Assessment of repeatability of a clinical automated pupillometer

Assessment of repeatability of a clinical automated pupillometer | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Assessment of repeatability of a clinical automated pupillometer View ORCID Profile Jacob Diaz , Jan Skerswetat , View ORCID Profile Andrew Browne doi: https://doi.org/10.1101/2025.05.03.25326928 Jacob Diaz 1 Department of Ophthalmology, University of California , 850 Health Sciences Road Irvine, California, 9269, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacob Diaz For correspondence: diaz1537{at}gmail.com Jan Skerswetat 1 Department of Ophthalmology, University of California , 850 Health Sciences Road Irvine, California, 9269, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew Browne 1 Department of Ophthalmology, University of California , 850 Health Sciences Road Irvine, California, 9269, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andrew Browne Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Purpose To determine the repeatability of a clinical pupillometer in healthy participants with a 5 and 30 − minute test − retest break for both Swinging-Flashlight and Low-High Luminance approach. Methods 20 healthy participants (mean age: 27 years ±5; 9 females) placed their heads into the device’s headrest and fixated a central spot. A Swinging-Flashlight approach evoked a pupillary light reflex, stimulating alternatingly 8 times each eye by a brief diffuse white light flash followed by a continuous measurement of constriction and dilation of the direct and consensual pupils. For the Low-High Luminance setting, continuous measurements of pupil diameters for a 5 second low luminance display followed by a 5 second high luminance white light. Pupillary light reflex parameters for each test and each eye were calculated by the device. Repeatability was investigated after a 5-minute break time and during a control experiment for 21 participants after a 30-minute break for each approach in counterbalanced order using Bland-Altman analysis. Results Overall, many parameters for both Swinging-Flashlight and Low-High Luminance approach showed retest biases for all pupil light reflex parameters after a 5-minute test-retest break. These biases were almost completely reduced after a 30-minute break between test and retest for both approaches. The test-retest variabilities as expressed using the Coefficient of Repeatability was reduced after 30-minutes for the majority of the Low-High Luminance results but not for results of the Swinging-Flashlight method. Conclusions Clinical pupillometry includes the Swinging Flashlight Test (SFL) and Low-High Luminance assays. In SFL, many pupillary dynamic metrics showed test-retest bias at a 5-minute interval, whereas relative afferent pupillary defect (RAPD) measurements remained unbiased at both 5 and 30-minute intervals. Similarly, Low-High Luminance testing showed minimal bias after 30 minutes but exhibited bias at the 5-minute interval. Thus, when evaluating multiple pupillary parameters in scientific or clinical settings, RAPD is less susceptible to bias, while other metrics require longer intervals between testing and retesting. 1. Introduction The pupillary light reflex (PLR) is an important neurological response that provides critical insights into the health of the autonomic nervous system and the functionality of the optic pathway. Phototransduction in the retina triggers a neurochemical signal that travels through the optic nerve, optic chiasm, and optic tract to the pretectal nucleus, which then relays it bilaterally to the Edinger-Westphal nucleus. 1 This nucleus sends efferent, parasympathetic signals via the oculomotor nerve, ciliary ganglion, and short ciliary nerves to the sphincter pupillae muscle, causing both pupils to constrict. 2 Any defect in this process can result in the PLR not functioning as expected. Relative Afferent Pupillary Defect (RAPD) is a clinical sign of asymmetry in the afferent visual pathway in which a pupil does not respond to light to the same degree as the opposite pupil. 