Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Men of any ethnicity with a family history of prostate cancer defined as:

* Men with a first degree relative (or second degree if through female line) with histologically or death certificate proven PrCa diagnosed at \<70 years
* Men with two relatives on the same side of the family with histologically or death certificate proven PrCa where at least one is diagnosed at \<70 years
* Men with three relatives on the same side of the family with histologically or death certificate proven PrCa diagnosed at any age

Men of black African or black African-Caribbean ancestry defined as:

Both parents and all 4 grandparents being of black African or black African-Caribbean ancestry.

Men of any ethnicity with a genetic predisposition to having prostate cancer e.g., being known to have inherited a gene mutation that increases risk of prostate cancer (gene mutation including BRCA1, BRCA2, ATM, PALB2, MLH1, MSH2, MSH6, CHEK2 and other DNA repair gene mutations as listed in the study protocol); and/or being known to have a high polygenic risk score (PRS) (defined as being in the top tenth percentile prior to enrolment).

All men will be offered a MRI and prostate biopsy and they can either opt to undergo these procedures at baseline irrespective of PSA level at baseline or they can undergo PSA-only screening until clinically indicated based on an age-defined PSA threshold, at which point, they will undergo prostate MRI and biopsy once their PSA reaches the threshold.

Prostate MRI and Biopsy

Elizabeth K Bancroft, PhD

Eva McGrowder, PhD

Rosalind A Eeles, FRCP FRFR

Rosalind A Eeles, FRCP FRCR

Rosalind A Eeles

Prostate cancer is now the most common cancer in men in the Western world. In the United Kingdom (UK), there were over 52,000 new cases diagnosed in 2016-2018 and a lifetime risk of 1 in 8. Prostate cancer (PrCa) can run in some families and research studies have identified several genetic changes in Caucasian populations that are thought to increase the risk of developing prostate cancer. Other studies have shown that men from certain ethnic groups also have a higher risk of prostate cancer, and this includes men of black African or black African-Caribbean ancestry. This study aims to look at men with a higher risk of prostate cancer based on their ethnicity, family history and/or genetic predisposition to see whether any of these genetic changes are present in their DNA (genetic material) and whether this could be a helpful screening tool in prostate cancer screening programmes. It is thought that many genetic changes are involved in the development of prostate cancer and research is being carried out worldwide to identify these genetic changes. Some of these changes may cause a very slight increase in prostate cancer risk while others may cause a much larger increase in risk of developing prostate cancer. The investigators will invite (i) men of any ethnicity with a family history of prostate cancer; (ii) men of black African or black African-Caribbean ancestry; and (iii) men of any ethnicity with a known genetic predisposition to having prostate cancer (e.g., being known to have inherited a gene mutation that increases risk of prostate and/or being known to be in the top tenth percentile of the polygenic risk score (high PRS score prior to enrolment) for targeted prostate screening (Prostate Specific Antigen (PSA) testing, MRI and a biopsy of the prostate gland) and genetic profiling. The outcome of these prostate cancer screening investigations will be compared with the genetic profiles of those taking part in the study in order to look for certain genetic changes in the gene code that are thought to increase prostate cancer risk. This research will help us to determine what the role of such genetic profiling is in a prostate cancer screening programme and if it helps identify men at high prostate cancer risk.

Purpose and Design

The aim of the PROFILE study is to investigate the role of targeted prostate cancer screening in men at a genetically higher risk to estimate the incidence of PrCa and the sensitivity and specificity of PSA screening in these populations and correlate this with genetic profiles and biological endpoints. Additionally, the study aims to identify biomarkers from biological samples (such as blood and urine) as well as imaging technologies (e.g. MRI and new imaging techniques) as predictive markers of the risk of developing PrCa and to correlate these with genetic risk. This study has been designed using an observational approach to look at the correlation of cancer incidence (on biopsy) with genetic profile. The aim is to evaluate targeted screening for prostate cancer in men at a genetically higher risk to estimate the incidence of prostate cancer and the sensitivity and specificity of PSA screening in these populations and correlate this with genetic profiles (i.e. single nucleotide polymorphism (SNP) profiles) and biological endpoints.

