CRYSTALSIGHT: ''Cohort 1.5" Clinical Investigation Study With OCCUTRACK and Tan Tock Seng Eye Clinic to Further Develop Remote Monitoring of Maculopathy at Home Using Artificial Intelligence for Eye Tracking
Conditions: Maculopathy, Maculopathy, Age Related, Macular Degeneration, Age-Related, Diabetic Retinopathy, Wet Age Related Macular Degeneration, Aged-related Macular Degeneration
Sponsor: Tan Tock Seng Hospital

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CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
CRYSTALSIGHT: ''Cohort 1.5” Clinical investigation study with OCCUTRACK and Tan 
Tock Seng Eye Clinic to further develop remote monitoring of maculopathy at home 
using artificial intelligence for eye tracking. 
 
Study Site: Tan Tock Seng Hospital 
 
Principal Investigator: 
Adj A/Prof Augustinus Laude 
Senior Consultant 
NHG Eye Institute, 
Tan Tock Seng Hospital 
National Healthcare Group, Singapore 
 
Co-Investigator(s): 
Dr Elizabeth May Chin Tan 
Senior Resident 
NHG Eye Institute, 
Tan Tock Seng Hospital 
National Healthcare Group, Singapore 
 
Collaborators: 
Mr Soh Zheng Kuang, Noel  
 
 
 Mr Mark Wong 
Clinical Research Coordinator 
 
 
Chief Executive Officer 
NHG Eye Institute, 
 
 
 
 
OCCUTRACK Medical Solutions Pte Ltd 
Tan Tock Seng Hospital 
National Healthcare Group, Singapore 
 
Background:  
Maculopathies such as age-related macular degeneration (AMD) is a prevalent, chronic, and 
progressive retinal degenerative disease of the macula [1-2]. One of the major clinical 
consequences of maculopathy is loss of central vision, which impacts daily living activities such 
as reading, driving and recognizing faces. 
 
Age-related macular degeneration accounts for 8-7% of all blindness worldwide and is the most 
common cause of blindness in developed countries, especially in people over 60 years of age.  
Its prevalence is likely to increase as a result of exponential population aging [3 -5]. The global 
pool prevalence of AMD (based on an age range of 45-85 years) for early, late, and any age-
related macular degeneration is 8.01% (95% CI: 3.98-15.49), 0.37% (0.18-0.77), and 8.69% 
(4.26-17.40), respectively [6].  
 

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The projected number of people with age-related macular degeneration was 196 million 
worldwide in 2020 (95% CI: 140-261) and is expected to increase to 288 million by 2040 [3].  
Previous studies have shown that the age-standardized prevalence of early and late AMD in 
Singapore was 5.1% and 0.5%, respectively [6]. It is interesting to note that there are no major 
racial differences in the prevalence of AMD in Singapore [6].  
 
In addition, AMD in Singapore is expected to increase over time due to the aging population and 
longer life expectancy. 
 
This CRYSTALSIGHT system is a proposed home-based precision monitoring telemedicine 
device that utilizes advanced eye tracking algorithms that enable comprehensive and intelligent 
assessment of a person’s visual performance non-invasively and from the comfort of their 
home, without the need for manual or expert intervention. CRYSTALSIGHT is an automated 
method and system for vision assessment of a subject. The method includes the following: 
determining a set of test patterns for the subject based on a preliminary assessment of an eye 
of the subject; displaying the set of test patterns sequentially to the subject; collecting data on 
the subject's gaze in response to each test pattern displayed; and correlating central vision 
function of the subjects to the collected gaze data. 
 
The underlying cause of AMD  
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in 
adults ≥ 60 years old [7]. The underlying defect appears to be premature dysfunction of the 
retinal pigment epithelium (RPE), a monolayer responsible for most of the maintenance 
functions of the neurosensory retina. 
 
The etiology of AMD is multifactorial, with both genetic and other modifiable risk factors 
contributing to personal risk. The phenotypic risk factors such as drusen and pigment 
abnormalities become more important to predict disease progression during the course of the 
disease. Demographic and environmental risk factors such as age and smoking are consistently 
found to be significantly associated with disease progression, while other risk factors such as 
sex, body mass index (BMI) and education are less commonly associated [8]. 
 
