Reporting Adult-Onset Genomic Results to Pediatric Biobank Participants and Parents
Phase: EARLY_PHASE1
Conditions: Hereditary Breast and Ovarian Cancer Syndrome, Lynch Syndrome, Familial Hypercholesterolemia
Sponsor: Geisinger Clinic

Protocol v1.23 6/28/23 
 
 
 
 
 
Reporting Adult-Onset Genomic Results to Pediatric Biobank Participants and Parents (PRoGRESS) 
 
NCT03832985 
 
July 31, 2023 
 
 
 

Protocol v1.23 6/28/23 
 
 
 
Title: Pediatric Reporting of Genomic RESults Study (PRoGRESS) 
Principal Investigator (P.I.): Adam Buchanan, MS, MPH, LGC 
PI Contact Phone Number: 570-214-4747 
Protocol Version Number & Date: Version 1.23; June 28, 2023 
IRB Number: 2018-0419 
 
Table of Contents 
1.0 Background and Significance. ...................................................................... 2 
2.0 Objective and Aims ....................................................................................... 6 
3.0 Procedures ..................................................................................................... 7 
3.1 Overall Research Design. ....................................................................... 7 
3.2 Detailed Study Procedures ................................................................... 10 
3.2.a. Retrospective Recruitment .................................................... 10 
3.2.b. Retrospective Study Population. ............................................ 11 
3.2.c. Retrospective Enrollment Procedures. .................................. 12 
3.2.d. Prospective Recruitment ........................................................ 16 
3.2.e. Prospective Study Population. ............................................... 16 
3.2.f. Prospective Enrollment Procedures. ...................................... 16 
3.3 Result Disclosure Procedures. .............................................................. 20 
4.0 Data Collection. ........................................................................................ 21 
4.1 Data Collection Procedures .................................................................. 22 
4.2 Participant Compensation. .................................................................... 24 
4.3 Data Management Procedures and Confidentiality. ............................. 24 
4.4 Data Safety and Monitoring Plan. ........................................................ 25 
4.5 Data Analysis ........................................................................................ 27 
5.0 Expected Risks. .......................................................................................... 28 
6.0 Expected Benefits. ..................................................................................... 29 
7.0 Bibliography.............................................................................................. 31 

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1.0 BACKGROUND AND SIGNIFICANCE: 
The potential benefits and harms of returning genomic results to children and their parents are 
matters of enduring controversy—especially genomic results for adult-onset conditions that are 
not medically actionable in childhood (e.g., hereditary breast and ovarian cancer syndrome and 
Lynch syndrome). Returning results for conditions that are medically actionable in childhood can 
yield benefits to children and their parents. Proponents of returning results for adult-onset 
conditions highlight the potential for initiating life-saving preventive measures in parents who 
are found to carry the same genomic variant as their children. Moreover, the legal “loss of 
chance” doctrine might provide added justification for returning these results to guide healthcare 
for parents of the affected children. However, pediatricians, geneticists, and bioethicists have 
expressed concerns that children who receive a result for an adult-onset condition might 
experience negative psychosocial outcomes such as distress, discrimination, loss of future 
autonomy, or altered family functioning. Empirical data to inform either position in this 
controversy, however, are lacking. As a result, policy makers cannot make evidence-based 
judgments about the potential benefits and harms of returning genomic results related to adult- 
onset conditions to children and their parents. 
 
The question of whether to return genomic results for adult-onset conditions to children has been 
hotly debated among pediatricians, geneticists and bioethicists. Exome- or genome-scale 
sequencing is used widely in clinical and research settings, both as a diagnostic tool and, in a few 
settings, as population screening in healthy individuals.1,2 This testing provides an opportunity to 
query sequence data for pathogenic variants in medically actionable genes – those with increased 
disease risk and established interventions to reduce risk. However, there has been considerable 
debate about whether the opportunity to investigate these genes is in fact an ethical or legal 
obligation or even ethically or legally permissive. This is particularly true for variants that are not 
of immediate clinical utility, as in the case of genomic findings in children associated with adult- 
onset disease.3,4 Mostly absent from the debate have been pediatric patients and their families—a 
perspective that is essential if one is committed to patient-centered care. 
 
The debate began in earnest with the 2013 publication of the American College of Medical 
Genetics and Genomics (ACMG) guideline that recommended that clinicians notify their patients 
with an incidental, medically actionable genomic finding on genome-scale testing, regardless of 
the age of the patient.5 Examples of medically actionable conditions include hereditary breast 

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and ovarian cancer (HBOC) syndrome (BRCA1/2 genes) and Lynch syndrome (MLH1, MSH2, 
MSH6 and PMS2 genes) and familial hypercholesterolemia (LDLR, APOB and PCSK9 genes), 
all of which have top-tier evidence for reducing morbidity and mortality.6 Among the conditions 
listed by the ACMG as being sufficiently actionable to merit notification of patients who were 
found incidentally to have an associated variant, 28 can have pediatric onset or initiation of risk 
reduction procedures.5,7 The two remaining conditions – HBOC and Lynch syndrome – do not 
typically lead to childhood onset of disease5,7 and are managed accordingly, with recommended 
risk reduction postponed until adulthood.8,9 Yet, the authors of the ACMG guidelines were 
compelled by the interests of adult relatives and of the children themselves. Identifying an adult- 
onset condition in a child could prompt relatives to be tested for a potentially life-threatening 
condition.5,10 Preventing these life-threatening conditions in adults can also protect the interests 
of children under their care.5,10 
 
The ACMG recommendation seemed to contradict long-standing guidance to defer testing for 
adult-onset genetic conditions until children reach adulthood and can decide whether to have 
testing.11-14 These professional guidelines have focused on the best interest of children, citing 
concern about potential psychosocial harm and corresponding lack of clear medical benefit.11-15 
Proposed harms include psychological harms (e.g., increased distress, negative impacts on self- 
image); negative impact on family relationships (e.g., differential treatment by parents, including 
the ‘vulnerable child syndrome’); discrimination; and failure to preserve autonomy (e.g., 
infringing upon a child’s right to an open future).11-13,16,17 
 
Others have countered that there might be benefits to returning adult-onset genomic findings to 
children. Beyond the ACMG’s rationale,5 proposed benefits include psychological benefits (e.g., 
opportunity for adjustment to hereditary disease), positive impact on family relationships, and 
promotion of autonomy.17 Further, the limited available evidence has not borne out the negative 
psychosocial impacts anticipated by those opposed to the return of genomic information to 
children. Reviews of psychosocial outcomes in children who underwent genetic testing have not 
shown clear evidence of a negative impact.18,19 
 
In contrast to professionals’ concerns, parents and adolescents have expressed interest in 
receiving genomic findings that may not immediately impact a child’s care.20-23 Adolescents in 
one study of stakeholders’ views of reporting results from genome-scale sequencing expressed 
interest in adult-onset results and in being involved in decision making about whether to learn 

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these results.23 Half of a sample of British adults felt that parents should be able to test their 
children for adult-onset conditions, even though some acknowledged that commonly stated 
reasons for deferring such testing to adulthood (e.g., stigma, fear of discrimination) were valid 
reasons.22 In other studies, parents have expressed interest in their children receiving adult-onset 
genomic results even if those results are not medically actionable.20,21 Parents have described that 
researchers have a responsibility to notify them of secondary genomic findings from research 
testing of their children, even of for untreatable adult-onset diseases like Huntington disease.21 
 
