Predicting Progression of Glaucoma fromRates of Frequency Doubling TechnologyPerimetry Change

Daniel Meira-Freitas, MD, PhD,1,2 Andrew J. Tatham, FRCOphth,1 Renato Lisboa, MD,1,2

Tung-Mei Kuang, MD, MPH,1,3,4 Linda M. Zangwill, PhD,1 Robert N. Weinreb, MD,1

Christopher A. Girkin, MD, MSPH,5 Jeffrey M. Liebmann, MD,6 Felipe A. Medeiros, MD, PhD1

Purpose: To evaluate the ability of longitudinal frequency doubling technology (FDT) to predict the devel-opment of glaucomatous visual field loss on standard automated perimetry (SAP) in glaucoma suspects.

Design: Prospective, observational cohort study.Participants: The study included 587 eyes of 367 patients with suspected glaucoma at baseline selected from

the Diagnostic Innovations in Glaucoma Study (DIGS) and the African Descent and Glaucoma Evaluation Study(ADAGES). These eyes had an average of 6.7�1.9 FDT tests during a mean follow-up time of 73.1�28.0 months.

Methods: Glaucoma suspects had intraocular pressure (IOP) >21 mmHg or an optic disc appearancesuspicious of glaucoma. All patients had normal or nonrepeatable abnormal SAP at baseline. Humphrey MatrixFDT (Carl Zeiss Meditec, Inc, Dublin, CA) testing was performed within 6 months of SAP testing. The study endpoint was the development of 3 consecutive abnormal SAP test results. Joint longitudinal survival models wereused to evaluate the ability of rates of FDT pattern standard deviation (PSD) change to predict the development ofvisual field loss on SAP, adjusting for confounding variables (baseline age, mean IOP, corneal thickness, andfollow-up measurements of SAP PSD).

Main Outcome Measures: The R2 index was used to evaluate and compare the predictive abilities of themodel containing longitudinal FDT PSD data with the model containing only baseline data.

Results: Sixty-three of 587 eyes (11%) developed SAP visual field loss during follow-up. The mean rate ofFDT PSD change in eyes that developed SAP visual field loss was 0.07 dB/year versus 0.02 dB/year in those thatdid not (P< 0.001). Baseline FDT PSD and slopes of FDT PSD change were significantly predictive ofprogression, with hazard ratios of 1.11 per 0.1 dB higher (95% confidence interval [CI], 1.04e1.18; P¼ 0.002) and4.40 per 0.1 dB/year faster (95% CI, 1.08e17.96; P¼ 0.04), respectively. The longitudinal model performedsignificantly better than the baseline model with an R2 of 82% (95% CI, 74e89) versus 11% (95% CI, 2e24),respectively.

Conclusions: Rates of FDT PSD change were highly predictive of the development of SAP visual field loss inglaucoma suspects. This finding suggests that longitudinal FDT evaluation may be useful for risk stratification ofpatients with suspected glaucoma. Ophthalmology 2014;121:498-507 ª 2014 by the American Academy ofOphthalmology.

Glaucoma is an optic neuropathy characterized by pro-gressive loss of retinal ganglion cells, which ultimatelycan lead to functional loss, visual disability, and blindness.1

Standard automated perimetry (SAP) using a white stimuluson a white background is the most commonly used methodfor detection of glaucomatous functional damage. However,histologic and clinical studies have shown that visual fielddefects on SAP often are detectable only after a substantialnumber of ganglion cells have been lost.2,3

Frequency doubling technology (FDT) perimetry hasbeen proposed as a test for the early detection of glaucom-atous functional damage.4,5 Testing involves presentation ofa frequency-doubling stimulus, and the contrast sensitivityof the stimulus is adjusted to determine the limit of detec-tion. Several independent studies have shown that FDThas high sensitivity and specificity for discriminating glau-comatous and healthy subjects.4,6e12 The 24-2 Matrix FDT

498 � 2014 by the American Academy of OphthalmologyPublished by Elsevier Inc.