In addition, molecular mechanisms involving the lipid-cholesterol pathway, angiogenic factors, 
inflammation and immune processes play a critical role in the pathophysiology of disease 
development and progression [9-10]. 
 

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Disease progression, immediate and late complications of AMD  
AMD can be classified as early, intermediate, or late stage [11]. Minimal visual disturbances 
may occur in a large proportion of patients with early and intermediate stages of AMD and 
eventually progress to advanced AMD. The development of these advanced subtypes of 
geographic atrophy (GA) and neovascular disease (NV) is commonly associated with visual 
impairment and blindness, which may affect quality of life and lead to loss of independence [12-
14]. 
 
Progression to Wet AMD (or) neovascular AMD (nAMD) is characterised by the formation of 
new fragile vessels originating from the choriocapillaris [8]. These new vessels grow into the 
retina with subsequent leakage and/or hemorrhage that can lead to serous RPE detachment 
accompanied by a rapid loss of vision and eventually causing a vision-threatening scar in the 
macula [15]. There are several risk factors that may influence the progression of disease, and 
the rate at which it progresses may vary among individuals [8].  
 
Imaging techniques that can detect the conversion of an early stage of AMD to late-stage Wet 
AMD include colour fundus photography (CFP), optical coherence tomography (OCT), 
fluorescein angiography (FAG), indocyanine green angiography (ICGA), and OCT angiography 
(OCTA). Whereas CFP, OCT, and FAG can detect exudative nAMD by fluid leakage and 
haemorrhage [8,16]. 
 
Treatment of Maculopathies 
Maculopathy is more prevalent with ageing and can result in blurred or distorted vision, often 
accompanied by a dark patch blocking the center of the visual field. In the management of age-
related macular degeneration (AMD), patients are required to attend regular check-ups at the 
specialist eye clinic by the clinician to monitor if their disease. The eye examinations that 
patients undergo during these clinic visits which may include fundoscopy and optical coherence 
tomography. A preventive treatment for exudative or wet AMD is the administration of an 
intravitreal injection of an anti-vascular endothelial growth factor (anti-VEGF) at these regular 
clinic sessions. 
 
Although anti-vascular endothelial growth factor (VEGF) injections are an effective treatment for 
many patients with NV [10, 17], some patients do not respond, there is a large treatment 
burden, and visual loss continues over time.  
 

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There is no treatment for GA. Thus, prevention of advanced disease and finding new and 
effective treatments remains a significant challenge. Identifying individuals with early and 
intermediate disease at high risk of progression to advanced stages would lead to earlier 
intervention and reduced burden of visual loss due to AMD [10]. 
 
There are many anti-VEGF treatment strategies aimed at minimizing intravitreal injections 
without compromising visual outcomes as well as to reduce the need for repeated treatments 
with the associated cumulative risk of endophthalmitis and other adverse events [18-19]. 
 
Currently available anti-VEGF treatment schedules include the “as-needed” (PRN) and the 
“treat-and-extend” regimens. In an “treat -as-needed” regimen, the patient is examined monthly 
but not always treated, and treatment can be given only if intraretinal or subretinal fluid is 
present [19-20]. In a “treat-and-extend” regimen, the patient is always treated, but the intervals 
between examinations are varied [19-20].  
 
Significance of the project and unmet clinical needs 
Although anti-vascular endothelial growth factor (VEGF) injections are an effective treatment for 
many patients with Wet-AMD [17], there are several unmet needs in treatment of AMD and 
none of them cures the disease or reverses its course [17, 21 – 23]. Some patients do not 
respond to VEGF injections. There are no standardized treatment schedules, there is a large 
treatment burden, and visual loss continues over time. Additionally, the main drawback of anti-
VEGF therapy is its high cost, which suppose a significant burden on health systems, and often 
makes such a regimen unaffordable in clinical practice [24] There is no treatment for GA.  
Therefore, the prevention of advanced disease like Wet-AMD and finding new and effective 
treatments remain a significant challenge.  
 