This interest among children and parents in learning adult-onset genomic findings is consistent 
with our preliminary studies. First, several members of the Geisinger Precision Health Youth 
Advisory Council of local 14- to 17-year-olds, most of whom are female, have expressed an 
interest in learning adult-onset genomic results (e.g., pathogenic BRCA1/2 variants). Second, we 
convened focus groups of parents of pediatric participants in Geisinger’s MyCode Community 
Health Initiative (a genomic biobank linked to electronic health record data) to assess their 
interest in receiving results for their children for an adult-onset condition such as Lynch 
syndrome. These focus groups used a deliberative engagement format and case scenarios to help 
parents understand professional organizations’ perspective and react to a hypothetical scenario 
of receiving a Lynch syndrome result for their child. Nearly all participants wanted Lynch 
results for their children, saying that the importance of these results to their children’s future 
health outweighed the right of children to make their own testing decisions once they reach 
adulthood.24 Consistent with similar research,21 parents proposed that some families would 
benefit from additional counseling to accompany the disclosure of results. Finally, we analyzed 
essays written by high school students for the 2016 American Society of Human Genetics 
(ASHG) DNA Day Essay Contest. Students were asked to name an adult-onset genetic 
condition and defend or refute the 2015 ASHG recommendation to defer testing for adult-onset 
conditions until adulthood.13 Of the 205 students who wrote about HBOC syndrome, 56% 
argued for BRCA1/2 testing before adulthood, citing reasons such as prevention and life 
planning.25 
 
In addition to these psychosocial and healthcare utilization concerns about informing children 
and their parents about adult-onset findings, deciding whether to disclose findings may have 
legal implications. Genetic professionals have long been concerned about legal liability,26 
including risk for liability associated with researchers’ decisions to return findings to or withhold 
them from individual participants. In a traditional tort action, a plaintiff must prove that there 

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was a breach of a duty (or failure to act according to the applicable standard) that caused an 
injury. The “loss of chance” doctrine is a legal theory27 available in some states that enables a 
plaintiff to recover money from a defendant whose breach of duty caused a reduction in the 
chance of a favorable outcome (such as a delayed diagnosis resulting in a diminished chance of 
recovery from a pre-existing medical condition). 
There is a paucity of critical analysis of the “loss of chance” doctrine as it relates to genomic 
research and medicine, particularly regarding returning or postponing the return of adult-onset 
genomic findings to children. This is despite the acknowledgement by some scholars of its 
relevance to the issue of secondary (or additional28) genomic findings.26,29 While the “loss of 
chance” doctrine made its first court appearance 50 years ago30 and its first law journal 
appearance 35 years ago,31 there remain very few entries in PubMed. The American Law 
Institute, which issues Restatements “to clarify, modernize, and otherwise improve the law,”32 
has not yet taken a position on the doctrine.33 This legal doctrine is poorly understood under any 
fact pattern or scenario in the context of returning adult-onset findings to children and manifested 
differently across the states34-37 (often with a commingling of distinct concepts of causation and 
valuation of compensable damages).31 Therefore, conclusions about the doctrine’s applicability 
to genomic medicine broadly or to the debate over returning adult-onset genomic findings to 
children specifically cannot be drawn from general legal discussions. 
 
A dearth of empirical data has prevented resolution of the debate over returning adult-onset 
genomic findings to children. The available evidence of children’s psychosocial outcomes is 
limited by the small number of studies; a focus on pediatric-onset conditions; methodological 
differences that hinder comparisons; and a lack of longitudinal follow-up that would facilitate a 
clear understanding of how adult-onset genomic findings impact children and families over 
time.18,19,38 There is broad recognition of this lack of data12,39 and strong support for using data to 
resolve the debate and develop best practices.11,38,40 
 
2.0 OBJECTIVE AND AIMS: 
 
Our program’s long-term goal is to determine how best to use genomic information to guide care 
over the course of a child’s development in ways that maximize the physical and psychosocial 
health of children and their families. As one of the first empirically driven studies designed to 
achieve this goal, we propose to assess the psychosocial, behavioral, and legal impact of 
disclosing adult-onset genomic findings to children and their parents. Leveraging our experience 

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in returning medically actionable genomic findings to adults enrolled in Geisinger’s MyCode 
Community Health Initiative, we will augment the existing Genomic Screening and Counseling 
program with support from clinical psychologists and social workers with expertise in pediatric 
and adolescent development. Based on available literature on the impact of informing children 
about their genetic condition or their hereditary breast cancer risk, and on our preliminary studies 
with parents of pediatric MyCode participants, we anticipate that there will be no difference in 
primary psychosocial outcomes between adolescents and parents who receive an adult-onset 
finding compared with those who receive a pediatric- onset finding or those who do not receive a 
genomic finding. Testing this hypothesis will provide a previously unavailable evidence base for 
programs that are wrestling with whether, or how, to disclose genomic results related to adult- 
onset conditions to children and families. 
This study will be conducted via two pathways for enrollment - retrospective and prospective. 
The prospective approach involves recruiting pediatric MyCode participants with an expected 
genetic testing result and their parents before confirming the result via clinical genetic testing (as 
described in the grant proposal). The retrospective approach involves beginning with contacting 
MyCode adult participants who have a clinically confirmed genetic test result (also known as 
MyCode probands) and recruiting their pediatric relatives (who may not be MyCode participants 
or even Geisinger patients). We will conduct a longitudinal, mixed-methods cohort study of 
primary and secondary psychosocial outcomes among pediatric participants and their parents, 
and health behaviors related to receiving an adult- or pediatric-onset genomic result. Data will be 
gathered via quantitative surveys using validated measures of distress, family functioning, 
quality of life, body image, perceived cancer/heart disease risk, genetic counseling satisfaction, 
genomics knowledge, and adjustment to genetic information. Data will also be gathered via 
qualitative interviews with adolescents and parents; electronic health record review, and self- 
reported performance of risk reduction behaviors. 
We will also conduct empirical and theoretical legal research to examine the loss of chance 
doctrine and its applicability to genomic research. In so doing, we will provide urgently needed 
empirical data regarding the psychosocial and behavioral impact of returning adult-onset 
genomic findings that will inform debates about whether children and families should be notified 
of such findings. The legal analysis will provide important context to further inform policy 
discussions, clarifying legal pressures that, if unaddressed by experts in ethical, legal and social 
implications, could require return of all findings regardless of timing of disease onset. 
The proposed study will address the following related, but not overly dependent, aims. 

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Aim 1: Determine whether anxiety, depression, family functioning, and health-related quality of 
life differ at 12 months post-disclosure among adolescents and parents who: 1) receive an adult- 
onset result; 2) receive a pediatric-onset result; or 3) do not carry a familial variant. 
Aim 2: Assess performance of recommended risk management behaviors among adolescent 
participants with a pediatric-onset result. 
Aim 3: Analyze the applicability of the “loss of chance” tort doctrine to policies regarding the 
return or deferral of adult-onset genomic results to children. 
Data from this innovative landmark study will inform policies and practices on national and 
international groups who are developing plans for performing genome-scale testing of children. 
3.0 PROCEDURES: 
3.1 Overall Research Design 
We propose a longitudinal, observational cohort study using mixed methods to compare 
change in psychosocial outcomes and health behaviors among three study groups of 
pediatric participants and their parents. 
1. Group 1 - those with a pathogenic variant in a gene associated with adult onset of 
disease (n=37 adolescents, 112 parents) 
2. Group 2 - those with a pathogenic variant in a gene associated with pediatric onset of 
disease or with risk reduction interventions that begin in childhood (n=37 adolescents, 
112 parents) 
3. Group 3 - those who do not carry the familial variant (n=37 adolescents, 112 parents) 
Patient identification and enrollment will use methods that are HIPAA-compliant, IRB-approved 
and recommended by the MyCode Ethics Advisory Council. The Council membership includes 
Geisinger patient representatives and nationally recognized bioethicists with expertise in genomic 
medicine, one of whom is a pediatrician. Both retrospective and prospective enrollment will 
include an informed consent visit in which psychosocial variables such as anxiety and depression 
will be assessed via a baseline survey among parents and adolescents at enrollment (T1). 
Consistent with Geisinger policy, children ages 7-17 will be asked to give assent to participate. If 
a child does not want to assent to participate, he or she will not be enrolled into the study 
(regardless of their parents’ preference regarding enrollment). Parents of children who do not give 
assent will be ineligible to participate. Parent-participants will be asked to assess psychosocial 
outcomes for themselves and for their children. Consistent with co-investigator Angela 
Bradbury’s research on the experience of adolescent girls from families at increased risk for breast 

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cancer,42 pediatric participants ages 11-17 years at enrollment (or who age into this adolescent age 
group) will also participate in quantitative surveys and qualitative interviews. 
 