2 It reflects an imbalance in the signal transmission from the retina to the brain, typically indicating unilateral or asymmetrical damage to the optic nerve or severe retinal disease. Instead of both pupils constricting as normal, there may be reduced or even no constriction when light is shined in the eye. 3 The presence of an RAPD is most commonly associated with conditions affecting the optic nerve such as ischemic optic neuropathy 4 , optic neuritis 5 and glaucoma 6 , however, it can also be seen age-related macular degeneration 7 retinal detachment 8 or traumatic brain injury 9 . Detecting RAPD is critical for diagnosing these pathologies, as it often presents before structural abnormalities that are visible via imaging modalities. Historically, RAPDs have been assessed using the swinging flashlight (SFL) test, a subjective method where the clinician observes the pupillary response as light is alternated between the two eyes in terms of size and velocity of constriction dilation. 1 , 6 , 7 , 8 Although this method is widely used, its effectiveness relies on the skill and experience of the examiner. Subtle RAPD cases, especially those in early disease stages, can be difficult to detect, leading to variability in diagnosis. 9 , 13 Moreover, the kinetics of pupil constriction and dilation cannot be quantified, but only qualitatively assessed this way. Consequently, there has been growing interest in developing automated, examiner-independent approaches to RAPD detection. 3 , 10 Pupillography, a technique that measures the PLR, typically use infrared eye trackers to continuously capture pupil diameters and then to fit a pupil light reflex function to estimate pupillary parameters such as the onset latency, constriction amplitude, and constriction and dilation velocities. 14 , 15 Therefore, pupillography provides a more comprehensive assessment of the PLR than the clinician-administered subjective approach. Moreover, pupillography has been shown to be able to detect diabetic retinopathy, 16 early-stage age-related macular degeneration 17 and other neurological conditions, e.g., Alzheimer’s disease 18 and therefore, it may be a suitable tool for screening and monitoring of ophthalmic and other neurological conditions. One such commercially available pupillography device is the EyeKinetix®. 19 This recently upgraded instrument uses software to assess RAPD in a SFL paradigm and pupil size changes during low and high luminance lighting. The latter assay was developed for ophthalmologists that plan contact lens, intra-ocular lens, or other refractive surgical interventions. 19 The current study’s goal was to investigate the repeatability for both pupillographic methods of this commercial device. Test-retest reliability is essential for any clinical test to ensure that measurements are reproducible and reflect the true clinical state of a patient. 20 For pupillography specifically, this reliability is crucial both physiologically—by confirming the stability of neural and autonomic pathways—and psychophysically—by minimizing the impact of participant variability and external factors. 21 Establishing high test-retest reliability in pupillographic assessments ultimately enhances diagnostic accuracy, aids in monitoring clinical progression, and supports evidence-based decision-making in both research and clinical setting. It is a common problem impeding the development of the automated pupilometer. 22 Previous work quantified the repeatability of the previous version of this device and its SFL test setting. 23 The researchers investigated test-retest repeatability using three separate tests that used inter-test break durations that varied from 10 to 20-minutes. Also, they deployed an Intra-Class Coefficient (ICC) analysis for each pupil light reflex parameter provided by the device and found that the outcome parameters showed ICCs ranging between 0.65 to 0.90. It is noteworthy that the mean parameter data after each test indicates a systematic reduction after each subsequent trial, suggestive of retest bias. 23 In the current study, we evaluated test-retest at 5 and 30 minutes to distinguish whether difference in recovery from the photo stress induced by the device during the test may alter results for the 5-minute interval retest group. Furthermore, ICCs have been criticized as inadequate analysis of repeatability due to ICC’s measuring association between variables while a Bland-Atman analysis measures the variation between tests. 