Sensitivity and Specificity of the Red Reflex Test for Detecting Anterior and Posterior Segment Ophthalmic Pathology in the Pediatric Population
Conditions: Abnormal Vitreous Humor Morphology, Abnormal Choroid Morphology, Optic Nerve Diseases, Retinal Disease, Retinal Hemorrhage
Sponsor: Children's National Research Institute

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Children’s Research Institute 
Behavioral/Procedural Intervention 
Study Protocol Template  
(for behavioral and non-drug interventions that do 
not fall under FDA regulations—support groups, 
questionnaires, blood draws, MRIs, etc.) 
 
Version 2.0, 21OCT2019 
 
  
 
 

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Sensitivity and Specificity of the Red Reflex Test for 
Detecting Anterior and Posterior Segment 
Ophthalmic Pathology in the Pediatric Population 
 
 
 
 
 
CN IRB Protocol Number: Pro00011173 
Principal Investigator: William Madigan, MD 
No Funding Sponsor 
 
 
 
 
 
 
Protocol Version Number: 1.0 
 10/21/2019 
 
 
 
 

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Table of Contents 
PROTOCOL REVISION HISTORY 
 
 
 
 
 
 
05 
 
LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
06 
 
PROTOCOL SUMMARY  
 
 
 
 
 
 
 
08 
 
Section 1 
KEY ROLES  
 
 
 
 
 
 
 
10 
 
Section 2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC  
 
 
RATIONALE 
 
 
2.1 
Background Information and Relevant Literature 
 
10 
 
 
2.2 
Scientific Rationale  
 
 
 
 
 
13 
 
 
2.3 
Potential Risks 
 
 
 
 
 
 
14 
 
 
2.4 
Potential Benefits 
 
 
 
 
 
 
14 
 
Section 3 
OBJECTIVES AND ENDPOINTS 
 
 
3.1 
Primary Objective(s) 
 
 
 
 
 
14 
 
 
3.2 
Secondary Objective(s) 
 
 
 
 
 
15 
 
 
3.3 
Primary Outcome Measure(s) 
 
 
 
 
15 
 
 
3.4 
Secondary Outcome Measure(s)  
 
 
 
15 
 
Section 4 
STUDY DESIGN 
 
 
 
 
 
 
 
15 
 
Section 5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
 
5.1 
Study Population, Recruitment Retention 
 
 
15 
 
 
5.2 
Inclusion Criteria 
 
 
 
 
 
 
15 
 
 
5.3 
Exclusion Criteria 
 
 
 
 
 
 
16 
 
 
5.4 
Vulnerable Subjects 
 
 
 
 
 
16 
 
 
5.5 
Recruitment  
 
 
 
 
 
 
16 
 
 
5.6 
Retention 
 
 
 
 
 
 
 
16 
 
 
5.7 
End of Participation Criteria and Procedures 
 
 
16 
 
Section 6 
STUDY PROCEDURES 
 
 
6.1 
Informed Consent/Assent and HIPAA Authorization 
 
17 
 
 
6.2 
Screening Process  
 
 
 
 
 
18 
 
 
6.3 
Study Interventions and Follow-Up 
 
 
 
18 
 
 
6.4 
Description of Study Procedures/Evaluations 
 
 
18 
 
 
6.5 
Study Team Training and Intervention Reliability 
 
19 
 
 
6.6 
Concomitant Interventions and Procedures 
 
 
19 
 
Section 7 
SAFETY ASSESSMENTS AND REPORTING 
 
 
7.1 
Adverse Events (AEs) 
 
 
 
 
 
19 
 
 
7.2  
Serious Adverse Events (SAEs)  
 
 
 
19 
 
 
7.3 
Unanticipated Problems (UPs) 
 
 
 
 
19 
 

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Section 8 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
 
8.1 
Statistical and Analytical Plans (SAPs)  
 
 
20 
 
 
8.2 
Statistical Hypotheses 
 
 
 
 
 
20 
 
 
8.3 
Analysis Datasets  
 
 
 
 
 
20 
 
 
8.4 
Description of Statistical Methods  
 
 
 
21 
 
 
8.5 
Sample Size  
 
 
 
 
 
 
21 
 
 
8.6 
Measures of Minimize Bias 
 
 
 
 
21 
 
Section 9 
DATA QUALITY AND OVERSIGHT 
 
 
9.1 
Study Team Quality Assurance and Quality Control 
 
22 
 
 
9.2 
Data Safety and Monitoring Plan  
 
 
 
22 
 
Section 10 
ETHICAL CONSIDERATIONS 
10.1  Ethical Standard 
 
 
 
 
 
 
22 
10.2 Institutional Review Board (IRB)  
 
 
 
22 
10.3 Maintaining Subject Privacy 
 
 
 
 
22 
10.4 Maintaining Study Data Confidentiality 
 
 
 
23 
10.5 Study Support and Conflicts of Interest  
 
 
23 
 
Section 11 
DATA HANDLING AND RECORD KEEPING 
 
 
11.1 Data Management Responsibilities 
 
 
 
23 
 
 
11.2 Data Capture Methods 
 
 
 
 
 
24 
 
 
11.3 Study Record Retention Policy 
 
 
 
 
24 
 
Section 12 
PUBLICATION POLICY 
 
 
 
 
 
 
25 
 
Section 13 
REFERENCES 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 

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Protocol Revision History 
 
Protocol Version with Summary of Changes  
 
 
    Version Date 
 
 
 
 
 
 
 
 
  
       
. 
 