Three cohorts will be recruited:

1. Men of any ethnicity with family history of prostate cancer.
2. Men of black African or black African-Caribbean ancestry.
3. Men of any ethnicity with a genetic predisposition to having prostate cancer (e.g., being known to have inherited a gene mutation that increases risk of prostate cancer (i.e. high-risk gene mutation) and/or being known to have a high polygenic risk score (high PRS score) defined as being in the top tenth percentile prior to enrolment.

Men with no prior screening will be offered biopsy and genetic profiling. This will provide data on genetic profiling and correlation with biopsy irrespective of PSA in men who have not had any previous screening.

A PSA screening algorithm was considered as an alternative to biopsy but there is great controversy over the PSA threshold that should be used as a cut-off. Recent data have shown that a considerable percentage of men with a PSA within normal range have cancer at biopsy. Therefore, it was decided by the Steering Committee that all participants should be offered a biopsy within this study. This will tell us the acceptability of this approach.

Some men may opt not to have biopsy at baseline (i.e. initial stage). These men will be followed up with annual PSA, whereby prostate biopsy would be offered if PSA is above or equal to 1.0ng/ml if the man is aged under 50 years, or where PSA is above or equal to 2.0ng/ml if the man is aged fifty years or over.

Eligibility and Recruitment

Either:

(1) Men of any ethnicity with a positive family history of PrCa defined as:

* Men with a first degree relative (or second degree if through female line) with histologically or death certificate proven PrCa diagnosed at \<70 years
* Men with two relatives on the same side of the family with histologically or death certificate proven PrCa where at least one is diagnosed at \<70 years
* Men with three relatives on the same side of the family with histologically or death certificate proven PrCa diagnosed at any age

Or (2) Men of black African or black African-Caribbean ancestry defined as:

Both parents and all 4 grandparents being either black African or black African-Caribbean.

Or (3) Men of any ethnicity with a genetic predisposition to having prostate cancer e.g., being found to have inherited a gene mutation that increases risk of prostate cancer (e.g. BRCA1, BRCA2, ATM, PALB2, MLH1, MSH2, MSH6, CHEK2 and other DNA repair gene mutations as listed in the study protocol); and/or being known to have a high polygenic risk score (PRS) (defined as being in the top tenth percentile prior to enrolment).

* Age 40- 69 years
* WHO performance status 0-2
* Absence of any psychological, familial, sociological or geographical situation potentially hampering compliance with the study protocol and follow up schedule.

Exclusion criteria

* Previous cancer with a life expectancy of less than five years.
* Previous PrCa
* Negative biopsy within one year before recruitment
* Comorbidities making prostate biopsy risk unacceptable (anticoagulants or antiplatelet medication including Warfarin, Clopidogrel, Apixaban, Dabigatran or other NOAC (Novel Oral Anti-Coagulant); poorly controlled diabetes, cardiovascular/respiratory disease, immunosuppressive medication or splenectomy).
* Men with body mass index (BMI) 40 and above.
* Men with BMI 35 and above plus other co-morbidities.
* Contraindications to having an MRI (non-MRI compliant pacemakers, aneurysm clips, metallic cardiac valve/stent, Ventriculo-Peritoneal (VP) shunt, cochlear implant, neurotransmitter, metallic foreign bodies in eye(s), other metalwork, claustrophobia)
* Any significant psychological conditions that may be worsened or exacerbated by participation in the study

Subject Withdrawal

o Subjects may withdraw from the study at any time if they so wish without giving a reason. No further data will be collected about that individual, and any unused samples will be destroyed. Data collected up to that point will be retained for audit purposes.

Cancer cases Men who are found to have prostate cancer at biopsy will be referred to their local urologist for treatment according to local policy. Men will be followed up for 10 years in order to evaluate the different treatment regimens.

Genetic Profiling All men will have genetic profiling to correlate with disease status and men will be given the results of this test. It will be emphasised that these are research results and written information will be provided as a reference guide.

Informed Consent All subjects will be informed of the aims of the study, the possible adverse events, the procedures and possible hazards to which he will be exposed, and the mechanism of treatment allocation if prostate cancer was to be diagnosed. He will be informed as to the strict confidentiality of his patient data, but that his medical records may be reviewed for trial purposes by authorised individuals other than their treating physician.