17 , 25 Therefore, the current study used Bland-Altman analysis 24 for each parameter as it captures the test-retest variance with limits of agreement, coefficient of repeatability, and mean bias metrics. Methods Participants were provided with detailed written and verbal information regarding the study in advance. Written informed consent was obtained from all participants prior to their involvement in the study. Ethical approval for the study was granted by the University of California, Irvine’s Institutional Review Board (IRB number: 20195254), in accordance with the ethical standards outlined in the Declaration of Helsinki (1975). Participants Eligible participants were screened using a demographic questionnaire that contained questions related to ocular health, past ocular interventions and current medical conditions and prescriptions to rule out any history of ophthalmic pathology or previous ocular surgeries. Interested participants were asked to abstain from vigorous exercise or caffeine one hour before and during test administration intervals. Distance visual acuities for OD, OS, and OU were estimated for all participants using a self-administered orientation judgment psychophysical task. 26 Procedure After consenting to take part in the research, participants performed visual screening and filled out demographic questionnaires. The main experiment then began by asking the participant to take a seat in a chair and to place their head into the device’s headrest. The experimenter instructed each participant to fixate the center of the crossing lines and to maintain it throughout each trial. The participants were also instructed to not move nor talk during the test and the ambient environment was sustained with no talking or background noises. The method order was counterbalanced between participants, with participants randomly being assigned to begin with either the Low-High Luminance method, or the SFL method. Low-High Luminance method The luminance function testing begins with a period of 5 seconds of dark adaptation where pupillary dilation is evoked, followed by a 5 second period of constant bright white light to stimulate pupillary constriction. Swinging Flashlight method Pupillary responses for the SFL test were evoked alternatingly 8 times to each eye by a 167 millisecond diffuse white light flash followed by 2.14 second continuous measurement of the PLR, specifically for the direct and consensual eyes pupil diameters. The protocol described above was repeated with 21 participants with a 30-minute break interval, 15 of whom were the same in each test group. Data analysis Pupillary response parameters for each test and each eye were captured, analyzed and calculated by the device’s software. Linear correlations were performed using Matlab’s corrplot function and applied Kendall method to measure the strength and direction of association between two ranked variables while note assuming a linear relationship or require normally distributed data. Repeatability for each methods outcome parameters were investigated using Bland-Altman analysis ( Figures 1 and 2 ). 24 Download figure Open in new tab Figure 1: Two example graphs from the SFL setting for the latency of constriction parameter of the direct response in OS. Bland-Altman plots are shown for 5-minute (A) and a 30-minute test-retest interval (B). The black dotted line represents the ideal no bias mark, each circle represented the mean difference between test and retest for each participant. The mean bias and its 95% confidence intervals are represented as the red line with shaded area, respectively. The proportional bias as a function of latency of constriction means is shown as green line. Upper and lower Limits of Agreement are depicted as blue dashed lines with their respective 95% confidence intervals. Download figure Open in new tab Figure 2: Two example graphs from the Low-High Luminance setting for the High-Low mean parameter in OD. Bland-Altman plots are shown after a 5-minute (A) and 30-minute break (B). The black dotted line represents the ideal no bias mark, each blue circle represented the mean difference between test and retest for each participant. The mean bias and its 95% confidence intervals are represented as the red line with shaded area, respectively. The proportional bias as a function of means is shown as green line. Upper and lower Limits of Agreement are depicted as