(Carl Zeiss Meditec, Inc, Dublin, CA) has been shown to besignificantly better than SAP at distinguishing eyes withearly glaucoma from healthy eyes and offers shorter testduration and less variability in areas of low sensitivity thanSAP.8,10,13,14

Baseline functional abnormalities detected by FDTperimetry have been shown to be predictive of future onsetand location of SAP visual field loss among glaucomasuspects.15e17 However, the predictive ability of infor-mation obtained from only the baseline visit is relativelyweak.16 Predictive models that take into accountlongitudinal information as it becomes available duringfollow-up could perform better than those using onlybaseline information. To the best of our knowledge, nostudy has yet evaluated the ability of longitudinal FDTdata in predicting the development of visual field loss inglaucoma.

ISSN 0161-6420/14/$ - see front matterhttp://dx.doi.org/10.1016/j.ophtha.2013.09.016

Meira-Freitas et al � FDT Perimetry Change in Glaucoma Progression

The purpose of the current study was to evaluate theability of longitudinal FDT measurements to predict thedevelopment of glaucomatous visual field loss on SAP ina cohort of glaucoma suspects.

Methods

This was an observational cohort study involving participants from2 prospective longitudinal studies designed to evaluate optic nervestructure and visual function in glaucoma: The African Descentand Glaucoma Evaluation Study (ADAGES) and the DiagnosticInnovations in Glaucoma Study (DIGS). The 3-site ADAGEScollaboration included the Hamilton Glaucoma Center at theDepartment of Ophthalmology, University of California, SanDiego (UCSD) (data coordinating center); the New York Eye andEar Infirmary; and the Department of Ophthalmology, Universityof Alabama, Birmingham. Although the DIGS includes onlypatients recruited at the UCSD, the protocols of the 2 studies areidentical. Methodological details have been described.18

All patients from the DIGS and ADAGES who met the inclu-sion criteria described next were enrolled in the present study.Informed consent was obtained from all participants. This pro-spectively designed study received institutional review boardapproval at each of the involved sites. The methodology adhered tothe tenets of the Declaration of Helsinki and to the Health Insur-ance Portability and Accountability Act.

At each visit during follow-up, subjects underwent a compre-hensive ophthalmologic examination, including review of medicalhistory, best-corrected visual acuity, slit-lamp biomicroscopy,intraocular pressure (IOP) measurement, gonioscopy, dilated fun-duscopic examination and stereoscopic optic disc photography, andSAP testing. Central corneal thickness (CCT) was calculated as theaverage of 3 measurements obtained during the same visit using anultrasound pachymeter (Pachette GDH 500; DGH Technology,Inc, Philadelphia, PA). For inclusion, subjects had to have openangles on gonioscopy. Subjects were excluded if they had a best-corrected visual acuity <20/40, spherical refraction outside �5.0diopters, cylinder correction outside 3.0 diopters, or a combinationthereof, or any other ocular or systemic disease that could affect theoptic nerve or the visual field.

This study included eyes suspected of having glaucoma at thebaseline visit. The diagnosis of suspect glaucoma was based on thepresence of suspicious appearance of the optic disc (neuroretinal rimthinning, excavation, or suspicious retinal nerve fiber layer defects)or elevated IOP (>21 mmHg). Because the study was designed toevaluate the predictive ability of FDT in glaucoma suspects, eyesthat had repeatable (at least 2 consecutive) abnormal SAP test resultsat baseline were excluded. During follow-up, each patient wastreated at the discretion of the attending ophthalmologist.

Visual Field Testing

Standard automated perimetry was obtained using the HumphreyField Analyzer II (Carl Zeiss Meditec, Inc, Dublin, CA) and the 24-2 Swedish Interactive Threshold Algorithm strategy. Frequencydoubling technology was performed using the Humphrey Matrix(Carl Zeiss Meditec, Inc) and the 24-2 threshold strategy. Onlyreliable SAP and FDT tests were included. A reliable visual fieldtest was defined as �33% fixation losses and false negatives, and<15% false positives. All visual fields were evaluated by theUCSD Visual Field Assessment Center.19 Each visual field test wasperformed twice at baseline within a 3-month period. The exami-nation protocol was repeated annually. When the FDT date did notmatch the SAP date, the tests were included in the study analysisonly if they were performed within 6 months apart. Visual fields

were reviewed for the following artifacts: lid and rim artifacts,fatigue effects, inappropriate fixation, evidence that the visual fieldresults were due to a disease other than glaucoma (e.g., homony-mous hemianopia), and inattention. If an artifact was identified,a repeat visual field test was requested.

