Biobanks and the importance of detailed phenotyping: a case study--the European Glaucoma Society GlaucoGENE project.

BACKGROUND: Dissecting complex diseases has become an attainable goal through large-scale collaborative projects under the term "biobanks." However, large sample size alone is no guarantee of a reliable genetic association study, and the genetic epidemiology of complex diseases still has many challenges to face. Among these, issues such as genotyping errors and population stratification have been previously highlighted. However, comparatively little attention has been given to accurate phenotyping. Study procedures of existing large-scale biobanks are usually restricted to very basic physical measurements and non-standardised phenotyping, based on routine medical records and health registry systems. DISCUSSION: Study procedures of existing large-scale biobanks are usually restricted. Considering that the objective of an association study is to establish genotype-phenotype correlations, it is doubtful how easily this could be achieved in the absence of accurate and reliable phenotype description. The use of non-specific or poorly defined phenotypes may partly explain the limited progress so far in glaucoma complex genetics. This report examines the European Glaucoma Society GlaucoGENE project, which is the only large multicentre glaucoma-specific biobank. Unlike previous biorepositories, this initiative focuses on detailed and standardised phenotyping and is expected to become a major resource for future studies on glaucoma.

Practical recommendations for measuring rates of visual field change in glaucoma.

To date, there has been a lack of evidence-based guidance on the frequency of visual field examinations required to identify clinically meaningful rates of change in glaucoma. The objective of this perspective is to provide practical recommendations for this purpose. The primary emphasis is on the period of time and number of examinations required to measure various rates of change in mean deviation (MD) with adequate statistical power. Empirical data were used to obtain variability estimates of MD while statistical modelling techniques derived the required time periods to detect change with various degrees of visual field variability. We provide the frequency of examinations per year required to detect different amounts of change in 2, 3 and 5 years. For instance, three examinations per year are required to identify an overall change in MD of 4 dB over 2 years in a patient with average visual field variability. Recommendations on other issues such as examination type, strategy and quality are also made.

Assessing visual fields for driving in patients with paracentral scotomata.

BACKGROUND: The binocular Esterman visual field test (EVFT) is the current visual field test for driving in the UK. Merging of monocular field tests (Integrated Visual Field, IVF) has been proposed as an alternative for glaucoma patients. AIMS: To examine the level of agreement between the EVFT and IVF for patients with binocular paracentral scotomata, caused by either ophthalmological or neurological conditions, and to compare outcomes with useful field of view (UFOV) performance, a test of visual attention thought to be important in driving. METHODS: 60 patients with binocular paracentral scotomata but normal visual acuity (VA) were recruited prospectively. Subjects completed and were classified as "pass" or "fail" for the EVFT, IVF and UFOV. RESULTS: Good agreement occurred between the EVFT and IVF in classifying subjects as "pass" or "fail" (kappa = 0.84). Classifications disagreed for four subjects with paracentral scotomata of neurological origin (three "passed" IVF yet "failed" EVFT). Mean UFOV scores did not differ between those who "passed" and those who "failed" both visual field tests (p = 0.11). Agreement between the visual field tests and UFOV was limited (EVFT kappa = 0.22, IVF kappa 0.32). CONCLUSIONS: Although the IVF and EVFT agree well in classifying visual fields with regard to legal fitness to drive in the UK, the IVF "passes" some individuals currently classed as unfit to drive due to paracentral scotomata of non-glaucomatous origin. The suitability of the UFOV for assessing crash risk in those with visual field loss is questionable.

A practical approach to measuring the visual field component of fitness to drive.