It will be emphasised that participation in this study is voluntary and that the subject is allowed to refuse further participation in the protocol whenever he wants. This will not prejudice the subject's subsequent care. Documented informed consent will be obtained, according to the principals of good clinical practice (GCP), for all subjects included in the study before they are registered onto the study.

Risks, burdens, benefits There is a risk of complications from having a prostate biopsy, and these complications are detailed in the patient information sheet, together with likelihood of incidence. Complications are rare and standard procedures will be followed at all sites to minimise their occurrence. The benefit of taking part may be that prostate cancer may be diagnosed in men previously unaware that they had the disease. While there is the potential for overdiagnosis of indolent disease, there is also the potential for detecting and treating clinically significant disease.

Provision of results from the genetic profiling One further consideration is the occurrence of anxiety as a result of taking part in the study, particularly in receiving research genetic test results. There is considerable uncertainty about how genetic profile relates to predicted risk of prostate cancer. For this reason individualised written information will be provided to each participant putting the research results in the context of the current population risks. It will be stressed that these are research results only and that the investigators do not fully understand the meaning of the results.

A psychosocial study is being run concurrently and will explore these issues in more depth and the participant's experience of receiving these results will be an important component of the evaluation of this study.

Confidentiality All information which is collected will be accessible only to the immediate study team. Any data that is shared will be de-identified and any published data will be anonymised so that no participant is recognisable from the results.

Medical records and the data collected for the study may be looked at by authorised persons from the Institute of Cancer Research, by regulatory authorities and by authorised people to check that the study is being carried out correctly. All will have a duty of confidentiality to participants.

End of Study Follow-up After the participant has completed the study they will be advised about any ongoing screening or follow-up that is required. This will be organised through the participants general practitioner (GP).

Use of samples in future research The informed consent process will explain that samples are donated as a "gift". If any of the samples collected are to be considered for use in future research projects this would have to be approved by the Ethics Committee first.

The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment

Anonymised data can be applied for via the Data Access Committee

To investigate the role of targeted prostate cancer screening in men at higher genetic risk (i.e. family history, ethnicity, gene mutation status), its association with specific genetic profiles and biomarkers as predictive tools of the risk of developing prostate cancer and to correlate these with genetic risk.

To determine the incidence and aggressiveness of prostate cancer in these men at a higher genetic risk.

To determine whether imaging techniques such MRI can be used to identify prostate cancer when compared to prostate biopsy results.

To determine the incidence of abnormal imaging at MRI in correlation with biopsy outcome.

To identify biomarkers from biological samples and determine their association with prostate biopsy result.

To identify imaging biomarkers and determine their association with prostate biopsy result.

Royal Marsden NHS Foundation Trust

University of Cambridge

University of Oxford

Queen Mary University of London

Institute of Cancer Research, United Kingdom

Participants will use a decision aid to learn about genomic sequencing and select which incidental findings they would like to receive from genomic sequencing. After using the decision aid the participants will speak with a genetic counsellor over the phone about their choice.

Participants will a genetic counsellor over the phone to learn about genomic sequencing and select which incidental findings they would like to receive from genomic sequencing.

The Genomics ADViSER is an decision aid designed to inform patients about genomic sequencing (GS) and aid them selecting which incidental findings they would like to receive from GS.

Decision Aid Plus Counselling

Participants will learn about genomic sequencing and incidental findings by speaking directly with a genetic counsellor and select which incidental findings they would like to receive with a genetic counsellor.

Genetic Counselling Only

Yvonne Bombard, PhD

Health care providers (HCP) are increasingly using genomic sequencing (GS) to target treatment for patients. However, GS may incidentally reveal inherited risks for thousands of current and future diseases. Guidelines recommend HCP inform patients of incidental GS results. No decision aid (DA) exists to guide patients' decisions about which incidental GS results they wish to learn. This study will evaluate whether the DA followed by genetic counselling (GC) reduces decisional conflict compared to GC alone in a randomized controlled trial (RCT) with 128 patients with a family history of cancer, who have had a negative genetic test and may eligible for GS. A qualitative component with a subset of participants (n=40) will explore patients' preferences for the types of incidental results they wish to receive and their decision making process.

