Between-Subject Variability in Healthy Eyes as a Primary Source of Structural-Functional Discordance in Patients With Glaucoma.

Glaucoma is a group of chronic progressive neurodegenerative conditions that lead to characteristic patterns of visual field loss. Various mechanisms have been proposed to explain its pathophysiology; ultimately, the condition leads to loss of ganglion cell function and cell death.1–3 Clinical diagnostic techniques rely on perimetric tests measuring the functionality of the ganglion cells and imaging tests, which assess the structural presence of the ganglion cells (directly or indirectly). Due to the differences in the methodology employed by structural and functional techniques, different artifacts influence them individually. Perimetric testing using Goldmann size III stimuli can be influenced by pupil size,4 peripheral refractive defocus,5 and the subject's internal criterion. Structural tests such as circumpapillary retinal nerve fiber layer (RNFL) thickness measured using optical coherence tomography (OCT) are influenced by disc area,6 axial length,6,7 and segmentation errors. Some factors such as ocular media opacity (introducing light scatter) and pupil size may impact both structural and functional techniques. On the other hand, each technique does also have its distinctive advantage. For example, functional tests (like perimetry) present clinicians with a unique opportunity to have an idea about the visual function of the patient. Relative to the perimetry, structural techniques have the advantage of being objectively acquired (although they require some operator dependent choices); they have also been shown to be fairly reproducible.8,9 The differences in the potential sources of artifact independently influencing structural and functional techniques of testing, as well as the relative advantage of one technique over the other provides a complementary effect when both techniques are used. Clinicians have therefore been encouraged to combine structural and functional tests to improve the certainties of diagnosis and to monitor progression.10 However, discordance in the structural–functional relationship has made the clinical usefulness of structural–functional comparison challenging. For example, some clinical trials found that functional tests show defects consistent with glaucomatous damage preceding structural defects while in other subjects structural damage precedes functional damage.10–12 Hood and Kardon13 explored the sources of discordance between results of static automated perimetry (SAP) and circumpapillary RNFL thickness. They found that a simple linear model could relate the two types of measurements and that the characteristics of the structural–functional discordance in patients could be predicted from the characteristics of the structural–functional relation in controls.14 Swanson et al.15 found that the limits of agreement between structural and functional measures in patients were very similar to the between-subject variability in healthy controls, as did a study comparing temporal disc rim area to macular perimetric sensitivity.16 In this paper, we integrated the function proposed by Hood at al.13 (relating RNFL thickness to perimetric sensitivity) with the Bland-Altman plots used by Swanson et al.15 to analyze an independent data set (gathered by another laboratory) to test the finding that between-subject variability in healthy eyes is the primary source of structural–functional discordance in patients with glaucoma. The motivation to maintain the analysis approach used by the previous studies (in which the data were collected and analysis techniques selected by the respective investigators) on an independent data set was to attenuate any unintentional bias in the design and choice of analysis technique that may have influenced the results of the previous studies.17,18 We further extended the hypothesis to include structural–structural discordance.