blue dashed lines with their respective 95% Confidence intervals. Results Means, standard deviations, and Bland-Altman statistics for direct and consensual pupil light reflexes are reported for the 5-minute and 30-minute groups in Appendix Table 1 for SFL method and Appendix Table 2 for the Low-High-Luminance method. Tables 2 and 3 summarize the key observations of biases for SFL test and LHL assays respectively. If the retest tends to give higher or lower values than the first test (instead of being about the same), that shows a bias toward the retest . While no test-retest biases were seen for the RAPD assay when evaluated for test-retest intervals of 5 or 30 minutes, many of the dynamic pupillography metrics did show biases for the 5-minute test-retest interval. View this table: View inline View popup Table 1: Demographic and ophthalmic screening summary for participants from both the 5-minute and the 30-minute experiments. View this table: View inline View popup Download powerpoint Table 2: Results for Swinging Flash-Light test in which an X indicates the presence of bias towards the retest and an O indicates the lack of bias towards the retest. Each parameter for the SFL setting is shown with the right eye and left eyes separated down the column and consensual and direct also separated. The first results show the 5-minute waiting period while the second showed the 30-minute rest period. Detailed reports of outcomes including numerical coefficients of repeatability, biases and basic statistics, are shown in Appendix Table 1 . View this table: View inline View popup Download powerpoint Table 3: Table showing results for Low-High Luminance test in which an X indicates the presence of bias towards the retest and an O indicates the lack of bias towards the retest. Each parameter for the Low-High Luminance setting is shown with the right eye and left eyes separated down the column. The first results show the 5-minute waiting period while the second showed the 30-minute rest period. Detailed reports of outcomes including numerical coefficients of repeatability, biases and basic statistics, are shown in Appendix Table 2 . To illustrate the analysis, example plots for the SFL experiment ( Figure 1 ), and the Low-High Luminance experiment ( Figure 2 ) are also shown. The significant mean bias toward the retest for the SFL assay after a 5-minute break duration was reduced for the cohort that had a 30-minute break. On the other hand, the Coefficient of Repeatability (CoR) and mean bias values tended to be more variant and further away from zero, respectively (see Appendix Table 1 ). The absolute mean biases were compared between the 30- and 5-minute conditions. Only 2/21 or 9.5% of CoRs were more negative after 30 minutes, indicating more variance after a 30-minute break. Interestingly, 6/21 (28.5%) absolute mean biases were closer to zero after a 30-minute break. Since the 30-minute cohort included several new participants (n=6) and participants (n=15) that performed both tasks, we re-ran the analysis but only with the participants that took part in both experimental sessions to investigate whether the variance was affected by the cohort difference. We found that 11/21(52%) CoR values that were closer after a 30-minute break and 9/21 (43%) mean biases that were closer to zero after a 30-minute break. The Low-High Luminance test’s results showed no significant mean bias, except in one setting of standard deviation for the low, after a 30-minute break. When comparing the 30-minute results with results after a 5-minute break, 66.7% and 58.3% of absolute mean biases and CoRs, respectively, also improved (Appendix Table 2 ), i.e., the mean biases were closer to zero and the CoR values were more negative, indicating less repeatability-related variability of the data. Additionally, we performed a linear correlation analysis for the first run’ data to test whether interocular visual acuity difference affected the RAPD score, but found no significant association (t= -0.13, p > 0.05). The Low-High Luminance test provides a low-to-high luminance difference measure, which we also correlated with interocular visual acuity difference. Visual acuity did also not correlate significantly with visual acuity of either left (t= 0.00, p>0.05) or right eye (t= 0.21, p>0.05). Discussion Automated