Pediatric participants (and potentially their untested parents) in the retrospective cohort will be 
offered cascade genetic testing as part of this study. Consistent with the original grant proposal, 
clinical confirmation of the expected pathogenic variant detected via MyCode sequencing will be 
a condition of enrollment for the prospective cohort. The outcome of the cascade genetic testing 
(for the retrospective cohort) or clinical confirmation testing (for the prospective cohort) will be 
disclosed during a disclosure visit with a genetic counselor. During this visit, genetic counselors 
will observe the participant’s reaction and will perform a psychosocial assessment. Genetic 
counselors are experts in conducting psychosocial assessment and brief psychosocial counseling. 
The study Clinical Psychologists will review the genetic counselor’s approach to psychosocial 
assessment and provide input in accord with the Psychologists’ expertise. During the disclosure 
visit, the Genetic Counselor will provide participants with contact information for the study 
Clinical Psychologists. Participants can reach out to the clinical psychologists if and whenever 
they feel necessary during the study. The study Clinical Psychologists will conduct therapeutic 
consults as needed and conduct periodic psychosocial assessments of adolescent participants 
with adult-onset results. The study Clinical Psychologists will also do a 1-month check-in (after 
T2 data collection) for psychoeducation and mood check for all participants in groups 1 & 2. 
Validated surveys will be used to measure outcomes (Table 1) in each study group at 1 month 
(T2), 6 months (T3), and 12 months (T4) post-disclosure visit. We will conduct qualitative 
interviews with a subset of at least 45 participants in each of the two study groups who receive a 
genomic result to better understand the lived experience of adolescents with an actionable 
genomic finding and their parents. Data collection will continue after the grant funding ends 
because of Geisinger Research Division’s commitment to following the study cohort. To address 
the legal specific aim, Dr. Wagner will lead the study team’s legal experts in examining and 
monitoring the loss of chance doctrine in medical malpractice cases in federal and state courts 
across the United States and in monitoring legislative developments relating to the loss of chance 
doctrine as it applies to returning adult-onset genomic results to children. 
Table 1. Outcomes, covariates, time points and validated measures in quantitative surveys. 
Data 
Collection 
Method 
Domain 
Validated Measure 
Time 
Points 
Completed 
By 
Aim 1 – Psychosocial Outcomes among Study Groups 

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Quantitative 
survey 
Outcomes – All Groups 
General anxiety and 
depression* 
• Assessment of symptoms of DSM-IV anxiety and 
depression in children (55) 
• Hospital Anxiety & Depression Scale (58) 
T1, T2, T3, 
T4 
P/A 
Family functioning 
and cohesion* 
General Functioning subscale (short form) of 
McMaster Family Assessment Device (59) 
T1, T2, 
T3, T4 
P/A 
Health-related quality 
of life* 
CDC HRQOL– 4 (56) 
T1, T2, 
T3, T4 
P/A 
Body image 
Body Image Scale (60) 
T1, T2, 
T3, T4 
A 
Self-esteem 
Rosenberg Self-Esteem Scale (61) 
T1, T2, 
T3, T4 
A 
Decision regret 
Decision Regret Scale (62) 
T2, T4 
P 
Patient satisfaction 
Genetic Counseling Satisfaction (63) 
T2 
P 
Family communication 
Family communication of genetic test results (66) 
T2, T4 
P 
Covariates – All Groups 
Psychological flexibility 
• Acceptance and Action Questionnaire – II (64) 
• Avoidance and Fusion Questionnaire for Youth(65) 
T1, T2, T3,
T4 
P/A 
Family communication 
Family communication of genetic test results 
T2 
P 
Lifestyle behaviors 
□ Physical activity, diet, smoking and vaping (67) 
□ Alcohol consumption (57) 
T1, T3, T4
A 
Information seeking 
Health Information Orientation Scale (68) 
T1 
P 
Personal utility 
Perceived utility of whole genome sequencing (69) 
T1, T2, 
T3, T4 
P 
Perceived risk 
Perceived cancer/heart disease risk (43, 70) 
T1, T2, 
T3, T4 
P/A 
Health literacy 
Brief health literacy scale (71) 
T1 
P 
Genomic Literacy 
Knowledge of genome sequencing (72) 
T1 
P 
Outcomes – Participants with Genomic Result – Groups 1 and 2 
Condition specific 
distress 
Children’s Revised Impact of Events Scale (75) 
T2, T3, T4
P/A 
Adjustment to genetic 
information 
Psychological adaptation to genetic information scale (74) 
T2, T3, T4
P 

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Patient education and 
empowerment 
Health Education Impact Questionnaire (76) 
T2, T3, 
T4, 
P 
Qualitative 
interview 
Constructs for which 
validated measures do 
not exist (e.g. vulnerable
child syndrome, right to 
an open future) 
N/A 
T2, T4 
P/A 
Psychosocial 
assessment 
Disclosure 
Visit 
P/A 
Observation 
of reactions to 
disclosure 
Disclosure 
Visit 
P/A 
Aim 2 – Risk reduction Initiation among Group 1 and 2 Parents 
Quantitative 
Survey 
Initiation of risk 
management behaviors* 
Adapted from risk management in unaffected women with 
pathogenic BRCA1/2 variants (73) 
T4 
P 
EHR Review 
Initiation of risk 
management behaviors* 
N/A 
T4 
*Primary outcomes, T1=baseline; T2= 1-month post-disclosure; T3=6-months post-disclosure; T4=12- months 
post-disclosure, P=Parent of minor (ages 0-17), A=Adolescent (ages 11-17). 
 
3.2 Detailed Study Procedures: 
3.2.a. Retrospective Recruitment 
For retrospective recruitment, we will ascertain study participants via adult MyCode 
probands, offer cascade testing to their minor relatives who have not had testing for a 
familial variant, and assign them into one of the three groups based on their result. At least 
one parent will participate for each pediatric participant. If the parent is a non-proband and 
has not undergone genetic testing for the family variant, the genetic counselor may offer 
genetic testing to the parent even before offering genetic testing to the child, as indicated. 
We will then assess psychosocial outcomes among adolescents (and parents) who receive 
an adult-onset result (group 1), pediatric-onset result (group 2), or do not carry the familial 
variant (group 3). We will also assess self-reported risk management behaviors among 
adolescents with a pediatric-onset result (group 2). 
Following the informed consent visit, psychosocial variables such as anxiety and depression will be 
assessed via a baseline survey among parents and adolescents at enrollment (T1). Participants will then 
be scheduled for a pre-test visit with a genetic counselor via telemedicine (with in-person appointments 
available per patient request). If the participant agrees to proceed with genetic testing after speaking 
with a counselor, they will provide either a buccal sample or blood sample for analysis. About a month 
later, the participant’s result (positive or negative) will be returned to the genetic counselor, who will 

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then conduct a telemedicine or in-person disclosure visit with the participant and their parent(s). 
During this visit, genetic counselors will observe the participant’s reaction and will perform a 
psychosocial assessment. 
 
