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FOREST  
FOREST (Family History and Cancer Risk Study)
Georgia L. Wiesner, MD
Director, Vanderbilt Hereditary Cancer Program Ingram Professor of Cancer Research and Medicine Created: November 27, 2019 Revised: April 6, 2020, June 29, 2021, September 17, 2021, October 26, 2021, July 14, 2022 1 FOREST
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table of contents study schema

1. **Background** 2. **Rationale and Specific Aims**
3. **Inclusion/Exclusion Criteria**
4. Enrollment/Randomization 5. Study Procedures 6. Reporting of Adverse Events 7. **Study Withdrawal/Discontinuation** 8. Statistical Considerations 9. Privacy/Confidentiality Issues 10. Follow-up and Record Retention 2 FOREST
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1. background

From the earliest recognition of cancer-prone families over 100 years ago, clinicians have depended on the family health history (FHH) to identify and treat patients and family members who may have a familial cancer syndrome. Once identified, patients can be offered lifesaving, evidence-based management strategies for many of these conditions. In order to fully realize the benefits of genetic healthcare, however, at risk individuals must be recognized, offered genetic counseling and testing, and then referred for specialized therapy or enhanced screening. While this is a promising time for these patients and families, there are significant challenges to implement a modern and efficient care delivery model across the many patient, provider and health system stakeholders.  
The practice of genetic medicine is changing as genetic discoveries are translated into new tests for an increasing number of health indications. In fact, the prevalence of high-risk individuals who are at risk for hereditary cancer has been rising due to new testing strategies. This has placed enormous pressure on the hospitals and clinics providing care for high risk patients. Coupled with the healthcare system's need for greater efficiency, the traditional genetic clinicbased practice has become untenable. Barriers and challenges include low numbers of trained genetic workforce, lack of integrated FHH platforms for patients and physicians, and long wait times for available clinic appointments. Further, while cancer syndromes are seen across all groups, gaps in care exist as underserved populations are often not recognized and referred for care.  
MeTree is a computer platform that has been developed by researchers at Duke University that electronically collects FHH information for hereditary cancer syndromes and other health conditions directly from the patient. MeTree then calculates hereditary cancer risks for the patient and creates a personalized patient report and evidence-based clinical decision support for the provider. In previous studies, MeTree demonstrated improvements in the identification of those at risk and highlighted ongoing challenges particularly around undergoing genetic counseling and testing, and awareness of risk. Co-investigators from Duke/MeTree collaborate on this grant.
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2. rationale and specific aims

SA1. Deploy a care delivery model that will facilitate systematic risk assessment for hereditary cancers in diverse clinical environments.  
- Up to 3,500 participants will be enrolled and complete the MeTree FHH risk assessment - Deploy in 2 academic medical centers; Vanderbilt University Medical Center (VUMC) and Meharry Medical College (MMC)
- Assess participants perceptions using online survey and qualitative semi-structured interviews SA2. Improve access to genetic **healthcare providers for participants at risk for hereditary cancer syndromes.**
- 300 high risk participants in the VUMC Hereditary Cancer Clinic will be enrolled - Extend clinic capacity by lessening the need for in-clinic family history collection and basic counseling
- Expand reach of clinic by using telephone and video genetic counseling; referral to specialists SA3. Explore the feasibility of our care delivery model to improve family engagement for cancer risk assessment
- Participants extend invitations to family members to MeTree's family resource center to share results of genetic tests
- Assist with education and referral needed for cascade testing for pathogenic variants FOREST
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3. inclusion/exclusion criteria exclusion

- Non-VUMC/MMC patients - Diagnosed with a terminal illness
- Unable to speak/read English
- Unable/unwilling to use the Internet (specifically MeTree)
- Previous genetic testing and/or counseling through the Hereditary Cancer Clinic
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4. enrollment

