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Much information on parental perspectives on the return of individual research results (IRR) in pediatric genomic research is based on hypothetical rather than actual IRR. Our aim was to understand how the expected utility to parents who received IRR on their child from a genetic research study compared to the actual utility of the IRR received. We conducted individual telephone interviews with parents who received IRR on their child through participation in the Manton Center for Orphan Disease Research Gene Discovery Core (GDC) at Boston Children's Hospital (BCH). Five themes emerged around the utility that parents expected and actually received from IRR: predictability, management, family planning, finding answers, and helping science and/or families. Parents expressing negative or mixed emotions after IRR return were those who did not receive the utility they expected from the IRR. Conversely, parents who expressed positive emotions were those who received as much or greater utility than expected. Discrepancies between expected and actual utility of IRR affect the experiences of parents and families enrolled in genetic research studies. An informed consent process that fosters realistic expectations between researchers and participants may help to minimize any negative impact on parents and families.

Background Genetic testing has become more complex with the transition from single gene testing to multi-gene panels and whole-exome sequencing. The adoption of more complex genetic testing and the promise of precision medicine has created a critical and urgent need for longitudinal clinical follow-up with patients who undergo cancer genetic testing given the residual uncertainty. There is an increasing need for multidisciplinary translational research that focuses on how to advance precision medicine discoveries into clinical practice and to capitalize on connectivity (e.g. digital health) interventions in ways that optimize cancer risk reducing behaviors in real-world clinical populations. Methods The overall goal of this Hybrid Type 1 effectiveness-implementation randomized study is to evaluate the effectiveness of the MyCancerGene intervention to improve longitudinal (short-term and long-term) understanding (e.g. knowledge) and reactions to (e.g. anxiety) clinical genetic testing compared to usual care. We hypothesize that access to MyCancerGene will be associated with short-term and post-disclosure increases in knowledge, decreases in distress, increases in communication with relatives and health care providers and performance of risk reducing health behaviors compared to usual care. Equally important, we hypothesize that our implementation process evaluation will inform recommendations for future adaptation and sustainability for other precision medicine applications. Discussion Given the increasing complexity of genetic testing applications (e.g. multi-gene testing, whole exome sequencing) and the need for post-disclosure follow-up, we expect this study to inform evidence-based practice guidelines for delivery of genetic medicine and potentially change the paradigm to include longitudinal care in precision medicine. To address the clinically significant gap in the delivery of genetic medicine, patient and provider stakeholder input have been used to develop a patient and provider informed centered genetic digital health portal to enhance patient understanding of, and affective and behavioral responses to genetic testing, particularly in the era of evolving evidence and risk information. Trial registration This protocol was registered at clinicaltrials.gov (NCT04774445) in February 18, 2021.

Background Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENG aging and A ctivating cancer survivors in Ge netic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. Methods The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. Discussion With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. Trial registration This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Purpose To examine the benefit of telehealth over current delivery options in oncology practices without genetic counselors. Methods Participants meeting cancer genetic testing guidelines were recruited to this multi‐center, randomized trial comparing uptake of genetic services with remote services (telephone or videoconference) to usual care in six predominantly community practices without genetic counselors. The primary outcome was the composite uptake of genetic counseling or testing. Secondary outcomes compare telephone versus videoconference services. Results 147 participants enrolled and 119 were randomized. Eighty percent of participants in the telehealth arm had genetic services as compared to 16% in the usual care arm (OR 30.52, p < 0.001). Five genetic mutation carriers (6.7%) were identified in the telehealth arm, compared to none in the usual care arm. In secondary analyses, factors associated with uptake were lower anxiety (6.77 vs. 8.07, p = 0.04) and lower depression (3.38 vs. 5.06, p = 0.04) among those who had genetic services. There were no significant differences in change in cognitive or affective outcomes immediately post‐counseling and at 6 and 12 months between telephone and videoconference arms. Conclusion Telehealth increases uptake of genetic counseling and testing at oncology practices without genetic counselors and could significantly improve identification of genetic carriers and cancer prevention outcomes. Providing remote telehealth genetic services increases uptake of genetic counseling and testing at oncology practices without genetic counselors. These data highlight the value of telehealth strategies to significantly improve identification of genetic carriers and cancer prevention outcomes.