3.2.b. Retrospective Study Population: 
The study sample will be drawn from all pediatric (ages 0-17 years) relatives of MyCode 
probands with an autosomal dominant condition and their parents. Both Geisinger and non- 
Geisinger minor participants are eligible for participation via the retrospective pathway. At 
least one parent will be enrolled for each pediatric participant. Parents of children ages 0- 
10 years at enrollment will participate in data collection; parents of children ages 11-17 
years at enrollment and their children will participate in data collection. 
 
Table 2: Ascertainment and Eligibility for Retrospective Enrollment 
Procedure 
Revised 
Ascertainment 
Begins with MyCode adult 
participant with clinically 
confirmed adult- or pediatric 
consent variant 
Eligibility – MyCode status 
Minor relatives of MyCode adult 
probands and minors’ parents 
Eligibility – Geisinger 
patient status 
Includes Geisinger and non- 
Geisinger minor participants 
Eligibility – genetic 
conditions 
Autosomal dominant conditions 
on MyCode genomic screening 
list are eligible (excludes 
hereditary hemochromatosis, 
MUTYH-associated polyposis, 
Wilson disease) 
Inclusion Criteria: 
• 
Any pediatric relative of a MyCode proband who has received an autosomal dominant 
result and at least one of their parents. 
Exclusion Criteria: 
• 
Individuals who have already had genetic counseling for any of the actionable target 
conditions as part of their routine clinical care or participation in other research. 
• 
Relatives of MyCode probands who are deceased or have withdrawn from MyCode will 
not be contacted for this study. 

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3.2.c. Retrospective Enrollment Procedures: 
 
1. Study staff will send adult MyCode probands who have received a result in an 
autosomal dominant condition (which excludes MUTYH and HFE genes) an online 
REDCap survey via the Patient Portal or email to determine whether they have minor 
relatives who have not had cascade testing for the familial genetic variant. Staff will not 
contact any MyCode probands who are deceased, have withdrawn from the study, or 
have asked not to be contacted (minimize contact group). Study staff (or the survey core 
group) will call MyCode probands who do not have a Patient Portal or email to 
determine if they have any eligible relatives that may be interested in the study. The 
survey will include the study phone number in the introduction text of the survey to give 
probands the option to call the study team directly if they do not wish to enter their 
relative’s information online. The survey will ask the proband if they have any of the 
following relatives who have not been tested for the familial variant: o Minor children o 
Adult children with minor children o Minor siblings o Minor nieces or nephews 
If the proband does have any of the minor relatives listed above, the survey will ask for 
the contact information for those minor’s parent/guardian (such as name, address, email, 
and phone number). 
2. Study staff or the survey core group may call probands who do not complete the survey 
(or partially complete) to complete the survey over the phone. If the proband then states 
that they have eligible untested minors, the survey core staff will proceed to offer a 
telemedicine appointment with a research assistant to discuss the study further. 
3. As survey responses are returned, study staff will send the parents of these potential 
participants a study introduction letter via a Patient Portal message, email, or mailed 
letter that describes the study, including a copy of the elements of informed consent, and 
an opportunity to opt out from any further contact. 
4. About two weeks after study introduction letters are sent, Geisinger’s Survey Research 
Core will call those potential participants who have not opted out and offer a 
telemedicine appointment to discuss a study on their beliefs about MyCode and 
receiving genomic results. In person consenting appointments may also be available per 
patient request. 
o If the participant agrees to attend a consenting visit, the Survey Core team will: 

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 Schedule the consenting visit with the study team’s research assistants 
using a shared calendar. 
 Collect the participant’s email address. This will be required for 
participants who choose to complete a telemedicine visit in order to send 
the telemedicine appointment invitation. 
o If the potential participant declines to participate in the study, the Survey Core 
member will ask the participant if they mind sharing why they are declining and 
will thank them for their time (see the revised recruitment phone script attached 
under study documents). 
5. Research assistants will be responsible for leading the telemedicine and in-person 
consenting visits. If the participant agrees to participate after learning about the study, 
research assistants will obtain written documentation of consent during the study visit. 
o For in-person visits, the participant will sign two hard copies of the consent form 
and will keep one of the copies for their records. Children of assenting age (7-17 
years) will also be required to sign the paper forms if they agree to assent. 
o For telemedicine consenting visits, the participant will provide their e-signature 
via a Geisinger-approved platform (e.g the InTouch platform approved for 
telehealth visits). Research assistants will explain the study, answer any questions 
the participant may have, and will share their computer screen so that they can 
review the consent form via the screen sharing feature. Children of assenting age 
(7-17 years), will also be asked to attend the telemedicine visit and sign the online 
form if they assent, with the research assistant as a witness. A PDF archive of the 
participant’s signed consent form will then be saved electronically and will be 
sent to the participant through the Patient Portal or email. 
6. During the consenting appointment, consenting parents and assenting adolescents ages 
11-17 years will be asked to complete a brief baseline survey (T1) assessing 
psychosocial outcomes and health behaviors and beliefs. If the visit is conducted in 
person, the survey will be completed on an iPad. If the visit is completed via 
telemedicine, the survey will be sent securely via email through REDCap for the 
participant to complete. The parent and adolescent participant will complete the survey 
during the telemedicine visit (privately and separately) so that study staff can assist if 
the participant has questions or technological issues. After completing the baseline 

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survey, participants will be scheduled for a pre- test visit with a genetic counselor prior 
to ending the telemedicine visit. 
Participants who live outside of the state of Pennsylvania will not be scheduled to see 
a Geisinger genetic counselor due to state licensure laws. Instead, our study team will 
refer that patient to Genome Medical™ to continue with pre-test counseling and 
potential genetic testing. Genome Medical™ is a genetic counseling company made 
up of counselors and physicians with licensures in all US states. Following the 
participant’s consent, Geisinger study staff would upload the participant’s name, date 
of birth, gene, variant of interest, and contact information into Genome Medical’s 
secure platform. The Geisinger study team will then immediately schedule the 
participant within the Genome Medical portal to see one of their genetic counselors at 
a date and time that is convenient. Genome Medical staff will send the participant an 
email with their appointment information and will conduct genetic counseling and 
testing for the participant. 
7. During the pre-test visit with the genetic counselor (at Geisinger or Genome Medical), 
the counselor will review the procedure for cascade testing and will review the possible 
testing outcomes (i.e., positive or negative for familial variant). If the parent and child 
(of assenting age) agree to proceed with cascade testing for the child, the counselor will 
obtain a blood or buccal sample in clinic, via home phlebotomy, or via a lab kit (for 
saliva). They will schedule a genetic counseling disclosure visit (either in person or via 
telemedicine, per participant’s preference and regular clinical genetic counseling 
practice) in about one month, which will allow sufficient time for clinical confirmation 
of variants. 
8. Participants in group 1 and 2 will take part in a genetic counseling visit via telemedicine 
(using the Geisinger-approved telehealth platform or Genome Medical’s telehealth 
platform) or in-person per the participant’s request. During this visit, participants in 
groups 1 and 2 will learn of their result (see Result Disclosure Procedures on page 11). 
Participants in group 3, those with a negative result, will be notified of their group 
status via a telephone call or a Patient Portal message. 
9. Following the genetic counseling disclosure visit, data collection will continue via 
REDCap surveys at specified timepoints, qualitative interviews, and electronic health 
record review (or self-report) of health behaviors associated with the genetic result. (See 

Protocol v1.23 6/28/23 
 
 
detailed study procedures for more information). Group 3 participants will only 
participate in survey data collection. 
 
