The Ocular Hypertension Treatment Study - Vision Research ...

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The Ocular Hypertension Treatment Study (OHTS) isa multicenter randomized clinical trial to evaluate thesafety and efficacy of topical ocular hypotensive therapy inpreventing or delaying the onset of visual field loss or opticnerve damage due to primary open-angle glaucoma inindividuals with ocular hypertension. 6 OHTS has 1,636participants who were randomized to either the closeobservation group or the medication group. Determinationof optic nerve damage is performed at the OHTS OpticDisc Reading Center by masked technicians because clinicpersonnel know the randomization assignment and clinicalstatus of participants. Several multicenter clinical trials inophthalmology, such as the Early Treatment DiabeticRetinopathy Study, 7 Cryotherapy for Retinopathy of Prematurity,8 Glaucoma Laser Trial, 9 and Central Vein OcclusionTrial 10 have employed photography readingcenters to provide unbiased, standardized assessment ofeligibility and outcome measures.Cost, efficiency, and reliability are key considerations inthe assessment of stereoscopic optic disk photographs by acentralized reading center. Several studies 2–5 have demonstratedfair-to-good agreement between observers when theobservers are glaucoma specialists. However, using glaucomaspecialists to evaluate stereoscopic optic disk photographswould have been prohibitively costly given thelarge sample size of OHTS. Klein and associates 11 describeda method for measuring cup/disk ratio using atemplate with circles that was specifically designed for useby technicians. However, the Klein protocol is timeconsuming, approximately 8 minutes/eye, or approximately16 minutes/patient.The OHTS Optic Disc Reading Center adopted aprotocol in which trained and certified technicians visuallyestimate horizontal cup/disk ratio. To our knowledge, thisis the first report to describe the reproducibility of visualestimates of cup/disk ratio by trained technicians. Thisprotocol is described in further detail in the Methodssection.This report is limited to data on horizontal cup/disk ratiowhich are collected in OHTS primarily for the purpose ofnumeric description and for use in statistical analysis. Theestimation of horizontal cup/disk ratio is only one aspect inthe determination of progressive optic disk damage inOHTS. The occurrence of progressive optic disk damage inOHTS is determined by a masked side-by-side comparisonof the baseline and follow-up stereoscopic optic diskphotographs. The determination of a difference betweenthe two sets of stereophotographs yields a “yes” or“ no”response, not a numeric value.Data collected by the OHTS provide a unique opportunityto study the reproducibility of horizontal cup/diskratio estimates using the Optic Disc Reading Centerprotocol. We report on agreement of cup/disk ratio estimatesfrom baseline stereoscopic photographs graded atentry and regraded annually thereafter in a masked fashion.The large sample permits us to examine several factorsfor their potential effect on agreement including cameratype (sequential full-frame vs simultaneous split-frame),observer (trained technician readers vs glaucoma specialists),and magnitude of cup/disk ratio (small-to-large cup/disk ratio). We also examine initial interobserveragreement between independent estimates by two primaryreaders before consensus and/or adjudication.METHODSTHE PROTOCOL AND BASELINE CHARACTERISTICS OF 1,636participants enrolled in the OHTS have been reportedelsewhere. 6 We report on the reproducibility of horizontalcup/disk estimates of stereoscopic optic disk photographswhich were graded at entry for eligibility determinationand regraded in a masked fashion annually during followup.Only OHTS certified photographers were permitted totake study optic disk stereophotographs. Certification ofphotographers required completion of stereo sets, bothright and left eyes of two patients, with adequate exposure,stereoscopic quality, proper labeling, and completion offorms.OHTS eligibility criteria required normal optic discs inboth eyes on clinical examination and on stereoscopicphotographs as determined by the Optic Disc ReadingCenter, Bascom Palmer Eye Institute, University of Miami,Miami, Florida. Exclusion criteria included the inability tovisualize or photograph the optic discs, the presence of adisk hemorrhage, notching, localized pallor, asymmetry incup/disk ratio of the two eyes 0.2 DD, or inability toadequately evaluate photographs due to poor photographicquality. Optic disk stereophotographs used to determineeligibility serve as the baseline. Horizontal cup/disk ratio ofbaseline optic disk stereophotographs was estimated atstudy entry and annually thereafter in the process of amasked, side-by-side comparison with follow-up photographs.This report only includes horizontal cup/disk ratiodata from baseline photographs graded at entry and regradedat years 1, 2, and 3.● PROTOCOL FOR OPTIC DISK STEREOPHOTOGRAPHY: A2X or 1.6X magnification lens is used or the highestmagnification for the fundus camera. All photographs aretaken on Ektachrome or Fujichrome 100 film. For sequentialfull-frame photography, starting with the right eye, theparticipant is instructed to follow the fixation light untilthe optic nerve is centered on the cross-hairs. The joystickis tilted to the right at the 3 o’clock position just outsidethe pupillary crescent focusing at the junction of theretinal pigment epithelium and the neuroretinal rim. Thisstep is repeated with the joystick at the 9 o’clock position.The same protocol is repeated for the left eye. Forsimultaneous split-frame photography, the participant’shead is positioned in the chin rest and the participant is20 AMERICAN JOURNAL OF OPHTHALMOLOGYJANUARY 2002
