucoma Trial. About 33,000 individuals were screened in Malm?. Subjects with a known diagnosis of glaucoma and those who had visited the department of ophthalmology during the year prior to their screening date were not invited to the screening. The participation rate was high, 77.5% of the invited were screened. We identified slightly more than 400 persons with previously undiagnosed glaucoma, and many had moderate to severe damage (4). As reported in earlier prevalence studies (5-9), about half of the glaucoma cases in the population were undiagnosed. The examination in Malm? is the largest screening for open-angle glaucoma up to this date.Several reports about the potential benefit of population screening on the risk of visual impairment due to glaucoma have been published (10-12). Most of the criteria for a screenable disease are fulfilled (13); there is evidence that treatment by reduction of the intraocular pressure lowers the risk of deterioration (14,15), there is sufficient knowledge of the natural history of the disease (14, 16-18), and adequate diagnostics to correctly perform a screening examination (19,20). There is yet no official recommendations on screening for glaucoma, and no studies of the effect of screening on visual impairment from glaucoma has been published. An evaluation of the screening in Malm? may provide evidence, which would be of great importance.Study objectivesPrimary Aim: to evaluate the effect of screening for open-angle glaucoma on the development of visual impairment from the disease.Secondary Aims: 1. To estimate the sojourn time, or pre-clinical detectable phase (PCDP), of open-angle glaucoma. This is an important part of the natural history of a chronic disease. 2. To evaluate at which age screening for glaucoma would be most effective, and with which interval repeated screening, if applicable, could be considered.Methods /designStudy design: Retrospective cohort study.ParticipantsPatient records for all patients with a documented diagnosis of open-angle glaucoma in the screen-invited birth cohorts 1918-1939, who had visited the department of Ophthalmology at Sk?ne University hospital in Malm? , Sweden between Jan 1st 1987 to Dec 31st 2017, will be reviewed to confirm the diagnosis. We estimate the number of records to review to be about 4,000 to be able to include about 2,000 patients into our evaluation. No randomization procedure and no assignment of a control group and was performed at the time for the start of the screening. In the current evaluation, we will use non-responders to the screening as the control group, and the patients diagnosed at or after the screening will be included as cases.Cases and controls will be matched for age and follow-up time. For the study of the primary aim, only patients diagnosed at or after the screening will be included. Study start is set at the date for screening of both cases and controls, the controls will be assigned the same date as their age matched screened patients. The use of the non-responders as the control group may create selection bias. Therefore, we will create a separate bias control group of patients managed for glaucoma at our department, older and younger than the screening-invited cohorts, and thus not part of the screening. They will be matched to the controls by age and follow-up time. Rates of visual impairment will be compared between the bias-control group and control group, and so will baseline risk factors for fast progression of glaucoma (fig. 1). Figure 1: Flowchart of selection and analysis of data in patient records. Screened and non-responders (left): main outcome is risk ratio of the cumulative incidence rate of bilateral visual impairment between screened and non-responders at the screening. Assessment of possible selection bias (right): outcome is risk ratio of the cumulative incidence rate of bilateral VI between controls and bias controls.OAG=open-angle glaucoma. Dx=diagnosis. RR=risk ratio. VI=visual impairment.EligibilityThe study population consists of subjects living in the city of Malm? during the period for the screening examination in 1992-1997, with open-angle glaucoma diagnosed at or after the screening.Inclusion criteriaMales or females born 1918-1932, and females born 1933-1939. Confirmed diagnosis of open-angle glaucoma, defined as primary open angle glaucoma or exfoliation glaucoma.The subject was a resident of Malm? at his/her respective screening date.Exclusion criteriaSubjects not living in Malm? during the screening examination in 1992-1997.Patients with a diagnosis of secondary glaucoma or pigment glaucoma. Data sourcesAn electronic patient administrative system at the Department of Ophthalmology at Sk?ne University Hospital in Malm? will be searched for patients of the screened age cohorts from 1 Jan, 1987 to Dec 31, 2017, with a diagnosis in ICD 10 of: H401, H401A, H401C, H401D, H409, and the respective codes in ICD 9. Screening status (invited, not invited) will be ascertained in paper screening records. These records also show if a person was a resident in Malm? at the time of the screening. Glaucoma is defined as presence of repeatable glaucomatous visual field defects with corresponding optic disc and/or retinal nerve fiber layer damage, regardless of the intraocular pressure level.Patient records are available in electronic form from 2005, and on paper before that. Data regarding the population size of the screened cohorts, will be retrieved from screening records and protocols in paper format, electronic patient records, and an electronic patient administrative system.Data to be collected from patient records:Date of birthGenderDate of diagnosis Presence of exfoliation syndromeIntraocular pressure at diagnosisAmount of visual field loss at diagnosis (Mean Deviation value)Age at study start and endVisual acuity at the last visitAmount of visual field loss at the last visit (Mean Deviation value)Presence of visual impairment, i.e. low vision and/or blindness, at study endCause and date of visual impairment. Visual impairment will be defined according to the WHO criteria (table 1)Date of deathTable 1. World Health Organization criteria for visual impairmentLow vision VA <0·3 (20/70) and 0·05 and/or a constriction of the central visual field to <20° and 10°BlindnessVA <0·05 (20/400) and/or a constriction of the central visual field to <10°VA=visual acuity.Ethics The EMGT (US National Institutes of Health Clinical identifier NCT00000132; registered Sept 23, 