Search

A considerable amount of theoretical neuroethics literature on deep brain stimulation (DBS) has focused on how DBS might impact agency and personal identity. The use of devices that stimulate speci...

Genomic sequencing and multigene panel tests are moving rapidly into clinical practice for a range of indications, but the evidence to guide appropriate use is currently limited. Well-crafted advice is needed to reduce unjustified practice variation, minimize risk of error and harm to patients, and encourage best practices. In the absence of definitive evidence, provisional advice can be helpful if it clarifies the potential benefits and risks of different courses of action and identifies the knowledge gaps most important to address in future research. This paper proposes an evolutionary process starting with clinical practice advisory documents (CPADs) and culminating in clinical practice guidelines (CPGs), using two case examples to illustrate the need for this process. When evidence is limited, CPADs can clarify current practice options and identify key knowledge gaps. Added evidence can then support updates to the CPADs over time. Ultimately CPADs can provide the foundation for definitive CPGs as the evidence base matures. This approach addresses an important challenge in genomics and may be applicable to other fields in which technology and practice are outpacing evidence generation.

In this paper, we develop the concept of a medical information commons, laying out its central features and exploring connections to several strands of commons theory. We then hone in on normative questions raised by efforts to create widely-shared informational resources in the biomedical research space. Addressing these questions involves examination of the claims of key stakeholders and excavation of the moral foundations of governance mechanisms. We believe this analysis yields several important lessons for leaders of current efforts. First, they should consider investing resources in empirical studies to inform evaluation of the trade-offs associated with alternative strategies for involving participants. Second, there is intrinsic as well as instrumental value to the engagement of all stakeholders on terms that approximate as closely as possible norms of mutual regard and equal respect, a standard that is demanding but also flexible. Third (and related), consistent with principles of adaptive governance, nesting, and institutional variety, differences of approach across efforts should be expected and are indeed desirable. Finally, while it is possible to combine insights from the public domain and common-pool resource strands of commons theory, there are tensions between the two approaches. The rhetoric of “broad sharing” and “openness” may obscure the need to make difficult decisions about the boundaries of a commons, allocation of resultant benefits and burdens, and enforcement of rules.

During its first 15 years, neuroethics research focused mostly on theoretical analysis of the ethical implications of emerging neuroscience knowledge and technologies. Kellmeyer and colleagues (201...

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell–based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care–related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.