 
 
 
 

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List of Abbreviations 
 
AACO 
American Association of Certified Orthoptists 
AE 
Adverse Event 
AAFP 
American Academy of Family Physicians 
AAO 
American Academy of Ophthalmology 
AAP 
American Academy of Pediatrics 
AAPOS 
American Association for Pediatric Ophthalmology and Strabismus 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
COC 
Certificate of Confidentiality 
CLIA 
CRI 
Clinical Laboratory Improvement Amendments 
Clinical Research Institute 
DCC 
DHHS 
Data Coordinating Center 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
eCRF 
FWA 
Electronic Case Report Form 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 

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MOP 
Manual of Procedures 
OHRP 
Office for Human Research Protections 
PD 
Protocol Deviation 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RE 
Reportable Event 
RPM 
Rotation/Revolutions per Minute 
RR 
Red Reflex 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SRC 
Scientific Review Committee 
UP 
Unanticipated Problem 
USPSTF 
US Preventative Services Task Force 
 
 

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Protocol Summary 
 
Title:  
 
Sensitivity and Specificity of the Red Reflex Test for 
Detecting Anterior and Posterior Segment Ophthalmic 
Pathology in the Pediatric Population 
Brief Summary: 
Early detection of ocular abnormalities is critical for the 
prevention of visual loss.  The American Association 
for Pediatric Ophthalmology and Strabismus (AAPOS), 
the American Academy of Ophthalmology (AAO), and 
the American Association of Certified Orthoptists 
(AACO) continue to support inclusion of the RRT as 
part of the ophthalmology screening exam in the 
general pediatrics clinic. While there is scientific 
evidence demonstrating that the RRT is a fairly reliable 
examination technique for identifying anterior segment 
pathology, studies to date have highlighted significant 
limitations of the RRT in accurately detecting posterior 
segment pathology. Delayed diagnosis of such 
conditions can lead to significant permanent visual 
impairment, and in rare cases, systemic morbidity for 
the child.  
 
Aims/Objectives:  The primary aim of this study is to 
determine the sensitivity and specificity of the RRT 
performed in a pediatric ophthalmology clinic, 
according to standardized practice guidelines, for 
detecting both anterior and posterior segment 
pathology in the pediatric population. The secondary 
aim of this study is to evaluate the impact of 
pharmacologic dilation on the sensitivity and specificity 
of the RRT in detecting anterior and posterior segment 
pathology in the pediatric population. We hypothesize 
that the sensitivity and specificity of the RRT will be 
sufficient for detecting anterior segment pathology but 
will be insufficient for detecting posterior segment 
ophthalmologic pathology with or without 
pharmacologic dilation.  
 
Study Population:  
The study population will include pediatric patients 
under 17 years old recruited in clinical practice with 
known anterior or posterior segment pathology as well 
as patients without anterior or posterior segment 
pathology. In order to determine sensitivity and 

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specificity of anterior and posterior segment pathology 
separately, we will split the patients with pathology into 
two groups, anterior and posterior.   
 
Ophthalmology residents who are blinded to the 
patient's ophthalmologic diagnosis (or lack thereof) will 
perform the standardized RRT, which includes both a 
lights on and lights off examination 
Study Site(s):  
 
Number of Participants: 
Children’s National Health System and Fairfax  
 
100-200 
 
Accrual Ceiling: 
 
Study Duration: 
200.  We estimate that all consented subjects will be 
able to participate in this routine vision exam. 
This study is expected to be completed within one 
year. 
 
Subject Duration:  
The subject duration is expected to be one outpatient 
clinic visit. 
Objective(s):  
 
 
 
 
 
 
 
 
Methodology: 
 
The primary aim of this study is to determine the 
sensitivity and specificity of the RRT performed in a 
pediatric ophthalmology clinic, according to 
standardized practice guidelines, for detecting both 
anterior and posterior segment pathology in the 
pediatric population. The secondary aim of this study 
is to evaluate the impact of pharmacologic dilation on 
the sensitivity and specificity of the RRT in detecting 
anterior and posterior segment pathology in the 
pediatric population. We hypothesize that the 
sensitivity and specificity of the RRT will be sufficient 
for detecting anterior segment pathology but will be 
insufficient for detecting posterior segment 
ophthalmologic pathology with or without 
pharmacologic dilation.  
 
Prospective study 
Outcome Measures: 
Sensitivity and specificity of the RR test to detect 

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anterior and posterior ocular abnormalities with and 
without pharmacologic pupillary dilation. 
Study 
Intervention/Procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis: 
 
Ophthalmology residents who are blinded to the 
patient's ophthalmologic diagnosis (or lack thereof) will 
perform the standardized RRT, which includes both a 
lights on and lights off examination. Patients will then 
be pharmacologically dilated and the RRT repeated. 
Results will be recorded for each. Pharmacological 
dilation will be achieved according to standard 
practices. For all patients, one drop of proparacaine 
hydrochloride ophthalmic solution will be instilled in 
each eye to achieve anesthesia. For patients under 1 
year old, one drop of Cyclomydril will then be instilled 
in each eye and followed second drop in each eye 5 
minutes later. For children over 1 year of age, 
pharmacologic dilation will be achieved with 1 drop of 
Cyclopentolate 1% and 1 drop of Phenylephrine 2.5% 
in each eye. Photography may be performed to 
document the presence or absence of anterior and/or 
posterior segment pathology.  
 
The baseline demographic data will be presented 
descriptively. Continuous data will be summarized as 
mean with standard deviation or median with 
interquartile range depending on the distribution of the 
data. Categorical data will be summarized using 
frequencies with percentage. Summary demographic 
statistics between patients with and without eye 
abnormalities will be compared using unpaired t-test 
(normal) and/or Mann-Whitney U test (skewed) for 
continuous data, and Chi-square test and/or Fisher’s 
exact test (if any of the expected cell frequencies are 
<5) for categorical data. Normality assumption will be 
cheeked by using statistical test (e.g., Shapiro Wilk 
test) as well as graphical methods (e.g., histogram, q-q 
plot). 
 
