Faculty Bibliography

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 x 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 x 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 x 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 x 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

PURPOSE: To develop and test a novel signal enhancement method for optical coherence tomography (OCT) images based on the high dynamic range (HDR) imaging concept. METHODS: Three virtual channels, which represent low, medium, and high signal components, were produced for each OCT signal dataset. The dynamic range of each signal component was normalized to the full gray scale range. Finally, the three components were recombined into one image using various weights. Fourteen eyes of 14 healthy volunteers were scanned multiple times using time-domain (TD)-OCT before and while preventing blinking in order to produce a wide variety of signal strength (SS) images on the same eye scanned on the same day. For each eye, a pair of scans with the highest and lowest SS with successful retinal nerve fiber layer (RNFL) segmentation was selected to test the signal enhancement effect. In addition, spectral-domain (SD)-OCT images with poor signal qualities were also processed. RESULTS: Mean SS of good and poor quality scans were 9.0 +/- 1.1 and 4.4 +/- 0.9, respectively. TD-OCT RNFL thickness showed significant differences between good and poor quality scans on the same eye (mean difference 11.9 +/- 6.0 mum, P < 0.0001, paired t-test), while there was no significant difference after signal enhancement (1.7 +/- 6.2 mum, P = 0.33). However, HDR had weaker RNFL compensation effect on images with SS less than or equal to 4, while it maintained good compensation effect on images with SS greater than 4. Successful signal enhancement was also confirmed subjectively on SD-OCT images. CONCLUSION: The HDR imaging successfully restored OCT signal and image quality and reduced RNFL thickness differences due to variable signal level to the level within the expected measurement variability. This technique can be applied to both TD- and SD-OCT images.

PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography with visual field progression using standard automated perimetry in glaucoma suspect and preperimetric glaucoma patients or perimetric glaucoma patients. DESIGN: Prospective, longitudinal clinical trial. METHODS: Eligible eyes with 2 years or more of follow-up underwent time-domain optical coherence tomography and standard automated perimetry every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (P < .05) negative visual field index slope over time. RNFL progression or improvement was defined as a significant negative or positive slope over time, respectively. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate. RESULTS: Three hundred ten glaucoma suspect and preperimetric glaucoma eyes and 177 perimetric glaucoma eyes were included. Eighty-nine eyes showed visual field progression and 101 eyes showed RNFL progression. The average time to detect visual field progression in those 89 eyes was 35 +/- 13 months, and the average time to detect RNFL progression in those 101 eyes was 36 +/- 13 months. In multivariate Cox models, average and superior RNFL losses were associated with subsequent visual field index loss in the entire cohort (every 10-mum loss; hazard ratio, 1.38; P = .03; hazard ratio, 1.20; P = .01; respectively). Among the entire cohort of 487 eyes, 42 had significant visual field index improvement and 55 had significant RNFL improvement (specificity, 91.4% and 88.7%, respectively). CONCLUSIONS: Structural progression is associated with functional progression in glaucoma suspect and glaucomatous eyes. Average and superior RNFL thickness may predict subsequent standard automated perimetry loss.

We propose a 2D continuous-time Hidden Markov Model (2D CT-HMM) for glaucoma progression modeling given longitudinal structural and functional measurements. CT-HMM is suitable for modeling longitudinal medical data consisting of visits at arbitrary times, and 2D state structure is more appropriate for glaucoma since the time courses of functional and structural degeneration are usually different. The learned model not only corroborates the clinical findings that structural degeneration is more evident than functional degeneration in early glaucoma and the opposite is observed in more advanced stages, but also reveals the exact stages where the trend reverses. A method to detect time segments of fast progression is also proposed. Our results show that this detector can effectively identify patients with rapid degeneration. The model and the derived detector can be of clinical value for glaucoma monitoring.

PURPOSE: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. METHODS: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) >/=22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women. RESULTS: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p