*MyCode probands may also be referred to the PRoGRESS study through the MyCode 
Genomic Screening and Counseling program at the time of their MyCode result 
disclosure. If a proband expresses interest in pursuing cascade testing for their child, the 
genetic counselor will introduce the PRoGRESS study to the patient. If the patient wants 
to learn more about the PRoGRESS study, the genetic counselor will contact the study 
team so that they can directly call the patient to schedule a consenting visit (step 5 
above). 
Additionally, through our partnership with Genome Medical, out of state relatives of 
MyCode probands who are seen by a Genome Medical genetic counselor will be provided 
a study information letter and will be directed to contact the study team by phone if they 
are interested in learning more and/or participating in PRoGRESS. 
 
Parents and adolescents who have consented to join the study but have not submitted a 
sample for testing and therefore have not had a disclosure visit with a genetic counselor 
will receive modified surveys at 6 and 12 months after their initial pre-test visit. 

Protocol v1.23 6/28/23 
 
 
Figure 1: Retrospective Enrollment Flowchart 
3.2.d. Prospective Recruitment 
Prospective recruitment for this study begins when a pediatric MyCode participant has a 
potential result in a gene that is on the Geisinger clinical return list. The study team will 
approach potential participants prior to clinical confirmation of any suspected 
pathogenic variants (i.e., after bioinformatic identification of a suspected pathogenic 
variant but before clinical confirmation of the variant’s pathogenicity). 
 
3.2.e. Prospective Study Population 
The study sample will be drawn from all pediatric (ages 0-17 years) MyCode probands 
with a suspected genetic result and their parents as well as age and sex matched controls 
and their parents. At least one parent will be enrolled for each pediatric participant. 
Parents of children ages 0-10 years at enrollment will participate in data collection; 

Protocol v1.23 6/28/23 
 
 
parents of children ages 11-17 years at enrollment and their children will participate in 
data collection. 
 
Inclusion Criteria: 
• 
Any pediatric MyCode proband who has a suspected autosomal dominant result and 
at least one of their parents. 
• 
Age- and sex-matched pediatric MyCode participants (who have not received a 
result) and at least one of their parents Exclusion Criteria: 
• 
Individuals who have already had genetic counseling for any of the actionable target 
conditions as part of their routine clinical care or participation in other research. 
• 
MyCode probands who are deceased or have withdrawn from MyCode will not be 
contacted for this study. 
 
3.2.f. Prospective Enrollment Procedures: 
1. Variant scientist will ask the Data Broker for a list of potential pediatric participants who 
have had a suspected pathogenic variant detected. 
2. Variant scientist will confirm that the participant is eligible for variant confirmation. 
3. Variant scientist will update a shared folder excel sheet with potential participants 
demographic and sample information. 
4. Research assistants will send the parents of these potential participants a letter via the 
Patient Portal, email, or mail that describes the study, including a copy of the elements of 
informed consent, and an opportunity to opt out from any further contact. 
5. About two weeks after this letter is sent, Geisinger’s Survey Research Core will call those 
potential participants who have not opted out and offer a telemedicine or in- person 
appointment to discuss a study on their beliefs about MyCode and receiving genomic 
results. 
o If the participant agrees to attend a consenting visit, the Survey Core team will: 
 Schedule the consenting visit with the study team’s research assistants 
using a shared calendar. 
 Collect the participant’s email address. This will be required for 
participants who choose to complete a telemedicine visit in order to send 
the telemedicine appointment invitation. 

Protocol v1.23 6/28/23 
 
 
o If the potential participant declines to participate in the study, the Survey Core 
member will ask the patient if they mind sharing why they are declining and will 
thank them for their time (see the revised recruitment phone script attached under 
study documents). 
o If parents decline participation and their child is suspected to have a pathogenic 
adult-onset result, the study team’s variant scientist will have their child’s sample 
held for clinical confirmation until the child reaches age 18 years. 
o If parents decline participation and their child is suspected to have a pathogenic 
pediatric-onset result, the variant scientist will proceed to clinical confirmation of 
the result and, if confirmed, follow the established clinical return procedure. This 
recruitment approach is consistent with the MyCode philosophy of notifying 
participants of actionable findings.41,43 
6. Research assistants will be responsible for leading the telemedicine and in-person 
consenting visits. If the participant agrees to participate after learning about the study, 
research assistants will obtain written documentation of consent during the study visit. 
o For in-person visits, the participant will sign two hard copies of the consent form 
and will keep one of the copies for their records. Children of assenting age (7-17 
years) will also be required to sign the paper forms if they agree to assent. 
o For telemedicine consenting visits, the participant will provide their e-signature 
via a Geisinger-approved platform (e.g the InTouch platform approved for 
telehealth visits). Research assistants will explain the study, answer any questions 
the participant may have, and will share their computer screen so that they can 
review the consent form via the screen sharing feature. If the participant agrees to 
consent in the study, they will provide their signature directly on the consent form 
using their mouse. Children of assenting age (7-17 years), will also be asked to 
attend the telemedicine visit and sign the online form if they assent, with the 
research assistant as a witness. A PDF archive of the participant’s signed consent 
form will then be saved electronically and will be sent to the participant through 
the Patient Portal or email. 
7. During the consenting appointment, consenting parents and assenting adolescents ages 11- 
17 years will be asked to complete a brief baseline survey (T1) assessing psychosocial 
outcomes and health behaviors and beliefs. If the visit is conducted in person, the survey 
will be completed on an iPad. If the visit is completed via telemedicine, the survey will be 
sent securely via email through REDCap for the participant to complete. The parent and 

Protocol v1.23 6/28/23 
 
 
adolescent participant will complete the survey during the telemedicine visit (privately and 
separately) so that study staff can assist if the participant has questions or technological 
issues. 
8. For prospective enrollees, we may require an additional MyCode blood sample from the 
child if there is not a sufficient sample in the MyCode biobank. This sample will be drawn 
and paid for by MyCode. Note: Obtaining an additional MyCode blood sample is covered 
under the MyCode protocol (IRB# 2006-0258). 
9. After completing the baseline survey, participants will be scheduled for a genetic 
counseling disclosure visit (either telemedicine or in-person, as per patient’s preference 
and regular clinical genetic counseling practice) in one month, which will allow sufficient 
time for clinical confirmation of variants in Groups 1 and 2 participants. 
10. Participants in group 1 and 2 will take part in a genetic counseling visit via telemedicine 
(using the Geisinger-approved telehealth platform) or in-person per the participant’s 
request. During this visit, participants in groups 1 and 2 will learn of their result (see 
Result Disclosure Procedures on page 11). Participants in group 3 will be notified of their 
group status via a telephone call or Patient Portal message. 
11. Following the genetic counseling disclosure visit, data collection will continue via 
REDCap surveys at specified timepoints, qualitative interviews, and electronic health 
record review (or self-report) of health behaviors associated with the genetic result. (See 
detailed study procedures for more information). Group 3 participants will only participate 
in survey data collection. 
 
