Title:
Glaucoma diagnostics.

Abstract:
This thesis addresses several aspects of glaucoma diagnostics from both a clinical and a screening perspective. New instruments for diagnosing glaucoma have been developed over the past years, but little information is available regarding their performance as screening methods and their usefulness in ordinary clinical practice. PURPOSE OF THE RESEARCH UNDERLYING THIS THESIS:  The objectives of this research were as follows: to compare the accuracy of results of analysis of the optic nerve head (ONH) achieved by computerized imaging using the Heidelberg Retina Tomograph (HRT) and by subjective assessment performed by physicians with different degrees of experience of glaucoma (paper III); to evaluate the effect of a continuous medical education (CME) lecture on subjective assessment of the ONH for diagnosis of glaucoma (paper II); to investigate subjective assessment of perimetric test results by physicians with varying knowledge of glaucoma with a trained artificial neural network (ANN) and to compare the certainty of the classifications (paper IV); and to compare the diagnostic performance of time-domain Stratus optical coherence tomography (OCT) with that of spectral-domain Cirrus OCT (paper I), frequency doubling technology (FDT) screening perimetry and scanning laser polarimetry with the GDx variable corneal compensator (VCC) in a random population-based sample and in patients with glaucoma of varying disease severity.
In evaluation of the ONH, use of the HRT statistical tools, Moorfields regression analysis (MRA) and the Glaucoma Probability Score (GPS) was compared with subjective assessment performed by 45 physicians. Optic nerve head images and photographs from 138 healthy and 97 glaucoma subjects were included. The sensitivity of MRA was higher (87-94%) than that of the average physician (62-82%), considerably greater than that of ophthalmologists with subspecialties other than glaucoma (53-77%) and non-significantly better than that of glaucoma experts (72-88%). Sensitivity achieved by GPS (79-93%) was also greater than that of the average physician. MRA correctly classified all eyes with advanced glaucomatous visual field defects, a result that was not achieved by GPS or even by the glaucoma experts. In eyes with small discs, MRA sensitivity (88%) was comparable with that of glaucoma experts (85%) and much better than that of GPS (50%). Also, the group comprising all physicians provided specificity (75-92%) similar to that of both MRA (69 - 86%) and GPS (72-94%) (Andersson et al. 2011a). A 1-hr CME lecture on ONH assessment led to a significant improvement in sensitivity (from 70% to 80%) and a significant decrease in uncertain assessments (from 22% to 13%), whereas specificity remained unchanged (68%) (Andersson et al. 2011b). A rise in sensitivity was seen in all subgroups of physicians, including glaucoma experts. Thirty physicians assessing standard automated perimetry (SAP) test results as Humphrey Field Analyzer single-field analysis printouts with full StatPac information from 99 patients with glaucoma and 66 healthy subjects were compared with a trained ANN regarding diagnostic performance. ANN reached significantly higher sensitivity (93%) than the average physician (83%), whereas specificity was similar for these two groups (91% and 90%, respectively). Diagnostic accuracy was similar among the different groups of physicians and seemingly rather independent of experience. Sensitivity ranged from 82% in the subgroup of other subspecialists to 87% in the glaucoma expert group, and specificity ranged from 88% among general ophthalmologists to 91% for glaucoma experts. The ANN attained certainty of classification that was in parity with that provided by the glaucoma experts and did not make any completely incorrect classifications of the visual fields (i.e. erroneous classifications were in the borderline zone) (Andersson et al. 2012). From a population-based randomly selected sample (n=308) of older subjects (aged ≥ 50 years) living in southern Sweden, 170 subjects underwent a comprehensive examination that included Stratus OCT, Cirrus OCT, an FDT screening programme and the GDx VCC. The same test protocol was applied to 138 randomized clinical patients with different stages of glaucoma. In the population-based sample, both Stratus and Cirrus OCT showed high diagnostic accuracy with area under the receiver-operating curve (aROC) values close to 1.0 (Bengtsson et al. 2012). Both OCT instruments correctly classified all of the clinical glaucoma patients with advanced disease. FDT screening showed high sensitivity (91%) but erroneously gave normal test results for some eyes with advanced disease. GDx VCC had lower sensitivity (73-92%) and also led to a large proportion of examinations with an atypical retardation pattern that is known to affect the diagnostic efficiency of this instrument.
The HRT MRA performed better than most physicians and was consistent with the glaucoma experts. These results suggest that MRA can be a valuable tool for diagnosing glaucoma in ordinary practice, particularly when only a few glaucoma experts are available. Even though MRA provided 100% sensitivity in eyes with advanced glaucoma, it probably does not offer sufficient specificity to make it suitable as a screening method. Continuing medical education on ONH analysis had a small, but positive effect on diagnostic accuracy for glaucoma. An ANN trained to classify visual fields seemed to perform at least as well as most of the participating physicians, whose performances were remarkably similar regardless of their level of experience. This indicates that available tools for interpreting SAP findings are helpful in assessments of visual field test results. However, SAP is associated with learning effects (Heijl et al. 1989) that may entail low specificity for untrained subjects, and hence, it is not an ideal screening method for glaucoma. By comparison, the screening test of FDT is rapid and easy, but it is probably less suitable for screening purpose, because some eyes with advanced glaucoma were missed in this investigation. GDx VCC images for a relatively large number of eyes could not be analysed and is thus not appropriate for screening. The OCT instruments offer both high sensitivity and high specificity, and all eyes with advanced disease were correctly classified as glaucomatous in this evaluation. However, these instruments are still expensive and require special operator skills. Additional development to obtain OCT instrument that is more compact, easier to use and less expensive might render such tomography suitable as a screening tool for glaucoma.