BACKGROUND: Health care providers are increasingly using GS to diagnose, prognose and treat diseases. GS offers increased sensitivity over classic genetic tests, decreasing time-consuming and costly diagnostic cascades. However, GS may also incidentally reveal inherited risks for many other cancers and diseases. Guidelines recommend doctors inform patients of their incidental GS results. Yet there are limited tools to communicate the scope and implications of the thousands incidental results available to help guide patients' decisions about which results they wish to learn.

Gaps: Decision aids (DAs) are best suited to meet this challenge, but no DA exists to guide patients' decisions about incidental GS results.

Rationale: It is not feasible to counsel patients on the thousands of incidental findings available to make informed choices about which incidental results they wish to receive because of the limited genomics expertise and capacity among oncologists, and the long wait times for genetic counseling. Our DA fills this critical care and translational gap by improving the quality of patients' decisions and saving oncologists time counseling patients on incidental findings.

Preliminary data: 1) DA development: We created an interactive online DA. It begins with a professional whiteboard video (by Dr. Mike Evans) that conveys the key concepts, risks and benefits of learning about incidental GS results to educate patients. It then prepares patients for decision-making using a values clarification exercise (with feedback of their preferences) and a knowledge questionnaire (with correct answers provided after). It ends by asking participants to select result categories they want to learn using a menu tool. 2) Usability testing: We also evaluated the DA's usability with 15 patients in 2 rounds. Interviews demonstrated strong face validity and content comprehension. Most patients found the amount of information 'just right' (11/15), clear (12/15) and balanced (14/15). All patients felt that the information was sufficient to reach a decision, that the DA was easy to use and would recommend it.

OBJECTIVES

1. Evaluate the efficacy of the DA compared to standard genetic counseling (GC)
2. Understand the decision-making patients' use regarding GS and selecting incidental findings.

METHODS

Phase 1 - RCT to evaluate the DA:

Methods: We will evaluate the efficacy of the DA in reducing decisional conflict compared to standard genetic counseling (GC) using a superiority trial.

Population: We will recruit adult cancer patients who are eligible to have GS (i.e., tested negative for the classic gene mutation associated with their cancer - e.g., BRCA1/2, MLH, MSH, PMS, APC, MUTYH) from genetics clinics at Mount Sinai Hospital, Princess Margaret Hospital and Sunnybrook Hospital in Toronto, ON Canada. We will include adults who speak and read English and exclude patients with metastatic/recurrent disease as incidental results are less consequential to this population.

Sample size: TThe primary outcome is decisional conflict; the study requires 64 patients/arm to detect the minimal clinically important difference (MCID) of 0.3 using the Decisional Conflict Scale (DCS) (Appendix 3), assuming a standard deviation of 0.6, an alpha of 0.05 (two-sided) and power of 0.815,16. In the last 3 months, 244 patients with a family history of breast and colon cancer tested negative for their associated classic mutations (BRCA1/2, MLH, MSH, PMS, APC, MUTYH) most of who would be eligible for GS. Extrapolating this over the next 9 months we estimate that there would be 732 eligible patients. It is highly feasible to reach our target of 128 patients.

Participants will be consecutively randomized and allocated from an existing list of eligible subjects using a computer-generated randomization in a 1:1 ratio with random permuted blocks of varying sizes. Patients from each clinic will be randomized separately to ensure we have an even distribution of this population in both arms of the study.

Intervention arm: Participants will view the online DA and then complete the online self-administered measures (below) in one sitting within 14 days of recruitment. Next, they will speak with a GC over the telephone after the DA, using a standardized script. They will then complete the same online measures again after speaking to the GC.

Control arm: The GC will conduct the GC session over the telephone within 14 days of recruitment. A topics script will be used to standardize GC discussions covering standard educational content to enable patients to select incidental GS results (participants will not view the DA nor the video). Participants will complete the online self-administered measures after speaking with the GC.