 
 
 
 
 
 
 
 
 
 

Protocol v1.23 6/28/23 
 
 
Figure 2: Study Groups Prospective Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol v1.23 6/28/23 
 
 
Figure 3: Prospective Enrollment Flowchart 
 
 
3.3 Result Disclosure Procedures (Retrospective and Prospective) 
Parents of pediatric participants with a clinically confirmed pathogenic result in one of the 
actionable genes of interest will learn of their result in an in-person or telemedicine consultation 
conducted by a genetic counselor. Telemedicine appointments through the Geisinger-approved 
system or Genome Medical’s telehealth platform allow the patient and counselor to join the visit 
from home, but still provide face to face care. We will disclose results to all pediatric participants 
who have assented to the study. If a child is of the age of assent and not present at the initial 
disclosure visit, the study team will work with the participants parent(s) to disclose the result to 
that child at a later date. 
We will ask parents for guidance on how to disclose results to their assenting children (e.g., at 
the initial disclosure consult or at a separate consult). As is standard of care in genetic 
counseling,44 discussion of the result will include medical interpretation of the result and 
associated risk management recommendations; referrals of patients to the appropriate clinicians 

Protocol v1.23 6/28/23 
 
 
for medical evaluation and, when indicated, initiation of risk reduction procedures; provision of 
emotional support; and a recommendation to encourage family communication of results and 
cascade testing. Given published concerns about psychosocial adjustment to this genomic risk 
information,11-17 one of the study Genetic Counselors (or one of Genome Medical’s genetic 
counselors) will perform a psychosocial assessment and will schedule separate therapeutic 
interactions with patients who exhibit clinically significant distress. The pediatric clinical 
psychologist will coordinate meeting at least every three months with all adolescents with an 
adult-onset genomic result and address any clinically significant distress per his standard clinical 
practice. These quarterly study visits will be covered by the study for the duration of the study. 
If the patient and psychologist decide to continue care outside of this study once it is over, they 
can do so but it will be considered routine care. We will also offer adult participants regular 
consults with the study’s adult clinical psychologist. 
Consistent with current practice among Geisinger genetic counselors returning genomic findings 
to adults, the study genetic counselor will contact parents at one- and six-months post-disclosure 
to assess ongoing informational and support needs. 
Because study clinical psychologists do not have licenses to practice outside the state of 
Pennsylvania, Genome Medical genetic counselors will manage any instances of psychological 
distress in out-of-state participants per Genome Medical’s standard practice, which includes 
coordinating care with a local psychologist. 
 
4.0 DATA COLLECTION: 
Data will be gathered from all study groups via quantitative surveys using validated measures of 
distress, family functioning, quality of life, body image, perceived cancer/heart disease risk, 
genetic counseling satisfaction, genomics knowledge, and adjustment to genetic information. 
Data also will be gathered via qualitative interviews with adolescents and parents; electronic 
health record review, and self-reported initiation of risk reduction behaviors among Group 2 
participants and parents. Group 3 participants will not be included in interviews or electronic 
health record review. Additionally, consented parents and adolescents who have not submitted 
a sample for testing will receive modified surveys at 6 and 12 months after their pre-test visit. 
 
We will also conduct empirical and theoretical legal research to examine the loss of chance 
doctrine and its applicability to genomic research. 
 
We will use a mixed-methods data collection approach. Quantitative surveys using validated 

Protocol v1.23 6/28/23 
 
 
measures of relevant psychosocial outcomes will be administered to participants in each study 
group at in-person or telemedicine enrollment and at 1 month, 6 months and 12 months post- 
disclosure visit. Surveys will be administered via participants’ preferred method, i.e., phone, 
online, or paper. We will conduct qualitative interviews with a subset of at least 45 participants 
each in the two study groups who receive a genomic result to better understand the lived 
experience of adolescents with an actionable genomic finding and of their parents. These 
interviews will be conducted at 1 month and 12 months post-disclosure. We will also query the 
electronic health record (EHR) when possible (for Geisinger patient-participants) and will assess 
the initiation of self- reported risk reduction behaviors among Group 2 participants and parents. 
Geisinger study staff will have access to Genome Medical’s patient portal for those out of state 
study participants to review any data, such as result disclosure information or referrals. 
4.1 Data Collection Procedures 
To ensure a high response rate, surveys will be offered via multiple modalities, including phone, 
Internet, and paper (if requested). At enrollment (T1), 1 month (T2), 6 months (T3), and 12 
months (T4) post-disclosure consultation, a secure REDCap link will be emailed to participants 
which will bring them to the quantitative survey. During the disclosure visit, no surveys will be 
conducted. If the participant does not complete the online survey within two weeks, study staff or 
data technicians in Geisinger’s Survey Research Core will contact the remaining participants to 
administer quantitative surveys over the telephone. Text message reminders may also be sent to 
select participants who have agreed to receive Geisinger text message reminders or have agreed 
to receive PRoGRESS project specific text messages during the consent process.  Phone surveys 
will be conducted using computer-assisted telephone interviewing to ensure completeness and 
reliability of data. Survey Core data technicians have substantial training in administering 
surveys to ensure high-quality data and will undergo additional project-specific training. We 
estimate that the T1 survey will take 30 minutes to complete; T2, T3 and T4 surveys should take 
25 minutes to complete.  
 
To more fully understand the lived experience of parents and pediatric participants, we will 
conduct semi-structured interviews via telephone with up to 45 participants in each of Groups 1 
and 2 (i.e., those with a genomic result, 90 participants total). We will not conduct interviews 
among Group 3 participants, as one key value of the proposed study lies in its focus on 
understanding the experience of children and families with genomic results. The interviews will 
be conducted among a sample of Group 1 and 2 participants in Years 1-4. About 15 interviews in 
each group will be conducted among parents of younger children (ages 0-10) and will, therefore, 

Protocol v1.23 6/28/23 
 
 
not include the child in the interview. Fifteen additional interviews will be conducted with 
parents of children ages 11-17, with a final 15 interviews being conducted among children ages 
11-17. Although some children may only have one parent-participant, we will encourage both 
parents to participate in a single interview when both parents are participating in the study. 
Because we recognize that interviewed participants may exhibit heterogeneity in condition type 
and age of the child, we are prepared to conduct additional interviews as necessary to achieve 
thematic saturation regarding common experiences as well as to illuminate possible breadth of 
experiences with this process. 
 
The semi-structured format will allow us to ask all participants about pre-selected constructs for 
which established measures do not exist (e.g., vulnerable child syndrome, right to an open future) 
while allowing them to inform us of constructs we might not have considered. Conducting 
interviews over the first four study years will allow for assessing changes in experience that may 
be related to changes in practice for the target conditions (e.g., changes in risk management 
recommendations). Should a participant exhibit clinically significant distress during an interview, 
the investigator conducting the interview will refer to clinical psychology as detailed in 
Protection of Human Subjects. Additional qualitative data on the immediate reactions to 
receiving a result will be gathered in clinical documentation during the disclosure visit by the 
Genetic Counselor. The visit will be audio recorded for future review. The study team 
psychologists will work with the Genetic Counselor (who is already trained in psychosocial 
assessment/counseling) to build metrics for identifying clinically significant distress during the 
visit. 
 
We will query the electronic health record, assess self-reported risk reduction behaviors, and 
survey adolescents and parents at 12 months post-disclosure (T4) to determine whether 
adolescents with a pediatric-onset genomic result have begun disease risk management 
behaviors. 
 
Using Westlaw Next, the “loss of chance” doctrine as it appears in medical malpractice cases 
filed in federal and state trial and appellate courts will be examined and monitored, with 
particular attention to cases involving returning or postponing adult-onset results to children (if 
any) and reasonably analogous fact patterns. A 50-state survey will be performed, with 
research focusing on cases filed in the most recent decade in federal and state courts. While 
medical malpractice is a matter of state law, the forum and venue in which such a case is 
litigated can be federal, as confirmed by our preliminary research. Standard legal research 
methodologies will be used to brief cases (e.g., examining the parties, relevant facts, procedural 

Protocol v1.23 6/28/23 
 
 
history, narrow and broad holdings, rules and standards applied, and rationale). Additionally, 
using Westlaw Next and OpenStates.org and Congress.gov, legislative developments relating 
to the “loss of chance” doctrine will be explored. Standard legal research methods (including 
textual analysis, structural analysis, stare decisis and original intent)45-47 will be used to parse 
and analyze bills and statutes identified. 
 