To assess our primary and secondary hypothesis, 
sensitivity and specificity of the red reflex test (RRT) 
will be determined along with their 95% confidence 
interval using contingency tables for both anterior and 
posterior segment pathology. Positive predictive value 
(PPV), negative predictive value (NPV), and area 
under ROC curve (AUC) will also be determined. We 

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will also compare sensitivity and specificity of RRT for 
both anterior and posterior pathology between with 
and without pharmacologic dilation using two-sided 
McNemar’s test for correlated proportions.  
 
All statistical tests will be two-sided and will be 
performed at the 5% level of significance unless 
otherwise stated. Stata 15.1 software will be used for 
all statistical analyses.  
 
Our sample size calculation is based on our primary 
hypothesis. Assuming a 75% prevalence of anterior or 
posterior segment pathology and a sensitivity of 90% 
in our sample, a total of 59 patients will be required to 
construct a two-sided 95% sensitivity confidence 
interval with a width of at most +/-10%. Under the 
same assumptions, the sample size needed for a two-
sided 95% specificity confidence interval of +/-10% 
around 80% is 280. We will take the larger one of 
these two, which is 280. The power analysis was 
carried out using PASS 2019 software. 
 
Section 1: Key Roles 
 
Principal Investigator 
William Madigan, MD, Vice-Chair, 
Ophthalmology 
Children’s National Health 
System 
111 Michigan Ave NW, 
Washington, DC 20010 
202-476-3015 
WMadigan@childrensnational.org 
 
Performance 
Performance Site PI 
Describe Activities Conducted at 

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Site(s) Name(S) 
(First and Last 
Name) 
Performance Site by PI and 
Research Team 
Children’s 
National Health 
System Fairfax 
William Madigan, 
MD 
1. RR exam using direct 
ophthalmoscope under 
physiologic and 
pharmacologically dilated 
conditions 
2. Automated vision screening 
using the Spot 
photoscreener under 
physiologic and dilated 
conditions. 
Children’s 
National Medical 
Center, Sheik 
Zayed campus 
William Madigan, 
MD 
Same 
 
 
 
 
 
 
 
 
Section 2: Introduction, Background Information and Scientific 
Rationale 
 
2.1 
Background Information and Relevant Literature 
 
The early detection of ophthalmic pathology is critical for the prevention of vision loss 
and systemic morbidity in rare cases.  The American Academy of Pediatrics (AAP), the 
American Association for Pediatric Ophthalmology and Strabismus (AAPOS), the 
American Academy of Ophthalmology (AAO), and the American Association of Certified 
Orthoptists (AACO) continue to advocate for inclusion of the red reflex test (RRT) as 
part of the ophthalmologic screening exam in the general pediatrics clinic. However, 
studies to date have demonstrated that there are potential limitations to the RRT, 
especially in its ability to accurately and reliably detect posterior segment pathology. 
 
Standard procedure for the RRT currently involves viewing both eyes at arms length in 
lighted room followed by a darkened room to assess for symmetry of the reflection in 
terms of brightness and color.  If an abnormality is suspected, then the operator may 
move closer for further inspection. With its current application, the RRT introduces 
subjectivity in interpretation and likely variation in pupillary reflection based on factors 
such as, the specific lighting condition, degree of physiologic dilation, and patient 
movement. Differences in operator experience with the RRT may further compound the 
shortcomings of this exam technique. These factors unfortunately reduce the accuracy 
and reliability of the RRT as a screening measure.  

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There is ample evidence in the literature validating the RRT as a useful screening tool 
for pediatric anterior segment ocular pathology, with consistently high sensitivity and 
specificity. However, studies describing its utility in detecting posterior segment disease 
are lacking. Two recent studies have attempted to address this issue.  Sun and 
colleagues used the RRT to screen over 7000 newborns followed by retinal imaging 
using a Retcam-3 with pharmacologic pupillary dilation.  They found that for anterior 
segment disease, the RRT had a sensitivity of 99.6% (95% CI 97.1%-100%) compared 
to only 4.1% (95% CI 3.3%-5.1%, χ 2 = 1521.382, φ = 0.836, P < .001) for posterior 
segment pathology. In a similar study, Ludwig and colleagues detected posterior 
segment pathology in 49 of 194 eyes examined using the Retcam-3 with pharmacologic 
dilation (sensitivity = 100%); however, no abnormalities were detected in this same set 
of eyes with the RRT performed by a pediatrician in the newborn nursery (sensitivity = 
0%).  
 
Based on these results, there is insufficient evidence that the RRT is an effective 
screening exam for detecting posterior segment pathology - even with physiologic 
dilation during the lights off portion of the RRT. It has been established that pupillary 
size and viewing angle certainly do impact the quality of a posterior segment exam. In a 
study by Li and colleagues, the rate of tumor detection in a model eye was optimized 
when viewing at an oblique angle through a maximally dilated pupil of 8 mm. Even 
under the darkest lighting conditions, physiologic mydriasis will be limited, and 
especially with introduction of the direct ophthalmoscope light for the RRT.  The 
average infant scotopic pupil size is 3.8 mm ± 0.9 mm in diameter. When light is shone 
from ophthalmoscope, pupils usually constrict by 2 mm. Pharmacologic dilation, 
however, is not currently included as part of the practice pattern guidelines outlining the 
RRT due to its perceived associated potential risks and side effects. 
 
Based on the above, additional investigation is needed to further clarify whether the 
sensitivity and specificity of the RRT for detecting posterior segment pathology are 
sufficient for its use as a screening tool, or if alternatively, this current standard practice 
simply offers a false sense of security. Evaluating the impact of pharmacologic dilation 
on the sensitivity and specificity of the RRT may help identify a potential avenue for 
improving the validity of the RRT as an ophthalmology screening tool. 
 
