Disclosure Of Secondary Findings Research Articles

Challenges of secondary finding disclosure in genomic medicine in rare diseases: A nation-wide survey of Japanese facilities outsourcing comprehensive genetic testing.

Comprehensive genome analysis may reveal secondary findings (SFs) including pathogenic variants of genes other than those originally targeted. Comprehensive genetic analysis of rare diseases is generally performed as research in Japan. Therefore, the status and difficulties in SF disclosure remain unclear. To obtain information for the appropriate disclosure of SFs in rare diseases, we conducted a survey on how SFs are handled in clinical practice by facilities that outsource comprehensive genetic testing to other facilities. The response rate was 66.7% (40/60). Among the responding facilities, 55% had a policy of disclosing SFs with clinical utility and considered targeting actionable SFs with high penetrance. These facilities had difficulties in determining the disclosure targets (51%) and in genetic counseling (38%). Improving genetic literacy, establishment of surveillance systems, and providing insurance coverage for medical care to unaffected carriers were commonly cited as solutions to these difficulties. A comparison of the willingness to disclose SFs between overseas and in Japan showed more reluctance in Japan (86% vs. 65% for actionable SFs and 62% vs. 16% for non-actionable SFs). The group with difficulty in determining disclosure targets was significantly more likely to discuss this at conferences with other facilities and to refer guidelines. This suggests that the group with difficulties was unable to make decisions solely at their own facility and sought collaboration with other facilities. These findings suggest the necessity for a system that allows consultation with experts across facilities and guidelines that set forth policies for determining SFs.

A Scoping Review of Global Guidelines for the Disclosure of Secondary Genomic Findings to Inform the Establishment of Guidelines in China.

The detection and disclosure of secondary findings (SFs) is a preventive strategy for medically-actionable hereditary health conditions. Some countries have guidelines on management and disclosure of SFs, while others avoid detection and disclosure of SFs. This study is a review of clinical guidelines from six countries and the European Union to identify similarities and differences among SF guidelines. Evidence from this review supports harmonization of guidelines across countries to promote broad international collaborations on genomics and to benefit precision medicine. This study can serve as a reference for development of SF management guidelines in China by contributing evidence from other countries to the ethical and methodological challenges under debate.

Physicians' perceptions of the factors influencing disclosure of secondary findings in tumour genomic profiling in Japan: a qualitative study.

Tumour genomic profiling (TGP), conducted in search of therapeutics, sometimes reveals potentially pathogenic germline variants as secondary findings (SFs). Physicians involved in TGP are often specialised in oncology and not in clinical genetics. To better utilise SFs, we explored issues physicians have during disclosure and the potential for collaborations with clinical genetics professionals. Semi-structured interviews were conducted with 14 physicians who had experience in handling outpatient TGP at designated core hospitals for cancer genomic medicine in Japan. The data were analysed thematically. The difficulties physicians experienced during informed consent (IC) included educating patients about SFs, providing detailed information on SFs, and explaining the impact of SFs on patients' family members. When SFs were detected, physicians had reservations regarding the relevance of the disclosure criteria. Confirmatory germline tests were performed using peripheral blood when tumour-only tests detected suspected SFs. Some physicians had reservations about the necessity of confirmatory tests when they did not affect the patients' treatment options. To encourage patients to receive confirmatory tests, improvements are necessary in the healthcare system, such as insurance reimbursements, education for physicians so that they can provide a better explanation to their patients, and genetic literacy of physicians and patients. The physicians offered insights into the challenges they experienced related to IC, disclosure of SFs, and expectations for active collaborations with clinical genetics professionals. Wider healthcare insurance coverage and better genetic literacy of the population may lead to more patients taking confirmatory tests when SFs are suspected.

Whether, when, how, and how much? General public\u2019s and cancer patients\u2019 views about the disclosure of genomic secondary findings

BackgroundData on the modalities of disclosing genomic secondary findings (SFs) remain scarce. We explore cancer patients’ and the general public’s perspectives about disclosing genomic SFs and the modalities of such disclosure.MethodsSixty-one cancer patients (n = 29) and members of the public (n = 32) participated in eight focus groups in Montreal and Quebec City, Canada. They were asked to provide their perspectives of five fictitious vignettes related to medically actionable and non-actionable SFs. Two researchers used a codification framework to conduct a thematic content analysis of the group discussion transcripts.ResultsCancer patients and members of the public were open to receive genomic SFs, considering their potential clinical and personal utility. They believed that the right to know or not and share or not such findings should remain the patient’s decision. They thought that the disclosure of SFs should be made mainly in person by the prescribing clinician. Maintaining confidentiality when so requested and preventing genetic discrimination were considered essential.ConclusionParticipants in this study welcomed the prospect of disclosing genomic SFs, as long as the right to choose to know or not to know is preserved. They called for the development of policies and practice guidelines that aim to protect genetic information confidentiality as well as the autonomy, physical and psychosocial wellbeing of patients and families.

Patients' and Oncologists' Knowledge and Expectations Regarding Tumor Multigene Next-Generation Sequencing: A Narrative Review.