4.2 Participant Compensation: 
Participants will receive a $25 check or gift card for each completed survey (baseline, T1-T3) and interview. 
Participants in groups 1-3 who complete a T4 (12 month) survey will receive a $50 check or gift card. 
 
4.3 Data Management Procedures and Confidentiality: 
Members of the Geisinger Survey Research Core, study staff (project manager and genomic 
counseling assistants), and the research data analyst will have access to PHI in the process of 
administering surveys and extracting data from the EHR, both of which will provide quantitative 
data. The research data analyst will serve as the study’s Data Broker within the Geisinger 
Phenomics and Clinical Data Core. Survey Research Core staff will use Computer Assisted 
Telephone Interviewing to collect and record phone survey data directly into the study’s database 
via procedures coordinated by the Data Broker. The Data Broker and project manager will 
manage all quantitative data, including data extracted from the electronic record and data 
collected via survey. S/he will be responsible for maintaining the study’s quantitative database 
and for de-identifying any shared data. S/he will maintain a separate electronic file linking study 
IDs to participants’ PHI that can be used to share data with the larger study team. Investigators 
will not have access to this file linking study ID to PHI. 
 
To enhance Aim 1 by examining how family communication features influence psychosocial and 
health-related outcomes among parents and adolescents following the disclosure of 1) an adult- 
onset genetic result, or 2) a pediatric-onset result, Dr. Skye Chernichky-Karcher from 
Bloomsburg University will help with the design and implementation of the proposed project 
additions, data analysis, and co-authoring manuscripts from the proposed additions to study Aim 
1. Dr. Skye Chernichky-Karcher will receive a limited data set of collected survey data for 
analysis and reporting of family communication outcomes derived from both parent and 
adolescent surveys and interviews. To protect confidentiality of the data, Dr. Skye Chernichky- 
Karcher may access elements of this limited dataset by remoting in to the Geisinger secured 
network via VPN. 

Protocol v1.23 6/28/23 
 
 
 
Qualitative interviews will be conducted by the study genomic counseling assistants under the 
direction of Mr. Buchanan and Drs. Rahm & Mozersky. The genomic counseling assistants will 
have access to the participants’ PHI; Mr. Buchanan and Drs. Rahm and Mozersky will not. 
Electronic recordings of these interviews will be de-identified before they are sent securely to 
transcriptionists. The investigators performing the qualitative data analyses from these 
transcriptions will therefore be unaware of the participants’ PHI. The genomic medicine 
assistants will work with the Data Broker to securely store the electronic file linking IDs from 
participants who have completed qualitative interviews to their PHI. 
 
Consistent with policies of Geisinger, the Geisinger-Regeneron collaboration, and the clinical 
genetic testing laboratories that perform clinical confirmation of research generated 
pathogenic/likely pathogenic results identified through MyCode, CLIA-confirmed genetic results 
generated through the Geisinger-Regeneron collaboration will be deposited in the ClinVar 
database. ClinVar has been chosen as a preferred repository for clinically relevant data because 
Geisinger is a member of the Clinical Genome Resource (ClinGen) grant. Data will be deposited 
according to the standard deposit schedule of the genetic testing laboratories. Data will be de- 
identified as set forth in the HHS Regulations for the Protection of Human Subjects and the 
HIPAA Privacy Rule. Data submission will be consistent, as appropriate, with applicable national, 
tribal, state laws, and regulations, as well as relevant institutional policies. Our current MyCode 
consent includes information about sharing of de-identified data for broad research use and is not 
restrictive as to the specific repositories that might be utilized.  
 
For out of state participants, patient data shared with Genome Medical™ will be protected to the 
same degree as Geisinger held data via Genome Medical’s secure patient portal. As a covered 
entity, Genome Medical™ has signed an attestation stating that their security controls in place for 
PHI are equivalent to the controls provided for by the National Institute of Standards and 
Technology Special Publication 800-53 (rev. 4), medium impact baseline. Geisinger will directly 
enter the necessary patient data (i.e. patient name, DOB, and contact information) into Genome 
Medical’s secure patient portal only following the participant’s written consent after completing 
the study consenting visit. Geisinger study staff will have access to Genome Medical’s patient 
portal for those out of state study participants to review any data, such as result disclosure 
information or referrals. 
The data generated during the course of this study shall be retained by the Principal Investigator 

Protocol v1.23 6/28/23 
 
 
(PI) for six years as required by Institutional Review Board (IRB) policy. Electronic data will be 
kept on a password protected computer on Geisinger’s secure network. Hard copies of 
documents will also be retained by the PI for at least six years, and maintained in a locked office. 
Data and Safety Monitoring Plan 
This study will utilize an Event Monitoring Committee (EMC) to provide independent study 
oversight focused on the psychosocial wellbeing of pediatric participants. Dr. Bradbury and 
colleagues have used this specialized version of a Data Safety and Monitoring Board (DSMB) 
in studies recruiting girls from families with increased breast cancer risk.1 The EMC improves 
upon the standard DSMB approach by providing additional oversight for studies in which the 
greatest potential risks are psychosocial. Dr. Bradbury and colleagues have suggested that 
EMCs have particular utility in genomic studies with vulnerable populations in which 
investigators are charged with providing additional protection, as is the case for the pediatric 
participants in the proposed study. The EMC takes a proactive approach to attempting to prevent 
adverse events and, if such events occur, rapidly responding to them. The EMC approach seeks 
to recommend study procedures that minimize risks, analyze anticipated and unanticipated 
adverse events, and advise study investigators on how to respond to such events if they occur. 
 
For the proposed study, the EMC will be asked to advise investigators on results disclosure and 
data collection procedures, review and refine protocols for detecting and intervening on clinically 
significant psychosocial outcomes, review de-identified quantitative and qualitative data for 
participant burden and psychosocial concerns, review survey data (e.g., anxiety/depression scale 
scores), and meet with investigators at least quarterly to review study progress and any adverse 
events. As one of their first tasks, the EMC will also determine the ‘stopping rules’ for the study 
(e.g., occurrence of self-injurious behavior or a preponderance of negative psychosocial 
outcomes in adolescent participants with an adult-onset genomic result). Should a serious 
adverse event occur, the EMC will be convened within a week to review the event, provide 
guidance on resolving it, and advise on methods for preventing future events. 
 
Consistent with Dr. Bradbury’s experience, we will seek a 5-member EMC with 
multidisciplinary representation, including an expert in adolescent health, and a biostatistician 
who can review results from the primary quantitative outcomes as the study progresses. 
 
