Randomized Controlled Trial to Assess EHR Prediction Model to Identify Pediatric Patients With Undiagnosed Genetic Disease"
Phase: NA
Conditions: Genetic Disease, Pediatrics, Predictive Model, Clinical Decision Support
Sponsor: Vanderbilt University Medical Center

 
1 
 
 
 
 
 
SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 
related documents* 
Section/item 
ItemNo Description 
Administrative information 
Title 
1 
Descriptive title identifying the study design, population, 
interventions, and, if applicable, trial acronym 
 
A Single-Center, Randomized Study to Evaluate the 
Effectiveness of the Systematic Identification of Genetic Health 
Testing (SIGHT) in Prompting Clinical Decision-Making for 
Genetic Testing in Pediatric Patients 
Trial registration 
2a 
Trial identifier and registry name. If not yet registered, name 
of intended registry 
 
Clinicaltrials.gov – NCT06744543 
2b 
 
 
All items from the World Health Organization Trial 
Registration Data Set 
 
See table 1. 
Protocol version 
3 
Date and version identifier 
 
Issue Date: 12-9-2024 
Protocol number 1 
Authors: LDR, DMR 
Revision chronology: Amendment 2, version 3 
9-9-2025 – Amended language around SIGHT probability vs 
scores, and secondary outcomes 
 
Funding 
4 
Sources and types of financial, material, and other support 
 
This study is being conducted without any external financial 
funding. All resources, including manpower, materials, and 
operational costs, are being provided by Vanderbilt University 
Medical Center (VUMC). This includes the use of existing 
facilities, equipment, and staff time, which are being allocated as 
part of the regular functioning of VUMC. No specific funding or 
material support has been received from external commercial, 
governmental, or non-governmental organizations. The study 
relies on the participation of the research team and the use of 
existing infrastructure at the participating centers. 
 
This statement acknowledges the lack of external funding while 
highlighting the contributions made by the participating 
institutions in terms of existing resources and efforts. 

 
2 
Roles and 
responsibilities 
5a 
Names, affiliations, and roles of protocol contributors 
 
Lucas D Richter 
Division of Genetic Medicine, Department of Medicine, 
Vanderbilt University Medical Center, Nashville, TN, USA. 
Vanderbilt Genetics Institute, Vanderbilt University Medical 
Center, Nashville, TN, USA. 
 
Theodore J Morley 
Division of Genetic Medicine, Department of Medicine, 
Vanderbilt University Medical Center, Nashville, TN, USA. 
Vanderbilt Genetics Institute, Vanderbilt University Medical 
Center, Nashville, TN, USA. 
 
Bryce A. Schuler, MD, PhD 
Assistant Professor 
Division of Medical Genetics and Genomic Medicine, 
Department of Pediatrics 
 
Qingxia "Cindy" Chen 
Vice Chair of Education, Department of Biostatistics 
Professor of Biostatistics, Biomedical Informatics, and 
Ophthalmology & Visual Sciences 
 
Lisa Bastarache 
Vanderbilt Genetics Institute, Vanderbilt University Medical 
Center, Nashville, TN, USA. 
Center for Precision Medicine, Department of Biomedical 
Informatics, Vanderbilt University Medical Center, Nashville, TN, 
USA 
 
Douglas M Ruderfer 
Division of Genetic Medicine, Department of Medicine, 
Vanderbilt University Medical Center, Nashville, TN, USA.  
Vanderbilt Genetics Institute, Vanderbilt University Medical 
Center, Nashville, TN, USA.  
Center for Digital Genomic Medicine, Department of Medicine, 
Vanderbilt University Medical Center, Nashville, TN, USA.  
Department of Psychiatry and Behavioral Sciences, Vanderbilt 
University Medical Center, Nashville, TN, USA. 
 
DMR conceived of the study. TM built and validated the 
predictive model. DMR initiated the study design and LR, LB, 
BS, aided with design and implementation. DMR and QC, 
provided statistical expertise in clinical trial design and is 
conducting the primary statistical analysis. All authors 
contributed to refinement of the study protocol. 
5b 
Name and contact information for the trial sponsor 
 
Lucas Day Richter, MGC CGC 
2525 West End Ave, Suite 700. Nashville, TN 37203 
Lucas.richter@vumc.org 
615-322-6105 

 
3 
 
5c 
Role of study sponsor and funders, if any, in study design; 
collection, management, analysis, and interpretation of 
data; writing of the report; and the decision to submit the 
report for publication, including whether they will have 
ultimate authority over any of these activities 
 
This study had no external funding source. Funding played no 
role in the design of this study and will not have any role during 
its execution, analyses, interpretation of the data, or decision to 
submit results. 
 