Inclusion
- Receiving medical care at Vanderbilt University Medical Center, Meharry Medical College, or Nashville General Hospital
- Age 18 years or older
- Able to read and communicate in English
- Willing to use the Internet - Current My Health at Vanderbilt (MHAV) user or willing to sign up and use (for Meharry/Nashville General, patient does not have to meet this criteria)
Participants will be enrolled on a rolling basis in a stepped wedge design. Participants will enroll through My Health at Vanderbilt (MHAV)*. MHAV is VUMC's patient portal where the patient may sign up and participate in managing his/her health care. MHAV can also be used for sending mass research recruitment messages to a predefined cohort of patients who meet certain study-specific inclusion/exclusion criteria, have explicitly said OK to Contact for research purposes, and have an active MHAV account. The messaging process is managed centrally by the VICTR/Health IT teams, sending the messages on behalf of the study team. Potential participants who have an explicit OK to Contact for research documented in eStar will receive the following, one-time, MHAV email message. If only text notifications are checked the patient will receive a text message similar to the ones sent for clinical communications. If email and/or text notifications for research are not checked, the study information will simply appear on their research studies page in MHAV. General MHAV Research Message (**Appendix G**)
Hello [insert patient name],
In the past, you've shown interest in learning about research studies at Vanderbilt. There's a new message in your My Health at Vanderbilt account about a research study that might be a good fit for you. Sign in to read your message. Thanks for using My Health at Vanderbilt, Vanderbilt University Medical Center Once a patient clicks on the link from the email/text notification or from the MHAV homepage, he/she will be taken to the Research Studies page. Here the new study will be listed under the heading - Studies you may be able to join - with the following information (**Appendix H**): FOREST If a patient clicks, I'm Interested, the REDCap Participant Updater Module will create a record in the study database that includes patient MRN and the enrollment status of Interested. Once the Updater Module creates a new record, it will trigger REDCap to fetch the email address to facilitate sending the follow-up email from REDCap, which will include more information about the study and a link to the survey. If a patient clicks, No, Thank You, the REDCap Participant Updater Module will create a record in the study database that includes patient MRN and the enrollment status of Not Interested. This will prevent any further communication to the patient about this study.  
Once the eligible participant enters the REDCap study pre-screen, they will be able to complete the eligibility survey, electronic consent, and pre-MeTree survey. At the end of the pre-MeTree survey, participants will be given a link to the MeTree platform to begin the questionnaire. At any time, they can leave MeTree and re-enter by using the link from the REDCap message or by the link in their MHAV portal. Participants will receive a $10 gift card for completing the eligibility, eConsent, and pre-MeTree surveys. After completing the eligibility, eConsent, and pre-MeTree surveys, participants will receive an email with the link to MeTree (**Appendix K**). Participants have three weeks to complete their MeTree questionnaire. After completing the questionnaire, participants will receive a report from MeTree. After receiving the report from MeTree, and once the study team has concluded the enrollment of the 3,500 participants, 300 "high risk" participants will be referred to the Hereditary Cancer Clinic to discuss their results with a Genetic Counselor. The consent will include information about this step to inform participants that they may be contacted for counseling. *My Health at Vanderbilt (MHAV) language is used to describe the workflow at Vanderbilt, however, Meharry will utilize a similar workflow using their online patient portal as well.
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5. study procedures