pupillography enables experimenter independent assessment of pupil light reflex kinetics, thereby generating computerized performance models for every trial. The current study’s main goal was to assess the repeatability of a clinical pupillography device, specifically its two integrated methods namely the SFL and Low-High Luminance tests. The results of the SFL test showed an overall trend towards a retest bias in most parameters with just a 5-minute test-retest interval ( Table 2 , Appendix Table 1 ). Zheng et al. validated a previous version of the device 23 using intraclass correlations (ICCs) to assess repeatability and found that the outcome parameters showed ICCs ranging between 0.65 to 0.90. Although they did not use Bland-Altman analyses, they reported that the means of each parameter were systematically reduced across three trials, which suggests a re-test bias. Zheng et al. did not standardize the duration between test and retest, reporting that the interval varied by more than 5 minutes and elsewhere reporting that the interval ranged from 10 to 20 minutes. 23 The retest bias after 5-minutes for the SFL test found in our study and the trend reported in Zheng et al.’s study may have been due to a lack of recovery time. Hence, we performed a control experiment with 30-minutes to test whether the retest biases would disappear and found that most biases were indeed eliminated for the SFL as well as the Low-High Luminance assays when the test retest interval was 30 minutes Interestingly the CoR values for each parameter during the SFL increased, indicating more variability after 30-minutes. As the 30-minute experiment included participants that took part in the 5-minute protocol as well, we re-ran the analysis of this subset of participants to check whether the variability was due to different groups. We found for the Low-High Luminance task that 67% (8/12) of the entire control cohort had smaller CoR values and 83% (10/12) for the subgroup that took part in both experiments (Appendix Tables 2 and 3 ). For the Swinging-Flash-Light method, the control experiment showed only 29% (6/21) of CoR values were smaller after the 30-minute break and when re-analyzing the subgroup of 15 participants that took part in both experiments only 14% (3/21) had smaller CoR (Appendix Tables 1 and 3 ). We conclude that for the Low-High Luminance test, 30-minute breaks eliminated retest bias and also reduced test-retest variability. For the SFL method on the other hand, retest bias was eliminated after 30-minute breaks however greater test-retest variability was introduced. Repeatability results of another study for a different device showed also a wide range of retest agreement i.e., ICCs from -0.2 to 0.8. 24 Notably, the retest bias was most pronounced in the Low-High Luminance test, indicating that specific test settings may be more susceptible to temporal influences, likely due to the 5 seconds of continuous, bright white light exposure that caused prolonged photostress and thus delayed recovery compared to the SFL protocol and its eight 167millisecond flashes that were separated by 2.1 seconds of recovery phases. These results underscore the importance of considering the timing of repeat measurements when utilizing the EyeKinetix in clinical or research settings. To ensure reliable and reproducible outcomes, a minimum interval of at least 30-minutes is indicated between tests for both Eyekinetix methods. The reduction of retest bias as a function of test-retest break duration suggests that photostress induced during each trial and the recovery thereafter to baseline was the driver of the observer the retest bias. Moreover, although the retest bias per parameter was also reduced for the Low-High Luminance method, some mean bias still persisted. Given its 5 second white light exposure, it is plausible that of the two methods, the Low-High Luminance test is more affected by photostress-recovery than the SFL method. It is noteworthy to list the current study’s limitations. While breaks between tests and retests were constant, time of day, and ambient noise were not. These two factors have been shown to affect the results of a pupillometry device 28 , 29 , potentially inducing confounding factors into the data. On the other hand, these factors are part of the clinical environment for which the