2.2 Scientific Rationale 
Question: Is the RRT a sensitive or specific screening tool for detecting anterior or 
posterior segment pathology under physiologic conditions or following pupillary dilation 
in the pediatric population? 
 
Hypothesis: The RRT is not a sensitive or specific screening tool for detecting anterior 
or posterior segment pathology in the pediatric population even following pharmacologic 
pupillary dilation. 
 
Visual acuity and disease are difficult to assess in the pediatric population and 
especially younger children due to normal developmental changes as well as 

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challenges in patient cooperation or symptom reporting. However, assessing 
visual and anatomic abnormalities in this age group remains of paramount importance 
to avoid visual morbidity, and rarely systemic complications, from undetected 
ophthalmic pathology.  The RRT is currently recommended by the Joint Committee as 
an initial screening test for anterior and posterior segment ocular abnormalities in the 
pediatric population. The recommendations suggest that dim room lighting aids in the 
accuracy of the RRT. However, limited available evidence to date has demonstrated 
that the RRT is not a sensitive or specific test for detecting posterior segment pathology. 
Furthermore, there are no studies to date specifically examining the effect of dim 
lighting conditions or pupillary dilation on the sensitivity and specificity of the RRT. 
 
This study aims to evaluate the sensitivity and specificity of the RRT for detecting 
anterior or posterior segment pathology in both ambient and dark lighting conditions, 
before and after pharmacologic dilation.  
 
2.3 
Potential Risks 
 
There is minimal immediate or long-term risk in this study.  The interventions used are 
included in a standard ophthalmologic exam.  Patient’s may experience mild discomfort 
from the light of the equipment (direct ophthalmoscope) shone into their eyes.  
Additionally, patients have a risk in breach of confidentiality from usage of PHI data.  
However, all steps in accordance with CNHS policy will be performed in order to ensure 
patient confidentiality.  These minimal risks are worth the potential benefit of 
understanding how to perform ophthalmologic screening in the pediatric medical home. 
 
 
2.4 
Potential Benefits 
 
Study benefits to subjects include, but are not limited to, careful evaluation of known 
anterior or posterior segment ophthalmologic disease. 
 
Study benefits to the greater community include, but are not limited to, helping improve 
vision screening guidelines for the early detection and treatment of eye disease. 
 
 
Section 3: Objectives and Endpoints 
 
3.1 
Primary Objective(s) 
 
The primary outcomes of this study will be the sensitivity and specificity of the RRT in 
detecting anterior segment pathology, as well as the sensitivity and specificity of the 
RRT in detecting posterior segment pathology. 
 
3.2 
Secondary Objective(s) 

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The secondary outcomes of this study will be the sensitivity and specificity of the 
RRT in detecting anterior segment or posterior segmented pathology following 
pharmacologic dilation.  
 
 
3.3 
Primary Outcome Measure(s)  
Number of eyes with posterior segment pathology correctly identified as having 
posterior segment pathology and incorrectly identified as not having pathology. Number 
of healthy eyes correctly identified as being healthy. 
 
3.4 
Secondary Outcome Measure(s) 
Number of eyes with anterior segment pathology correctly identified as having anterior 
segment pathology and incorrectly identified as not having pathology. Number of 
healthy eyes correctly identified as being healthy. 
 
 
Section 4: Study Design 
 
Prospective study 
 
 
Section 5: Study Enrollment and Withdrawal 
 
5.1 Study Population, Recruitment and Retention 
 
Pediatric patients will be recruited through clinical practice at the designated study 
sites. Participants with known anterior segment or posterior segment pathology will 
be eligible for inclusion. Patients who have a history of disease, treatments and/or 
surgical procedures affecting the ability for normal pupillary reaction are excluded. 
An equal number of age matched participants with a normal anterior and posterior 
segment exam will be recruited from routine outpatient clinic visits. Informed consent 
will be obtained and will include an option to be considered for medical photography. 
Participants may opt out of photography and still be included in the study. For 
Spanish speaking participants, a telephone interpreter will be used for study 
recruitment and informed consent. A Spanish informed consent (developed by a 
Spanish medical translator from our English written consent) will be provided. 
Current estimated number of subjects required for the study is 200 total including 
100 controls.  Patient charts will be accessed from date of birth to patient's current 
age using either Cerner or Epic depending on the study site location. Examiners will 
include ophthalmology residents with one completed year of ophthalmology training. 
They will be blinded to participants' ophthalmologic history. 
 
5.2 
Inclusion Criteria 

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There is no difference in criteria for screening and enrollment. Patients 
with general eyelid pathology, ptosis, corneal pathology, astigmatism, cataract, 
vitreous pathology, vitreous detachment, vitreous hemorrhage, retinal pathology, 
retinopathy of prematurity, retinal detachment, retinal tear, retinal hemorrhage, 
retinoblastoma, other intraocular tumors overlying or outside of the central visual 
axis, retinal pigmented epithelial cell pathology, choroidal pathology, optic nerve 
pathology, retinal artery or vein pathology may be included.  
 
5.3 
Exclusion Criteria 
Patients who have a history of disease, treatments and/or surgical procedures 
affecting the ability for normal pupillary reaction are excluded. 
 
5.4  
Vulnerable Subjects 
  
Subjects 3 years old and under will be recruited because this study is evaluating 
a routine examination in this population.  This study has no more than minimal 
risk to the patient. 
 