1999) and the screening were approved by the Ethics Committee in Lund, Sweden, in 1992. The EMGT was also approved by the Committee on Research Involving Human Subjects at the State University of New York at Stony Brook, USA.The current study was approved by the Ethics Committee in Lund, Sweden in 2006, with extensions most recently approved in 2019. Patients will notified by an advert in the local newspaper before data collection begins, with directions of how to opt out of the study. No written consent is required for the current study according to the Ethics Committee at Lund University. The study follows the tenets of Helsinki.Outcome measuresVisual impairment, including both bilateral low vision and blindness the from glaucoma, calculated as cumulative rates, and risk ratios with confidence limits between cases (the screened population) and controls (the non-responders). The detectable pre-clinical phase, or sojourn time, will be estimated by dividing the prevalence of screen-detected open-angle glaucoma with the population incidence in absence of screening: P/I=D, where P= prevalence, I= incidence, D= duration of disease. It is also possible to estimate with the “catch-up time” method, where the duration is derived from the point where the incidence of glaucoma in the screened population catches up with the expected incidence after the screening. The estimation of the age at which screening for glaucoma would be most effective, will be conducted in the same way as for the primary aim, with calculation of cumulative rates and risk ratios with confidence limits for visual impairment between cases and controls, but with a separation of patients in five-year age intervals. Cost-effectiveness calculations including QALYs will be included. The estimation of the interval of repeated screening is dependent on the results of the estimates of the sojourn time and the age at which screening for glaucoma would be most effective.Measures to avoid selection bias of the control groupThe use of the non-responders as the control group may create selection bias. Therefore, we plan to create a separate bias control group of patients managed for glaucoma at our department, older and younger than the screening-invited cohorts, and thus not part of the screening. They will be matched to the controls by age and follow-up time. Rates of visual impairment and baseline risk factors for fast progression of glaucoma and for blindness will be compared between bias controls and controls. If possible differences are revealed between the groups, appropriate corrections of the main results will be made. GeneralisabilityOpen-angle glaucoma is a disease of the elderly, with a higher prevalence in black people with origins in West Africa, and Latinos. There is no evidence of differences in prevalence or severity described regarding sex, socio-economic status, rural or urban populations. No clear associations with other medical conditions have been reported. The prevalence in European derived populations, such as ours, is quite uniform, and we believe that our results could be generalized to other European derived populations.Funding Swedish Research Council grant K98-27X and K2002-74X-10426-10A, the U.S. National Eye Institute grant U10EY10260 and U10EY10261, regional agreements between Lund University and Sk?ne Regional Council (ALF), and grants from the Herman J?rnhardt Foundation, the Foundation for Visually Impaired in Former Malm?hus County and the Margit and Kjell Stoltz Foundation. References1. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. The Lancet Global health. 2017 Dec;5(12):e1221–34.?2. Leske MC. Open-Angle Glaucoma - An Epidemiologic Overview. Ophthalmic Epidemiology. 2007 Jul;14(4):166–72.?3. Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in primary open-angle glaucoma prevalence by age, gender, and race: a Bayesian meta-analysis. Investigative ophthalmology & visual science. 2006 Oct;47(10):4254–61.4. Gr?dum K, Heijl A, Bengtsson B. A comparison of glaucoma patients identified through mass screening and in routine clinical practice. Acta Ophthalmol Scand. 2002 Dec;80(6):627-31.5. Bengtsson B. The prevalence of glaucoma. Br J Ophthalmol. 1981 Jan;65(1):46-9.6. Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, Singh K. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991 Aug;109(8):1090-5.7. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbee DE, de Jong PT. The prevalence of primary open-angle glaucoma in a population-based study in The Netherlands. The Rotterdam Study. Ophthalmology. 1994 Nov;101(11):1851-5.8. Ekstr?m C. Prevalence of open-angle glaucoma in central Sweden. The Tierp Glaucoma Survey. Acta Ophthalmol Scand. 1996 Apr;74(2):107-12.9. Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology. 1996 Oct;103(10):1661-9.10. Hatt S et al. 2006. Screening for prevention of optic nerve damage due to chronic open angle glaucoma. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006129.11. Weinreb RN, et al. Glaucoma screening. The 5th consensus report of the World Glaucoma Association. Kugler publications 2008.12. Moyer VA. Screening for glaucoma. US Preventative Services Task Force recommendation statement. Annals of Internal Medicine. 2013, 159(7): 484-89.13. Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. WHO Chronicle. 1968;22(11):473.14. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M. Early Manifest Glaucoma Trial Group; Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002 Oct;120(10):1268-79.15. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-13.16. Drance S, Anderson DR, Schulzer M. Collaborative Normal-Tension Glaucoma Study Group: Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001 Jun;131(6):699-708.17. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):714-20.18. Wilson MR, Kosoko O, Cowan CL, Jr., et al. Progression of visual field loss in untreated glaucoma patients and glaucoma suspects in St. Lucia, West Indies. Am J Ophthalmol. 2002;134(3):399-405.19. Bengtsson B, Heijl A. SITA Fast, a new rapid perimetric threshold test. Description of methods and evaluation in patients with manifest and suspect glaucoma. Acta Ophthalmol Scand. 1998;76(4):431-7.20. Robin TA, Muller A, Rait J, Keeffe JE, Taylor HR, Mukesh BN. Performance of community-based glaucoma screening using Frequency Doubling Technology and Heidelberg Retinal Tomography. Ophthalmic Epidemiol. 2005 Jun;12(3):167-78.? ................
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