Spatial and spatio-temporal statistical analyses of retinal images: a review of methods and applications.

Background: Clinical research and management of retinal diseases greatly depend on the interpretation of retinal images and often longitudinally collected images. Retinal images provide context for spatial data, namely the location of specific pathologies within the retina. Longitudinally collected images can show how clinical events at one point can affect the retina over time. In this review, we aimed to assess statistical approaches to spatial and spatio-temporal data in retinal images. We also review the spatio-temporal modelling approaches used in other medical image types. Methods: We conducted a comprehensive literature review of both spatial or spatio-temporal approaches and non-spatial approaches to the statistical analysis of retinal images. The key methodological and clinical characteristics of published papers were extracted. We also investigated whether clinical variables and spatial correlation were accounted for in the analysis. Results: Thirty-four papers that included retinal imaging data were identified for full-text information extraction. Only 11 (32.4%) papers used spatial or spatio-temporal statistical methods to analyse images, others (23 papers, 67.6%) used non-spatial methods. Twenty-eight (82.4%) papers reported images collected cross-sectionally, while 6 (17.6%) papers reported analyses on images collected longitudinally. In imaging areas outside of ophthalmology, 19 papers were identified with spatio-temporal analysis, and multiple statistical methods were recorded. Conclusions: In future statistical analyses of retinal images, it will be beneficial to clearly define and report the spatial distributions studied, report the spatial correlations, combine imaging data with clinical variables into analysis if available, and clearly state the software or packages used

Early detection of diabetic macular oedema

Background Diabetic retinopathy (DR) is the second leading cause of visual loss in working-age adults in the United Kingdom (UK) after inherited eye disease, and is asymptomatic in its early stages. Visual loss from DR is commonly due to diabetic macular oedema (DMO) which current screening methods cannot detect directly. The handheld radial shape discrimination (hRSD) test, has been approved by the US Food and Drug Administration (FDA) as a means of detecting metamorphopsia, and therefore maculopathy. There is also emerging evidence that DR is a neurodegenerative disease resulting in thinning of the ganglion cell complex detected by optical coherence tomography (OCT) in early DR. This thesis describes studies of people with diabetes (PWD) and healthy controls (HC) investigating two emerging approaches, namely hRSD and OCT in the early detection of DMO. Methods Macular function was measured using hRSD, distance and near visual acuity (VA) and macular structure was assessed using Heidelberg Spectralis OCT. Retinal layers segmentation and mean thicknesses were measured across all Early Treatment Diabetic Retinopathy Study (ETDRS) subfields using the Heidelberg auto-segmentation software with manual adjustment as needed. One eye from each participant was randomly selected for analysis. Results 292 PWD (mean±SD 54±14 years, 175 males) referred from the local screening programme to hospital clinics as being at risk of DMO were recruited. 229 healthy participants (age 44±18 years; 94 males) were also recruited, of whom 50 (55±14 years, 26 males) were used as age-matched controls for the PWD. Compared to HC, hRSD performance and distance VA were progressively worse in PWD with no or minimal DR, (hRSD logMAR: HC -0.77±0.11, no DR -0.68±0.18, minimal DR -0.61±0.25, ANOVA p<0.001; distance VA logMAR: HC -0.08±0.12, no DR 0.03±0.15, minimal DR 0.06±0.16, ANOVA p<0.001). Compared to HC there was a reduction in full retinal thickness across most subfields in PWD with no or minimal DR. This reduction was driven by thinning in the outer nuclear layer (ONL) in the central subfield (CSF), ganglion cell layer (GCL) and inner plexiform layer (IPL) in the inner subfields and retinal nerve fibre layer (RNFL) in the outer subfields compared to HC. In the outer subfields, there was also thinning in the retinal pigment epithelium (RPE) in PWD with no DR and thinning in the GCL and IPL in PWD with minimal DR. Longitudinal data were available for 159 PWD (54±15 years, 97 males) who attended for a second visit after 191±86 days. In PWD with no or minimal DR, there was a significant decrease in GCL (visit 1 37.73±3.56µm, visit 2 37.27±3.84µm, t=2.523, p=0.020), IPL (visit 1 31.98±2.48µm, visit 2 31.61±2.69µm, t=2.517, p=0.020) and inner nuclear layer (INL) (visit 1 33.89±1.92µm, visit 2 32.96±1.11µm, t=3.129, p=0.005) between visits. Conclusions Functional and structural changes are detectable in the early pathogenesis of DR, consistent with neuroretinal thinning developing before microvascular abnormalities. Functional changes detected by the hRSD test in PWD with early DR have not been previously demonstrated. Findings from the Early Detection of Diabetic Macular Oedema (EDDMO) study add further support to the concept of pre-clinical retinopathy