Adverse events will be monitored by the Project Manager (PM). All study staff and clinicians 
will be trained to report adverse events to the PM within 72 hours, with serious adverse events 
reported to the PM and PI within 24 hours. Potential adverse events for this project include 

Protocol v1.23 6/28/23 
 
 
adverse psychological outcomes (e.g., distress), up to and including self-injurious behaviors. Any 
adverse events that occur during a genomic medicine consultation will be managed clinically as 
per the clinical psychologist-led protocol described below under Expected Risks. The study’s 
clinical psychologists will also manage adverse events that occur during quantitative or 
qualitative data collection as described below under Expected Risks. If the genetic counselor 
notes the need for referral to mental health services while conducting a follow-up call with a 
participant, the counselor will enact the protocol described below under Expected Risks. With 
input from the Survey Research Core staff, clinical psychologists and genetic counselor, we will 
actively track and respond to all adverse events and protocol deviations. Once data collection 
begins, investigators, the PM, and Data Broker will meet at least monthly to discuss project 
implementation, address questions or concerns that might arise, and monitor the safety of the 
data collection. The PM will record, review and discuss any deviations or adverse events that 
have occurred since the last meeting. Adverse event forms will be used to report all unanticipated 
events. The report will include date, description and outcome of the event. Unanticipated adverse 
events will be reported within 7 days to the Geisinger IRB, study EMC, and to NHGRI. A 
written follow-up will be submitted within 30 calendar days. All adverse events (serious or not, 
related or unrelated, anticipated or unanticipated) will be reported in regular reporting to the 
EMC and NHGRI. 
 
The Data Broker will maintain security of the study database and file linking study IDs to PHI 
by storing them behind the Geisinger firewall and password encrypting these files. The servers 
on which study data will be kept are in a secure computer room and are backed up daily. 
 
All individuals involved in data collection and clinical care will be trained to document and report 
any deviations from the protocol, adverse events, or unusual responses immediately to the PM and 
PI. The PM, PI, and biostatisticians will monitor data collection procedures on a regular basis for 
quality assurance purposes. 
 
4.4 Data Analysis/ Statistical Considerations: 
For psychosocial outcomes in Aim 1, we have specified a priori each pairwise comparison to be 
of interest. Therefore, all calculations assume 80% power and 5% significance level. Assuming a 
10% dropout and a minimum detectable effect size (change in standard deviation units) for the 
key quantitative psychosocial outcomes is 0.4 for each of the comparison of Group 1 vs. Group 
2, Group 1 vs. Group 3, and Group 2 vs. Group 3, we will need a sample size of at least 447 
participants (112 parents and 37 adolescents in each group). If we are successful in recruiting a 

Protocol v1.23 6/28/23 
 
 
second parent for some of the minors, then we can expect the minimum detectable difference to 
decrease. This effect size is considered moderate in size and is less than the effect size seen in a 
previous study that used the Hospital Anxiety and Depression scale in a sample of adolescent 
girls from families with BRCA1/2 variants5. 
We anticipate that there will be a sufficient sample population to achieve the enrollment goal of 
447 participants (336 adults and 111 adolescents). As of 8/1/2020, 1,582 MyCode participants 
have received a pathogenic/likely pathogenic variant in a gene on the MyCode gene list. 
Excluding autosomal recessive conditions (hereditary hemochromatosis, MUTYH-associated 
polyposis) leaves 1,379 probands we could approach to determine whether they have minor 
relatives who have not been tested for the familial variant. Based on a review of the family 
histories of 100 of these individuals and accounting for 10% of probands being deceased and 
10% of relatives having had cascade testing, we estimate that there will be approximately 1,525 
minor first- and second-degree relatives who have not had cascade testing. To reach the 
enrollment goal, we would need to enroll 22% of available parents and adolescents (336/1,525 
and 112/508, respectively). This recruitment rate seems feasible based on the experience of other 
studies on MyCode participants and their families. Note, too, that the sample population will 
continue to rise through 2021 as several hundred more MyCode probands receive a 
pathogenic/likely pathogenic variant in a gene on the MyCode list. 
5.0 Table 3. EXPECTED RISKS: 
Proposed Harm 
Protection Plan 
Psychological harms 
• 
Negative impact on self- 
esteem/bodyimage 
• 
Stigmatization 
• 
Increased anxiety 
• 
Distress 
• 
Development/worsening of depression 
□ Assess self-esteem, body image, anxiety, 
distress and depression in quantitativesurveys 
□ Survey research staff trained to notify pediatric 
clinical psychologist of clinically relevant 
scale scores 
□ Qualitative researchers notify pediatric clinical 
psychologist of psychological concerns that 
arise during qualitativeinterviews 
□ Pediatric clinical psychologist intervenes 
therapeutically when scale scores are 
clinically 
significant 
or 
qualitative 
interviewers note psychological concerns 

Protocol v1.23 6/28/23 
 
 
 
□ Pediatric clinical psychologist assesses these 
psychological constructs during regular 
sessions and intervenes therapeutically per 
usual clinical practice 
 
Negative effect on family 
 
• 
Negative impact on 
familyrelationships 
 
• 
Distortion of parental impression 
ofchild’s capacity (vulnerable child 
syndrome) 
□ 
 
□ 
Assess family functioning and cohesion in 
quantitative surveys 
Survey research staff trained to notify study 
psychologists of scale scores that indicate 
family is at risk of dysfunction 
□ 
Qualitative researchers notify clinical 
psychologists of family functioning 
concerns that arise during qualitative 
interviews 
□ 
Psychologists and social worker leadfamily 
therapy sessions for families at risk of 
dysfunction 
□ 
Pediatric clinical psychologist assesses 
child’s perceptions of family functioning 
during regular sessions and intervenes 
therapeutically per usual clinical practice 

Protocol v1.23 6/28/23 
 
 
 
Social discrimination and restrictions 
• 
Insurance discrimination 
• 
Social discrimination by peers 
• 
Employment discrimination 
• 
Educational discrimination 
• 
Restricted life choices 
□ 
Insurance 
and 
employment 
discrimination prohibited by Genetic 
Information Nondiscrimination Act of 
□ 
2008 
Pediatric clinical psychologist will assess 
child’s 
perceptions 
of 
school 
performance/treatment 
during 
regular 
sessions and intervene therapeutically per 
□ 
usual clinical practice 
Informed consent and assent process 
notes the potential risk of restricted life 
choices; family cannot participate 
unless child assents 
Autonomy 
• 
Failure to respect future autonomy 
• 
Breach of confidentiality due to 
results disclosure to parents 
• 
Risk of child misunderstanding 
information 
□ 
Informed consent and assent process 
notes the potential risks to autonomy 
and  confidentiality;  family  cannot 
□ 
participate unless child assents 
Risk   of   misunderstanding   of 
information minimized by having a 
genetic counselor experienced with 
pediatric cancer genetics disclose 
results to all assenting pediatric 
participants 
6.0 EXPECTED BENEFITS: 
The study will assess psychosocial outcomes among pediatric participants who do and do not 
receive a genomic result. It will also assess psychological and behavioral outcomes among their 
parents. It is possible that the relatives of participants in Group 1 (adult-onset result) will benefit 
by detecting a previously undetected genetic risk that prompts them to initiate performance of 
behaviors known to greatly reduce cancer or cardiovascular disease risk. As noted above, such 
risk reduction in parents could also directly benefit their children by preventing illness in the 
children’s caretakers. Additional theoretical benefits to pediatric Group 1 participants include 
preparing for the future, positively incorporating the results into their self- image, adopting 
healthy behaviors, and preventing a missed opportunity to report their results to them once they 
reach the age of majority. Pediatric and adult relatives of Group 2 participants may also benefit 
from using this genomic information to reduce their morbidity and mortality. Group 3 

Protocol v1.23 6/28/23 
 
 
participants might benefit by learning that genetic testing found that they do not carry the 
familial pathogenic variant. More broadly, study outcomes will inform best practices for 
incorporating genomic information into the care of pediatric patients and their families. Given 
these anticipated benefits, the risks of participation described above are reasonable. 
 
7.0 BIBLIOGRAPHY 
1. Suckiel SA, Linderman MD, Sanderson SC, et al. Impact of Genomic Counseling on 
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