instructed to fixate on the fixation light. The photographerfocuses on the participant’s eye.Fundus cameras used by clinical centers include Zeiss,Kowa, or Topcon cameras to obtain full-frame stereoscopicimages sequentially or Topcon or Nidek cameras to obtainsplit-frame images simultaneously. The Donaldson Viewer(George Davco, Holbrook, MA 02343) is used to read twofull-frame 35 mm by 25 mm transparencies and the AsahiStereo Viewer II (Pentax Corp, Englewood, CO 80112) isused to read single split-frame 35 mm by 25 mm transparencies.● CERTIFICATION OF OPTIC DISK READERS AT OPTICDISC READING CENTER: To be certified as an optic diskphotography reader, technicians have to successfully gradea test set of stereophotographs (provided by Joseph Caprioli,MD) side by side with a glaucoma specialist. Trainingof readers was performed largely by DRA. Upon thesuccessful completion of the test set, the trainee completedindependent readings of 50 consecutive sets of slides takenfrom OHTS. To complete certification, the trainee had todemonstrate the ability to agree to within 0.1 DD of theofficial reading on all 50 eyes. Complete details of thetraining of readers at the Optic Disc Reading Center canbe found in the OHTS Manual of Procedures. 12● MEASUREMENT OF HORIZONTAL CUP/DISK RATIO: Stereophotographsare sent to the OHTS Optic Disc ReadingCenter where they are logged, labeled with random identifiers,and graded. Readers are masked as to randomization,clinic, patient ID, visit, prior gradings, fellow eyegrading, and clinical status of the eye. Two primary readersfirst independently grade the photographs for quality (clarityand stereo). If the two primary readers disagree, thestereophotographs are reviewed by a senior reader whosequality grading becomes the official decision. Photographswhose quality is too poor for assessment are not evaluatedfurther and a new set of photographs is requested.The primary readers independently conduct side-by-sidecomparisons of technically adequate baseline and follow-upstereophotographs masked as to their order. Thereaders estimate horizontal cup/disk ratio of both baselineand follow-up optic disk stereophotographs thereby regradingthe baseline stereophotographs with each new set ofannual follow-up stereophotographs. The primary readersvisually estimate the horizontal cup/disk ratio (3:00 to 9:00meridian) to the nearest 0.1 DD. The cup is determined bycontour. Assignment is straightforward when the orientationof both the disk and the cup are cylindrical andparallel to the optical axis. When the cup is conical, theplane midway between the surface of the disk and thedepth of the cup is used as the standard reference plane.When the optic nerve enters the sclera obliquely and theanatomic configuration is tilted with respect to the opticalaxis, an estimate is made of the horizontal cup/disk ratio atthe plane perpendicular to the axis of the insertion of theoptic nerve to the eye. This conceptual midplane perpendicularto the optic nerve axis is chosen to provide thegreatest consistency of the reading for the frequent conditionin which the nasal edge of the cup is steep and thetemporal edge is sloping.If the estimates of horizontal cup/disk ratio of the twoprimary readers are within 0.2 disk diameters (DD) of eachother, the official horizontal cup/disk ratio is the average ofthe two estimates. If the primary readings differ by morethan 0.2 DD, the primary readers attempt to arrive at aconsensus and the official horizontal cup/disk ratio becomesthe average of the two post-consensus estimates. Ifagreement within 0.2 DD is not possible, the senior reader,who is a glaucoma specialist, determines the official horizontalcup/disk ratio. The Optic Disc Reading Centerprotocol was prepared by DRA.● ANALYSIS: We assessed reproducibility of horizontalcup/disk ratio over time with the intraclass correlationcoefficient. 13–16 The intraclass correlation is an index ofagreement that weights disagreement as the squared distancefrom perfect agreement. For descriptive purposesonly, when the official horizontal cup/disk estimate was theaverage of two readers’ estimates, we rounded the averagedvalue to the nearest 0.1 DD to allow direct comparisons topublished studies. We report the mean and standarddeviation of horizontal cup/disk ratio of baseline photographsgraded at study entry and regraded at annualfollow-up visits at years 1, 2, and 3. We report the meandifference between these readings (follow-up horizontalcup/disk ratio minus entry horizontal cup/disk ratio) andthe 95% confidence intervals of the differences. A paired ttest was used to determine if the difference betweenreadings was greater than zero, that is, greater than or lessthan expected by chance alone.To determine if technician readers differed from glaucomaspecialists, we compared the horizontal cup/disk ratioof the same optic disk stereophotographs as graded bytechnician readers and glaucoma specialists. This analysiswas conducted on a subset of stereophotographs whichwere graded by two glaucoma specialists who served asprimary readers early in the study and which were regradedby two technician readers later in the study. We computedintraclass correlation coefficients to describe agreementbetween glaucoma specialists and technician readers andused a paired t test to determine if the difference wasgreater than expected by chance.To estimate interobserver agreement between the twoprimary readers who graded each set of stereoscopic photographsindependently, we sampled the primary readers’worksheets before consensus and/or adjudication. Left eyesof 100 OHTS participants were randomly selected with acomputer uniform random number generator. The differencesbetween the primary readers’ horizontal cup/diskratio measurements before consensus and adjudicationVOL. 133, NO. 1 REPRODUCIBILITY OF CUP/DISK RATIO MEASUREMENTS OVER TIME21
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Page 5 and 6: photographs appeared comparable and
Page 7 and 8: TABLE 5. Observer Agreement by Came
Page 9 and 10: Schwab, MD; Ingrid J. Clark, COA, V

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