As described in Section 4, participants will be recruited and enrolled electronically. * This process will take approximately 30-45 minutes, depending on the answers to screening questions and whether or not they are existing MHAV users. Once enrolled, they will be asked to complete the MeTree Family Health History (FHH) questionnaire (See Appendix A for actionable conditions, Appendix B for actionable recommendations, Appendix C for MeTree participant report example, and Appendix D for MeTree provider report example).  
Upon entry into the MeTree platform, participants will be able to immediately enter FHH information into the program or download the worksheet for collecting the information requested by MeTree from family members and return later to enter the information into the MeTree platform (The printable worksheet is named Appendix E). The time involved to complete MeTree may vary significantly depending upon the number of relative's participants enter data on and the availability of the FHH information. This will be mitigated by providing a smart link to finish the FHH in pieces, rather than all at once. Participants are advised in the consent form that answering the FHH questions may make them uncomfortable. For participants who may want additional instructions for the MeTree questionnaire, we will provide a how-to power point (included as Appendix F). FOREST
Participants who do not access MeTree within 30 days of consent will be sent reminder emails once per week for up to 4 weeks. Once participants complete data entry in MeTree and the post-MeTree survey, participants will be sent a $20 gift card (by the recommendations at Community Engagement Studios, Meharry may increase their gift cards to $45-50, and may offer cash instead of gift cards).  
Once data entry in MeTree is complete all participants will receive a personalized patient report within the platform outlining their familial and genetic risk status the included medical conditions according to current evidence-based guidelines. Participants' providers will be notified via one of several methods (email without PHI, EPIC messaging, or an alert) that their patient has a MeTree clinical decision support report available in the medical chart (accessible via a SMART link). Outside providers will receive an email or letter. The templates for these messages is located in Appendix I. The process to upload the MeTree report and provide accessibility to providers is approved by the Medical Forms Committee and the Center for Health Information Management (CHIM) Committee.  
Participants will be sent a web-based survey via an email link 4 to 6 weeks after completing MeTree (post-MeTree survey). If the survey is not completed within 1 week of the initial invitation, reminder emails will be sent weekly for up to 4 weeks. Participants will receive a $20 gift card for completing the post-MeTree survey. As previously stated, in Aim 2 participants who are identified as at high genetic risk (n=300) will be contacted by the study nurse (as part of their standard of care) to schedule a genetic counseling appointment (Appendix J, High risk patient email). The number and length of genetic counseling appointments will be recorded in order to evaluate the change in clinic capacity for those with a pre-recorded FHH in the MeTree platform as compared to routine patients who have not participated in the study and completed MeTree. The frequency of genetic testing and outcomes of the testing will also be recorded in REDCap from data collection in the Hereditary Cancer Clinic at VUMC. To analyze the time saved by completing MeTree prior to a clinic visit, the study team will perform a retrospective review of control patients, selected by the study team, to assess the amount of time in clinic with the genetic counselors. This will be done through time stamps in eStar and chart review. Control patients will not be a part of the study, nor will their information be shared with anyone. The study team will only review for time spent in clinic versus the study participants' clinic visits.  
Additionally, genetic counselors who see participants from this study will be surveyed to better understand their perspective of the use of MeTree. This portion of the study will be in a separate IRB. To promote awareness of the need for cascade testing among relatives, participants who undergo genetic counseling and testing in the Hereditary Cancer Clinic and are found to have a strong family history and/or a pathogenic gene mutation, will be encouraged to share the study information with family members (Aim 3). We will not ask for identifying information regarding their family members. The study team will only accrue data on how many times the participant's MeTree web link was shared and accessed (clicked on). Patients are not required to share any information with family members if they feel uncomfortable.  
The timeline below reflects an individual's timeline from entry into the study.  
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*We will attempt to enroll participants electronically when possible. However, we understand that there are some participants who may not be able to enroll electronically and manual enrollment (by paper, tablet, or phone) will be available and will conform *to all CDC pandemic guidelines.* As a result of reviews from the first third of completed MeTree reports, a notes section was added to the MeTree reports to indicate any versioning/changes to the report. The notes will include any changes to the report (such as an updated pedigree) and where they can be found. If any technical or clinical changes are made to reporting, participants may receive an updated report, and will be notified if an updated report is available. Updated reports may or may not affect their high-risk report status or report recommendations.
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6. reporting of adverse events

All researchers will report all events that are serious, unexpected, and study-related to the PI by phone, fax or email within 24 hours of becoming aware of the event. We will promptly report to the IRB any participant complaints about the conduct of any element of the study or concerns about potential harms, including copies of any written communication with the participant addressing those concerns. Further, all conversations with participants that indicate a level of concern about a study component - even if not a complaint - will be documented and distribution of any participant education materials in response to such queries will be documented in the participant's research (REDCap)
record. FOREST Participants can choose to stop being a part of the study at any time. Participants will need to notify the study team either by a phone call to (615) 936-2660 or email to Cancer_Susceptibility_Team@vumc.org. The participant may be taken out of the study if:
- They do not complete the MeTree Survey within 12 months of enrolling - If they move out of the state
- Or stop receiving care at VUMC
Withdrawing participation We will continue to utilize the participant data in analyses unless the participant asks for the data to be withdrawn. Data will still be within the EHR, MeTree, and the research database (REDCap), but data will be excluded from analyses. Active declining participation Some participants may begin the study but at some point, feel uncomfortable continuing to participate. Participants who decline to further participate may withdraw from the study if they wish. If the participant declines to continue and alerts the study team, the protocol above will be followed. If the participant declines to proceed any further, study data will continue to be used in pertinent analyses.  
Surveys of declination or withdrawal Participants that decline or withdraw from the study will be asked why they are making this choice.  
Non-responders (Passive Decline)
Participants who enroll but do not complete the MeTree questionnaire or subsequent surveys will be treated as enrolled but excluded participants (i.e., non-responders). Participants who are delayed in filling out the questionnaire but still complete the questionnaire prior to analyses of the data will be included, despite the delay. Deceased participants The study will utilize the data of deceased participants even if they pass before the conclusion of the study.
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8. statistical considerations