devices are purposefully built. The current study tested healthy, young participants. Future studies may test the repeatability of older cohorts or cohorts with ophthalmic conditions. Some participants wore contact lenses with their correction whereas other participants performed experiments without best correction. A linear correlation was performed, specifically correlating interocular outcome measures of both tests with interocular visual acuity difference. The results showed no significant effect of visual acuity on the pupillary outcomes for both tests. One study of a pupillometer reported that the device reduced retest bias and less variability compared standard manual assessment of a trained clinician. 27 A future study may repeat that protocol using the Eyekinetix by comparing its repeatability with manually gathered results to investigate whether the Eyekinetix generates also less retest bias and variability. Whether 30-minutes are sufficient for older patients or clinically affected cohorts is unclear and hence invites future research. Pupillography is a relatively new field with many different uses in the ophthalmology clinic besides the detection of RAPDs. 10 However, clinicians often are under a time constraint with patients and a 30-minute waiting period where the patient cannot be dilated is not conducive to clinical flow. It is then recommended that staff members be appropriately trained in the device so that the need for retesting is minimized, reducing the clinical burden of this confounding factor. A future study may repeat that protocol using the Eyekinetix by comparing its repeatability with manually gathered results to investigate whether the Eyekinetix generates also less retest bias and variability. Conclusions In this study, we assessed the repeatability of a clinical pupillography system in young, healthy participants. The primary aim was to evaluate the test-retest repeatability of the device in measuring the relative afferent pupillary defect (RAPD) by using a SFL approach and the Low-High Luminance variation in pupillary diameter for test-retest intervals of 5and 30-minutes. The key findings demonstrated retest bias after a 5-minute interval for SFL and Low-High luminance tests. However, RAPD assessment, which is arguably the most useful metric provided by this form of pupillography, introduced bias when test-retest intervals were 5 or 30 minutes. The retest bias was resolved when measurements were repeated after 30-minutes for the SFL method and significantly reduced for the Low-High Luminance method. After a 30-minute break, the SFL setting showed more variability whereas the Low-High Luminance test results showed less variability. These results suggest that pupillography assay is repeatable with a 30-minute break between test and retest. Data Availability All relevant data are within the manuscript and its Supporting Information files. Authors contributions Conceptualization : All authors Data Curation : Jacob Diaz Formal Analysis : Jacob Diaz, Jan Skerswetat Funding Acquisition : Andrew Browne Investigation : Jacob Diaz Methodology : All authors Project Administration: Andrew Browne Resources: Andrew Browne Software: Jan Skerswetat Supervision: Andrew Browne Validation: All authors Visualization: Jacob Diaz, Jan Skerswetat Writing – Original Draft Preparation: Jacob Diaz, Jan Skerswetat Writing – Review and Editing: All authors Funding: Andrew Browne Competing interests None Supplemental Tables View this table: View inline View popup Supplemental Table 1: Summary of basic and Bland-Altman statistics for the Swinging-Flash-Light approach. The results for the 30-minute break interval condition are in italic font below each 5-minute results. Means (µ), standard deviations (σ), Coefficients of Repeatability (CoR), Mean and Proportional Biases (Prop. Bias) are shown. Parameters are: Relative Afferent Pupillary Defect (RAPD) score, Amplitude of Constriction (AC), Latency of Onset-Constriction (LoC), Latency of Peak Constriction (LPC), Velocity of Constriction (VC), and Velocity of Recovery (VR). *highlights p-values which are smaller than 0.05; ̈ indicates CoR results for 30-minutes that are more negative than results during the 5-minute break interval; ̈̈ indicates absolute mean bias results for the 30-minute break interval that are smaller than