Dilated Wavefront Versus Non-Dilated Wavefront for Metric-Optimized Refraction Procedure for Individuals With Down Syndrome
Phase: PHASE2
Conditions: Down Syndrome, Refractive Errors
Sponsor: Ohio State University

Dilated Versus Non-Dilated Wavefront Corrections for Patients with Down 
Syndrome 
NCT# 05059041 
9/15/2021 
 

Research Protocol 
 
Dilated Wavefront versus Non-Dilated Wavefront for Metric-Optimized Refraction Procedure 
 
Study Objectives: 
 
To determine whether dilation can be eliminated as part of the process to identify spectacle 
refractions from wavefront aberration measures. 
 
We will test the following hypothesis: 
 
1. Differences between refractions determined pre and post dilation are within the 
repeatability of subjective refraction (0.62D). 
2. Differences between distance acuity obtained through refractions determined pre and 
post dilation are within the repeatability of acuity testing (7 letters). 
3. Participant ratings of vision and refraction preference do not differ between refractions 
determined pre and post dilation. 
4. Differences between near acuity obtained through refractions determined pre and post 
dilation are within the repeatability of acuity testing (1 line). 
 
Background and Rationale: 
 
Justification 
Identifying the best performing refraction for a patient with Down syndrome can be challenging 
due to both the elevated optical distortions commonly found in eyes of patients with Down 
syndrome, as well as the cognitive deficits that make performance of routine clinical tests 
challenging.  The study team has previously investigated the use of objective measurements of 
the eye’s optics (wavefront aberrometry) to determine the refraction predicted to perform the 
best for the patient (Ravikumar, 2019; Anderson, 2021). The first iteration of our work to 
identify optimized corrections was based upon post-dilation measures of wavefront aberrations 
in adults with Down syndrome and subsequent calculation of refractions after the participant’s 
visit concluded. Prior to incorporating this technique in a clinical setting, the calculation of a 
metric-optimized refraction would ideally occur during the same visit. This would meet the 
patient expectation that refractions and spectacle prescriptions are provided in a single 
encounter and it would afford the practitioner the opportunity to evaluate the performance of 
the refraction prior to finalizing the prescription. Dilation is thus a barrier to the clinical 
application of this technique and evaluating the use of dilated versus non-dilated wavefront 
measures for the calculation of metric-optimized refractions is a necessary endeavor to refine 
this technique for clinical deployment. 
 
It is well established that the magnitude of higher order aberrations increase with increasing 
pupil diameter (Wang, 2003), and thus the optimal refraction for a given eye could conceivably 
depend upon pupil diameter, particularly for highly aberrated eyes. In our previous studies we 
investigated this hypothesis by calculating metric-optimized refractions from dilated measures 

of the eyes of 30 adults with Down syndrome re-sized to both 6mm and a 4mm pupil 
diameters, after which we converted refractions to vector notation and calculated the dioptric 
difference (Raasch, 2001) between refractions. While some differences between refractions 
were found (mean difference = 0.26 ± 0.50D), the differences did not exceed the repeatability 
of clinically utilized subjective refraction techniques (Anderson, 2019). In our clinical trial 
whereby refractions were dispensed to participants with DS, we dilated the eye to obtain 
wavefront aberration measures, but identified metric-optimized refractions after re-sizing the 
images to match the non-dilated, habitual pupil diameter of each individual participant 
(Anderson, 2021). Using this methodology, we observed good performance of metric-optimized 
refractions evidenced by the finding that all metric-optimized refractions passed the initial 
safety check to be dispensed in the trial. This suggests that if wavefront aberrations were 
measured at the habitual pupil diameter rather than the fully dilated diameter, the method 
could be equally (and potentially even more) successful. 
 