5.5 
Recruitment 
  
Subjects will be recruited through clinical practice at Children’s National Health 
System and its Fairfax outpatient site. Subjects will be identified by the PI, Dr. 
William Madigan, Vice-Chair, Department of Ophthalmology, in a review of 
medical records after a HIPAA authorization waiver for recruitment is granted. 
Subjects will be approached at a clinical care visit or an IRB approved study 
information letter will be sent to the participant’s legally authorized representative 
(LAR). If the LAR expresses interest in the study, a copy of the IRB approved 
consent will be provided to the LAR.  The informed consent will be signed by the 
LAR and assent will be obtained from the patient at an in-person visit before any 
research procedures or interventions are done. 
 
The privacy of patients received for screening will be protected by password file 
encryption on Children’s National Health System computers/hardware and will be 
viewable only to the PI, treating physicians and study staff.  All study data that 
have been de-identified and requiring transport will be done in an encrypted flash 
memory drive.   
 
5.6  
Retention 
There are no procedures in place to ensure retention as this study will be 
completed in one outpatient clinic visit for each subject. 
 
5.7 
End of Participation Criteria and Procedures 
 
Participants are free to withdraw from participation in the study at any time upon 
request. An investigator may terminate subject study participation if: 
• 
Any adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study 
would not be in the best interest of the participant. 

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• 
The participant meets an exclusion criterion (either newly 
developed or not previously recognized) that precludes further study 
participation. 
 
This study may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause. Written notification, documenting the reason for 
study suspension or termination will be provided by the suspending or 
terminating party to participants, site investigators, the funding agency and 
regulatory authorities (e.g. OHRP). If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB and will provide the reason(s) for 
the termination or suspension. 
 
Circumstances that may warrant study termination or suspension include, but are 
not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to 
participants 
• 
Insufficient study team or site participant compliance to protocol 
requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
The study may resume once any concerns about safety, protocol compliance, 
data quality or funding are addressed and satisfy the sponsor, IRB and OHRP. 
 
Section 6: Study Procedures 
 
6.1 
Informed Consent/Assent and HIPAA Authorization  
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study.  It continues throughout the individual’s study 
participation. Consent and assent forms will be IRB-approved.  The 
participant/LAR will be asked to read and review the consent document(s). 
Extensive discussion of risks and possible benefits of participation will be 
provided to the participants and their families/LAR in a language they 
understand.  An IRB approved short form consent and a translator will be used 
when consenting participants who do not speak English.  Illiterate subjects will 
have the consent form read to them aloud.  Participant/parental consent will then 
be documented by having participants make their “mark” on the consent 
document in the presence of a non-study team member witness to avoid any 
possible coercion.  The investigator will explain the research study to the 
participant/LAR/parent and answer any questions that may arise. All 
participants/parents will receive a verbal lay explanation of the purposes, 
procedures, and potential risks of the study and of their rights as research 
participants. Participants/LARs/parents will have the opportunity to carefully 

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review the written consent form and to ask questions prior to signing.  
Consent of at least one parent/LAR will be documented on the consent form (or 
as determined by the IRB).  Assent for subjects aged 0 – 3 years old will be 
obtained and documented on the parental/LAR consent form.   
 
Participants/parents will be given the opportunity to discuss the study with their 
surrogates and other care providers prior to agreeing to participate. The 
participant/parent and/or LAR will sign the informed consent document(s) prior to 
any procedures being done specifically for the study. The participants/LAR may 
withdraw consent at any time throughout the course of the trial. A copy of the 
informed consent document(s) will be given to the participant/LAR/parent for their 
records. The rights and welfare of the participants will be protected by 
emphasizing that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
 
6.2 
Screening Process 
 
Screening Visit Day -30 to the day of the first in-person outpatient clinic visit 
• 
Informed consent discussion 
• 
Eligibility confirmation 
• 
Medical history (diagnoses and medications) 
• 
Demographics (date of birth) 
 
6.3 
Study Interventions and Follow-Up 
Patients will undergo a routine red reflex examination using a direct 
ophthalmoscope in a lighted and darkened exam room before and after 
pharmacologic dilation.   
 
The study will only take place over one outpatient clinic visit, and there will be no 
follow-up other than continued medical care. 
 
 
6.4 
Description of Study Procedures/Evaluations 
• 
Medical history—ocular history from prenatal care and on will be obtained 
through the medical record or in person. 
• 
Medication history—Current medications taken required. 
• 
Physical examinations—Subject’s red reflex and pupillary size will be 
examined using a direct ophthalmoscope in bright and dim room lighting 
conditions as well as before and after pharmacologic dilation. Automated 
vision screening using the Spot photoscreener will be performed before 
and after dilation. 
• 
The results of the red reflex exam will be discussed with the patient during 
the clinic visit.  
• 
Photographs of the subject’s red reflex may be taken and edited to ensure 
anonymity.  These photographs will allow for digital analysis of the 
patients red reflex.  These photographs will be kept on password 

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protected computers at Children’s National Health System and on 
password protected encrypted flash drives.  These photographs may be 
used for dissemination of study results such as in conference abstracts 
and medical journals.  Once the study is complete, original photographs 
may be destroyed. 
 
6.5 
Study Team Training and Intervention Reliability 
 
The study PI will be present and ensure the blinded examiner perform the red 
reflex test according to the current guideline recommendations. 
 
6.6  
Concomitant Interventions and Procedures 
There are no concomitant interventions or procedures in this study. Any 
additional studies as part of the patient’s care which may interfere with the red 
reflex test will be performed after the red reflex test. 
 
Section 7:  Safety Assessments and Reporting 
 
The intervention in this study is less than minimal risk. The highest level of patient 
safety will be ensured as part of routine clinical care. 
 