AIMS: To determine the level of agreement between merged monocular visual field tests (the integrated visual field) and the binocular Esterman visual field test in classifying patients' visual status for UK legal fitness to drive. To examine the link between these two tests and the useful field of view (UFOV) test, a test which is considered to be a surrogate for the visual capability for safe driving. METHODS: Primary open angle glaucoma patients with bilateral overlapping visual field defects were recruited prospectively. Patients performed the bilateral monocular field tests (to generate the integrated visual field), the Esterman test and the UFOV test on the same visit. Patients were classified as "pass" or "fail" by both the integrated visual field and the Esterman test. UFOV risk scores were calculated for each patient. RESULTS: 65 patients were recruited. Substantial agreement was found between the integrated visual field and the Esterman test in classifying patients as "pass" or "fail" (kappa = 0.69). No patients classified as "pass" by the integrated visual field test were classified as "fail" by the Esterman test. Eight patients who were classified as "pass" by the Esterman test were classified as "fail" by the integrated visual field test. The UFOV risk characteristics of these eight patients suggested they were more similar to those of the 13 patients who were classified as "fail" by both the tests, than the 44 patients who were classified as "pass" by both tests. CONCLUSIONS: The integrated visual field test agrees well with the current method (Esterman) of classifying visual fields with regard to legal fitness to drive in the United Kingdom in patients with glaucoma; it appears superior to the current method in identifying those with reduced fitness to drive as measured by the UFOV. The integrated visual field test could perform a valuable screening or diagnostic role in the assessment of glaucoma patients' fitness to drive.

Randomised controlled trial comparing the effect of brimonidine and timolol on visual field loss after acute primary angle closure.

AIM: To compare the effect of brimonidine and timolol in reducing visual field loss in patients with acute primary angle closure (APAC). METHODS: In addition to standard acute medical treatment, patients presenting with APAC were randomised to either brimonidine 0.2% or timolol 0.5% upon diagnosis, then twice daily for 4 weeks. After laser peripheral iridotomy (LPI), subjects underwent three baseline perimetry tests during the first week, and then at weeks 4, 8, 12, and 16. Pointwise linear regression analysis was applied to the field series of each of these subjects starting with the third test (total of five tests per subject). Progression was defined as a significant regression slope (p<0.05) showing 1 dB per year or more of sensitivity loss at the same test location in the series. Patients were also compared for prevalence of abnormal fields at 16 weeks, which was defined as an abnormal glaucoma hemifield test result and/or corrected pattern standard deviation outside the 95% confidence limits. RESULTS: 59 subjects (31 in the brimonidine group; 28 in the timolol group) completed the study. There were 47 females (79.7%), the majority of subjects (94.9%) were Chinese and the mean age was 59.2 (SD 7.2) years. There were no significant differences between the two groups with respect to demographic features, presenting intraocular pressure (IOP), duration of symptoms, time from presentation to LPI, or mean IOP at each study visit. Over the 16 week study period, despite adequate statistical power, no difference was found between groups in terms of the number of patients with progressing locations, the mean number of progressing locations per subject, or the mean slope of the progressing locations. Nine (29%) subjects in the brimonidine group and 10 (35.7%) in the timolol group were found to have significant visual field defects at 16 weeks (p = 0.58). 15 out of these 19 subjects (78.9%) already had these visual field defects in the first week. CONCLUSIONS: In the first 16 weeks after APAC, there was no difference in the prevalence of visual field defects or rate of visual field progression between brimonidine and timolol treated groups.

Interobserver agreement on visual field progression in glaucoma: a comparison of methods.

AIM: To examine the level of agreement between clinicians in assessing progressive deterioration in visual field series using two different methods of analysis. METHODS: Each visual field series satisfied the following criteria: more than 19 reliable fields, patient age over 40 years, macular threshold at least 30 dB. The first three fields in each series were excluded to minimise learning effects: the following 16 were studied. Five expert clinicians assessed the progression status of each series using both standard Humphrey printouts and pointwise linear regression (PROGRESSOR). The level of agreement between the clinicians was evaluated using a weighted kappa statistic. RESULTS: A total of 432 tests comprising 27 visual field series of 16 tests each were assessed by the clinicians. The level of agreement on progression status between the clinicians was always higher when they used PROGRESSOR (median kappa = 0.59) than when they used Humphrey printouts (median kappa = 0.32). This was statistically significant (p = 0.006, Wilcoxon matched pairs signed rank sum test). CONCLUSIONS: Agreement between expert clinicians about visual field progression status is poor when standard Humphrey printouts are used, even when the field series studied are long and consist solely of reliable fields. Under these ideal conditions, clinicians agree more closely about patients' visual field progression status when using PROGRESSOR than when inspecting series of Humphrey printouts.