Dilation not only impacts pupil diameter, but also paralyzes accommodation (the focusing 
ability of the eye), eliminating the confounding factor of instrument myopia during aberration 
measures, which could be an argument for maintaining dilation in the methodology. While it is 
common clinical practice to paralyze accommodation in young children to avoid instrument 
myopia (a measured increase in myopic refractive error related to the patient increasing the 
focus of the eyes when looking into a closed-field instrument), the phenomenon is less likely to 
be observed in patients with Down syndrome who are known to have significant 
accommodative (focusing) deficits, even in early childhood (Woodhouse, 1993; Anderson, 
2011). Additionally, while paralyzing accommodation reveals the full defocus of the eye, it 
potentially creates new challenges if the patient rejects a more hyperopic correction identified 
during paralysis of accommodation when the correction is later applied after accommodation 
resumes. Based on evidence that pupil diameter was not a significant factor in the 
determination of metric-optimized refractions for adults with Down syndrome and given that 
poor accommodative ability is likely to protect against instrument myopia, it is reasonable to 
hypothesize that dilation can be eliminated in the identification of metric-optimized refractions. 
 
Anticipated Results & Potential Pitfalls 
We expect refractions obtained from pre- and post-dilation measures will not differ 
significantly. The exception could be for participants who have accurate accommodative 
responses. For these participants, it is anticipated that refractions may differ if the participant 
exhibits instrument myopia during aberration measures, evidenced by more hyperopic (less 
myopic) post-dilation refractions. Analysis of dioptric differences by secondary factors, such as 
accommodative ability, will permit detection of subgroups for whom dilation may be important. 
In addition, we expect refractions obtained from pre- and post-dilation measures to result in 
similar acuity performance when tested on study participants through the use of trial frames. 
One potential problem associated with this metric is that visual acuity measures will be taken 
with trial frames rather than ground spectacle lenses. Particularly when refractive error is high 
and significant magnitudes of astigmatism are present, building a prescription in a trial frame 
becomes challenging in that vertex distance is more difficult to control and reflections from 
lenses can interfere with performing an acuity task. That said, this is an accepted first step in 

evaluating refractions in the clinic, and the necessity of dilation for metric-optimized spectacle 
prescriptions and producing ground spectacles for this one-time assessment would not be 
fiscally appropriate. The analysis for this experiment is based upon a comparison of acuity 
between refractions, and thus both conditions will experience the same challenges and there is 
unlikely to be a bias toward one type of refraction (pre- versus post-dilation) over the other. 
 
Lastly, we will compare participant ratings and preference of refractions obtained pre- and 
post-dilation through use of a 5 point rating scale depicting a series of faces from frowning to 
neutral to smiling.  We anticipate no difference in ratings for the two refraction types; however, 
one challenge with this goal is that participants may be unable to provide adequate 
discrimination of preferences using the scale.  While we did use this scale previously in studies 
with adult participants, this new study includes children with Down syndrome who may be less 
cognitively advanced and thus unable to provide responses on such a survey.  Although it is 
possible we will not successfully obtain data from all participants, we feel it is important to 
attempt to capture subjective feedback regarding the corrections. 
 
Significance & Potential Benefit 
If this study demonstrates that dilation can be eliminated as part of the optimized refraction 
process, it will result in a procedure that is much more easily deployed in a clinical setting, 
resulting in decreased examination time, increased patient comfort, and eliminate the need for 
a second office visit to finalize the refraction.  While there is no direct benefit to the 
participants in this study, there is the potential for the community at large to benefit, 
particularly individuals with Down syndrome for whom this refraction strategy may most likely 
be adopted. 
 
Procedures: 
 
Research Design 
This is an experimental, multi-site, clinical treatment trial with a randomized cross-over design 
to evaluate two spectacle prescriptions in-office.  Treatments will not be dispensed to 
participants. 
 
Sample 
The sample size for this study is 20 adults with Down syndrome enrolled at University of 
Houston College of Optometry and 20 children with Down syndrome enrolled at The Ohio State 
University College of Optometry.  Sample size was calculated for each site separately and is 
based upon 90% power to detect differences in refractions as small as 0.42D between 
prescriptions.  In addition, a sample size of 20 provides 80% power to identify moderate 
correlations (0.60 or higher) between refraction differences and demographic factors and 
clinical characteristics.  A sample size of 20 provides power in excess of 99% to detect 
differences in visual acuity of 7 letters or more between refractions. 
 