Outcome: Consistent with the Ottawa Decisional Support Framework, our primary outcome is decisional conflict. Secondary outcomes are: knowledge of GS, satisfaction with decision, preparation for decision-making and anxiety.

Measures: We will use validated scales to assess decisional conflict, knowledge, anxiety, satisfaction with the decision and preparation for decision-making. We will develop a standardized topic script for the GC in each arm, as well as a questionnaire to collect intervention fidelity (e.g., usage statistics, duration of counseling sessions), demographic and clinical characteristics (e.g., cancer status and genetic testing).

Analysis: Consistent with the Ottawa Decision Support Framework, our primary outcome is decisional conflict, assessed via the validated Decisional Conflict Scale (DCS). Knowledge is the secondary outcome, will be measured by the Cliseq genomic sequencing questionnaire and a set of internal developed knowledge questions. Satisfaction and anxiety with also be assessed. Satisfaction will be measured using the Satisfaction with Decision scale (SWD) and the Preparation for Decision Making scale (PrepDM). Anxiety will be measured using the state subscale of the State-Trait Anxiety Inventory (STAI). We will also include a demographics and cancer history questionnaire.

The analysis of outcomes will follow the intention-to-treat (ITT) approach. Mean DCS, SWD, PrepDM and STAI scores will be compared using a t-test. Knowledge scores will be assessed by summing the number of correct responses to the questions, and compared using t-tests. Linear regression will be used in a secondary analysis to account for known predictors for decisional outcomes such as education. Secondary analyses will compare the mean DCS, knowledge, SWD, PrepDM and STAI scores before and after GC in the intervention arm to explore the additional benefit of GC after the DA. Un/adjusted mean differences and 95% confidence intervals will be reported. We will use descriptive statistics to report participants' characteristics.

Phase 2 - qualitative study of decision making for incidental results:

A subset of study participants will be asked to take part in a qualitative interview about their decision-making regarding selecting incidental findings. These semi-structured interviews will take place over the phone with a total of 40 participants. For the qualitative component a purposeful sample of study participants will be used. We will target a mix of participants across ages, cancer type and stage, gender, and study group to assess the varying approaches to decision-making. At total of 40 participants will take part in the qualitative component.

Analysis: Qualitative data analysis will draw on grounded theory methodology. We will sort the data by searching for themes/patterns and variations within and across interviews using HypeRESEARCH. Coding, which is the first stage in the analysis process, will involve 'labeling' the data with descriptive codes. Two team members will independently code each transcript. Consensus on coding will be reached through comparison and discussion among these members. The second stage will involve constant comparison, where codes and their content will be compared across interviews to discern common and divergent themes and issues across them. The final stage is selective coding, which integrates all the codes under a central phenomenon to build a theory. Validation methods include triangulation and member checking.

Evaluation of a Decision Aid for Incidental Genomic Findings

Randomized Controlled Trial of a Decision Aid for Incidental Genomic Findings

The Ottawa Decision Support Framework measure of decisional conflict, a 16 item scale - developed by O'Connor et al.

Knowledge is measured using a genomics knowledge scale developed by Clinseq

A 10 item scale measuring how useful a user finds the decision aid or other intervention

A six item scale measures a patient satisfaction with a health care decision

Mesured using the 20 item State-trait scale

Canadian Institutes of Health Research (CIHR)

Unity Health Toronto

Digestive System Diseases

Symptoms and General Pathology

Wounds and Injuries

Behaviors and Mental Disorders

Liver Diseases

Hyperthermia

Fever

Gastrointestinal Diseases

Body Temperature Changes

Stress Disorders, Traumatic

Heat Stress Disorders

Undergo personal and family history-based risk assessment and make recommendations for managing risk.

Disease Risk Assessment

Alexander S Parker, PhD

Kathryn Carpenter, MS

Lori Orlando, MD

The "Genomic medicine Risk Assessment Care for Everyone" (GRACE)" intervention project will develop a scalable end-to-end solution for risk assessment and management that meets the needs of those populations living in low resource settings. The long-term goal is to increase access to and uptake of risk-informed evidence-based guidelines that will improve population health through better patient outcomes, higher quality of life, and decreased costs. The three primary aims are:

Aim 1: Develop a scalable implementation framework that guides each unique clinical setting, including low resource settings, in deploying GRACE effectively for the needs of their patients and providers.