5d 
Composition, roles, and responsibilities of the coordinating 
centre, steering committee, endpoint adjudication 
committee, data management team, and other individuals 
or groups overseeing the trial, if applicable (see Item 21a 
for data monitoring committee) 
 
Principal investigator 
Design  
Preparation of protocol and revisions 
Preparation of provider documentation and educational 
materials 
Managing CTO [clinical trials office] 
Publication of study reports 
(see above for members) 
Agreement of final protocol 
Audit of interim analysis for power calculation revisions 
Reviewing progress of study and if necessary, agreeing 
changes to the protocol. 
Trial manager - Lucas Day Richter, MGC CGC 
Study planning 
Organization of committee meetings 
Responsible for trial master file 
Audit of 1 year monthly feedback. 
Assistance with internal review, board/independent ethics 
committee applications 
Data verification 
Randomization 
Data collection 
Data manager - Theodore Morley 
Randomization 
Allocation 
Maintenance of trial IT system and data entry 
Data verification 
 
Introduction 
 
 

 
4 
Background and 
rationale 
6a 
Description of research question and justification for 
undertaking the trial, including summary of relevant studies 
(published and unpublished) examining benefits and harms 
for each intervention  
Roughly 5% of the world’s population is afflicted with rare 
diseases, the majority of which are genetic. Genetic testing 
represents a standard means to diagnose a patient with a 
genetic disease. However, current approaches that determine 
which patients receive a genetic test are inconsistent, 
inequitable and incomplete. 
The first step in determining which patients might benefit from 
genetic testing is risk identification and prognostication. 
Researchers like our team have developed and validated 
predictive models that use routinely collected Electronic Health 
Record (EHR) data like past diagnoses to predict individuals at 
risk of having genetic disease. Our machine-learning model is 
known as the Systematic Identification of Genetic Health Testing 
(SIGHT). SIGHT has been validated internally and externally 
and shown to identify more patients needing a genetic test while 
maintaining or increasing the proportion having a putative 
genetic disease compared to the current nonsystematic 
approach (Morley et al, 2021). 
 

 
5 
 
6b 
Explanation for choice of comparators  
 
The trial adopts a superiority framework to assess the 
effectiveness of SIGHT in improving clinical decision-
making regarding genetic testing. Participants will be 
randomized into one of two arms: the standard care arm, 
which follows the traditional approach to genetic testing, 
and the SIGHT-guided intervention arm, which uses a 
data-driven strategy facilitated by SIGHT.  
Healthcare providers of the patients in the SIGHT-guided 
intervention arm will receive alert messages, 
recommending consideration of genetic testing and referral 
to the genetics clinic. In contrast, providers of the patients 
in the standard care arm will not receive such alerts and 
will proceed with usual care practices. Patients with a 
score greater than equal to 0.30 and who have a 
scheduled visit at POD-C will be randomized in a 1:1 ratio 
to either the usual care or SIGHT-guided arm. 
Randomization will be stratified within the VUMC pediatric 
POD-C clinic. Patients will be excluded if they have 
already undergone Chromosomal Microarray testing at 
VUMC.  
 
 
 

 
6 
Objectives 
7 
Specific objectives or hypotheses  
 
This study will evaluate the effectiveness of SIGHT as a 
clinical support system to prompt provider/patient 
discussion and shared decision making regarding the need 
for genetic testing in form of a chromosomal microarray. 
We seek to study if identifying patients with high SIGHT 
scores will decrease the duration of time to testing and 
increase diagnostic yield. SIGHT only relies on data 
already collected in routine clinical encounters and is 
calculated prior to a clinical visit at VUMC.  
SIGHT does not replace clinical judgment in determining 
the necessity for genetic testing, but we seek to measure 
whether SIGHT increases the rates at which the important 
problem of elucidating the genetic etiology of disease is 
addressed. Our SIGHT-guided intervention group will be 
patients with high SIGHT scores where their provider 
receives a clinical communication recommending ordering 
of a genetic test and referral to the genetics clinic. Our 
comparison group will be patients with equivalently high 
SIGHT scores that receive usual care (i.e., do not receive 
a provider message). Patients will be from the POD-C 
pediatric primary care clinic at the Vanderbilt University 
Medical Center (VUMC) One Hundred Oaks location 
(OHO).  
 

 
7 
Trial design 
8 
Description of trial design including type of trial (eg, 
parallel group, crossover, factorial, single group), allocation 
ratio, and framework (eg, superiority, equivalence, 
noninferiority, exploratory) 
 
This study is a randomized, controlled trial with a parallel group 
design, focusing on the utilization of SIGHT in a pediatric clinical 
setting. The trial employs a superiority framework to evaluate 
the effectiveness of SIGHT in enhancing clinical decision-
making regarding genetic testing. Randomization will be 
assigned in a 1:1 allocation ratio to either the intervention group, 
receiving a SIGHT-prompted provider message, or the control 
group, receiving usual care without the SIGHT-prompted 
message. The randomization process will be automated with 
SIGHT scores generated prior to regular scheduled patient visits 
at the POD-C pediatric primary care clinic at the Vanderbilt 
University Medical Center (VUMC) One Hundred Oaks location 
(OHO). 
 
This trial design allows for a robust comparison between the 
standard approach to genetic testing and an innovative, data-
driven strategy facilitated by SIGHT. The primary objective is to 
assess whether the SIGHT model can effectively increase the 
number of patients who receive a genetic diagnosis, while 
potentially decreasing the time to genetic testing and increasing 
diagnostic yield in pediatric patients. 
Methods: Participants, interventions, and outcomes 
Study setting 
9 
Description of study settings (eg, community clinic, 
academic hospital) and list of countries where data will be 
collected. Reference to where list of study sites can be 
obtained 
 
The study will take place in Nashville TN and consist of pediatric 
patients visiting the POD-C pediatric primary care clinic at the 
Vanderbilt University Medical Center (VUMC) One Hundred 
Oaks location (OHO as part of the usual course of care. 

 
8 
Eligibility criteria 
10 
Inclusion and exclusion criteria for participants. If 
applicable, eligibility criteria for study centres and 
individuals who will perform the interventions (eg, 
surgeons, psychotherapists) 
 
Inclusion criteria will consist of patients  > 1 year old, < 20 years 
of age with a visit to the POD-C pediatric primary care clinic at 
the Vanderbilt University Medical Center (VUMC) One Hundred 
Oaks location (OHO. 
 