Standard automated perimetry test results were defined asabnormal if they had a pattern standard deviation (PSD) withP< 0.05 or a Glaucoma Hemifield Test outside normal limits.Each patient was required to have a minimum of 12 months offollow-up.

Follow-up and Definition of Study End Points

The study end point was defined as the development of repeat-able abnormal SAP defects during follow-up. A repeatable SAPdefect was defined by the presence of 3 consecutive abnormalSAP test results during follow-up. Eyes that developed an endpoint during follow-up (i.e., progressed to a SAP defect) weredesignated “progressors,” whereas eyes that did not develop thestudy end point were designated “nonprogressors.” Because thepurpose of the study was to evaluate the prediction of early SAPvisual field loss, the time of progression was defined as the dateof the first abnormal SAP test result. For progressors, follow-uptime was defined as the time between the FDT baseline visit andthe date of the first abnormal SAP result (the study end point).For nonprogressors, follow-up time was defined as the timebetween the FDT baseline visit and the date of the last availablefollow-up.

To evaluate whether FDT measurements were predictive of thestudy end points, only FDT tests acquired before the event datewere analyzed in the study. Eyes that did not develop the study endpoint were considered censored at the last follow-up visit. All FDTtests up to the last available follow-up date were analyzed for theseeyes.

Statistical Analysis

The primary purpose of the study was to evaluate the ability oflongitudinal FDT measurements to predict the development ofglaucomatous SAP visual field loss. To assess the relationshipbetween the longitudinal FDT measurements and the developmentof glaucomatous visual field loss on SAP, we used a joint modelincorporating longitudinal and survival data. The parameter PSDwas selected to represent the FDT longitudinal measurementsbecause it has been identified in previous studies as having the bestoverall performance for early glaucoma diagnosis.12,20 The jointmodels of longitudinal and survival data are ideally suited to studythe association between changes in a longitudinal marker and therisk for an event, and have been described in detail by Wulfsohn andTsiatis.21 We have previously reported on the use of these models tostudy the association between glaucoma biomarkers and diseaseprogression.22 In brief, they are composed of a longitudinalsubmodel and a survival submodel, which are tied together bysharing random effects. The longitudinal submodel was composedof a linear mixed model with the following formulation:8<

:yiðtÞ ¼ miðtÞ þ εiðtÞmiðtÞ ¼ Xibþ Zibi

biwNð0;DÞ; εiðtÞwNð0; s2ÞThe model specifically accounts for measurement error of themarker by postulating that the observed level of the outcome yi(t),corresponding to the FDT measurements, equals the unobservedtrue value mi(t) plus a random error term, εi(t). The mixed modelassumes random slopes and random intercepts, allowing differentrates of change and intercept values for each eye.

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Table 1. Baseline Demographic and Clinical Characteristics ofStudy Patients

Variables Progressors (n[63) Nonprogressors (n[524)

Age at baseline (yrs) 61.6�10.0 56.1�11.4Gender (% female) 74.6 65.4RaceCaucasian, % 50.8 54.2African-American, % 49.2 40.8

Spherical equivalent (D) 0.13�1.8 �0.41�1.8IOP (mmHg) 17.3�4.7 18.1�4.8CCT (mm) 538.6�38.8 546.6�38.7SAP MD (dB) �0.61�1.0 �0.01�1.11SAP PSD (dB) 1.83�0.48 1.56�0.31FDT MD (dB) �2.17�2.96 �1.19�2.80FDT PSD (dB) 3.18�0.73 2.85�0.66

CCT ¼ central corneal thickness; D ¼ diopters; FDT ¼ frequencydoubling technology; IOP ¼ intraocular pressure; MD ¼ mean deviation;PSD ¼ pattern standard deviation; SAP ¼ standard automated perimetry.

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To quantify the strength of the association between the longi-tudinal marker and the risk for the event (development of SAPvisual field loss), a survival submodel was used with the form:

hiðtÞ ¼ h0ðtÞexp�gT1wi þ gT

2 vi þ a1miðt0Þ þ a2m’iðtÞ

�;

where m’i ¼ d

dt miðtÞ;

In the survival submodel, hi(t) determines the hazard function attime t, h0 denotes the baseline hazard function specified bya Weibull distribution, wi is a vector of baseline covariates withcorresponding vector of coefficients (g1), and vi is a vector of time-dependent covariates with corresponding vector of coefficients(g2). This model was estimated jointly with the longitudinal sub-model and allowed an evaluation of the relationship betweenthe true marker values mi(t) and the risk for the event. We weremainly interested whether the slopes of change in the marker (i.e.,FDT PSD) were associated with risk of progression. Therefore, mi’measured the first derivative (slope) of the marker profile and thecoefficient a2 measured how strongly associated was the value ofthe slope of the true longitudinal marker at time t with the risk foran event at the same time point, adjusting for the intercept valueand values of other covariates. The interpretation of a2 isstraightforward as in regular survival models, with exp(a2) corre-sponding to the hazard ratio (HR) for a 1-unit change in the slopeof the marker.