Advances in imaging and genetics and molecular technologies have led to the identification of 
new risk factors for disease progression, but not all have been evaluated in comprehensive 
prediction models [8]. Perhaps, comprehensive prediction models could lead to the 
development of tailored, individualized therapy and improve the personalised healthcare. 
 
The management of AMD is diagnosed and monitored today using clinic-based Optical 
Coherence Tomography (OCT), however this requires burdensome visits. This 
CRYSTALSIGHT system is a proposed home-based precision monitoring telemedicine device 
that utilizes advanced eye tracking algorithms that enable comprehensive and intelligent 

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assessment of a person’s visual performance non-invasively and from the comfort of their 
home, without the need for manual or expert intervention.  
 
As such, the application of this next-generation OCCUTRACK Technology to develop a 
comprehensive risk score algorithm and to estimate the risk scores to identify individuals at high 
risk for disease progression to advanced stages would result in earlier intervention and reduced 
burden of visual loss due to maculopathy. This approach could enable the tailored individualized 
Anti-VEGF Therapy to promote personalized medicine and improve the quality of life for these 
patients. 
 
As such, the application of this next-generation OCCUTRACK Technology to develop a 
comprehensive risk score algorithm and to estimate the risk scores to identify individuals at high 
risk for disease progression to advanced stages would result in earlier intervention and reduced 
burden of visual loss due to AMD. This approach could enable the tailored individualized Anti-
VEGF Therapy to promote personalized medicine and improve the quality of life of patients with 
Wet-AMD. 
 
A Proof-of-Concept (POC) was completed by TTSH clinician (Augustinus Laude) and AStar-I2R 
scientist to co-develop and patent a software, Automated Vision Assessment and Impairment 
Detection through Gaze Analysis (AVIGA). AVIGA is now referred to as "CRYSTALSIGHT" as 
part of the commercialization branding. A local medical incubator, Trendlines Medical 
Singapore, has licensed it from the research party. This led to the spin-off of a new company- 
OCCUTRACK Pte Ltd to continue the collaboration with TTSH, focusing on the 
commercialization of the CRYSTALSIGHT.  
 
AVIGA previously used a costly commercial tobii gaze tracker that could potentially limit 
consumer adoption, the CRYSTALSIGHT system was designed to mitigate costs by 
incorporating an AI-augmented video camera with gaze tracking algorithms designed to provide 
a comprehensive assessment of a patient's vision. With this noninvasive technology, retinal 
specialists can monitor the real time progression and prognosis of patients with AMD while they 
are in the comfort of their own home without the need for manual or skilled intervention and 
expensive equipment. 
 
 
 
 

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CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
2. STUDY DESIGN 
The development of a next-generation 'CRYSTALSIGHT' solution using combinations of a novel 
and cost-effective eye-tracking system with artificial intelligence-based eye-tracking algorithms 
that detect macular abnormalities and enable clinicians to review and monitor the prognosis of 
patients via a web platform through the following deliverables.  
 
a. Evaluate and improve a home-monitoring regimen involving the self-tests of the 
CRYSTALSIGHT gaze-tracking system. 
b. To demonstrate that CRYSTALSIGHT has the same or superior gaze-tracking capacities as 
Tobii.  
c. Evaluate the CRYSTALSIGHT device for its functionality and ease of use as a qualitative 
measurement tool for patients.  
d. Develop the Design History File (DHF) for regulatory filing requirements.  
 
2. This study will improve on the existing gaze-based scoring methodology for disease activity 
monitoring over time (delta-change) by quantitatively measuring saccadic speed, pursuit and 
micro-saccades. 
 
Validation of the machine learning algorithm has been completed with an accuracy of  xxx > 85% 
against gold standard test. The Gold Standard Tests used in this validation of the machine 
learning algorithm are standard visual acuity (VA) and central visual field (VF) test, which are 
currently used in standard routine clinical practice.   
 
Using fixation data, the accuracy is 0.91, the sensitivity and specificity are 0.76 and 0.95, 
respectively. Using smooth pursuit, the accuracy is 0.92, the sensitivity and specificity are 0.82 
and 0.95, respectively. 
 