Exclusion criteria will consist of patients who have been 
programmatically excluded due to having already received a 
chromosomal microarray at VUMC, and patients > 20 years of 
age and < 1 year of age 
 
All ordering providers (i.e. APRN’s and physicians) in the POD-
C pediatric primary care clinic at the Vanderbilt University 
Medical Center (VUMC) One Hundred Oaks location will be 
receive an intervention in form of a SIGHT prompted message 
from a genetic counsellor for each patient meeting criteria (see 
below). No direct patient interventions will be provided from the 
study team. 
Interventions 
11a 
Interventions for each group with sufficient detail to allow 
replication, including how and when they will be 
administered  
 
Eligible patients will be randomized to the intervention or 
comparator arm with the intervention arm having a SIGHT 
predicted score of 0.3 or greater. For patients randomized to the 
SIGHT- prompted provider message, the clinician responsible 
for care in that encounter (determined in the usual course of 
care) will receive a message showing the relevant diagnostic 
codes contributing to the high score. 
 
Providers screening for or otherwise aware of SIGHT- predicted 
risk will have full discretion to offer genetic testing and/or refer to 
genetics providers. The management of screening will follow 
usual care at VUMC.  
 
Patients will experience usual care until providers screen for the 
need of genetic testing which they might not otherwise do 
without the SIGHT-prompted provider message for those 
identified at highest risk.  
 

 
9 
11b 
Criteria for discontinuing or modifying allocated 
interventions for a given trial participant (eg, drug dose 
change in response to harms, participant request, or 
improving/worsening disease) 
 
This protocol presents minimal risks to participants, adverse 
events or other problems are not anticipated. Risks include 
discomfort among both providers and patients in discussing the 
sensitive but important topic of being at risk of genetic disease. 
The risk model is not perfect and might not identify patients who 
are at risk – it is not intended to pre-empt providers screening 
any patient for genetic disease if they choose to do so. The risk 
model might also identify those not at risk, leading to questions 
of genetic susceptibility being asked unnecessarily.  
 
Providers may dismiss the SIGHT – prompted provider 
message and not act on its recommendations at any time. No 
other intervention is planned. Patients would be unaware of the 
providers’ decisions in that case unless the provider chooses 
independently to discuss the SIGHT score with them. 
 
11c 
Strategies to improve adherence to intervention protocols, 
and any procedures for monitoring adherence (eg, drug 
tablet return, laboratory tests) 
 
Adherence meetings are held prior to study implementation with 
POD-C physicians. These providers will be more likely to 
provide constant care in the clinic over the duration of the study 
as opposed to those physicians who have interim appointments. 
The Directors of the POD-C clinic can also request an education 
session at any time or new provider training if needed. 
Additionally, training materials will be readily accessible via all 
SIGHT provider prompted messaging. Strategies to improve 
adherence for the pediatric patients flagged by the SIGHT 
model is not applicable as they will follow usual care at VUMC 
and will not be consented and enrolled by the study team. 
11d 
Relevant concomitant care and interventions that are 
permitted or prohibited during the trial 
 
Usual pediatric care and treatments that are unrelated to genetic 
testing are permitted and expected to continue as normal. 
Interventions and treatments necessary for the immediate health 
and well-being of the patient, regardless of their relation to 
genetic testing, are anticipated as part of usual care. Any 
intervention by the study team that could influence the 
healthcare provider’s decision-making process regarding 
genetic testing, outside of the SIGHT model's recommendations 
will be avoided. Interventions specifically aimed at influencing 
the study outcomes, such as additional prompts or incentives for 
genetic testing are prohibited. 

 
10 
Outcomes 
12 
Primary, secondary, and other outcomes, including the specific 
measurement variable (eg, systolic blood pressure), analysis 
metric (eg, change from baseline, final value, time to event), 
method of aggregation (eg, median, proportion), and time point 
for each outcome. Explanation of the clinical relevance of 
chosen efficacy and harm outcomes is strongly recommended 
 
Primary Outcome: 
Specific Measurement Variable: Number of patients 
diagnosed via a Chromosomal Microarray. 
Analysis Metric: Chi-square test. 
Method of Aggregation: Direct case control comparison of the 
raw count of patients diagnosed, presented as a percentage. 
Time Point: Assessed after one year to include enough time for 
patients to undergo testing through usual care. 
 
Secondary Outcomes:  
Specific Measurement Variable: Duration of time to genetic 
testing. 
Analysis Metric: Time to event, measured from the initial 
patient visit to the time genetic testing is conducted. 
Method of Aggregation: Median time in days 
 
Specific Measurement Variable: Rates of genetic testing. 
Analysis Metric: Proportion of patients who received testing 
Method of Aggregation: Proportion of patients, presented as a 
percentage 
Time Point: Assessed after one year to include enough time for 
patients to undergo testing through the usual course of care. 
 
Specific Measurement Variable: Diagnosis via any genetic 
testing. 
Analysis Metric: Proportion of patients diagnosed with a 
genetic disease following molecular testing or clinical evaluation. 
Method of Aggregation: Proportion of patients, presented as a 
percentage. 
Time Point: Assessed after one year to include enough time for 
patients to undergo additional testing through usual care. 
 