Aim 2: Facilitate the potential for genomic medicine to promote population health by broadening access to and uptake of genomic risk assessment by the general population through a pragmatic implementation-effectiveness trial of GRACE.

Aim 3: Reduce health disparities related to genomic medicine by allowing individual adaption of GRACE to suit their level of resources, education, and access within a pragmatic implementation-effectiveness trial.

Three sets of participants will be engaged: patients (n=750), providers (n=25), and family members of "probands" (i.e., patients that have a genetic change that increases risk, n\~500).

Patient participants will be asked to complete a baseline survey, enter their family health history information into MeTree (a family health history web-based platform) and complete a survey about their experience using the platform. Subsequent study procedures will depend on: 1) the results of their MeTree risk evaluation, 2) their acceptance/declination of genetic testing (for those categorized as needing testing by MeTree), and 3) the results of the test (for those accepting testing).

Provider participants will be providers who are the primary care physicians treating one or more patients enrolled in the patient participant group. Providers will be notified on a patient by patient basis once the patient participant under their care has complete the risk assessment process and the risk report is available from MeTree. At study completion, provider participants will be asked to complete a survey about their demographics, practice, and experiences with the study.

Blood relatives of the probands who are identified by the proband as open to engaging with the study will be contacted and offered genetic counseling and genetic testing.

The "Genomic medicine Risk Assessment Care for Everyone" (GRACE)" project will define, deploy and evaluate a new care delivery model. Specifically, the GRACE project will develop a scalable end-to-end solution for risk assessment and management that meets the needs of those populations living in low resource settings. The long-term goal is to increase access to and uptake of risk-informed evidence-based guidelines that will improve population health through better patient outcomes, higher quality of life, and decreased costs. The central hypothesis is that combining a Family Health History (FHH) -driven risk assessment tool (in this case MeTree), family engagement, and a genetic testing delivery system, will create a solution that engages and increases the proportion of diverse patients who are identified as at increased risk, who undergo testing, and, when appropriate, who initiate cascade genetic testing among relatives. The three primary aims are:

Aim 1: Develop a scalable implementation framework that guides each unique clinical setting, including low resource settings, in deploying GRACE effectively for the needs of their patients and providers.

Aim 2: Facilitate the potential for genomic medicine to promote population health by broadening access to and uptake of genomic risk assessment by the general population through a pragmatic implementation-effectiveness trial of GRACE.

Aim 3: Reduce health disparities related to genomic medicine by allowing individual adaption of GRACE to suit their level of resources, education, and access within a pragmatic implementation-effectiveness trial.

This trial is a cluster step wedge design, meaning that while the trial will ultimately be implemented in five family medicine clinics at the University of Florida Health System, it will be implemented in only one clinic at a time.

Briefly, when one clinic has completed enrollment of the target number of patients (n=150) and providers (n=3-5), then the investigators will advance to enrolling patients and providers in the next clinic. That is, the investigators will not wait until blood relatives of the probands are recruited before moving to the next clinic. Finally, in the spirit of implementation science, the investigators will evaluate the lessons learned, barriers and facilitators from each clinic and use this knowledge so that the next clinic will benefit from the experiences of the previous ones.

Three sets of participants will be engaged: patients (n=750), providers (n=25), and family members of "probands" (i.e., patients that have a genetic change that increases risk, n\~500).

Patient participants will be asked to complete a baseline survey, enter their family health history information into MeTree (a family health history web-based platform) and complete a survey about their experience using the platform. Once data entry in MeTree is complete, all participants will be able to view and download a personalized patient report within the platform outlining their familial and genetic/hereditary risk status that includes medical conditions according to current evidence-based guidelines. The report will indicate whether the participant has a) population-level risk (also referred to as not at high risk) suggesting nothing different needs to be done with their preventive care, b) familial risk (suggesting a change in care, but no need for genetic testing), or c) hereditary risk (suggesting a need for genetic testing and that they might also meet criteria for changes in preventive care).