 
Potential participants will be recruited in the following manners: 

 
• Patients at The Ohio State University and University of Houston clinics may be given 
informational brochures 
• Paper flyers may be posted in The Ohio State University and University of Houston 
clinics 
• Paper flyers and brochures may be distributed to the Nisonger Center program facilities, 
Special Olympics Ohio, and the Down Syndrome Association of Central Ohio 
• Electronic announcements may be posted to the college of optometry social media 
pages for the respective sites 
• Email announcements may be distributed to the college of optometry 
faculty/staff/student/alumni listserves for the respective sites 
• Email announcements may be distributed to members of the Nisonger Center programs, 
Special Olympics Ohio, and the Down Syndrome Association of Central Ohio 
• Electronic announcements may be posted on the social media account and the research 
tab of the website for the Down Syndrome Association of Central Ohio 
• Records reviews will be conducted by study personnel to identify potential participants 
from the college of optometry clinics at the respective sites.  Potential participants that 
are identified through records reviews will be contacted either via email or phone by 
study personnel using recruitment scripts. 
 
Potential participants will be screened by study personnel at the first study visit for the 
following eligibility criteria: 
 
• Self (or guardian) reported diagnosis of Down syndrome 
• Age of 5 – 17 years (OSU) or minimum age of 18 years (UH) 
• Able to be dilated (no medical history contraindicating use of dilation drops, no ocular 
signs contraindicating use of dilation drops such as narrow anterior chamber angles or 
elevated IOP) 
• No nystagmus (inability to fixate steadily due to involuntarily eye movements) 
• No history of intraocular or refractive surgery 
• No corneal or lenticular opacities that would hinder wavefront measurements 
• No history of ocular disease 
• Behaviorally able to fixate for study measures 
• Behaviorally able to respond for visual acuity testing 
 
Measurement 
The refractions used as the treatment in this trial will be determined from mathematical 
analysis of wavefront measures as previously defined (Ravikumar, 2019).  The outcome 
measures listed below will be used to test the hypotheses. 
 
Dioptric Difference:  Each of the pre- and post-dilation refractions will be converted to vector 
notation (three dimensional coordinates) and the dioptric distance between vectors for each 
refraction calculated to quantify the difference between refractions (Raasch, 2001). 

 
Distance Visual Acuity:  Visual acuity will be measured for distance viewing with the British 
Standard Letter set or the four letter (HOTV) set depending upon the participant’s cognitive 
ability.  The acuity testing will be performed one eye at a time and then binocularly using a 
computerized letter presentation during which participants begin with large letters and work 
down to smaller letters until 5 total mistakes are made.  This acuity protocol has previously 
been utilized with patients with Down syndrome and demonstrated to have a repeatability of 
approximately 7 letters (Ravikumar, 2018; Anderson, 2021). 
 
Near Visual Acuity:  Visual acuity will be measured binocularly at 40cm using a plastic card with 
a four letter set (HOTV).  Participants will name or match letters at the largest print size and 
work down until 50% or more letters of a particular size are identified incorrectly.  This test has 
previously been utilized with patients with Down syndrome and demonstrated to have a 
repeatability of 1 line (Anderson, 2021). 
 
Participant Survey:  Participants will be asked to rank vision at each distance and near viewing 
on a 5 point scale by pointing to a face depicting their feeling about their vision.  In addition, 
participants will be asked to select the refraction that they prefer.  Reliability data is not 
available for this instrument. 
 
Detailed Study Procedures 
This study will enroll 40 individuals with Down syndrome age 5 years and older for evaluation of 
refractions calculated from pre-dilation wavefront aberration measures versus refractions 
calculated from post-dilation wavefront aberration measures. Twenty children with Down 
syndrome will recruited at The Ohio State University site and 20 adults with Down syndrome 
will be recruited at University of Houston. This is a lab-based study and the treatment being 
studied, pre and post-dilated refractions, will not be dispensed to participants outside of the lab 
study visit. All participants will be tested with both treatments in random order in the lab-
setting. 
 