Response time prolongation for a motion stimulus in patients with glaucoma and its relationship with elevation of the motion threshold.

PURPOSE: To investigate whether response times for a motion stimulus are prolonged in glaucoma and to investigate the relationship between response time prolongation and motion threshold elevation in glaucoma. METHOD: Motion displacement thresholds and response times were measured in 15 patients with glaucoma and 18 age-matched control subjects. RESULTS: Mean test response times were significantly prolonged in the glaucomatous eyes than in the control eyes, with a mean delay of 200 milliseconds. After correcting for threshold elevation, response times at the motion threshold showed no significant difference between the groups. CONCLUSIONS: Response times for motion detection are significantly prolonged in glaucoma and are accounted for by the threshold elevation in patients with glaucoma. The implications of these results are discussed in terms of the use of response time analysis to determine subject reliability.

Detection of optic disc change with the Heidelberg retina tomograph before confirmed visual field change in ocular hypertensives converting to early glaucoma.

AIM: To determine whether analysis of sequential optic disc images obtained with the Heidelberg retina tomograph (HRT) is able to demonstrate optic disc change before the development of reproducible field defects in a group of ocular hypertensive (OHT) patients converting to early glaucoma. METHODS: Two groups were analysed: (1) 13 eyes of 13 OHT patients who subsequently developed reproducible field defects (converters); and (2) 13 eyes of 11 normal control subjects. Two sequential optic disc images were obtained using the HRT (median separation between images was 12 months for the converters and 13 months for the normals). The second image in the converter group was obtained before confirmed visual field loss. The optic disc variables were analysed both globally and segmentally using HRT software version 1.11. The Wilcoxon signed rank test was used to determine if there were any significant differences between the variables of the two image sets. RESULTS: Significant optic disc change was demonstrated in the group of converters: (1) global variables: the cup area increased by 9.7%, the C/D area ratio increased by 10.5%, and the rim area decreased by 6.9%; (2) segmental variables: the superonasal cup area increased by 11.0%, the superonasal C/D area ratio increased 11.7%, and the inferonasal cup volume increased by 28.4%. The temporal rim volume decreased by 15.6%, the inferotemporal rim volume decreased by 23.6%, and the rim area in the superonasal and superotemporal segments decreased by 6.6% and 6.9% respectively. CONCLUSION: Analysis of sequential optic disc images on the HRT allowed the detection of glaucomatous change before confirmed visual field change in a group of OHT patients converting to early glaucoma.

Severity and stability of glaucoma: patient perception compared with objective measurement.

OBJECTIVE: To elucidate the relationship between the subjective assessment in patients with glaucoma of (1) the severity of their visual loss, and (2) any deterioration in their visual function and their objective visual fields as measured by computed perimetry. DESIGN: First, patients completed a questionnaire relating to perceived visual disability and underwent binocular visual field testing. Second, a separate group of patients answered a question about perceived visual deterioration: their monocular visual field tests were analyzed retrospectively by pointwise linear regression to establish stability or deterioration. SETTING: The Glaucoma Service of a specialist eye hospital, which is a tertiary referral center and serves the local community. SUBJECTS: One hundred twenty-three patients with glaucoma including 62 for the severity arm of the study and 61 for the progression arm. MAIN OUTCOME MEASURES: Questionnaire responses, Esterman binocular disability score, and objective visual field deterioration. RESULTS: Questions strongly associated with Esterman binocular disability scores related to bumping into things, problems with stairs, and finding things that have been dropped. There was a strong association between perceived visual deterioration and measured bilateral visual field deterioration (P<.01). CONCLUSIONS: There is a strong association between some types of perceived visual disability and the severity of binocular field loss. A patient who notices gradual visual deterioration is twice as likely to have bilateral visual field deterioration as not. The findings in this sample of patients with mild-to-moderate glaucoma challenge the belief that glaucoma is an insidious process in which the symptoms do not appear until the end stage of the disease.