7.1  
Adverse Events (AEs) 
There are no AEs anticipated in this study. 
 
7.2  
Serious Adverse Events (SAEs) 
There are no SAEs anticipated in this study. 
 
7.3  
Unanticipated Problems (UPs)   
OHRP considers unanticipated problems involving risks to participants or others 
to include any incident, experience, or outcome that meets all of the following 
criteria: 
• 
Unexpected in terms of nature, severity, or frequency given the research 
procedures described in the study documents (e.g., consent, protocol) the 
participant population; AND 
• 
Related or possibly related to participation in the research.  “Possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research; AND 
• 
Suggests that the research places participants or others at a greater risk 
of harm (including physical, psychological, economic or social harm) than 
was previously known or recognized. 
 
At each study visit, the study team will ask the participant/LAR if any 
AE/SAE/UPs have occurred since the last study contact.  All adverse events will 
be captured on the adverse events CRF. Information collected includes event 
term, onset date, severity, relationship to study intervention (assessed and 
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resolution/stabilization. All events occurring while on study must be 
documented, regardless of relationship to the research intervention(s).  All events 
which meet the definition of a serious adverse event or unanticipated problem 
that occur during the study visit will be followed until resolved or stable. 
 
Any medical condition that is present before the first study intervention will be 
considered a baseline condition; it will not be reported as an AE.  
 
Serious Adverse Event and Unexpected Problem Reporting 
All suspected adverse reactions to study interventions (including comparators) 
that are both serious AND unexpected should be reported to the IRB.  The 
reporting time frames are as follows: 
• 
Report the death of a Children’s National subject enrolled in an 
interventional study if the death is unexpected (not due to disease 
progression) and related or possibly related to the research within one (1) 
business day of learning of the event.  A follow-up report must be 
submitted within two (2) business days.   
• 
Report all other unanticipated problems to the IRB within seven (7) days.   
 
If any needed information is missing or unknown at the time of initial reporting, 
the study team will actively try to obtain it.  The study team will maintain records 
of efforts to obtain additional follow-up information.  Any additional relevant 
information to a previously submitted report will be submitted to oversight bodies 
as soon as the information is available.   
 
All SAEs and UPs will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or stable. Other supporting 
documentation of the event may be requested by oversight bodies and should be 
provided as soon as possible. 
 
 
 
Section 8:  Statistical Considerations and Analysis  
 
8.1 
Statistical and Analytical Plans (SAP) 
Statistical analysis of the data will be formed at the conclusion of the study.  
Study examiners will be blinded until the results have been completed.  
 
8.2 
Statistical Hypotheses 
Our hypothesis is that the sensitivity and specificity of the RRT in detecting 
posterior ocular abnormalities in children will be poor in lighted or dim room 
lighting conditions or following pharmacologic dilation. 
 
The null hypothesis is that the sensitivity and specificity of the RRT for detecting 
posterior ocular abnormalities in children will improve significantly under dim 
room lighting conditions and/or following pharmacologic dilation. 
 

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8.3 
Analysis Datasets 
The baseline demographic data will be presented descriptively. Continuous data will be 
summarized as mean with standard deviation or median with interquartile range 
depending on the distribution of the data. Categorical data will be summarized using 
frequencies with percentage. Summary demographic statistics between patients with 
and without eye abnormalities will be compared using unpaired t-test (normal) and/or 
Mann-Whitney U test (skewed) for continuous data, and Chi-square test and/or Fisher’s 
exact test (if any of the expected cell frequencies are <5) for categorical data. Normality 
assumption will be cheeked by using statistical test (e.g., Shapiro Wilk test) as well as 
graphical methods (e.g., histogram, q-q plot). 
 
8.4 
Description of Statistical Methods 
To assess our primary and secondary hypothesis, sensitivity and specificity of the red 
reflex test (RRT) will be determined along with their 95% confidence interval using 
contingency tables for both anterior and posterior segment pathology. Positive 
predictive value (PPV), negative predictive value (NPV), and area under ROC curve 
(AUC) will also be determined. We will also compare sensitivity and specificity of RRT 
for both anterior and posterior pathology between with and without pharmacologic 
dilation using two-sided McNemar’s test for correlated proportions.  
 
All statistical tests will be two-sided and will be performed at the 5% level of significance 
unless otherwise stated. Stata 15.1 software will be used for all statistical analyses.  
 
 
8.5 
Sample Size 
Our sample size calculation is based on our primary hypothesis. Assuming a 
75% prevalence a of anterior or posterior segment pathology and a sensitivity of 
90% in our sample, a total of 59 patients will be required to construct a two-sided 
95% sensitivity confidence interval with a width of at most +/-10%. Under the 
same assumptions, the sample size needed for a two-sided 95% specificity 
confidence interval of +/-10% around 80% is 280. We will take the larger one of 
these two, which is 280. The power analysis was carried out using PASS 2019 
software. 
 
8.6 
Measures to Minimize Bias 
Blinding 
Examiners performing the red reflex test will be blinded to all subjects and results 
until all study data have been collected. 
 
Breaking the Study Blind 
Breaking the study blind for red reflex performers will be at the conclusion of the 
study data collection period. Intentional and unintentional breaking of the blind 
should be reported to the PI.  
Section 9: Data Quality and Oversight 
 

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9.1 
Study Team Quality Assurance and Quality Control 
 
Study data will be historical in nature, and therefore will be accurate to the 
patient’s current diagnosis.  All further evaluation will be reported by the red 
reflex examiner and this original data will be used in the analysis.  Protocol 
deviations will be reported immediately or witnessed in person by the PI/co-
investigator/study coordinator. Documents to be reviewed include clinic notes. 
The PI/co-investigator/study coordinator are responsible for reviewing the data 
each time the red reflex test is performed. The PI/co-investigator/study 
coordinator is responsible for addressing data quality issues.  
 