The hypothesis of this study is to show that a person’s visual performance can be assessed 
non-invasively and from the comfort of their home, without the need for manual or expert 
intervention, by utilizing the newly developed 'CRYSTALSIGHT' device. A previous study 

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utilized a commercial gaze-tracker "Tobii ET5L", the hypothesis of this study establishes that the 
CRYSTALSIGHT eye tracking device has comparable non-inferior performance to the 
commercial camera and generates an objective score while minimizing patients' need to interact 
with the machine. Tobii ET5L is an infrared gaze-tracking camera, whilst CRYSTALSIGHT is a 
video-based camera. The quantitative outcome of the study may enable the clinical trial team to 
determine that the CRYSTALSIGHT device performs with acceptable or similar performance 
metrics to the commercial device, which provides an indicative score for disease activity in 
patients with maculopathies. The findings of this study could also potentially show that the 
CRYSTALSIGHT device may be used in a home-based setting to determine macular disease 
activity over time.  
 
Previous studies have shown the potential of gaze tracking to provide an objective score with 
relevant diagnostic assistance information while minimizing patients' need to interact with the 
machine. 
 
Study Design: 
 
Study population: Consecutive patients with vision problems who have been diagnosed with 
Wet-AMD attending SOC eye clinics will be recruited in the study after meeting the inclusion 
and exclusion criteria. 
 
Inclusion Criteria: 
1. Participants between ages 21 and 100 
2. Both genders 
3. Subjects with maculopathies 
4. Ability to comply with the study protocol, in the investigator's judgment 
5. Subjects must have the cognitive capacity to provide personal consent (i.e. no 
cognitively impaired persons will be recruited). 
 
Exclusion Criteria: 
1. Uncontrolled blood pressure, defined as systolic blood pressure >180 millimeters of 
mercury (mmHg) and/or diastolic blood pressure >100 mmHg while a patient is at rest.  
2. Any concurrent intraocular condition in the study eye that, in the opinion of the 
investigator, could either reduce the potential for visual improvement or require medical 
or surgical intervention during the study.  
3. History of idiopathic or autoimmune-associated uveitis in either eye.  
 

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CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
4. Active ocular inflammation or suspected or active ocular or periocular infection in 
either eye.  
5. Other protocol-specified exclusion criteria may apply.  
6. Individuals with indications of cognitive impairment and unable to make decisions 
for themselves to provide informed consent will be excluded from the study. 
 
Study Procedure: 
This cohort study will involve 1 study visit. 
 
Pre-specified clinical outcome: The prespecified adverse clinical outcome used in this study 
will be the maculopathy which will be identified by an increase in central retinal thickness 
(CRT) of at least 100 microns or a loss of best-corrected VA of 5 letters or more.  
 
Clinical Validation will be a cohort study design to evaluate the diagnostic accuracy of the 
CRYSTALSIGHT device compared to the Tobii gaze-tracker in patients with macular diseases 
recruited from the medical retina specialty clinic.  
 
This study will be conducted in accordance with the tenets of the Declaration of Helsinki.  
 
The goal is to recruit a minimum number of 20 patients with diagnosed indication of 
maculopathies who fit the inclusion and exclusion criteria. Adult individuals will be voluntarily 
recruited from Tan Tock Seng Hospital (TTSH) Ophthalmology SOC clinics after they had been 
assessed for eligibility based on established clinical diagnosis from the case notes through 
TTSHs NGEMR. Informed consent for participation in this study will be obtained. Eye gaze 
tracking test will be automated, and patients will only need to follow through the stimulus/image 
shown without physical contact with the eye gaze tracker using CRYSTALSIGHT and Tobii. A 
series of stimulus dots in the form of a pursuit (moving stimulus) or saccade (fixed stimulus and 
fixed speed) will be presented on the screen and the user under test (UAT) will need to look at 
the targets presented. The test is similar to Microperimetry and Humphrey's visual field test. A 
score will be generated at the end of the test.  
 