Specific Measurement Variable: Adherence to the SIGHT-
prompted provider message. 
Analysis Metric: Frequency of provider actions via referral to 
genetics and ordering a patient CMA following receipt of a 
SIGHT-prompted message.  
Method of Aggregation: Proportion of instances where the 
provider follows the SIGHT recommendation. 
Time Point: Information will be collected at the end of the study. 

 
11 
Participant 
timeline 
13  
Time schedule of enrolment, interventions (including any 
run-ins and washouts), assessments, and visits for 
participants. A schematic diagram is highly recommended 
(see Figure) 
 
1. Enrollment Process: Eligibility Screening: Conducted at 
the initial patient visit. Consent Process: Following 
eligibility screening, informed consent will not be 
obtained as patients are following usual care.  
2. Interventions: SIGHT-Prompted Provider Message: 
Initiated following screening for patients who meet the 
predefined risk threshold. 
3. Assessments: Baseline Assessment: Conducted during 
the initial visit, including collection of patient health data. 
Follow-up Assessments: Scheduled after initial visit to 
monitor the outcomes, such as number of patients 
receiving a diagnosis, time to genetic testing, and 
diagnostic yield. 
4. Visits: Initial Visit: SIGHT prompted provider message 
followed by review of referrals and documentation 
attributable to the initial patient visit. Subsequent Visits: 
Regular follow-ups as per usual pediatric care, during 
which recommendations and any genetic testing 
decisions are documented and assessed. 
5. Study Close-Out: Final Assessment: Conducted at the 
end of the study period to collect the final data on all 
outcomes. 
 
Sample size 
14 
Estimated number of participants needed to achieve study 
objectives and how it was determined, including clinical 
and statistical assumptions supporting any sample size 
calculations 
Previous data suggest that, under the usual course of care, 9% 
of high-risk patients (those with a predicted score of ≥ 0.3) had 
genetic testing. Of those, 9% received a genetic diagnosis, 
resulting in a genetic diagnosis rate of 0.81% (0.09 * 0.09) 
among high-risk patients  
One thousand high‐risk patients (score ≥0.3) will be randomized 
1:1 (500 per arm). This sample size provides 80% power to 
detect an increase in the genetic diagnosis rate from 0.81% 
under standard care to at least 3.6% with the SIGHT 
intervention (chi‐square test, α=0.05) 

 
12 
Recruitment 
15 
Strategies for achieving adequate participant enrolment to 
reach target sample size 
 
The VUMC POD-C pediatric clinic has had over 200,000 patient 
encounters from over the last five years with more than 30,000 
unique patients and over 10,000 unique patients in 2023. The 
clinic averages 144 visits per day (median = 165). Estimates 
indicate potentially 1-2 patients flagged per day which should 
readily provide enough patients for an adequate sample size 
over a two to three-year period. 
Methods: Assignment of interventions (for controlled trials) 
 
 
 

 
13 
Allocation:  
Sequence 
generation 
16a 
Method of generating the allocation sequence (eg, 
computer-generated random numbers), and list of any 
factors for stratification. To reduce predictability of a 
random sequence, details of any planned restriction (eg, 
blocking) should be provided in a separate document that 
is unavailable to those who enrol participants or assign 
interventions. 
 
The SIGHT study will utilize a computer-generated assignment 
schedule for all patients seen in the POD-C pediatric clinic with 
a score greater than or equal to 0.3 for allocation into the 
intervention group. A computer-generated randomization 
schedule will be used for assigning participants to the control 
group. This is completed using the built-in random module of 
python, assigning patients with equal scores either 0 (control) or 
1 (intervention) to each patient who has met all previously 
defined criteria, with assignments saved to a log file. 
  
The allocation will be done with a 1:1 ratio. This randomization 
process is designed to ensure that patients surpassing a 
previously defined threshold for predicted risk of needing 
genetic testing are randomly selected for the intervention group. 
A SIGHT-prompted provider message will be generated for 
patients in the intervention group, while patients in the control 
group will receive usual care without this prompted message. 
  
Patients who exceed a predefined risk threshold and are 
scheduled for their first visit within a year will be eligible for 
randomization to the intervention group. An estimated 500 
patients will be randomly selected to receive a SIGHT-prompted 
provider message as part of the intervention. 
  
The comparator arm will consist of the random eligible patients 
who do not receive the intervention. These patients will not be a 
typical control group to avoid ethical concerns related to 
withholding potentially important care but will follow usual care 
and may still get genetic testing.  
  
To maintain the integrity of the randomization process, the study 
will employ random allocation to intervention and comparator 
arms with the expectation of a 1:1 ratio over time. 
  
This method of randomization aligns with ethical standards and 
the goal of the study to evaluate the effectiveness of the SIGHT 
intervention while ensuring that all patients receive the usual 
care appropriate to their clinical needs. 

 
14 
Allocation 
concealment 
mechanism 
16b 
Mechanism of implementing the allocation sequence (eg, 
central telephone; sequentially numbered, opaque, sealed 
envelopes), describing any steps to conceal the sequence 
until interventions are assigned. 
 
The allocation sequence will be implemented using a secure, 
computerized system to ensure allocation concealment. This 
system will generate the allocation sequence and assign 
patients who surpass the predefined risk threshold to either the 
intervention or the comparator group. 
 
The allocation system will maintain concealment by ensuring 
that randomization is not processed until a patient has been 
identified as eligible. This process occurs after the patient's 
eligibility is confirmed but before any intervention is assigned, to 
prevent selection bias and to maintain the integrity of the 
randomization process. 