9.2 
Data Safety and Monitoring Plan 
N/A 
Section 10: Ethical Considerations 
 
10.1  Ethical Standard 
 
The study team will ensure that this study is conducted in full conformity with the 
Regulations for the Protection of Human Subjects of Research codified in 45 Part 
46 of the Code of Federal Regulations, Children’s National Policies and 
Procedures and Good Clinical Practices.    
 
10.2 Institutional Review Board (IRB) 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Children’s National IRB for review and 
approval. Approval of both the protocol and the consent form will be obtained 
before any participant is consented. Any change to the protocol, consent, 
recruitment materials and participant information sheets or letters will require IRB 
approval before implementation and use.  The IRB will determine whether 
previously consented participants need to be re-consented and whether consent 
of more than one parent is required for minors.   
 
The IRB will be notified of study team updates via an amendment.  DSMB 
Reports will be submitted at the time of the continuing review or with another 
applicable IRB transaction.   
 
Other study events (e.g., protocol deviations, data monitoring reports) will be 
submitted per the Children’s National IRB Reportable Events Module. 
 
10.3 Maintaining Subject Privacy 
All patients will be taken to a private area for consenting and results discussions. 
No appointment reminders left on answering machines. All evaluations will be 
conducted in a private clinical room. 
 
10.4 Maintaining Study Data Confidentiality 

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Participant confidentiality is strictly held in trust by the participating 
investigators, their staff, the sponsor and their agents. This confidentiality is 
extended to cover the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the 
sponsor. 
  
The sponsor representatives and regulatory authorities (e.g., IRB, OHRP) may 
inspect all documents and records required to be maintained by the investigator.    
The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each study 
site for internal use during the study. At the end of the study, all research records 
will be stored in a secure location for the time period stated by the institutional 
regulations. 
 
The research data will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study 
management systems used by research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at 
Children’s National. 
 
Certificate of Confidentiality 
To further protect study participants, a Certificate of Confidentiality has been 
obtained from the NIH. This certificate protects identifiable research information 
from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research 
participation in any civil, criminal, administrative, legislative, or other proceeding; 
whether at the federal, state, or local level. The certificate protects researchers 
and institutions from being compelled to disclose information that would identify 
research participants,  
 
 
10.5 Study Support and Conflicts of Interest 
There is no external funding, support or conflicts of interest regarding this study. 
Section 11: Data Handling and Record Keeping 
 
11.1 Data Management Responsibilities 
All data will be handled by the study staff.  The study team will enter the data 
from source sheets electronically into Microsoft Excel.  The analysis and 
interpretation of study data will be performed electronically.  Storage and 
maintenance of data will be on password protected computers at Children’s 

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National Health System or on flash drives with password protection and 
encryption. Data collected will accurate, consistent, complete, and reliable and in 
accordance with good clinical practices. 
 
11.2 Data Capture Methods 
Data collection is the responsibility of the trial staff.  The PI is responsible for 
ensuring the accuracy, completeness, legibility, timeliness and completeness of 
the data reported. 
 
Sites will maintain all relevant source data. Source data include all information 
and original records of clinical findings, observations, or other activities 
necessary for the reconstruction and evaluation of the trial. Examples of original 
source documentation include electronic medical records, laboratory reports, 
memoranda, subject diaries, subject questionnaires and recorded data from 
automated instruments. 
 
Source documents should be neat and legible. When making changes or 
corrections, the original entry should be crossed out with a single line, initialed 
and dated. 
  
Paper copies of the electronic CRF (eCRF) will be provided for use as source 
documents.  Study data will be recorded for each participant enrolled in the 
study. Data reported in the eCRF derived from source documents should be 
consistent with the source documents.  Any discrepancies between the eCRF 
and source documentation should be explained via a CRF comment or a note to 
file. 
 
Research data will be entered into Microsoft Excel.  Data will be password 
protected, secure and de-identified and Health Insurance Portability and 
Accountability Act (HIPAA) compliant. 
 
Only Institutional Review Board (IRB) approved research team members who 
have current HIPAA and Collaborative Institutional Training Initiative (CITI) Good 
Clinical Practice (GCP) and human subjects protection training will be authorized 
to extract data from source documents and enter it into the protect Excel 
document. 
 
Data should be entered directly from the source documents in to Excel within 10 
days of collection. 
 
11.3 Study Record Retention Policy 
Study data will be maintained for up to 2 years after the study period. After, all 
clinical data will be archived on Children’s National Health System computers 
and the study data will be permanently destroyed. Physical data will be shredded 
and electronic data will be permanently deleted.  
 

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Section 12: Publication Policy 
 
Publication rights and authorship will consist of the study staff and examiners that fulfill 
the criterion for authorship as described by the publisher.  
 