The initial study visit will be conducted by a clinical examiner who will: 1) ask medical and 
ocular history questions of the participant’s parent/guardian, 2) evaluate the participant’s 
eligibility for the study by measurement of vision, eye teaming skills, and ocular health, and 3) 
assess the participant’s safety for dilation.  Participants meeting eligibility criteria will have 
measurements of the focusing ability of the eye and measurements of the optical distortions of 
the eye (wavefront aberration) taken both prior to and after dilation with clinical dilation drops.   
 
The following is a list of the clinical tests/instruments and estimated test times for the initial 
study visits. 
 
• Questions regarding participant demographics, medical history, and ocular history (5 
minutes) 
• Participants identifying letters and shapes to assess  visual acuity at both distance and 
near viewing and depth perception (15 minutes) 

• Participants looking at letters, lights, or pictures while an examiner observes the 
movement of the eyes and the eye teaming skills, such as through covering an eye with 
a plastic paddle (3 minutes) 
• Assessing pupil responses with lights (1 minute) 
• Evaluating ocular health through use of a biomicroscope (3 minutes) 
• Evaluating ocular pressure through use of a non-contact tonometer (i.e. air puff test) or 
the EyeCare tonometer (micro probe that does not require ocular anesthetic) (5 
minutes) 
• Measurement of the refractive power of the eye and focusing ability with the Grand 
Seiko Autorefractor as participants view pictures or letters at both distance and near 
(non-invasive commercially available instrument that measures the eye using infrared 
light) (4 minutes) 
• Measurement of the wavefront aberrations of the eye with the COAS Wavefront 
aberrometer (non-invasive commercially available instrument that measures the eye 
using infrared light) (10 minutes) 
• Dilation of the eyes using 1% tropicamide and 2.5% phenylephrine (5 minutes) 
• Repeated measurements with the Grand Seiko autorefractor and COAS Wavefront 
aberrometer 30 minutes post dilation (14 minutes) 
 
The total time for visit 1 is anticipated to be 1.5 hours. 
 
Following the initial study visit, the investigator will use software designed to identify the 
optimum spectacle prescription of the eye (i.e. the prescription that is predicted to provide the 
best focus of light on the retina) for both the images obtained pre-dilation as well as the images 
obtained post-dilation. Next, participants will return for a second study visit to perform 
subjective testing with each refraction. Both the pre- and post-dilation refractions will be 
evaluated in random order through the use of a trial frame with loose lenses. Refractions will 
not be produced into standard spectacle frames. An un-masked investigator will build each trial 
frame and disguise the spectacle powers with tape over the lens handles. An investigator who is 
masked to the refraction in the trial frame will conduct visual acuity testing on the participant 
for distance and near viewing, followed by asking the participant to rate their vision on a five 
point scale. Testing will be repeated with the other refraction on the same day. Following acuity 
and subjective rating testing, participants will be asked to compare the two refractions and 
select the one they rate best. 
 
The following is a list of the clinical tests/instruments and estimated test times for the second 
study visit. 
 
• Participants identifying letters and shapes to assess  distance and near visual acuity and 
depth perception with each refraction (30 minutes) 
• Measurement of the refractive power of the eye and focusing ability with the Grand 
Seiko Autorefractor as participants view pictures or letters at both distance and near 

(non-invasive commercially available instrument that measures the eye using infrared 
light) (4 minutes) 
• Participants completing a survey rating each refraction (termed the ‘Smile Survey’ for 
this study – attached later in this submission) (5 minutes) 
• Participants making a direct comparison between the two refractions to select their 
preferred refraction (5 minutes) 
 
The total time for visit 2 is estimated to be 40 minutes. 
 