Subsequent study procedures will depend on: 1) the results of their MeTree risk evaluation, 2) their acceptance/declination of genetic testing (for those categorized as needing testing by MeTree), and 3) the results of the test (for those accepting testing). Based on these three factors, patients will fall into one of five groups (see below).

GROUP 1: Not at High Risk, No Testing Recommended (n\~400).

GROUP 2: Familial Risk, Genetic Testing not recommended, clinical care recommended (n\~100).

GROUP 3: Genetic Risk, Testing Recommended, Testing Declined, (n\~60)

GROUP 4: Genetic Risk, Testing Recommended, Testing Accepted, Negative Test Result (n\~140)

GROUP 5: Genetic Risk, Testing Recommended, Testing Accepted, Positive Test Result (n\~50)

Participants in Groups 1 and 2 will be asked to complete a survey to assess their reflections on their risk assessments. After completing this survey, they will have completed all study activities.

Study procedures for participants in Groups 3-5 (those identified as having a hereditary risk) will be determined by the number of diseases they are at risk for according the MeTree risk assessment.

* Patient participants identified to be at genetic risk of multiple diseases under study (i.e. certain cancers and/or cardiovascular and/or liver diseases) will be contacted a genetic counselor who will provide clinical pre-test genetic counseling, which is part of normal clinical care for genetic counseling. The genetic counselor will offer these patient participants genetic testing, which they can decline. Of note, their acceptance/declination and the results of the test (for those who accept testing) will determine if they are in Group 3, 4 or 5).
* Patient participants identified to be at genetic risk for a single disease under study (i.e. certain cancer, cardiovascular, or liver diseases) will be provided with access a virtual Genetic Information Assistant (GIA) chatbot that is specific to their risk category. They will also be invited to view a short video describing the purpose of the chatbot. Once in the chatbot, participants will be offered genetic counseling through GIA or the option to obtain clinical genetic counseling through a study genetic counselor. If the participant does not access the GIA chatbot within 2 weeks after having access, a team member will contact the participant to offer support for GIA or genetic counseling with a study genetic counselor.
* Patient participants who decline to undergo genetic counseling or testing (Group 3) will be asked why they elected not to receive genetic counseling or genetic testing. They will also be asked to complete a survey about their experience with the study. After completing this survey, participants in Group 3 will have completed the study.
* Patient participants who agree to undergo genetic counseling and genetic testing will receive a saliva collection test kit for genetic testing to mail to Invitae, the company that will assist with genetic testing. A mobile phlebotomy unit will also be available and can be deployed to collect blood for genetic testing, if preferred/needed.

  * For patient participants whose genetic test result is negative (Group 4), suggesting no evidence of a genetic change that increases risk of diseases under study, results will be returned by GIA if they had pre-test counseling by GIA or by a study genetic counselor if they had pre-test counseling by a study genetic counselor. After the genetic test results are returned, participants in this group will be asked to complete a survey about their experience with genetic counseling. After completing this survey, participants in Group 4 will have completed the study.
  * For patient participants whose genetic test result is positive (Group 5), suggesting evidence of a genetic change that increases risk of one or more of the diseases under study, a study genetic counselor will return their results and encourage them to share their results with blood-related family members, as is standard practice during routine return of result counseling for those with a positive finding. The study genetic counselor will give the patient participant a standard family member letter to help facilitate sharing of information and cascade screening. Participants will be asked to complete a post genetic counseling/genetic testing survey, which includes questions regarding whether they shared information with blood-related family members, with whom, and contact information for adult blood-related family members who have indicated they are receptive to direct contact by the study team about cascade screening. After completing this survey, these participants will have completed the study.