The use of multigene panels has significantly increased the likelihood that genetic testing will leave patients with uncertainties regarding test interpretation, implications, and recommendations, which will change over time. Effective longitudinal care models are needed to provide patients with updated information and to obtain patient and family history updates. To bridge this gap, we aimed to develop a patient- and genetic provider-informed digital genetic health portal (GHP), MyCancerGene, to improve longitudinal patient understanding of and responses to genetic testing. We used a 5-step process to develop MyCancerGene. To better understand their interest in and willingness to use a digital GHP, we surveyed 307 patients who completed genetic testing (step 1). We completed qualitative interviews with 10 patients and a focus group with 17 genetic providers to inform the content and function of MyCancerGene (step 2). Next, we developed initial intervention content (step 3) and completed user testing of intervention content with 25 providers and 28 patients (step 4). After developing the prototype intervention, we completed usability testing with 8 patients for their feedback on the final content, functions, and ease of use (step 5). In surveys conducted in step 1, 90% of patients with positive results reported interest in a digital GHP, and over 75% of participants with variants of uncertain significance or uninformative negative results reported similar interest. The most frequently reported advantages among patients were increasing accessibility, convenience, and efficiency (103/224, 46%); keeping genetic information organized (54/224, 24.1%); and increasing or maintaining patient understanding of the information (38/224, 17%). In qualitative interviews (step 2), both patients and genetic providers endorsed the benefit of the tool for updating personal and family history and for providers to share new risk information, test interpretation, or other medical changes. Patient and provider input informed eight key components of the tool: (1) Landing Page, (2) Summary of Care page, (3) My Genetic Test Results page, (4) My Family History page, (5) Provide an Update page, (6) Review an Update page, (7) Resources page, and (8) the Screenings Tracker. They also recommended key functions, including the ability to download and print materials and the inclusion of reminders and engagement functions. Potential challenges identified by patients included privacy and security concerns (67/206, 32.5%) and the potential for electronic information to generate distress (20/206, 9.7%). While patients were comfortable with updates (ie, even variant reclassification upgrades or clinically significant results), 44% (11/25) of genetic providers were uncomfortable sharing variant reclassification upgrades through MyCancerGene. MyCancerGene, a patient-centered digital GHP, was developed with extensive patient and genetic provider feedback and designed to enhance longitudinal patient understanding of and affective and behavioral responses to genetic testing, particularly in the era of evolving evidence and risk information.

Germline BRCA1 and BRCA2 testing is a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. With Food and Drug Administration approval for poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors in patients with metastatic breast, ovarian, pancreatic, and prostate cancer, there is an additional therapeutic rationale for testing all patients with these cancers for germline BRCA1 and BRCA2 mutations. However, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified. The eREACH (A Randomized Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Predisposition in Metastatic Breast, Ovarian, Prostate, and Pancreatic Cancer Patients) study evaluates the effectiveness of a theoretically and stakeholder-informed eHealth (eg, digital) delivery alternative to traditional genetic counseling for patients with metastatic breast or prostate cancer or advanced or metastatic ovarian or pancreatic cancer referred for genetic testing to determine whether they are candidates for a PARP inhibitor. The eREACH study is a randomized noninferiority study using a 2 × 2 design to test a self-directed digital intervention to deliver clinical genetic testing for patients with metastatic cancers. The traditional standard-of-care pretest (visit 1) and posttest (visit 2-disclosure) counseling delivered by a genetic counselor is replaced with our patient-informed digital intervention. The four arms were as follows: arm A, genetic counselor for visits 1 and 2; arm B, genetic counselor for visit 1 and digital intervention for visit 2; arm C, digital intervention for visit 1 and genetic counselor for visit 2; and arm D, digital intervention for both visits. Participants were adults with advanced or metastatic breast, ovarian, pancreatic, and prostate cancer. The primary outcomes of this study were change in genetic knowledge and anxiety from baseline to postdisclosure assessment. We will test whether the digital intervention is noninferior to standard-of-care counseling with a genetic counselor using a modified noninferiority ANOVA of the posttest disclosure minus baseline change scores. In secondary analyses, we will test pairwise differences among the 4 groups. As of January 2025, we have completed enrollment of 229 participants. Data analysis is ongoing, and we expect the results to be published in 2025. Increasing indications for BRCA1 and BRCA2 testing create a pressing need to evaluate alternative delivery models to increase access and uptake of these tests while maintaining adequate patient cognitive, affective, and behavioral outcomes. The eREACH study evaluates the effectiveness of an interactive, patient-centered digital intervention to deliver clinical genetic testing to patients with metastatic cancers. We expect that this work will inform evidence-based guidelines and the standard of care for delivery of genetic testing, and it is designed to be broadly applicable and easily adaptable for other populations and settings even beyond oncology. ClinicalTrials.gov NCT04353973; https://clinicaltrials.gov/study/NCT04353973. DERR1-10.2196/72515.

Family health history is often collected through single-item queries that ask patients whether their family members are affected by certain conditions. The specific wording of these queries may influence what individuals report. Parents of Boston Children’s Hospital patients were invited to participate in a Web-based survey about the return of individual genomic research results regarding their children. Participants reported whether 11 types of medical conditions affected them or their family. Randomization determined whether participants were specifically instructed to consider their extended family. Family health history was reported by 2,901 participants. Those asked to consider their extended family were more likely to report a positive family history for 8 of 11 medical conditions. The largest differences were observed for cancer (65.1 vs. 45.7%; P < 0.001), cardiovascular conditions (72.5 vs. 56.0%; P < 0.001), and endocrine/hormonal conditions (50.9 vs. 36.7%; P < 0.001). Small alterations to the way family health history queries are worded can substantially change patient responses. Clinicians and researchers need to be sensitive about patients’ tendencies to omit extended family from health history reporting unless specifically asked to consider them. Genet Med18 12, 1308–1311.