Study Risks 
The risks involved in participation in this study are no greater than that incurred during a 
routine eye examination with dilation.  Participants will be screened for safety to dilate and will 
not pass the eligibility criteria evaluation if they have indications of narrow anterior chamber 
angles or medical conditions and/or medication use that would contraindicate the use of 
dilation drops.  While IOP measures will be attempted as the gold standard of care prior to 
dilation, obtaining these measures on all participants may not be possible due to behavioral 
challenges related to intellectual disability.  Dilation without IOP measures is still common 
clinical practice for pediatric patient populations and/or those with intellectual disability.  Given 
these precautions, the likelihood of an adverse event from dilation is extremely low.  For 
participants who do experience an adverse event, care can be sought through the site clinics as 
disclosed in the parental permission document.  All other study procedures are non-invasive 
and only involve lights as the participant places his/her chin on a chinrest and looks straight 
ahead.  Some participants, particularly children, may find the tasks boring or challenging, but 
participants will be given breaks and time allotted during study visits to work at the pace of the 
participant. 
 
Data Collection and Participant Confidentiality 
Data collected for this study on commercial instruments (autorefractor, wavefront 
aberrometer) will be stored using unique study IDs for each participant that do not contain 
personally identifiable information.  For instruments requiring a birthdate, only the 
participant’s birth year will be input.  Printouts from instruments will be scanned and stored 
under the participant’s unique study ID on the PI’s secure network storage.  Medical history 
data and other clinical findings will be recorded directly into REDCap and stored using only the 
unique study ID and no personally identifying information.  The link between the identifier and 
the participant’s personal information will be maintained with the signed consent documents in 
a locked lab accessible only to the study team at each site.  This personal information will be 
stored for no more than 3 years after completion of data collection and analysis for the study. 
 
 
Internal Validity 
The order of refraction testing will be randomized at study visit 2.  Study personnel who are not 
participating in the testing will prepare the trial frames in advance and tape over the handles to 
mask the powers of the lenses to both the patient and the investigator conducting the testing.  
Both the investigator administering the acuity testing and survey, as well as the study 

participant, will be masked to the refraction being tested.  Testing distance for acuity will be 
measured and monitored throughout testing. 
 
Data Analysis 
We will report descriptive statistics for all demographic and clinical measures. All analyses will 
be completed using SAS version 9.4 (Cary, NC). 
 
Research hypothesis 1: Dioptric difference pre- and post-dilation 
A one-sample t-test will be used to compare the dioptric difference in refractions obtained pre- 
and post-dilation to 0.62 (clinically relevant). Additionally, the impact of various demographic 
and clinical measures on the observed dioptric difference will be assessed using regression 
analyses. Potential covariates include participant age, refractive error magnitude and type (e.g. 
myopia vs. hyperopia), accommodation (Grand Seiko autorefractor measures), and higher order 
RMS. If necessary based on distribution of dioptric difference values, non-parametric regression 
analysis methodology will be utilized. 
 
Research hypothesis 2: Binocular visual acuity at distance 
Comparison of visual acuity in each metric-optimized refraction type (pre- or post-dilation) will 
be completed using a dependent t-test. As with dioptric difference, regression analyses will be 
used to test the association of difference in visual acuity and the demographic and clinical 
measures investigated in earlier modeling. 
 
Research hypothesis 3: Subjective satisfaction with refraction 
Subjective satisfaction outcome (pictorial scale ranging from very unhappy to very happy) will 
be dichotomized for statistical analysis. An initial comparison of these responses after wear of 
each refraction will be done using a McNemar’s test. Generalized estimating equations (GEE) 
will be used to identify any demographic or clinical measures that might impact the agreement 
of the subjective quality outcome. 
 
Research hypothesis 4: Binocular visual acuity at near 
Comparison of visual acuity in each metric-optimized refraction type (pre- or post-dilation) will 
be completed using a dependent t-test. As with dioptric difference, regression analyses will be 
used to test the association of difference in visual acuity and the demographic and clinical 
measures investigated in earlier modeling. 
 
 
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