title: Localized glaucomatous change detection within the proper orthogonal decomposition framework.
abstract: OBJECTIVE
  To detect localized glaucomatous structural changes using proper orthogonal decomposition (POD) framework with false-positive control that minimizes confirmatory follow-ups, and to compare the results to topographic change analysis (TCA).
  
  
  METHODS
  We included 167 participants (246 eyes) with ≥4 Heidelberg Retina Tomograph (HRT)-II exams from the Diagnostic Innovations in Glaucoma Study; 36 eyes progressed by stereo-photographs or visual fields. All other patient eyes (n = 210) were non-progressing. Specificities were evaluated using 21 normal eyes. Significance of change at each HRT superpixel between each follow-up and its nearest baseline (obtained using POD) was estimated using mixed-effects ANOVA. Locations with significant reduction in retinal height (red pixels) were determined using Bonferroni, Lehmann-Romano k-family-wise error rate (k-FWER), and Benjamini-Hochberg false discovery rate (FDR) type I error control procedures. Observed positive rate (OPR) in each follow-up was calculated as a ratio of number of red pixels within disk to disk size. Progression by POD was defined as one or more follow-ups with OPR greater than the anticipated false-positive rate. TCA was evaluated using the recently proposed liberal, moderate, and conservative progression criteria.
  
  
  RESULTS
  Sensitivity in progressors, specificity in normals, and specificity in non-progressors, respectively, were POD-Bonferroni = 100%, 0%, and 0%; POD k-FWER = 78%, 86%, and 43%; POD-FDR = 78%, 86%, and 43%; POD k-FWER with retinal height change ≥50 μm = 61%, 95%, and 60%; TCA-liberal = 86%, 62%, and 21%; TCA-moderate = 53%, 100%, and 70%; and TCA-conservative = 17%, 100%, and 84%.
  
  
  CONCLUSIONS
  With a stronger control of type I errors, k-FWER in POD framework minimized confirmatory follow-ups while providing diagnostic accuracy comparable to TCA. Thus, POD with k-FWER shows promise to reduce the number of confirmatory follow-ups required for clinical care and studies evaluating new glaucoma treatments. (ClinicalTrials.gov number, NCT00221897.).
authors.affiliation: Hamilton Glaucoma Center, Department of Ophthalmology, University of California San Diego, LaJolla, California 92093, USA.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Balasubramanian
authors.forename: David J
authors.initials: DJ
authors.lastname: Kriegman
authors.forename: Christopher
authors.initials: C
authors.lastname: Bowd
authors.forename: Michael
authors.initials: M
authors.lastname: Holst
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Sample
authors.forename: Linda M
authors.initials: LM
authors.lastname: Zangwill
mesh_terms: D000328:Adult; D018450:Disease Progression; D005500:Follow-Up Studies; D005901:Glaucoma / Q000175:diagnosis* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000175:diagnosis* / Q000503:physiopathology; D009887:Ophthalmoscopy / Q000379:methods; D009898:Optic Disk / Q000473:pathology*; D009901:Optic Nerve Diseases / Q000175:diagnosis; D015203:Reproducibility of Results; D041623:Tomography, Optical Coherence / Q000379:methods*; D014794:Visual Fields