 
15 
Implementation 16c 
Who will generate the allocation sequence, who will enrol 
participants, and who will assign participants to 
interventions 
 
Allocation Sequence Generation 
The allocation sequence will be generated by the study’s data 
management team using a computer-based randomization 
function. Any pediatric patient scheduled for a visit in the POD-C 
pediatric primary care clinic at VUMC One Hundred Oaks 
(OHO) who meets or exceeds the predefined risk threshold will 
be flagged as eligible. These flagged patients will then be 
randomly assigned to either the intervention arm (SIGHT-
prompted provider message) or the usual care arm (no provider 
message). 
 
Participant Enrollment 
Patients aged 1 to 20 years who have not previously undergone 
chromosomal microarray testing at VUMC will be automatically 
included in the randomization pool once they have a scheduled 
visit at the OHO clinic. As this study follows standard clinical 
care, patients themselves do not undergo a separate consent 
process for randomization. Instead, their providers will be 
informed of any SIGHT alerts only if the patient is randomized to 
receive them. 
 
Assignment of Participants to Interventions 
For those randomized to the intervention arm, a SIGHT-
prompted provider message is generated within EPIC by a 
genetic counselor on the research team. This message 
indicates the patient’s increased risk level and recommends 
considering a chromosomal microarray and referral to genetics. 
The provider maintains full discretion to act upon or dismiss this 
recommendation. By contrast, providers in the usual care arm 
receive no automated messages about SIGHT risk, and patients 
continue under routine care practices. 
 
Concealment of Allocation 
The randomization process is integrated into the workflow so 
that neither providers nor the study team can predict a patient’s 
assignment prior to the system’s automated allocation. This 
design ensures there is no foreknowledge of group 
assignment—preventing selection bias and preserving the trial’s 
integrity. 

 
16 
Blinding 
(masking) 
17a 
Who will be blinded after assignment to interventions (eg, 
trial participants, care providers, outcome assessors, data 
analysts), and how 
 
There will be no blinding of participants or physicians as patients 
and providers will follow usual care. Providers may dismiss the 
SIGHT – prompted provider message and not act on its 
recommendations at any time. No other intervention is planned. 
Patients would be unaware of the providers’ decisions in that 
case unless the provider chooses independently to discuss the 
SIGHT score with them. 
 
A sample size re-estimation will be conducted after 250 patients 
have been randomized to account for uncertainty, and 
adherence rates for the initial test-referral rate used in the 
sample size calculation. An independent analyst, who will be 
blinded to the randomization assignment, will calculate the 
observed test-referral rate across all patients. This analysis will 
focus on updating the test-referral rate parameter to ensure the 
study is adequately powered. The updated test-referral rate will 
be used to reassess and, if necessary, adjust the total sample 
size to maintain the study's power at 80%. This process will 
ensure the trial remains robust and capable of detecting 
meaningful differences between the usual care and SIGHT-
guided intervention arms.  
 
 
 
17b 
If blinded, circumstances under which unblinding is 
permissible, and procedure for revealing a participant’s 
allocated intervention during the trial 
 
NA 
Methods: Data collection, management, and analysis 

 
17 
Data collection 
methods 
18a 
Plans for assessment and collection of outcome, baseline, 
and other trial data, including any related processes to 
promote data quality (eg, duplicate measurements, training 
of assessors) and a description of study instruments (eg, 
questionnaires, laboratory tests) along with their reliability 
and validity, if known. Reference to where data collection 
forms can be found, if not in the protocol 
 
The trial will utilize the SIGHT predictive model to generate a 
score for all POD-C patients. Data collection will include 
baseline and outcome data assessed via EHR data queries for 
internal genetic test orders in form of a CMA, referrals to 
pediatric genetics, and attributable dates. All queried metrics 
and additional metrics related to genetic testing results will be 
assessed and verified through chart review performed by a 
clinician (genetic counselor or geneticist) for the intervention and 
comparator arm for patients seen in the POD-C clinic. The 
validity and reliability of the SIGHT predictive model, as well as 
the data collection methods, have been ensured through pilot 
testing and chart review prior to study implementation. All data 
collected and related documentation will be available in the trial 
master file with data availability based upon institutional policy. 
 
18b 
Plans to promote participant retention and complete follow-
up, including list of any outcome data to be collected for 
participants who discontinue or deviate from intervention 
protocols 
 
There will be no plan to promote participant retention and 
complete follow-up as patients are following usual care and may 
or may not undergo genetic testing as per the choice of the 
patient and family.   
Data 
management 
19 
Plans for data entry, coding, security, and storage, 
including any related processes to promote data quality 
(eg, double data entry; range checks for data values). 
Reference to where details of data management procedures 
can be found, if not in the protocol 
 
Data will be extracted EPIC’s Clarity and then stored on 
VUMC's ACCRE cluster, which is designed for secure handling 
of export-controlled data, PHI, and human genotype and 
phenotype data. EPIC’s Clarity and the ACCRE cluster feature 
rigorous backup protocols ensuring data integrity and recovery. 
Details of data management procedures, including security 
protocols, access controls, and data backup schedules, are 
detailed at https://www.vanderbilt.edu/accre/overview/. 