Step-wedge designs are useful to evaluate the effect of time on the intervention. By the end of the study, all participants will have received the intervention, although the order in which participants receive the intervention is determined at random. We believe this is the most effective method to analyze the MeTree platform's effect on hereditary cancer testing and outcomes. Power calculations estimate a sample size of up to 3,500 (minimum of 3,000) is needed to produce statistically significant results. In the graph below, the blue line represents 90% power to detect the primary endpoint with a p-value of 0.05, the green line, 85% power, and the red, 80% power. The x-axis represents how many participants are identified as being at high risk by MeTree.  
 FOREST In prior studies of primary care populations, on average 20% were newly found to be at high risk (had not previously identified). However, in order to accommodate differences in a population that has a proactive hereditary cancer clinic, we used a lower estimate of 10% for the power analyses. Thus at 10% risk identification and 95% power we estimated that we would need at a minimum 1,000 participants for a single site and 2,000 participants total to detect differences in identification at the 2 sites (Meharry and Vanderbilt). In addition, these participants flow into aim 2. Based on power analysis to detect an increase in clinic capacity, we need to have 150 high risk patients who complete MeTree in Aim 1 to see a genetic counselor in the hereditary cancer clinic at Vanderbilt. At a 10% identification rate and a 50% follow up rate (estimate based on literature review and the clinic's attendance rate), a minimum of 3,000 participants will need to complete MeTree in Aim 1. We are therefore enrolling 3,000-3,500 participants for this study. Data elements considered for this analysis: Primary Endpoint: Participant designated as high risk for cancer.  
Assessment pre: chart review (any indicator prior to MeTree, not time-frame dependent)
Assessment post: MeTree report (measured when the report is generated, independent of amount of follow-up time)
Hypothesis: MeTree will increase the proportion of high-risk individuals identified.  
Statistical interpretation of the hypothesis: P(of high risk) is a function of the intervention
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9. privacy/confidentiality issues

The study data live in a REDCap database. *This project will utilize the REDCap platform for data collection and* management. Project team members listed as Key Study Personnel with existing electronic health record (EHR) system access rights may also be granted use of REDCap Clinical Data Interoperability Services (CDIS) tools. These tools are designed to enable transfer of relevant study-related data from the Vanderbilt Research Derivative and/or directly from the EHR into REDCap. Participant answers to the survey are linked only to a study ID number in a password protected electronic database. Only study staff will have access to the information, and any paper records are kept in a locked drawer in the study manager's desk. Pragmatic studies are considered minimal risk. All data will be gathered and stored using protocols and privacy &
security standards that comply with HIPAA and, where applicable, GINA. All patient FHH data will be gathered from patient portal applications and transmitted to and from the algorithm and clinical decision support databases using industry standard encryption protocols, including HTTPS and TLS. The healthcare systems employ additional protections for the data, including detailed audit logs, insulation from direct SQL queries, and detailed version control. FOREST While participant data such as demographics are collected from the VUMC Epic instance, data are delivered by SFTP to the MeTree platform, housed at Duke University, for participants to complete the FHH questionnaire. FHH results will be transmitted by API to a secure REDCap project at VUMC or MMC. *
*This process is approved by the VUMC Architecture Review Board.  
All data gathered for the proposed studies will be treated with the same degree of confidentiality as a medical record.  
Confidentiality will be maintained for the identity of participants in this study except as necessary for oversight by the Secretary of the Department of Health and Human Services or his designated representative. Only group information without personal identifiers will be included when sharing process implementation data and outcomes with approved collaborators. FHH data collection is already considered standard of care for medical practice and the risk associated with this information or risk-based prevention strategies is considered to be no more than that associated with routine clinical care.  
At the beginning of the study, participants will provide the study team with their VUMC health care provider's name.  
After the participant completes the MeTree questionnaire, a message will be sent to the provider via REDCap to their eStar message basket alerting them that their patient has completed the questionnaire and that there is a providerversion report available for them to view. The provider can click a link in the message and be sent to MeTree, where they can locate the report.  
For contact purposes, we will give participants the option to provide a secondary contact in case the participant cannot be reached. This will only be used if the study team loses contact with the participant (i.e., phone line disconnected, email no longer active).  
Regardless of primary or secondary findings, the participant is allowed to provide any findings to their family. The study team will not contact family members of the participants, even in the case of death.
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10. follow-up and record retention

The study will last 4 years. Paper records will be kept for up to six years after the study ends. Electronic data will be kept indefinitely. Research data entered into REDCap will be kept for an unknown length of time.