The survival model including the longitudinal FDT measure-ments information (intercepts and slopes) was adjusted for thebaseline covariates age, CCT, and mean IOP, and for the time-dependent covariate SAP PSD. These variables have been reportedto be significantly associated with the risk of development of glau-comatous visual field loss among patients with ocular hypertensionor suspected glaucoma.23e25 Mean IOP was calculated as thearithmetic mean of all available IOP measurements per eye.

To assess and compare the importance of variables in determiningthe outcome, we used an R2 index proposed by Royston.26 Themodified R2 index is equivalent to the coefficient of determinationof a linear model and measures the amount of variation in theoutcome (survival time) explained by the predictor or, in otherwords, the strength of the relationship between the predictor and theoutcome in a survival model. The modified R2 index has beenproposed as the best way to assess prognostic information ofsurvival models.27 Confidence intervals (CIs) for the modified R2

indices were obtained by bootstrapping, with 1000 replications.The mean rates of FDT PSD change of progressors and non-

progressors were compared using generalized estimating equationswith robust standard errors to adjust for potential correlationsbetween both eyes of the same individual.

All statistical analyses were performed with commerciallyavailable software (STATA, version 12; StataCorp LP, CollegeStation, TX). The a level (type I error) was set at 0.05.

Results

The study included 587 eyes of 367 patients classified as glaucomasuspects at the baseline visit. These eyes had an average (median,interquartile range) of 5.8 (6.0, 4.0e7.0) FDT tests and 6.0 (6.0,5.0e7.0) SAP tests during a mean (median, interquartile range)follow-up time of 73.1 (83.8, 48.3e97.2) months. Sixty-three eyes(11%) progressed and developed repeatable SAP defects duringfollow-up. Table 1 shows baseline demographic and clinicalcharacteristics of the study patients. For progressors, the mean(median, interquartile range) time until the development ofa repeatable SAP defect was 45.5 (37.9, 23.9e63.2) months. Fornonprogressors, the mean (median, interquartile range) follow-uptime was 76.4 (85.6, 49.7e97.8) months.

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Figure 1A shows the longitudinal trajectories of rawmeasurements of FDT PSD in nonprogressors and progressors,and Figure 1B shows the longitudinal trajectories of rawmeasurements of SAP PSD in nonprogressors and progressors.Comparison of locally weighted scatterplot smoothing curvesoverlaid to the longitudinal trajectories of these indices for theprogressor group suggested that FDT PSD measurements startedto increase earlier than SAP PSD measurements.

The average rate of FDT PSD change in all eyes was 0.03 dB/year. The mean (� standard deviation) rate of FDT PSD change forprogressors was significantly faster than for nonprogressors(0.07�0.02 dB/year vs. 0.02�0.02 dB/year, respectively;P< 0.001). Figure 2 illustrates the distribution of slopes of changein the 2 groups.

Table 2 shows the multivariable HRs with 95% CIs for eachputative predictive factor obtained with the joint model oflongitudinal FDT PSD evaluation and time until developmentof a repeatable SAP defect. In the multivariable survival model,slopes of FDT PSD change were significantly associated withrisk of developing an SAP defect. Each 0.1 dB/year faster rate ofFDT PSD change was associated with 4 times higher riskof developing an SAP defect (adjusted HR, 4.40; 95% CI,1.08e17.96; P¼ 0.04). The baseline FDT PSD measurement(intercept) also was a significant predictive factor for developingan SAP defect in the multivariable model. Each 0.1 dB largerFDT PSD at baseline was associated with an 11% higher risk ofdeveloping a glaucomatous SAP defect (adjusted HR, 1.11; 95%CI, 1.04e1.18; P¼ 0.002). Other significant predictive factorsfor developing an SAP defect in the multivariable model wereSAP PSD, mean IOP, and CCT.