As members of the National Academies of Sciences, Engineering, and Medicine committee that wrote the report on the return of individual research results ([ 1 ][1]), we reject the allegations in the Policy Forum “Return of results and data to study participants” (S. M. Wolf and B. J. Evans, 12 October, p. [159][2]) that the report is paternalistic, misunderstands the law, burdens Institutional Review Boards (IRBs), and creates barriers to the return of results. In the National Academies report, we advocate regulatory changes to expand the opportunities to give research participants access to their individual results. The Centers for Medicare and Medicaid Services (CMS) interprets the law governing laboratory standards as prohibiting any communication about research results to participants unless the laboratory is certified according to the Clinical Laboratory Improvement Amendments of 1988 (CLIA). Wolf and Evans contend that CMS does not have the statutory authority for this restriction. However, there is no consensus regarding this position ([ 2 ][3], [ 3 ][4]) and CMS's interpretation has not been overruled by the courts. Given substantial penalties for noncompliance, many research institutions abide by CMS's interpretation. Our report recommends an explicit change to the regulations to bring clarity to the field that will not be achieved by assuming that CMS's position can be ignored, as Wolf and Evans suggest. We recommend that the Office of Civil Rights (OCR) clarify what research results participants have a right to under the Health Insurance Portability and Accountability Act (HIPAA) rule by clearly defining the Designated Record Set (DRS) to include all research results generated in laboratories that meet an accepted quality standard. Although the DRS includes information maintained by a covered entity that could be used for individual decision-making ([ 4 ][5]), there is no consensus about what research data should be included. In the absence of guidance from OCR, some institutions are excluding some research data from the DRS ([ 5 ][6]). Our recommendation supports broadening participant access to high-quality research results while adhering to the principle that results lacking demonstrated quality should not be used by participants or their health care providers for individual decision-making. We disagree with the notion that our recommendations are paternalistic. During our study, we consulted a diverse group of community members, study participants, and advocacy groups to fully understand how individuals might use results, as well as barriers to using and understanding results. The committee sought a balance that promotes broad access to results while addressing public expectations that results are accurate. Disclosing poor-quality results reflects bad science and does not respect participant autonomy or welfare. We maintain that quality standards for research laboratories will better ensure accurate results that meet the expectations of participants and will enhance the overall validity and reproducibility of the research enterprise. We believe that IRBs are up to the challenge of addressing the new responsibilities recommended by our report, although we acknowledge that these demands cannot be addressed overnight. The report recommends that investigators work with stakeholders to develop plans on whether and how to disclose results as protocols are developed. The informed consent process is key to fostering participant understanding of their options for return of results and to documenting expression of their preferences. IRBs must be involved in evaluating the return of results plan and consent process and, over time, will need to develop expertise and policies for this purpose. We are confident that our recommendations break down many of the existing barriers to the return of individual research results and, if followed, will enhance the collaboration among all stakeholders. Return of individual results is not a common practice ([ 6 ][7]) despite existing guidelines, and research participants rarely request results under their HIPAA access rights. Our report promotes the routine consideration of return of results by funders, researchers, and participants; the development of standards and policies to foster return, greater transparency, and engagement with participants; and an informed consent process that informs participants of their opportunities and rights. 1. [↵][8]The National Academies of Sciences, Engineering, and Medicine, “Returning individual research results to participants: Guidance for a new research paradigm” (Consensus Study Report, 2018); . 2. [↵][9]1. M. Barnes et al ., “The CLIA/HIPPA conundrum of returning test results to research participants,” Medical Research Law & Policy Report (2015); [www.ropesgray.com/~/media/Files/articles/2015/July/2015-07-15-Bloomberg-BNA.ashx][10]. 3. [↵][11]U.S. Department of Health and Human Services, Office for Human Research Protections, “Attachment C: Return of individual results and special consideration of issues arising from amendments of HIPAA and CLIA,” Office for Human Research Protections (2015); [www.hhs.gov/ohrp/sachrp-committee/recommendations/2015-september-28-attachment-c/index.html][12]. 4. [↵][13]U.S. Department of Health and Human Services, § 164.501 Definitions (2004); [www.gpo.gov/fdsys/pkg/CFR-2004-title45-vol1/pdf/CFR-2004-title45-vol1-sec164-501.pdf][14]. 5. [↵][15]Johns Hopkins Medicine, Office of Human Subjects Research—Institutional Review Board, HIPAA Questions and Answers Relating to Research, VI: Subject Requests for Access to Research Data or Test Results ([www.hopkinsmedicine.org/institutional\_review\_board/hipaa\_research/faq\_research.html#access][16]). 6. [↵][17]1. P. S. Appelbaum et al ., Gen. Med. 17, 644 (2015). [OpenUrl][18] [1]: #ref-1 [2]: http://www.sciencemag.org/content/362/6411/159 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #ref-5 [7]: #ref-6 [8]: #xref-ref-1-1 "View reference 1 in text" [9]: #xref-ref-2-1 "View reference 2 in text" [10]: http://www.ropesgray.com/~/media/Files/articles/2015/July/2015-07-15-Bloomberg-BNA.ashx [11]: #xref-ref-3-1 "View reference 3 in text" [12]: http://www.hhs.gov/ohrp/sachrp-committee/recommendations/2015-september-28-attachment-c/index.html [13]: #xref-ref-4-1 "View reference 4 in text" [14]: http://www.gpo.gov/fdsys/pkg/CFR-2004-title45-vol1/pdf/CFR-2004-title45-vol1-sec164-501.pdf [15]: #xref-ref-5-1 "View reference 5 in text" [16]: http://www.hopkinsmedicine.org/institutional_review_board/hipaa_research/faq_research.html#access [17]: #xref-ref-6-1 "View reference 6 in text" [18]: {openurl}?query=rft.jtitle%253DGen.%2BMed.%26rft.volume%253D17%26rft.spage%253D644%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

Objective To examine communication patterns and behaviors during disclosure of exome sequencing (ES) results to parents of pediatric cancer patients, and describe common themes in parental communication. Methods Using mixed methods, we analyzed transcripts of sessions where parents of pediatric cancer patients received ES results from an oncologist and genetic counselor. Seventy-six transcripts were analyzed for frequency of clinician information-giving, partnering-supportive talk, and active parent participation. A subset of 40 transcripts were analyzed using thematic content analysis. Results Disclosures consisted mostly of clinician talk (84% of total talk), which was focused on providing information (62% of clinicians’ utterances) with occasional partnering-supportive talk (7% of clinicians’ utterances). Most parents assumed a passive, listening role (16% of total talk). Themes in parental communication included expressing relief and the significance of an answer, concern about sharing results and responsibility for inheritance, and seeking clarification of health implications of results. Conclusion Our finding of low levels of active parent participation during ES disclosures highlights the need to improve patient/parent engagement and understanding in a genetic setting. Practice implications Clinician communication strategies that could encourage parent participation and understanding include checking for parent understanding, partnership-building, and tailoring ES discussions to address parent concerns and preferences.