Blood relatives of the probands who are identified by the proband as open to engaging with the study will be contacted. If they are a resident in North Carolina, Florida, South Carolina, West Virginia, New York, Maine, Texas, Mississippi, Missouri, Kansas, Colorado, Arizona, or Alaska, they will be offered genetic counseling with study genetic counselor. GRACE study genetic counselors are licensed in both Florida and North Carolina. The other states listed do not require in-state licensure for genetic counseling. If the blood relative is not a resident in one of these states, a study team member will provide recommendations for genetic counseling and testing, including through a) University of Pennsylvania's eREACH 2.0 study where participants can receive free genetic counseling and family variant testing regardless of state of residence, b) Genome Medical (a company associated with Invitae who will do the proband's genetic testing), who offers pre- and post-test genetic counseling sessions for $199. The family variant testing itself is free through Invitae, and c) the National Society of Genetic Counselors "Find a Genetic Counselor" resource. Approximately 3 months after consenting to participate in the study, blood relatives will receive a survey about their perceptions and experience with the direct contact process, what the patient participant shared with them prior to contact by the study team member, if they have been given the family member letter, what information they found helpful, if they had any concerns about the process, what information helped them decide whether to get counseling, what their decision was, what information was helpful in making this decision, and what factors informed their decision to get testing or not. After completing the survey, blood relatives will have completed the study.

Provider participants will be providers who are the primary care physicians treating one or more patients enrolled in the patient participant group. Providers will be notified on a patient by patient basis once the patient participant under their care has complete the risk assessment process and the risk report is available from MeTree. Providers will be notified via EPIC messaging or an alert that their patient has a MeTree clinical decision support report available in the patient's electronic medical record. Whether the provider reviews the risk assessment or changes patient care based on risk assessment recommendations is part of standard clinical care and will be evaluated as a study outcome. Notification will also occur when a patient declines genetic counseling, declines genetic testing, or has completed genetic testing return of results. Eligibility for genetic counseling will be noted in the medical record if a patient declines. If the patient undergoes genetic counseling, as is standard of care, genetic counseling recommendations for testing, and testing outcomes will also be documented in the medical record. When all patient participants in a clinic have completed all study procedures, provider participants will be asked to complete a survey, which will include questions about their demographics, practice, and experiences with the study. After completing the survey, provider participants will have completed the study.

Everyone who consents is enrolled in the risk assessment pipeline.

Genomic Medicine Risk Assessment Care for Everyone - Implementation Phase

Deploying a Genomic-medicine Risk Assessment Model for Diverse Primary Care Populations and Settings

Diagnostic genomic testing data will be deposited in an appropriate NIH data repository once the study team makes a final determination (e.g., dbGaP). Additional data documentation and de-identified data will be deposited along with phenotypic data, which includes demographics, family history of diseases collected through the MeTree program, and diagnosis, consistent with applicable laws and regulations. The study investigators will comply with the NIH genome-wide association studies (GWAS) Policy and the funding IC's existing policies on sharing data on specified disease genetics to include secondary analysis of data resulting from a genome wide association study through the repository. Meta-analysis data and associated phenotypic data, along with data content, format, and organization, will be available. Submitted data will conform to relevant data and terminology standards.

The number of participants completing MeTree relative to the number of participants who consented to the study.

The number of participants newly identified as at increased risk for familial and/or heritable conditions warranting genetic counseling and/or genetic testing.

The number of participants who complete genetic counseling/the number of participants who are recommended for genetic counseling.

The number of participants who undergo genetic testing/the number of participants recommended for genetic testing.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment	NCT02543905	Prostate Cancer Prostate Biopsy Genetic Counsel... Genetic Markers	Prostate MRI an...	40 Years - 69 Years	Institute of Cancer Research, United Kingdom
Evaluation of a Decision Aid for Incidental Genomic Findings	NCT03244202	Cancer	Decision Aid Pl... Genetic Counsel...	18 Years -	Unity Health Toronto
The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment	NCT02543905	Prostate Cancer Prostate Biopsy Genetic Counsel... Genetic Markers	Prostate MRI an...	40 Years - 69 Years	Institute of Cancer Research, United Kingdom
Genomic Medicine Risk Assessment Care for Everyone - Implementation Phase	NCT06278883	Cardiovascular ... Cancer Liver Diseases Hyperthermia	Disease Risk As...	18 Years -	Duke University
Genomic Medicine Risk Assessment Care for Everyone - Implementation Phase	NCT06278883	Cardiovascular ... Cancer Liver Diseases Hyperthermia	Disease Risk As...	18 Years -	Duke University

Spots Global Cancer Trial Database for genetic counselling