Discussions about disclosing individual genetic research results include calls to consider participants’ preferences. In this study, parents of Boston Children’s Hospital patients set preferences for disclosure based on disease preventability and severity, and could exclude mental health, developmental, childhood degenerative, and adult-onset disorders. Participants reviewed hypothetical reports and reset preferences, if desired. Among 661 participants who initially wanted all results (64%), 1% reset preferences. Among 336 participants who initially excluded at least one category (36%), 38% reset preferences. Participants who reset preferences added 0.9 categories, on average; and their mean satisfaction on 0 to 10 scales increased from 4.7 to 7.2 (p < .001). Only 2% reduced the number of categories they wanted disclosed. Findings demonstrate the benefits of providing examples of preference options and the tendency of participants to want results disclosed. Findings also suggest that preference-setting models that do not provide specific examples of results could underestimate participants’ desires for information.

Background With the advent of FDA approved anti‐amyloid therapy and recognition of increased side effects in APOE e4 carriers, APOE testing is now recommended for patients considering anti‐amyloid therapies such as lecanemab. Given the therapeutic implications and anticipated volume of eligible patients, the traditional model of in‐person, pre‐ and post‐test genetic counseling is not feasible to incorporate in clinical pathways. Alternative delivery models, including digital tools and telehealth, will be key in providing APOE genetic counseling support. Methods The Penn Telegenetics Program provided APOE genotype disclosure to cognitively intact participants across the United States in two Alzheimer’s prevention studies (API Generation Studies 1 and 2). An ancillary, multi‐site randomized study (CONNECT 4 APOE) evaluated the relative advantages of real time videoconference over telephone for disclosure of APOE genotype results within the API Generation Program. Outcomes of these studies informed the development of digital tools to support genetic counseling and educational needs specific to this patient population. Standard user and usability testing as well as rapid cycle testing were used in the development of digital tools. Results Over 2600 API Generation Program participants received APOE genotype disclosure via the Penn Telegenetics Program, and over 600 participants enrolled in the ancillary CONNECT 4 APOE protocol. This work informed the development of clinical chatbots for patients undergoing APOE testing for anti‐amyloid therapy. These chats include an education chat for patients prior to receiving APOE results and an APOE result specific chat to provide support to patients after receipt of results. Chatbot development and results of rapid cycle testing with patients will be described. Additionally, experiences with initial implementation of these digital tools and requests for genetic counseling among patients and their relatives will be reported. Conclusions Harnessing the experiences and outcomes from the described studies provides a unique opportunity to better understand use of telehealth modalities for APOE genotype disclosure and launch the development of digital tools that can further support the genetic counseling needs of this patient population. As indications for APOE testing rapidly increase, alternative delivery models will be critical to maximizing benefits and limiting harms.

APOE genotyping is increasingly important to identify candidates eligible for Alzheimer's prevention trials. Such testing is also now commonplace for patients considering new anti-amyloid treatments, given that APOE4 carriers are at elevated risk for treatment side effects. Data to inform best practices for sharing APOE results are needed. CONNECT4 is a multi-center, randomized trial (NCT02978729) comparing disclosure of APOE4 genotype by remote videoconference (VD) or telephone (TD) with a genetic counselor in cognitively unimpaired adults 60-75 YO. It was ancillary to the Generation 1 prevention trial, enrolling at 20 US sites. Patient-reported outcomes (PROs) were collected at 2-7 days (T1), 6 weeks (T2), and 6 months (T3) following APOE4 disclosure. Primary outcomes were change in genetic knowledge and disease-specific distress (T0-T1) and satisfaction (T1). We used T-tests and Fisher's exact tests to compare arms and carrier groups. 274 participants were randomized to TD and 267 to VD. Of those with complete data (n = 409, 76%), the mean age was 67.1 YO, 64.1% were female, 92.2% were white; 77.8% reported a family history of AD and 29.8% were APOE4 homozygotes, 40.4% were heterozygotes and 29.8% were noncarriers. There were no significant differences among arms in knowledge or distress, but slightly higher satisfaction with TD (Table 1). There were no significant differences in secondary PROs. By genotype, the only differences by arm included change in perceived lifetime numerical risk from T0-T1 among homozygotes (TD -5.19 v. VD +4.07, p = 0.018), and T0-T2 among noncarriers (TD -13.33 v. VD -22.28, p = 0.053) and satisfaction with genetic services among heterozygotes (TD 40.46 v VD 38.65, p = 0.01). In analyses evaluating moderators of PROs that adjusted for result, state anxiety increased under TD and decreased under VD for non-White participants (T0-T1), but declined by a similar amounts under both modalities for White participants (p = 0.039). Both telephone and videoconference are reasonable options for disclosure of APOE results in cognitively unimpaired individuals across all genotypes. While satisfaction was slightly higher with TD, small differences in numerical perceived risk by genotype and reductions in state anxiety among non-white participants, suggest potential small benefits to VD for some subgroups.