 
18 
Statistical 
methods 
20a 
Statistical methods for analysing primary and secondary 
outcomes. Reference to where other details of the 
statistical analysis plan can be found, if not in the protocol 
The primary and secondary outcomes of this trial will be 
analyzed using appropriate statistical tests to compare the 
intervention arm (SIGHT-prompted provider message) against 
the control (patients receiving usual care provided through the 
POD-C pediatric primary care clinic at the Vanderbilt University 
Medical Center (VUMC) One Hundred Oaks location (OHO). 
The primary outcome measure will be the difference in number 
of patients who receive diagnoses via a Chromosomal 
Microarray between the two groups. 
The statistical analysis will utilize a chi-square test for binary 
outcomes such as the presence or absence of a genetic 
diagnosis as identified by the test or provider adherence to 
SIGHT message recommendations. For continuous secondary 
outcomes, such as the time to genetic testing, a T-test or Mann-
Whitney U test will be used depending on data distribution. 
Subgroup analyses will involve regression methods to assess 
the differential effects of the intervention across subgroups 
defined by baseline demographic characteristics (e.g. age, sex, 
race). Multivariate analyses will be conducted using logistic 
regression for binary outcomes and linear or Cox proportional 
hazards regression for continuous or time-to-event outcomes, 
respectively. Model assumptions will be checked through the 
assessment of residuals and model fit will be evaluated 
accordingly. 
When indicated, a two-sided p-value of less than 0.05 will be 
considered statistically significant. The Bonferroni correction will 
be applied to account for multiple comparisons when analyzing 
multiple outcomes. R will be used to perform all analyses. The 
analysis plan will follow the intention-to-treat principle, with all 
randomized participants included in the analysis according to 
the group to which they were allocated. 
Variable/outcome 
Hypothesis 
Outcome measure 
Methods of analysis 
Primary 
 
 
R will be used to perform all 
analysis. 
 Number of diagnoses 
via CMA 
More patients are diagnosed being 
flagged by SIGHT via a 
Chromosomal Microarray 
Number of patients flagged by 
SIGHT who receive a diagnosis via 
CMA over one year vs controls 
[binary] 
Chi-square test 
Secondary 
 
 
 
      a. Time to genetic 
test 
Patients in the intervention arm will 
receive genetic testing faster than 
those in the control arm. 
Duration in days for which 
patients flagged by SIGHT receive 
a genetic test vs control 
[continuous] 
Cox proportional Hazards to 
compare the time to event (in this 
case genetic testing) between two 
groups while controlling for 
covariates. 
      b. Rates of genetic 
testing 
Increased rates of genetic testing in 
the intervention arm 
Rates of genetic testing ordered 
by providers between cases and 
controls over a one-year period 
after POD-C visit [continuous’ 
Binary logistic regression to 
calculate the odds ratio for the 
likelihood of receiving a genetic test 
in the intervention arm compared to 
the controls 
      c. Diagnosis via any 
test (molecular   
confirmation) 
More patients will receive a 
diagnosis from molecular 
confirmation outside of firs tier 
testing via a CMA. 
Number of patients flagged by 
SIGHT who receive a diagnosis via 
any test over one year vs controls 
[binary] 
Chi-square test 
      d. Adherence to 
Intervention 
Providers who Receive SIGHT 
prompts demonstrate higher 
adherence recommendations 
compared to controls 
Proportion of eligible patients 
where providers ordered a CMA 
and place genetics referrals after 
receiving a prompt [binary] 
Chi-square test; logistic regression 
adjusting for covariates 

 
19 
 
20b 
Methods for any additional analyses (eg, subgroup and 
adjusted analyses) 
 
Subgroup analysis within demographic groups (sex, race, age) 
will be performed as described in the primary analysis but within 
each group or stratified by age. 
 
20c 
Definition of analysis population relating to protocol non-
adherence (eg, as randomised analysis), and any statistical 
methods to handle missing data (eg, multiple imputation) 
 
Non-adherence and missing data for the SIGHT protocol are 
non-applicable in this context as patients will follow usual care. 
Patients who are lost to follow up or have no follow up care 
during the duration of the study will remain included in the 
analysis.  
Methods: Monitoring 
Data monitoring 
21a 
Composition of data monitoring committee (DMC); 
summary of its role and reporting structure; statement of 
whether it is independent from the sponsor and competing 
interests; and reference to where further details about its 
charter can be found, if not in the protocol. Alternatively, an 
explanation of why a DMC is not needed. 
 
This study does not require a DMC as the protocol presents 
minimal risks to participants and adverse events or other 
problems are not anticipated. In the unlikely event that such 
events occur, unanticipated problems involving risks to subjects 
or others will be reported immediately to the PI and and within 7 
days of the PI’s notification of the event to the IRB.  
 
 
21b 
Description of any interim analyses and stopping 
guidelines, including who will have access to these interim 
results and make the final decision to terminate the trial 
 
As stated in item 21a the SIGHT study will not have a DCM but 
rather report all outcomes to the IRB. Given that the study 
maintains low risk for patient harm, stoppage of the study is not 
anticipated but in the event of unforeseen circumstances the PI 
has full authority to end the study. An interim analysis for 
sample size re‐estimation will be conducted after approximately 
250 patients have been enrolled to refine the test‐referral rate 
and ensure the study is adequately powered. An independent 
analyst, blinded to arm assignment, will perform this 
recalculation. This is not an efficacy or early‐stopping analysis 
but a parameter update. 
 
Harms 
22 
Plans for collecting, assessing, reporting, and managing 
solicited and spontaneously reported adverse events and 
other unintended effects of trial interventions or trial 
conduct 

 
20 
 
 
 
This protocol presents minimal risks to participants and adverse 
events, or other problems are not anticipated. Risks include 
discomfort among both providers and patients in discussing the 
sensitive but important topic of being at risk of genetic disease. 
The risk model is not perfect and might not identify risk in those 
who are at risk – it is not intended to pre-empt providers 
screening any patient (or all patients) for genetic disease if they 
choose to do so. The risk model might also identify risk in those 
not at risk, leading to questions of genetic susceptibility being 
asked unnecessarily.  
 