The R2 index was used to evaluate and compare the predictiveabilities of the model containing only longitudinal FDT PSD datawith the model containing only FDT baseline data. The longitu-dinal model performed significantly better than the baseline model,presenting an R2 of 82% (95% CI, 74e89) versus 11% (95% CI,2e24), respectively.

Results of the joint model allowed survival predictionsfor individual eyes to be obtained. The survival probabilityindicated the probability of retaining a normal SAP visualfield during follow-up, that is, not developing a glaucomatousdefect. Figure 3 shows 2 cases of suspected glaucoma withdifferent outcomes predicted by the longitudinal evaluationof FDT PSD. Figure 3A shows a case of an eye with

A

B

Figure 1. A, Longitudinal trajectory of frequency doubling technology (FDT) pattern standard deviation (PSD) raw measurements in progressors (right) andnonprogressors (left). B, Longitudinal trajectory of standard automated perimetry (SAP) PSD raw measurements in progressors (right) and nonprogressors(left). dB ¼ decibels.

Meira-Freitas et al � FDT Perimetry Change in Glaucoma Progression

increasing values of FDT PSD over time. Predicted survivalprobabilities for this eye were low, indicating a high chanceof developing visual field loss. This eye showed glaucomaprogression during follow-up with the development of anSAP visual field defect. Figure 3B shows an eye with stableFDT PSD and high predicted survival probabilities. This eye

did not show progression based on SAP during the follow-uptime of the study.

Figure 4 shows how survival probabilities can be continuouslyupdated during follow-up as more information becomes available.The time course of FDT PSD changes, as seen in the patterndeviation plots for the same eye, also is shown. The predicted

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Figure 2. Distribution of rates of frequency doubling technology (FDT)pattern standard deviation (PSD) change in eyes that developed standardautomated perimetry (SAP) visual field loss versus eyes that did notdevelop SAP visual field loss. Eyes that developed SAP visual field loss hadconsiderably faster rates of FDT PSD change when compared with eyes thatdid not develop SAP visual field loss. dB ¼ decibels.

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survival probabilities were relatively high when only baselinemeasurements were considered. As more information becameavailable and a clear trend of FDT PSD increase was observed, themodel estimated lower probabilities of survival. The reported eyelater developed an SAP visual field defect.

The predictive abilities of baseline and longitudinal modelsincluding FDT mean deviation (MD) were also tested. However,

Table 2. Results of the Joint Longitudinal Survival Model Inves-tigating the Effect of Longitudinal Changes in Frequency DoublingTechnology Pattern Standard Deviation in Predicting Risk ofDevelopment of Visual Field Loss, While Adjusting for Con-

founding Factors

Longitudinal Submodel

Parameter Coefficient 95% CI P

Constant 2.85 2.81e2.90 <0.001Time 0.029 0.018e0.039 <0.001

Survival Submodel

Parameter Coefficient 95% CI PHazardRatio

Slope of FDT PSD, per 0.1dB/yr higher

1.48 0.08e2.89 0.039 4.40

Intercept (baseline FDTPSD), 0.1 dB higher

0.10 0.04e0.17 0.002 1.11

Age, per decade older 0.22 �0.06e0.49 0.119 1.25Mean IOP, per 1 mmHghigher

0.08 0.008e0.15 0.029 1.08

CCT, per 40 mm thinner 0.40 0.10e0.70 0.009 1.50SAP PSD*, per 0.1 dB higher 0.11 0.09e0.14 <0.001 1.12

CCT ¼ central corneal thickness; FDT ¼ frequency doubling technology;IOP ¼ intraocular pressure; PSD ¼ pattern standard deviation; SAP ¼standard automated perimetry.*Time-dependent variable.

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they did not show statistically significant predictive abilities afteradjustment for age, mean IOP, CCT, and time-dependent SAP PSD(P> 0.05 for both models).

Discussion

This study demonstrated that longitudinal evaluation ofpatients with suspected glaucoma using FDT perimetry wasuseful for predicting future development of SAP visual fieldloss. Subjects with faster slopes of change in FDT PSD hada greater risk of developing functional glaucomatousdamage on SAP than those with relatively slower changes.In addition, models including longitudinal FDT PSDmeasurements were better predictors of future SAP defectsthan models including only baseline information. Thesefindings may have significant implications for the use ofFDT perimetry in clinical practice and for evaluation ofglaucoma progression.