Tumor multigene next-generation sequencing (NGS) is increasingly being offered to cancer patients to guide clinical management and determine eligibility for clinical trials. We undertook a review of studies examining the knowledge and attitudes of patients and oncologists regarding the primary results and potential secondary findings of such testing. A search was conducted through the MEDLINE database using the following keywords: "neoplasms" and "molecular sequencing / genome sequencing / tumor profiling / NGS / whole exome sequencing" and "patient / oncologist" and "knowledge / attitudes / satisfaction / experience / evaluation / perspective / practice / preference." Articles meeting the inclusion criteria and additional relevant articles from their references were selected. From 1,142 publications identified by the search and 9 from references, 21 publications were included in the final review. Patients generally had positive attitudes toward tumor NGS despite relatively little knowledge of test-related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes toward disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy; they communicated challenges with tempering patient expectations and deciding what information to disclose. Patients considering undergoing tumor NGS should be provided with easily understandable resources explaining the procedure, goals, and probable outcomes, whenever possible based on evidence-based guidelines. Continuing medical education programs on this topic for oncology health care professionals should strive to improve their genomic literacy and instruct them on how to optimally present this information to their patients. Oncologists are increasingly offering tumor multigene testing to patients with advanced cancers to guide more "personalized" treatment and/or determine eligibility for clinical trials. However, patients often have inadequate understanding and unrealistic expectations. Oncologists must ensure that they themselves have sufficient knowledge of the benefits and limitations of testing and must provide their patients with appropriate educational resources. Prior to testing, patients should be told the likelihood of finding a mutation in their specific tumor type for which a targeted treatment or clinical trial is available. Patients also need clear information about the possibility and implications of secondary findings.

Attitudes among South African university staff and students towards disclosing secondary genetic findings.

The present study represents an initial step in understanding diverse academic perspectives on the disclosure of secondary findings (SFs) from genetic research conducted in Africa. Using an online survey completed by 674 university students and academic staff in South Africa, we elicited attitudes towards the return of SFs. Latent class analysis (LCA) was performed to classify sub-groups of participants according to their overall attitudes to returning SFs. We did not find substantial differences in attitudes towards the return of findings between staff and students. Overall, respondents were in favour of the return of SFs in genetics research, depending on the type. The majority of survey respondents (80%) indicated that research participants should be given the option of deciding whether to have genetic SFs returned. LCA revealed that the largest group (53%) comprised individuals with more favourable attitudes to the return of SFs in genetics research. Those with less favourable attitudes comprised only 4% of the sample. This study provides important insights that may, together with further empirical evidence, inform the development of research guidelines and policy to assist healthcare professionals and researchers.

Disclosure of secondary findings in exome sequencing of 2480 Japanese cancer patients.

High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-related genes. Majority of the participants (68.9%; 1709/2480) opted for disclosure of their SFs. Thirty-two pathogenic or likely pathogenic variants, including BRCA1 (7 patients), BRCA2 (4), CHEK2 (4), PTEN (3), MLH1 (3), SDHB (2), MSH6 (1), NF1 (1), EXT2 (1), NF1 (1), NTRK1 (1), MYH7 (3), MYL2 (1), TNNT2 (1), LDLR (2), FBN1 (1), and KCNH2 (1) were recognized in 36 patients (1.5%). Twenty-eight (77.8%) patients underwent genetic counseling and received their SF results. Eighteen (64.3%) patients underwent clinical management for SFs. Genetic validation tests were administered significantly more frequently to patients with than without a SF-related personal history (P = 0.025). This was a first attempt at a large-scale systematic exome analysis in Japan; nevertheless, many cancer patients opted for disclosure of SFs and accepted or considered clinical management.

Do health professionals value genomic testing? A discrete choice experiment in inherited cardiovascular disease

Next generation sequencing (NGS) approaches are moving from research into clinical practice. However, the optimal NGS approach in well-defined adult-onset familial diseases, such as inherited cardiovascular disease, remains unclear. We aimed to determine which attributes encouraged or discouraged the uptake of genomic tests in this context, and whether this differed by test type. We conducted a web-based discrete choice experiment in health professionals in the UK who order NGS tests for inherited cardiovascular disease. Respondents completed 12 hypothetical choice tasks in which they selected a preferred test from four alternatives: whole genome sequencing, whole exome sequencing, panel testing and genetic testing not indicated. Tests were specified in terms of five attributes: diagnostic yield, detection rate for variants of unknown significance, cost, quantity of counselling received and disclosure of secondary findings. Mixed logit regression analysis was used to analyse the choice data. We found that uptake of NGS increases if tests identify more pathogenic mutations, identify fewer variants of unknown significance, or cost less. Respondents were willing to pay £117 for every 1% increase in diagnostic yield. Considerable heterogeneity was observed around preferences for several test attributes. Overall, panel testing had the highest predicted uptake rate. Our results indicate that NGS tests are valued by health professionals for well-defined adult-onset familial diseases, however, these professionals have strong preferences for panel testing rather than whole genome sequencing and whole exome sequencing. This finding suggests that different uptake rates should be explicitly modelled when designing and evaluating future genomic testing services.

Chapter 3 - Ethical issues in neurogenetics

Many neurogenetic conditions are inherited and therefore diagnosis of a patient will have implications for the patient's relatives and can raise ethical issues. Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients' autonomy and informed, voluntary decision making. Beneficence and nonmaleficence both need to be considered when making decisions about disclosure and nondisclosure of genetic information and test results. There can be disclosure concerns and challenges in determining whose autonomy to prioritize when a patient makes a genetic testing decision that can reveal the genetic status of a relative (e.g., testing an adult child when the at-risk parent has not been tested). Ethical issues are prominent when genetic testing for neurogenetic conditions is requested prenatally, on minors, adoptees, adult children at 25% risk, and for individuals with psychiatric issues or cognitive impairment. Neurogenetic conditions can result in cognitive decline which can affect decisional capacity and lead to ethical challenges with decision making, informed consent, and determining the patient's ability to comprehend test results. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of apolipoprotein E testing in clinical and research settings, are also discussed. Resources for information about genetic testing practice guidelines, insurance laws, and directories of genetics clinics are included.