A research collaboration agreement was established between TAN TOCK SENG HOSPITAL 
PTE. LTD. and OCCUTRACK MEDICAL SOLUTIONS PTE LTD on the research project titled: 
CRYSTALSIGHT: “Cohort 1.5” clinical investigation study with OCCUTRACK and Tan Tock 

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CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
Seng Eye Clinic to further develop remote monitoring of age-related macular degeneration at 
home using artificial intelligence for eye tracking.  
 
Research Procedures:  
1) CRYSTALSIGHT  
2) Tobii 
 
Subjects perform the CRYSTALSIGHT test monocularly and pursue a pre-determined target 
moving in a customized waveform across the computer screen. The trail of the gaze points 
generated by the subject following the target is simultaneously recorded and stored. Eye dilation 
will not be required for the purpose of this research study as fundoscopy nor OCT imaging will 
not be performed.  
 
As part of the clinical evaluation of subjects during the analysis phase, access and extraction of 
data will be limited to TTSH's NGEMR and Heidelberg Eye Explorer platform. Clinical 
information collected for the purposes of this study would include current diagnosis, co-mormid 
information e.g DM, hyperlipidemia, and hypertension histories along with prior visual 
assessments documented by optometrists as well as recent OCT imaging.  
 
In addition, this is also to note that NEHR cannot and will not be used for research. Assess of 
medical records for the purpose of data collection will also be limited to the period dated from 1 
March 2025 to 28 February 2026. Clinical information/data collected will be done once off 
during, or retrospectively after the study visit. 
 
Measurements at Baseline (Day – 1)  
The following variables will be collected at initial baseline visit.  
- 
Demographic data (age, gender) 
- 
Phenotypic risk factors such as drusen and pigment abnormalities 
- 
Smoking status  
- 
Co-morbidity status such as diabetes, Cancers, CVD, strokes, kidney 
diseases 
- 
Drugs history (Eye related) 
- 
Drugs history (Co-morbidity status)  
- 
Eye measurements:  
o CRYSTALSIGHT  

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CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
o AVIGA 
o BCVA (Best Corrected visual acuity)  
 
Sample size calculation 
The sample size calculation is based on the intraclass correlation between CRYSTALSIGHT 
and Tobbi. Our minimum acceptable intraclass correlation coefficient (ICC) is 76% between 
CRYSTALSIGHT and Tobbi, and the expected ICC is 93%, basing on two- sided significance 
level of 0.05 and power 0.8, a total of 20 subjects are required. Statistical analysis to assess the 
eye-tracking performance of CRYSTALSIGHT, will be applied through the following methods:  
 
- The Bland and Altman plot will be used to assess the agreement between CRYSTALSIGNT 
and Tobbi. The difference between CRYSTALSIGHT and Tobbi of each subject will be plotted 
on the vertical axis, again, the mean of the two readings of each subject on the horizontal axis. 
Limits of agreement will be presented in the plot.  
 
- Intraclass correlation Coefficient will be computed using a random effect model, including 
device type (CRYSTALSIGHT vs. Tobbi) as a fixed factor and subject as a random effect. This 
model accounts for variability between subjects while assessing agreement between the two 
devices. 
 
In literature, gaze-tracking accuracy measures such as K-means clustering and Euclidean 
distances were used and will be evaluated for suitability [35, 36] 
 
 
References:  
1 
Cheung LK, Eaton A. Age-related macular degeneration. Pharmacotherapy. 2013; 
33(8):838–855. https://doi.org/10.1002/phar.1264 
2 
Gheorghe A, Mahdi L, Musat O.  Age-related macular degeneration. Rom J Ophthalmol. 
2015 59(2):74–77.  
3 
Wan Ling Wong, Xinyi Su, Xiang Li, Chui Ming G Cheung, Ronald Klein, Ching-Yu 
Cheng, Tien Yin Wong. Global prevalence of age-related macular degeneration and 
disease burden projection for 2020 and 2040: a systematic review and meta-analysis. 
Lancet Glob Health. 2014;2(2):e106-16. 