Because SAP is the current standard for glaucomadiagnosis and is widely available in clinical practice, thisstudy was designed to assess whether the longitudinalevaluation of FDT perimetry could provide any additionalbenefit for early diagnosis by predicting future developmentof glaucomatous defects on SAP. To account for the likelyscenario of FDT being used to supplement rather thanreplace SAP, the FDT predictive models were adjusted withSAP measurements. As shown by the multivariable analy-ses, FDT perimetry still provided additional independentinformation. Therefore, the results of this study suggest thatthere may be value to including FDT in the assessment ofglaucoma suspects.

Eyes that developed SAP visual field defects duringfollow-up had significantly faster rates of change in the FDTPSD parameter compared with eyes that did not developvisual field defects. The mean rate of FDT PSD change foreyes that progressed was 0.07 dB/year, which was morethan 3 times faster than for eyes that did not show visualfield loss by SAP (0.02 dB/year). This finding suggests thatFDT PSD measurements could be used for monitoringglaucoma suspects with normal SAP and is in agreementwith previous studies that demonstrated FDT abnormalitiespreceding SAP abnormalities.28e30 Bayer and Erb28

reported that C-20 FDT progression preceded SAPprogression in 74% of patients with open-angle glaucoma.Nakagawa et al29 showed progressive C-20 FDT abnormalityoccurring on normal SAP hemifield of patients with normaltension glaucoma. However, they did not report whethersubsequent SAP loss developed in patients with progressiveFDT defect. Haymes et al30 demonstrated C-20 FDTprogressive abnormalities in patients with open-angle glau-coma, but also did not report rates of change or whether theFDT abnormalities preceded SAP loss. Differences in studyfeatures, such as design, selection criteria, and methods ofanalysis, hindered further comparison of these studies withours. The present study was the first to report the relationbetween the rates of FDT measurement changes and the riskfor development of visual field defect on SAP in a cohort ofglaucoma suspects.

A B

Figure 3. Predicted survival probabilities for 2 eyes, 1 that showed a relatively fast rate of frequency doubling technology (FDT) pattern standard deviation(PSD) change during follow-up (A) and 1 that showed stable measurements over time (B). A comparison of the predicted survival probabilities shows thatthe eye with fast progression had lower predicted probabilities of survival, that is, retaining a normal standard automated perimetry (SAP) visual field. Theformer showed development of visual field loss during follow-up, whereas the eye with stable FDT PSD measurements did not develop any SAP field defect.dB ¼ decibels.

Meira-Freitas et al � FDT Perimetry Change in Glaucoma Progression

The use of a joint longitudinal survival model allowedus to quantify the ability of rates of change in FDT PSD topredict the risk of developing an SAP defect, while alsotaking into account the censored aspect of the data andadjusting for the effect of confounding variables. Each 0.1dB/year faster rate of FDT PSD change corresponded to 4.4times higher risk of progression over time in a multivariablemodel adjusting for age, CCT, mean IOP, and longitudinalSAP PSD measurements. The predictive ability of thelongitudinal model was significantly better than the modelincluding only baseline information. The longitudinal modelincluding baseline and rates of change in FDT PSDmeasurements had an R2 of 82%, that is, this model was ableto explain 82% of the variation in the outcome defined bySAP visual field loss. The model including only baselineFDT PSD data performed worse than the longitudinal model,with an R2 of only 11%. This result suggests that thelongitudinal evaluation of FDT PSD measurements seem toprovide additional information that can help to identify thoseglaucoma suspects more likely to develop SAP visual fielddefects. This result was expected because the longitudinalanalysis evaluates all test results available during thefollow-up period of interest. The longitudinal approach canprovide estimates of rates of visual field progression overtime, allowing the identification of patients with a higherrisk of developing functional impairment as a result of thedisease.

