Glaucoma is the second most common cause of blindness worldwide. Our broad, long-term objectives are to investigate innovative technologies and methods that will accurately and reproducibly provide the earliest possible evidence of glaucoma and its progression so as to prevent blindness. We have improved on the program that we have pursued for the past ten years in a number of ways, but importantly we have assembled a unique collaborative group for this project. This team includes ophthalmologists, engineers, computer scientists and statisticians, as well as appropriate support personnel, from the University of Pittsburgh, Tufts University, Massachusetts Institute of Technology and Carnegie Mellon University. We have brought excellent investigators from disparate fields to bring new insights, knowledge and skills from outside of ophthalmology to bear on innovations in technology for glaucoma disease and progression detection. We will accomplish this via cross-sectional and longitudinal studies using cohorts of healthy, glaucoma suspect and glaucomatous subjects. Our Specific Aims are to (1) detect the earliest possible evidence of glaucomatous damage and progression. We will compare objective, quantitative ocular structural measurements obtained by ocular imaging and functional measurements, to test the prediction that changes structural functional change, and to characterize those changes, (2) advance optical coherence tomography (OCT) software innovations that assess the intra-retinal layers in the peripapillary and macular areas as well as the optic nerve head (ONH). This aim includes employing innovative image processing and image analysis techniques, as well as new techniques to improve scan quality post hoc, (3) identify the particular clusters of clinical characteristics distinct to specific glaucoma diagnostic technologies resulting in the earliest detection of glaucoma and its progression. We will use innovative automated machine classifiers and state-of-the-art statistical methods which use the best combination of parameters generated by the imaging devices in order to determine the optimal use of each device in assessing disease and progression, (4) advance micron-scale tomographic imaging using OCT for improved understanding of the anatomical and biomechanical properties of the ONH and intra-retinal substructure in the macular and peripapillary regions in health and in glaucoma. These are key areas involved in the glaucomatous process. This experiment is designed to improve our understanding of glaucoma and potentially create a new glaucoma diagnostic. Swept-source and ultra-high speed spectral- domain OCT will be used to obtain detailed information in the ONH, lamina cribrosa and retina. Rapid image acquisition by these devices will minimize OCT scanning artifact, and modulation of OCT light source wavelengths will allow optimization of imaging at various tissue depths. We expect that these studies will lead to our ability to detect glaucoma and its progression earlier than ever before with high sensitivity and specificity, enabling early intervention to prevent glaucoma blindness.