results during the 5-minute break interval . View this table: View inline View popup Supplemental Table 2: Low-High Luminance Test results summary for basic statistics mean (m) and standard deviations (σ) and Bland-Altman statistics. The results for the 30-minute break interval condition are in italic font below each 5-minute result. Means (m), standard deviations (σ), Coefficients of Repeatability (CoR), Mean and Proportional Biases (Prop. Bias) are shown. Parameters are: Mean (µ) Low, Mean (µ) High, Relative Change, Standard Deviation (σ) High, Standard Deviation (σ) Low, and Low-High Difference. * highlights p-values which are smaller than 0.05; ̈ indicates CoR results for 30-minutes that are more negative than results during the 5 minute break interval; ̈̈ indicates absolute mean bias results for the 30-minute break interval that are smaller than results during the 5-minute break interval . View this table: View inline View popup Supplemental Table 3: Control analysis for both SFL and LHLum test for 15 participants that took part in both experiments. Acknowledgments The authors acknowledge that Konan Medical provided the EyeKinetix device at no cost to the UC Irvine Department of Ophthalmology in exchange for the predecessor instrument, RAPDx, which was also manufactured and distributed by Konan Medical and previously purchased by the UC Irvine Department of Ophthalmology. References 1. ↵ Thompson HS , Corbett JJ , Cox TA . How to measure the relative afferent pupillary defect . Surv Ophthalmol . 1981 ; 26 ( 1 ): 39 – 42 . doi: 10.1016/0039-6257(81)90124-7 OpenUrl CrossRef PubMed Web of Science 2. ↵ Belliveau AP , Somani AN , Dossani RH . Pupillary Light Reflex . In: StatPearls . StatPearls Publishing; 2024 . http://www.ncbi.nlm.nih.gov/books/NBK537180/ 3. ↵ Pinheiro HM , da Costa RM . Pupillary light reflex as a diagnostic aid from computational viewpoint: A systematic literature review . J Biomed Inform . 2021 ; 117 : 103757 . doi: 10.1016/j.jbi.2021.103757 OpenUrl CrossRef PubMed 4. ↵ Takizawa G , Miki A , Maeda F , et al. Association between a relative afferent pupillary defect using pupillography and inner retinal atrophy in optic nerve disease . Clinical Ophthalmology . 2015 ; 9 : 1895 – 1903 . doi: 10.2147/OPTH.S91278 OpenUrl CrossRef PubMed 5. ↵ Siebald F , Grittner U , Otto C , et al. Ultrasound pupillometry for the detection of a relative afferent pupillary defect (RAPD): Systematic evaluation in patients with optic neuritis and comparison with infrared video pupillometry . PLoS One . 2025 ; 20 . doi: 10.1371/journal.pone.0315712 OpenUrl CrossRef 6. ↵ Chang DS , Xu L , Boland M V. , Friedman DS . Accuracy of pupil assessment for the detection of glaucoma: A systematic review and meta-analysis . Ophthalmology . 2013 ; 120 : 2217 – 2225 . doi: 10.1016/j.ophtha.2013.04.012 OpenUrl CrossRef PubMed Web of Science 7. ↵ Takayama K , Ito Y , Kaneko H , et al. Cross-sectional pupillographic evaluation of relative afferent pupillary defect in age-related macular degeneration . Medicine (United States) . 2016 ; 95 . doi: 10.1097/MD.0000000000004978 OpenUrl CrossRef 8. ↵ Yari N , Morgan M , Almarzouqi SJ , Lee AG . RAPD (Relative Afferent Pupillary Defect) . In: Encyclopedia of Ophthalmology. Springer Berlin Heidelberg ; 2016 : 1 – 2 . doi: 10.1007/978-3-642-35951-4_1269-1 OpenUrl CrossRef 9. ↵ Rauchman SH , Zubair A , Jacob B , et al. Traumatic brain injury: Mechanisms, manifestations, and visual sequelae . Front Neurosci . 2023 ; 17 . doi: 10.3389/fnins.2023.1090672 OpenUrl CrossRef 10. ↵ Philibert M , Milea D . Basics, benefits, and pitfalls of pupillometers assessing visual function . Eye (Basingstoke) . 2024 ; 38 ( 12 ): 2415 – 2421 . doi: 10.1038/s41433-024-03151-9 OpenUrl CrossRef 11. Beisse F , Ring A , Wilhelm H , Beisse C . The Swinging Flashlight Test - Flawed Execution and Interpretation in Ophthalmological Routine . Klin Monbl Augenheilkd . 2020 ; 237 ( 11 ): 1278 – 1285 . doi: 10.1055/a-1271-6993 OpenUrl CrossRef PubMed 12. Groot SG de, Gebhard JW . Pupil Size as Determined by Adapting Luminance* . JOSA . 1952 ; 42 ( 7 ): 492 – 495 . doi: 10.1364/JOSA.42.000492 OpenUrl CrossRef PubMed 13. ↵ Boucher T , Fortin É , Evoy F . The standard swinging flashlight test: reliable or not (P1.9-009) . Neurology . 