Among progressors, FDT PSD measurements startedto increase earlier than the corresponding SAP PSDmeasurements, whereas no differences were seen for non-progressors (Fig 1). The FDT measurements were stillpredictive of progression despite inclusion of longitudinalSAP PSD measurements in the same model. This resultsupports the concept that the FDT perimetry may bevaluable for the detection of early glaucomatousdamage.7,16,20,31e34 However, the biological basis for this

finding is still unclear. The frequency doubling illusionphenomenon was initially thought to be mediated bya subset of magnocellular retinal ganglion cells,6 whichhave been proposed to be relatively more vulnerable toearly glaucomatous damage.35 However, selective lossof magnocellular over the parvocellular function inglaucoma has not been consistently demonstrated inprevious studies.36e38 Recent research has suggested thatthe origins of the response to the frequency doubling illu-sion to be most likely cortical, rather than ocular.39,40

Whatever the mechanism underlying detection of the FDTstimulus might be, our results support the importance ofthis test as an additional tool for detection of early func-tional losses in glaucoma. A possible explanation forfinding that additive ability of FDT to predict the futuredevelopment of SAP defects is that the test stimuli of FDTperimetry and SAP have different spatial and temporalcharacteristics, and cover different receptive fields. More-over, FDT and SAP use different threshold strategies anddifferent decibel scales.41 Differences in FDT and SAP testresults are therefore to be expected and have been found inprevious studies. For example, although the global indicesof SAP and second-generation FDT perimetry are highlycorrelated, FDT has been found to produce narrowertesteretest intervals at test locations with lower sensitivity,which could provide advantages for the monitoring ofpatients with glaucoma.13,41

Although the present study found the longitudinal eval-uation of FDT to be a useful predictor of the development ofan SAP defect, it is possible that any worsening perimetrictest may be able to predict the development of a defect inanother perimetric device. Therefore, we also investigatedwhether longitudinal measurements of SAP PSD wouldpredict glaucoma progression based on FDT perimetry,defined as the development of a repeatable FDT defect(PSD<5% or Glaucoma Hemifield Test outside normal

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Figure 4. Example of how survival probabilities can be updated as more information on predictive factors becomes available during follow-up. A, Left:Survival probabilities after considering only the baseline data. The model estimated that the probability of retaining a normal standard automated perimetry(SAP) visual field over time was relatively high. As more information became available (middle and right), the survival probabilities were updated. Theestimated survival probabilities became lower as the result of progressive increase of frequency doubling technology (FDT) pattern standard deviation (PSD)over time. B, Corresponding FDT pattern deviation plot showing progressive deterioration. C, SAP visual fields for the same eye showing development ofa repeatable defect at the end of follow-up. dB ¼ decibels; GHT ¼ Glaucoma Hemifield Test; MD ¼ mean deviation.

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limits), in a cohort of patients without repeatable abnormalFDT at baseline. The analysis revealed that although thebaseline values of SAP PSD were significant predictors of

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FDT progression (HR, 1.10 per 0.1 dB higher; 95% CI,1.03e1.18; P¼ 0.004), the rates of SAP PSD change werenot significant predictors of FDT progression during follow-

Meira-Freitas et al � FDT Perimetry Change in Glaucoma Progression

up (HR per 0.1 dB/year higher, 0.93; 95% CI, 0.46e1.89;P¼ 0.85).

The joint longitudinal survival model presented in ourstudy also allowed estimation of individual survival proba-bilities over time. With the use of this model, the risk ofdevelopment of SAP visual field loss can be updatedas information on predictive factors is made continuouslyavailable over time. Such an approach offers significantadvantages over currently available predictive models orrisk calculators designed to estimate risk of glaucomadevelopment.42,43 Currently available risk calculators useonly baseline information on predictive factors, which haslimited value in predicting outcomes. As Figure 4 illustrates,the probabilities of progression can be continuously updatedas more information becomes available, resulting in moreeffective use of clinical information. Likewise, the 2 eyesshown in Figure 3 had similar baseline FDT PSD values,but their risks of progression were different whenlongitudinal information was incorporated into the model.

In contrast to models including FDT PSD, thoseincluding baseline and longitudinal FDT MD were notsignificantly predictive of the development of a SAP defect.Baseline FDT MD has been reported to be a poor predictorof progression in a previous study of glaucoma suspects,using an older version of FDT perimetry.16 The OcularHypertension Treatment Study also found that PSD, notMD, was a predictor of glaucoma development.23,42 Thesestudies suggest that PSD is an important index for detectingearly disease. Mean deviation, as a center-weighted averageof decibel deviation, is useful for staging visual loss;however, PSD better reflects the presence of focal visualfield defects that are common in early stages of disease.44,45

Mean deviation also is less specific for glaucomatousdamage and affected more by media opacities, common inthe glaucomatous population. A disadvantage of PSD is thatit decreases in moderate to advanced disease as areas oflocalized loss progress to become diffuse. For this reason,the optimal use of FDT PSD, as found in this study, is likelyto be in detecting early functional damage.