Reporting of Adverse Events or Unanticipated Problems 
involving Risk to Participants or Others 
 
The study coordinator, with PI oversight, is responsible for 
ensuring protocol compliance, data integrity, and participant 
safety. This protocol presents minimal risks to participants and 
adverse events, or other problems are not anticipated. In the 
unlikely event that such events occur, unanticipated problems 
involving risks to subjects or others will be reported immediately 
to the PI, and in writing within 7 days to the IRB. The PI will 
apprise fellow investigators and study personnel of all adverse 
events that occur during the conduct of this research project 
through regular study meetings. Annual reports will be submitted 
to the IRB summarizing study progress, adverse events, 
complaints about the research, and any protocol violations. 
 
Auditing 
23 
Frequency and procedures for auditing trial conduct, if any, 
and whether the process will be independent from 
investigators and the sponsor 
 
Given the SIGHT study’s design, including data management 
and monitoring processes, small scale and low risk to patients, 
independent auditing is not required or necessary. 
Ethics and dissemination 

 
21 
Research ethics 
approval 
24 
Plans for seeking research ethics committee/institutional 
review board (REC/IRB) approval 
 
This protocol, including all materials such as provider 
educational materials, clinical letter of support, and 
methodology, will undergo thorough review and approval by 
VUMC institutional review boards/ethical committees 
(IRBs/ECs) for adherence to scientific standards and 
compliance with research and human subject regulations. 
  
All materials related to the SIGHT study will be subjected to 
ethical review. Any modifications to these documents will also 
require re-approval. 
  
Following initial approval, the local IRBs/ECs will conduct an 
annual review of the protocol. The principal investigator is 
responsible for submitting annual safety and progress reports to 
the IRBs/ECs and within three months of study termination or 
completion at their site.  
Protocol 
amendments 
25 
Plans for communicating important protocol modifications 
(eg, changes to eligibility criteria, outcomes, analyses) to 
relevant parties (eg, investigators, REC/IRBs, trial 
participants, trial registries, journals, regulators) 
 
Modifications to the SIGHT study protocol that impact study 
conduct, patient safety, or potential benefits, including changes 
in study objectives, design, patient population, or significant 
administrative aspects, will require a formal amendment. These 
amendments will be agreed upon by the PI and study team and 
approved by the Ethics Committee/IRB prior to implementation. 
Such amendments will also be notified to health authorities in 
accordance with local regulations. 
 
For administrative changes that are minor and do not affect the 
study conduct, these will be documented in a memorandum. 
The Ethics Committee/IRB may be notified of these changes at 
the discretion of the study team. 
 
Consent or 
assent 
26a 
Who will obtain informed consent or assent from potential 
trial participants or authorised surrogates, and how (see 
Item 32) 
 
Patients are following usual care and do not require specific 
informed consent for participation. Providers will be responsible 
for deciding whether to act on SIGHT recommendations. 
 
26b 
Additional consent provisions for collection and use of 
participant data and biological specimens in ancillary 
studies, if applicable 
 
NA 

 
22 
Confidentiality 
27 
How personal information about potential and enrolled 
participants will be collected, shared, and maintained in 
order to protect confidentiality before, during, and after the 
trial 
 
We will deploy the model via Vanderbilt’s ACCRE cluster to 
HealthIT’s secure, PHI-approved managed platform Clarity This 
will allow us to configure a nightly job that will process the billing 
codes stored in the Clarity data warehouse to identify patients 
that are eligible for the order and referral.  
 
In the SIGHT study, the confidentiality of personal information 
for all participants is paramount. Therefore, the following 
measures will be implemented: 
1. Documentation: No documents with personal identifiers 
will be obtained. 
2. Coded Identification: All study-related records will be 
identified only by a unique coded ID number to ensure 
participant anonymity.  
3. Password-Protected Databases: Digital databases 
containing participant data will be password-protected 
and accessible only to authorized personnel. 
4. Staff Confidentiality Agreements: All study staff will be 
required to undergo HIPPA training for compliance and 
sign agreements to uphold the privacy of participants. 
5. Controlled Information Release: Participant 
information will not be released outside the study except 
as required for monitoring by regulatory authorities or as 
mandated by law. 
6. Data Transmission Security: When transmitting data 
(i.e. SIGHT prompted messages) from genetic counselor 
to physicians, secure methods such as virtual private 
networks (VPN) and electronic health record 
communication via EPIC will be utilized to preserve data 
confidentiality. All other data will be stored via ACCRE 
as mentioned above. 
 
Declaration of 
interests 
28 
Financial and other competing interests for principal 
investigators for the overall trial and each study site 
 
Dr. Ruderfer has served on advisory boards for Illumina and 
Alkermes and has received research funds unrelated to this 
work from PTC Therapeutics. There is no external funding 
source for this trial. 