Page 11 of 13 
CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
4 
Klaver CC, Assink JJ, van Leeuwen R, et al. Incidence and progression rates of age-
related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci 2001; 42: 2237–
2241. 
5 
Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular 
degeneration in Asians: a systematic review and meta-analysis. Ophthalmology 2010; 
117: 921–27. 
6 
Chui Ming Gemmy Cheung, Xiang Li, Ching-Yu Cheng, Yingfeng Zheng, Paul 
Mitchell, Jie Jin Wang, Tien Yin Wong. Prevalence, racial variations, and risk factors of 
age-related macular degeneration in Singaporean Chinese, Indians, and Malays. 
Ophthalmology 2014;121:1598–1603. 
7 
Sources for Macular Degeneration: Facts & Figures [http://www.brightfocus. 
org/sources-macular-degeneration-facts-figures]. Accessed 28 Oct 2015. 
8 
Thomas J Heesterbeek, Laura Lor_es-Motta, Carel B Hoyng, Yara T E Lechanteur 
andAnneke I den Hollander. Risk factors for progression of age-related macular 
Degeneration. Ophthalmic and Physiological Optics. 2020;40(2): 140 – 170. 
9 
Katie L. Pennington and Margaret M. DeAngelis. Epidemiology of age-related macular 
degeneration (AMD): associations with cardiovascular disease phenotypes and lipid 
factors. Eye and Vision (2016) 22; 3:34 - 64. 
10 
Johanna M. Seddon, MD, ScM1 and Bernard Rosner. Validated Prediction Models for 
Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High 
Risk Individuals.  Am J Ophthalmol. 2019; 198: 223–261. doi:10.1016/j.ajo.2018.10.022 
11 
Ferris FL, Wilkinson CP, Bird A, Chakravarthy U, Chew E, Csaky K, Beckman Initiative 
for Macular Research Classification Committee et al (2013) Clinical classification of age-
related macular degeneration. Ophthalmology 120(4):844–851.  
12 
Alexander MF, Maguire MG, Lietman TM, Snyder JR, Elman MJ, Fine SL. Assessment 
of Visual Function in Patients With Age-Related Macular Degeneration and Low Visual 
Acuity. Arch Ophthalmol. 1988;106(11):1543–1547.  
doi:10.1001/archopht.1988.01060140711040 [PubMed: 3190538] 
13 
Alexander MF, Maguire MG, Lietman TM, Snyder JR, Elman MJ, Fine SL. Assessment 
of Visual Function in Patients With Age-Related Macular Degeneration and Low Visual 
Acuity. Arch Ophthalmol. 1988;106(11):1543–1547. 
doi:10.1001/archopht.1988.01060140711040 [PubMed: 3190538] 
14 
Williams RA, Brody BL, Thomas RG, Kaplan RM, Brown SI. The Psychosocial Impact of 
Macular Degeneration. Arch Ophthalmol. 1998;116(4):514–520. 
doi:10.1001/archopht.116.4.514 [PubMed: 9565052] 