Section 13: References 
 
1. 
AAP. Red Reflex Examination in Neonates, Infants, and Children. Pediatrics. 
Dec 2008; 122:6. 
2. 
Swati S. Deshmukh M.E., A.D. Gawande, A.B.Deshmukh. Detection and 
Correction of Red Eye in Digital Photograph. IJARCET. Jun 2013; 2:6. 
3. 
Kolb H. Facts and Figures Concerning the Human Retina. 2005 May 1 
[Updated 2007 Jul 5]. In: Kolb H, Fernandez E, Nelson R, editors. 
Webvision: The Organization of the Retina and Visual System [Internet]. 
Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. 
Available from: https://www.ncbi.nlm.nih.gov/books/NBK11556/ 
4. 
Van Buren JM. The retinal ganglion cell layer. Springfield (IL): Charles C. 
Thomas; 1963. 
5. 
Digvijay Singh, Rohit Saxena, Pradeep Sharma, Vimla Menon. Understanding 
your Direct Ophthalmoscope. Delhi Journal of Ophthalmology. 2013 Sep 25. 
http://www.djo.org.in/articles/21/3/understanding-your-direct-
ophthalmoscope.html 
6. 
Harry A. Quigley, MD; Andrew E. Brown; John D. Morrison, MD. The Size and 
Shape of the Optic Disc in Normal Human Eyes. Arch Ophthalmol. 
1990;108(1):51-57. doi:10.1001/archopht.1990.01070030057028. 
7. 
AAP, AAPOS, AACO, and AAO Hoskins Center for Quality Eye Care. 
Procedures for the Evaluation of the Visual System by Pediatricians: Clinical 
Report – 2016. https://www.aao.org/clinical-statement/procedures-
evaluation-of-visual-system-by-pediatri. 
8. 
John D. Roarty, MD; John L. Keltner, MD. Normal Pupil Size and Anisocoria in 
Newborn Infants. Arch Ophthalmol. 1990;108(1):94-95. 
doi:10.1001/archopht.1990.01070030100037. 
9. 
Larry D.RoeM.D.David L.GuytonM.D. The red reflex from retinoscopy's point of 
view. Reflections on a small area. Survey of Ophthalmology. Volume 28, 
Issue 4, January–February 1984, Pages 345-348. 
10. George T. Timberlake, Ph.D., Michael Kennedy, M.D. The Direct 
Ophthalmoscope How it Works and How to Use It. 
http://web.media.mit.edu/~raskar/Eye/TheDirectOphthalmoscope.pdf.  

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11. Lim LS, Chong GH, Tan PT, et al. Distribution and Determinants of Eye 
Size and Shape in Newborn Children: A Magnetic Resonance Imaging 
Analysis. Investigative Ophthalmology & Visual Science July 2013, Vol.54, 
4791-4797. doi:10.1167/iovs.12-10713.  
12. Trattler WB, Kaiser PK, Friedman NJ. Review of Ophthalmology: Expert 
Consult. Saunders; 2 edition (March 6, 2012) 
13. Sun M, Ma A, Li F, et al. Sensitivity and Specificity of Red Reflex Test in 
Newborn Eye Screening. J Pediatr. 2016 Dec;179:192-196.e4. 
14. COMMITTEE ON PRACTICE AND AMBULATORY MEDICINE, SECTION ON 
OPHTHALMOLOGY, AMERICAN ASSOCIATION OF CERTIFIED 
ORTHOPTISTS, AMERICAN ASSOCIATION FOR PEDIATRIC 
OPHTHALMOLOGY AND STRABISMUS, AMERICAN ACADEMY OF 
OPHTHALMOLOGY. Visual System Assessment in Infants, Children, and 
Young Adults by Pediatricians. Pediatrics 2016;137. 
15. Sean P. Donahue, MD, PhD, FAAP, Cynthia N Baker, MD, FAAP, 
COMMITTEE ON PRACTICE AND AMBULATORY MEDICINE, SECTION 
ON OPHTHALMOLOGY, AMERICAN ASSOCIATION OF CERTIFIED 
ORTHOPTISTS, AMERICAN ASSOCIATION FOR PEDIATRIC 
OPHTHALMOLOGY AND STRABISMUS, AMERICAN ACADEMY OF 
OPHTHALMOLOGY. Procedures for the Evaluation of the Visual System by 
Pediatricians. Pediatrics 2016;137. 
16. Jennifer Li, MD, David K. Coats, MD, Derrick Fung, MD, E. O’Brian Smith, PhD, 
and Evelyn Paysse, MD. The Detection of Simulated Retinoblastoma by 
Using Red-Reflex Testing. Pediatrics 2010;126:e202–e207. 
17. Mirhadi Mussavi, MD; Khairollah Asadollahi, MD, PhD; Farhad Janbaz, MD; 
Esmaiil Mansoori, MD; Nasser Abbasi, PharmD. The Evaluation of Red 
Reflex Sensitivity and Specificity Test among Neonates in Different 
Conditions. Iran J Pediatr Dec 2014; Vol 24 (No 6), Pp: 697-702.  
18. Christopher B. Estopinal, BS, Sean P. Donahue, MD, PhD, and Gary N. 
Gitschlag, MD. Retinoblastoma in a Child After Normal Autorefraction and 
Traditional Vision Screening. Pediatrics 2011;128:e1285–e1288. 
19. David H. Abramson, MD; Carol L. Shields, MD; Francis L. Munier, MD; 
Guillermo L. Chantada, MD, PhD. Treatment of Retinoblastoma in 2015 
Agreement and Disagreement. JAMA Ophthalmol. 2015;133(11):1341-
1347.  
20. Daniel E. Jonas, MD, MPH; Halle R. Amick, MSPH; Ina F.Wallace, PhD; 
Cynthia Feltner,MD, MPH; 
1. Emily B. Vander Schaaf,MD, MPH; Callie L. Brown, MD, MPH; Claire Baker. 
Vision Screening in Children Aged 6Months to 5 Years Evidence Report and 

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Systematic Review for the US Preventive Services Task Force. JAMA. 
2017;318(9):845-858. 
21. US Preventive Services Task Force. Vision Screening in Children Aged 
6Months to 5 Years US Preventive Services Task Force Recommendation 
Statement. JAMA. 2017;318(9):836-844. 
22. US Preventive Services Task Force. Vision Screening for Children 1 to 5 Years 
of Age: US Preventive Services Task Force Recommendation Statement. 
Pediatrics 2011;127:340–346. 
23. Cassie A. Ludwig, MD, MS; Natalia F. Callaway, MD, MS; Mark S. 
Blumenkranz, MD; Douglas R. Fredrick, MD; Darius M. Moshfeghi, MD. 
Validity of the Red Reflex Exam in the Newborn Eye Screening Test Cohort. 
Ophthalmic Surg Lasers Imaging Retina. 2018;49:103-110.