Simulating binocular visual field status in glaucoma.

AIMS: To simulate the central binocular visual field using results from merged left and right monocular Humphrey fields. To assess the agreement between the simulation and the binocular Humphrey Esterman visual field test (EVFT). METHOD: 59 consecutive patients with bilateral glaucoma each recorded Humphrey 24-2 fields for both eyes and binocular EVFT on the same visit. EVFT results were used to identify patients exhibiting at least one defect (< 10 dB) within the central 20 degrees of the binocular field. This criterion is relevant to a patient's legal fitness to drive in the UK. Individual sensitivity values from monocular fields are merged to generate a simulated central binocular field. Results are displayed as a grey scale and as symbols representing defects at the < 10 dB level. Agreement between patients failing the criterion using the simulation and the EVFT was evaluated. RESULTS: Substantial agreement was observed between the methods in classifying patients with at least one defect (< 10 dB) within the central binocular field (kappa 0.81; SE 0.09). Patients failing this criterion using the EVFT results were identified by the binocular simulation with high levels of sensitivity (100%) and specificity (86%). CONCLUSIONS: Excellent agreement exists between the simulated binocular results and EVFT in classifying glaucomatous patients with central binocular defects. A rapid estimate of a patient's central binocular field and visual functional capacity can be ascertained without extra perimetric examination.

How often do patients need visual field tests?

BACKGROUND: This study was undertaken to determine whether the interval between visual field tests affects the ability to detect progressive glaucomatous field loss. METHODS: One hundred and nineteen retinal locations which were deteriorating significantly by > or = 1 dB/ year (untreated normal tension glaucoma patients: 6 eyes) were studied. Analysis was repeated using 'thinned' visual field tests: one test per year instead of the complete three per year over a period of 4 years. RESULTS: The 'thinned' tests identified only 45.4% of the deteriorating points over the 4-year period. Furthermore, there was a mean delay of 1.10 years in detection (P < 0.01). CONCLUSIONS: Less frequent visual field testing detects fewer progressing locations and detects them later.

Early detection of visual field progression in glaucoma: a comparison of PROGRESSOR and STATPAC 2.

AIM: To compare the performance of PROGRESSOR (pointwise linear regression) and STATPAC 2 (comparison with baseline values) in detecting early deterioration in the visual fields of glaucoma patients. METHODS: Visual field series from 19 untreated normal tension glaucoma eyes which were deteriorating on clinical grounds were analysed by PROGRESSOR and STATPAC 2. Progression criteria for PROGRESSOR were (1) inner points: slope < -1 dB/year, p < 0.05 and (2) edge points: slope < -2 dB/year, p < 0.05. Criteria for STATPAC 2 were p < 0.05 change probability for any point on three consecutive fields. Detection time was defined as the time interval between the initial field and the first field in which at least one progressing point was identified. Detection times produced by the two techniques were compared. RESULTS: PROGRESSOR and STATPAC 2 agreed on progression in all 19 eyes. Mean detection time for PROGRESSOR was 1.077 (SD 0.985) years and for STATPAC 2 was 2.161 (1.357) years. PROGRESSOR detected progression sooner than STATPAC 2 in 18 eyes (p < 0.01), Wilcoxon matched pairs signed rank test). PROGRESSOR detected progression earlier by a mean of 1.085 (0.936) years. CONCLUSIONS: PROGRESSOR consistently detected progression earlier than STATPAC 2. The PROGRESSOR software is a useful tool for the early detection of visual field deterioration in glaucoma.