Study Limitations

Pattern standard deviation is a global visual field indexthat numerically describes the uniformity of the visual fieldand reflects the contour of the island of vision. Althoughits increase is generally related to the development orworsening of a true visual field defect, PSD also couldincrease as the result of artifacts, for example, if thecorrective lens is poorly positioned or there is eyelid ptosis,refractive scotoma, or patient inattention. To avoid suchconfounding effects, visual fields were reviewed for thepresence of artifacts and abnormalities due to diseases otherthan glaucoma and the repetition of such tests was requestedwhen necessary. Another limitation of the study is that FDTtests were only repeated annually. It is possible that morefrequent tests could improve the predictive ability of FDT.Finally, we evaluated the ability of FDT in predicting SAPvisual field defects. Although SAP defects have beenshown to be associated with quality of life measures inpatients with glaucoma,46 future studies should evaluate

whether FDT tests are predictive of vision-related qualityof life outcomes in glaucoma.

It is important to note that clinicians frequently faceconstraints about the number of tests that can be performedon an individual patient in clinical practice. Therefore,before recommending including FDT tests in clinical prac-tice, it will be important to assess their benefit in relation tothe actual number of other tests that can be performed underrealistic scenarios. Future studies should evaluate issues ofcostebenefit analysis of including multiple structural andfunctional tests for glaucoma management.

In conclusion, the results of this study demonstrate thatbaseline and longitudinal evaluations of FDT perimetry areable to predict the development of glaucomatous visual fieldloss on SAP in patients with suspected glaucoma. Further-more, longitudinal evaluation of FDT PSD rates of changewas better than baseline data at predicting which glaucomasuspect eyes develop functional glaucoma progressionduring follow-up. These findings suggest that the addition oflongitudinal evaluation of FDT may be advantageous asa clinical tool for risk stratification of patients with sus-pected glaucoma.

References

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Footnotes and Financial Disclosures

Originally received: April 8, 2013.Final revision: August 20, 2013.Accepted: September 12, 2013.Available online: November 27, 2013. Manuscript no. 2013-575.1 Hamilton Glaucoma Center and Department of Ophthalmology, Univer-sity of California, San Diego, California.2 Department of Ophthalmology, Federal University of São Paulo, Brazil.3 Department of Ophthalmology, Taipei Veterans General Hospital, Taipei,Taiwan.4 Department of Ophthalmology, School of Medicine, National Yang-MingUniversity, Taipei, Taiwan.5 Department of Ophthalmology, University of Alabama, Birmingham,Alabama.6 Department of Ophthalmology, New York Eye and Ear Infirmary, NewYork, New York.

Financial Disclosure(s):The author(s) have made the following disclosure(s): D.M-F., A.J.T., R.L.,and T-M.K., none. L.M.Z., financial support from Carl Zeiss Meditec and

Heidelberg Engineering. R.N.W., financial support from Alcon, Allergan,Merck, Bausch & Lomb, Carl Zeiss Meditec, Optovue, Novartis, Nidek,Topcon, and Aeries. C.A.G., financial support from Carl Zeiss Meditec.J.M.L., financial support from Carl Zeiss Meditec and Heidelberg Engi-neering. F.A.M., financial support from Alcon, Allergan, Merck, Bausch &Lomb, Nidek, Carl Zeiss Meditec, and Heidelberg Engineering.

Supported in part by National Institutes of Health/National Eye InstituteGrants EY021818 (F.A.M.), EY11008 (L.M.Z.), EY14267 (L.M.Z.),EY019869 (L.M.Z.); Brazilian National Research Council-CNPq Grant200178/2012-1 (D.M.-F.); an unrestricted grant from Research to PreventBlindness (New York, NY); and grants for participants’ glaucoma medi-cations from Alcon, Allergan, Pfizer, Merck, and Santen.

Correspondence:Felipe A. Medeiros, MD, PhD, Hamilton Glaucoma Center, University ofCalifornia, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 E-mail:fmedeiros@glaucoma.ucsd.edu.

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