Page 12 of 13 
CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
15 
Campochiaro PA, Soloway P, Ryan SJ & Miller JW. The pathogenesis of choroidal 
neovascularization in patients with age-related macular degeneration. Mol Vis 1999; 5: 
34. 
16 
Treister AD, Nesper PL, Fayed AE, Gill MK, Mirza RG & Fawzi AA. Prevalence of 
subclinical CNV and choriocapillaris nonperfusion in fellow eyes of unilateral exudative 
AMD on OCT angiography. Transl Vis Sci Technol 2018; 7: 19. 
17 
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for Neovascular Age-Related 
Macular Degeneration. N Engl J Med. 2006;355(14):1419–1431. 
doi:10.1056/NEJMoa054481 [PubMed: 17021318].  
18 
Victor M. Villegas, Luis A. Aranguren, Jaclyn L. Kovach, Stephen G. Schwartz & Harry 
W. Flynn Jr. (2016): Review: Current advances in the treatment of neovascular age-
related macular degeneration, Expert Opinion on Drug Delivery, DOI: 
10.1080/17425247.2016.1213240. http://dx.doi.org/10.1080/17425247.2016.1213240 
19 
"Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, Feuer W, Davis JL, Flynn 
HW Jr, Esquiabro M. A variable-dosing regimen with intravitreal ranibizumab for 
neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J 
Ophthalmol. 2009 Jul;148(1):43-58.e1." 
20 
Fung AT, Kumar N, Vance SK, Slakter JS, Klancnik JM, Spaide RS, Freund KB. Pilot 
study to evaluate the role of high-dose ranibizumab 2.0 mg in the management of 
neovascular age-related macular degeneration in patients with persistent/recurrent 
macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST 
Study). Eye (Lond). 2012;26(9):1181-1187. 
21 
Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. 2008; N Engl J Med 
358(24):2606–2617 
22 
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY et al. ANCHOR Study 
Group. Ranibizumab versus verteporfin for neovascular age-related macular 
degeneration. 2006; N Engl J Med 355(14):1432–1444. 
https://doi.org/10.1056/NEJMoa062655 
23 
"Kaiser PK, Blodi BA, Shapiro H, Acharya NR. MARINA Study Group.Angiographic and 
optical coherence tomographic results of the MARINA study of ranibizumab in 
neovascular age-related macular degeneration. 2007; Ophthalmology 114(10):1868–
1875. https://doi.org/10.1016/j.ophtha.2007.04.030" 
24 
Jose´ M. Ruiz-Moreno . Luı´s Arias . Maximino J. Abraldes . Javier Montero . Patricia 
Udaondo . The RAMDEBURS study group.  Economic burden of age-related macular 
degeneration in routine clinical practice: the RAMDEBURS study. Int Ophthalmol. 2021 
Oct;41(10):3427-3436. doi: 10.1007/s10792-021-01906-x.  

Page 13 of 13 
CRYSTALSIGHT Cohort 1.5 Study Protocol V1.0, Dated 30 May 2025 
25 
Liu, H., et al. Determining the difference in eyegaze measurements in individuals with 
Age related Macular Degeneration. in 2016 38th Annual International Conference of the 
IEEE Engineering in Medicine and Biology Society (EMBC). 2016. IEEELiu, H., et al. 
Detecting impaired vision caused by AMD from gaze data. in 2017 39th Annual 
International Conference of the IEEE Engineering in Medicine and Biology Society 
(EMBC). 2017. IEEE. 
26 
Chow, S.C., Shao, J., and Wang, H. 2008. Sample Size Calculations in Clinical 
Research, Second Edition.Chapman & Hall/CRC. Boca Raton, Florida. 
27 
D'Agostino, R.B., Chase, W., and Belanger, A. 1988. 'The Appropriateness of Some 
Common Procedures for Testing the Equality of Two Independent Binomial Populations', 
The American Statistician, August 1988, Volume 42, Number 3, pages 198-202. 
28 
Fleiss, J. L., Levin, B., and Paik, M.C. 2003. Statistical Methods for Rates and 
Proportions. Third Edition. John Wiley & Sons. New York. 
29 
Lachin, John M. 2000. Biostatistical Methods. John Wiley & Sons. New York. 
30 
Machin, D., Campbell, M., Fayers, P., and Pinol, A. 1997. Sample Size Tables for Clinical 
Studies, 2nd Edition. Blackwell Science. Malden, Mass. 
31 
Ryan, Thomas P. 2013. Sample Size Determination and Power. John Wiley & Sons. 
Hoboken, New Jersey. 
32 
Lemeshow S, Hosmer DW Jr: A review of goodness of fit statistics for use in the 
development of logistic regression models. Am J Epidemiol 1982; 115:92–106.  
33 
Van Houwelingen JC, Le Cessie S: Predictive value of statistical models. Stat 
Med 1990; 9:1303–1025.  
34 
Cole TJ: Scaling and rounding regression coefficients to integers. Appl Stat 1993; 
42: 261–268. 
35 
Housholder, A., et al. Evaluating Accuracy of the Tobii Eye Tracker 5. in 
International Conference on Intelligent Human Computer Interaction. 2021. 
Springer. 
36 
Macinnes, J.J., et al., Wearable Eye-tracking for Research: Automated dynamic 
gaze mapping and accuracy/precision comparisons across devices. bioRxiv, 
2018: p. 299925