2019 ; 92 ( 15_supplement ): P1.9 – 009 . doi: 10.1212/WNL.92.15_supplement.P1.9-009 OpenUrl CrossRef 14. ↵ Lemanski B , Lemanski N , Cheng M . Clinical utility of quantitative pupillometry (QP) for the detection of afferent pupillary defects (APDs) . Invest Ophthalmol Vis Sci . 2022 ; 63 ( 7 ): 4545 – F0459 . OpenUrl 15. ↵ Volpe NJ , Dadvand L , Kim SK , et al. Computerized binocular pupillography of the swinging flashlight test detects afferent pupillary defects . Curr Eye Res . 2009 ; 34 ( 7 ): 606 – 613 . doi: 10.1080/02713680902993891 OpenUrl CrossRef PubMed 16. ↵ Erdem S , Karahan M , Ava S , Pekkolay Z , Demirtas AA , Keklikci U . The effectiveness of automatic pupillometry as a screening method to detect diabetic autonomic neuropathy . Int Ophthalmol . 2020 ; 40 : 3127 – 3134 . doi: 10.1007/s10792-020-01499-x OpenUrl CrossRef PubMed 17. ↵ Decleva D , Vidal KS , Kreuz AC , de Menezes PAHL , Ventura DF . Alterations of color vision and pupillary light responses in age-related macular degeneration . Front Aging Neurosci . 2023 ; 14 . doi: 10.3389/fnagi.2022.933453 OpenUrl CrossRef 18. ↵ Frost S , Kanagasingam Y , Sohrabi H , et al. Pupil Response Biomarkers for Early Detection and Monitoring of Alzheimer’s Disease . Curr Alzheimer Res . 2013 ; 10 : 931 – 939 . doi: 10.2174/15672050113106660163 OpenUrl CrossRef PubMed 19. ↵ Inc KMUSA . EyeKinetix®, the 2nd Generation Automated, Objective Pupillograph Developed by Konan Medical, is Now Available in the USA . https://www.prweb.com/releases/eyekinetix-r-the-2nd-generation-automated-objective-pupillograph-developed-by-konan-medical-is-now-available-in-the-usa-860569655.html 20. ↵ Leppink J , Pérez-Fuster P . We need more replication research – A case for test-retest reliability . Perspect Med Educ . 2017 ; 6 : 158 – 164 . doi: 10.1007/s40037-017-0347-z OpenUrl CrossRef PubMed 21. ↵ Sarker P , Zaman N , Ong J , et al. Test–Retest Reliability of Virtual Reality Devices in Quantifying for Relative Afferent Pupillary Defect . Transl Vis Sci Technol . 2023 ; 12 ( 6 ). doi: 10.1167/tvst.12.6.2 OpenUrl CrossRef 22. ↵ Rattan Y , Girgla KK , Prasher P , Mahajan G . Recent Advances in Pupillometry . In: New Advances in Medicine and Medical Science Vol. 1 . Book Publisher International (a part of SCIENCEDOMAIN International); 2023 : 31 – 46 . doi: 10.9734/bpi/namms/v1/5021e OpenUrl CrossRef 23. ↵ Zheng D , Huang Z , Chen W , et al. Repeatability and clinical use of pupillary light reflex measurement using RAPDx® pupillometer . Int Ophthalmol . 2022 ; 42 ( 7 ): 2227 – 2234 . doi: 10.1007/s10792-022-02222-8 OpenUrl CrossRef PubMed 24. ↵ Altman DG , Bland JM . Measurement in Medicine: The Analysis of Method Comparison Studies . The Statistician . 1983 ; 32 : 307 . doi: 10.2307/2987937 OpenUrl CrossRef Web of Science 25. ↵ Gerke O . Reporting standards for a bland-altman agreement analysis: A review of methodological reviews . Diagnostics . 2020 ; 10 ( 5 ). doi: 10.3390/diagnostics10050334 OpenUrl CrossRef PubMed 26. ↵ Skerswetat J , He J , Shah JB , Aycardi N , Freeman M , Bex PJ . A new, adaptive, self-administered, and generalizable method used to measure visual acuity . Optometry and Vision Science . 2024 ; 101 ( 7 ): 451 . doi: 10.1097/OPX.0000000000002160 OpenUrl CrossRef PubMed 27. ↵ Nyholm B , Obling L , Hassager C , et al. Superior reproducibility and repeatability in automated quantitative pupillometry compared to standard manual assessment, and quantitative pupillary response parameters present high reliability in critically ill cardiac patients . PLoS One . 2022 ; 17 . doi: 10.1371/journal.pone.0272303 OpenUrl CrossRef 28. ↵ Steinhauer SR , Bradley MM , Siegle GJ , Roecklein KA , Dix A . Publication guidelines and recommendations for pupillary measurement in psychophysiological studies . Psychophysiology . 2022 ; 59 . doi: 10.1111/psyp.14035 OpenUrl CrossRef PubMed 29. ↵ Winn MB , Wendt D , Koelewijn T , Kuchinsky SE . Best Practices and Advice for Using Pupillometry to Measure Listening Effort: An Introduction for Those Who Want to Get Started . Trends Hear . 2018 ; 22 . doi: 10.1177/2331216518800869 OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted May 06, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Assessment of repeatability of a clinical automated pupillometer Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 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