 
23 
Access to data 
29 
Statement of who will have access to the final trial dataset, 
and disclosure of contractual agreements that limit such 
access for investigators 
Summary level data regarding genetic testing prompted by 
SIGHT will be available via supplementary materials. All 
requests for raw (for example temporal data regarding genetic 
testing for cases and controls) are reviewed by Vanderbilt 
University Medical Center to determine whether the request is 
subject to any intellectual property or confidentiality obligations. 
For example, patient-related data not included in the paper may 
be subject to patient confidentiality. Any such data and materials 
that can be shared will be released via a material transfer 
agreement.  
Ancillary and 
post-trial care 
30 
Provisions, if any, for ancillary and post-trial care, and for 
compensation to those who suffer harm from trial 
participation 
 
This protocol presents minimal risks to participants and adverse 
events, or other problems are not anticipated. Provisions for trial 
care will not be necessary as patients are following usual care at 
VUMC and will not be directly enrolled in the study. 
Dissemination 
policy 
31a 
Plans for investigators and sponsor to communicate trial 
results to participants, healthcare professionals, the public, 
and other relevant groups (eg, via publication, reporting in 
results databases, or other data sharing arrangements), 
including any publication restrictions 
 
The PI will submit the results of the study for publication even in 
the absence of statistically significant results. 
 
 
31b 
Authorship eligibility guidelines and any intended use of 
professional writers 
 
All SIGHT study team personnel will be listed as authors with 
appropriate contributions. No professional writers will be used 
for publication. 
 
31c 
Plans, if any, for granting public access to the full protocol, 
participant-level dataset, and statistical code 
 
Summary level data regarding genetic testing prompted by 
SIGHT will be available via supplementary materials. All 
requests for raw (for example temporal data regarding genetic 
testing for cases and controls) are reviewed by Vanderbilt 
University Medical Center to determine whether the request is 
subject to any intellectual property or confidentiality obligations. 
For example, patient-related data not included in the paper may 
be subject to patient confidentiality. Any such data and materials 
that can be shared will be released via a material transfer 
agreement. 
Appendices 
 
 

 
24 
Informed consent 
materials 
32 
Model consent form and other related documentation given 
to participants and authorised surrogates 
 
The only documentation generated will be educational material 
and SIGHT provider prompted messages for providers. All, 
material has undergone an internal review and will be approved 
by the clinical directors and the VUMC IRB before 
implementations of the SIGHT study. 
Biological 
specimens 
33 
Plans for collection, laboratory evaluation, and storage of 
biological specimens for genetic or molecular analysis in 
the current trial and for future use in ancillary studies, if 
applicable 
 
No specimens will be collected by the study team or stored for 
future use. All, study related data will be collected via the 
electronic health record by following patients being seen at 
VUMC via usual care. 

 
25 
Data category 
Information 
Primary registry and 
trial identifying number 
ClinicalTrials.gov – NCT06744543  
 
Date of registration in 
primary registry 
**11 February, 2025** 
Secondary identifying 
numbers 
NA 
Source(s) of monetary 
or material support 
No funding source 
Primary sponsor 
NA 
Secondary sponsor(s) 
NA  
Contact for public 
queries 
Lucas Day Richter, MGC CGC lucas.richter@vumc.org 
Contact for scientific 
queries 
Lucas Day Richter, MGC CGC lucas.richter@vumc.org 
Vanderbilt University Medical Center Department of Medicine, Division of Genetic Medicine, Nashville 
TN 
Center for Digital Genomic Medicine 
Vanderbilt Genetics Institute 
Public title 
Clinical Decision Support to Find Individuals at Risk of Genetics Disease 
Scientific title 
Integrating Machine Learning into Clinic: Systematic Identification of Genetic Health Testing (SIGHT) 
Randomized control trial. 
Countries of recruitment United States 
Health condition(s) or 
problem(s) studied 
Genetics Disease in the Pediatric Population 
Intervention(s) 
Active comparator:  Patients having a SIGHT predicted score greater than equal to 0.30 with a score 
less than 0.30 seen in the  POD-C pediatric primary care clinic at the Vanderbilt University Medical 
Center (VUMC) One Hundred Oaks location (OHO . 
Controls: Randomized pediatric patients who meet criteria without intervention seen at POD-C 
pediatric primary care clinic at the Vanderbilt University Medical Center (VUMC) One Hundred Oaks 
location (OHO).. 
Key inclusion and 
exclusion criteria 
Ages eligible for study: >1 years and < 20 years of age 
Sexes eligible for study: both 
Inclusion criteria: Inclusion criteria will consist of patients  > 1 year old, < 20 years of age with a visit to  
POD-C pediatric primary care clinic at the Vanderbilt University Medical Center (VUMC) One Hundred 
Oaks location (OHO). 
Exclusion criteria: Exclusion criteria will consist of patients who have been programmatically excluded 
due to having already received a chromosomal microarray at VUMC, and patients > 20 years of age. 
Study type 
Interventional 
Allocation: Randomized intervention model.  
 
 
Date of first enrolment 
February 2025 
Target sample size 
1000 
Recruitment status 
Recruiting 
Primary outcome(s) 
Number of cases diagnosed via a Chromosomal Microarray compared to the controls 

 
26 
*It is 
strongly 
recommend
ed that this 
checklist be 
read in 
conjunction 
with the 
SPIRIT 
2013 Explanation & Elaboration for important clarification on the items. Amendments to the 
protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 
Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 
license. 
 
 
 
 
 
Data category 
Information 
Key secondary 
outcomes 
1. 
Time to patients receiving genetic testing 
2. 
Rate of genetic testing  
3. 
Satisfaction of physicians who received a SIGHT prompted provider message 
4. 
Number of patients receiving a diagnosis via any test (molecular confirmation), or a clinical 
diagnosis by a pediatric geneticist following the course of usual care. 

 
27