On April 24, 2018, a suspect in California's notorious Golden State Killer cases was arrested after decades of eluding the police. Using a novel forensic approach, investigators identified the suspect by first identifying his relatives using a free, online genetic database populated by individuals researching their family trees. In the wake of the case, media outlets reported privacy concerns with police access to personal genetic data generated by or shared with genealogy services. Recent data from 1,587 survey respondents, however, provide preliminary reason to question whether such concerns have been overstated. Still, limitations on police access to genetic genealogy databases in particular may be desirable for reasons other than current public demand for them.

© 2018 American Society of Human Genetics The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.

Background Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. Methods Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. Results Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (

BACKGROUND AND OBJECTIVES: There is interest in applying genomic sequencing (GS) to newborns’ clinical care. Here we explore parents’ and clinicians’ attitudes toward and perceptions of the risks, benefits, and utility of newborn GS compared with newborn screening (NBS) prior to receiving study results. METHODS: The BabySeq Project is a randomized controlled trial used to explore the impact of integrating GS into the clinical care of newborns. Parents (n = 493) of enrolled infants (n = 309) and clinicians (n = 144) completed a baseline survey at enrollment. We examined between-group differences in perceived utility and attitudes toward NBS and GS. Open-ended responses about risks and benefits of each technology were categorized by theme. RESULTS: The majority of parents (71%) and clinicians (51%) agreed that there are health benefits of GS, although parents and clinicians agreed more that there are risks associated with GS (35%, 70%) than with NBS (19%, 39%; all P < .05). Parents perceived more benefit and less risk of GS than did clinicians. Clinicians endorsed concerns about privacy and discrimination related to genomic information more strongly than did parents, and parents anticipated benefits of GS that clinicians did not. CONCLUSIONS: Parents and clinicians are less confident in GS than NBS, but parents perceive a more favorable risk/benefit ratio of GS than do clinicians. Clinicians should be aware that parents’ optimism may stem from their perceived benefits beyond clinical utility.

The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.

The 24 April 2018 arrest of Joseph James DeAngelo as the alleged Golden State Killer, suspected of more than a dozen murders and 50 rapes in California, has raised serious societal questions related to personal privacy. The break in the case came when investigators compared DNA recovered from victims and crime scenes to other DNA profiles searchable in a free genealogical database called GEDmatch. This presents a different situation from the analysis of DNA of individuals arrested or convicted of certain crimes, which has been collected in the U.S. National DNA Index System (NDIS) for forensic purposes since 1989. The search of a nonforensic database for law enforcement purposes has caught public attention, with many wondering how common such searches are, whether they are legal, and what consumers can do to protect themselves and their families from prying police eyes. Investigators are already rushing to make similar searches of GEDmatch in other cases, making ethical and legal inquiry into such use urgent.

* Abbreviation: HEADSSS — : home life, education, activities, drugs, sexual activity, safety, and suicide and/or depression Social media intertwines itself with the adolescent experience in our country. Friendships, family ties, romantic relationships, academic pursuits, and even dining all have an inseparable electronic component for this generation. Social media is defined as electronic communication, especially applications and Web sites, through which users create and share information, ideas, and personal messages in an online community.1 The most prominent platforms for this activity are Facebook, Instagram, Twitter, and Snapchat. Research regarding the merge of social media and clinical practice has grown in the last decade, and we’ve now learned that there are clear correlations between patients’ mental health and social media usage. Aberrant and/or excessive social media usage may contribute to the development of mental health disturbance in at-risk teenagers, such as feelings of isolation, depressive symptoms, and anxiety.2,3 In addition, many mentally ill teenagers express their daily thoughts and stressors via social networking platforms. Thus, gathering information on teenagers’ social media activities may provide a more complete picture of their psychosocial risk profile. Social networking media involves active and passive consumption that can directly influence, if not replace, face-to-face contact. Usage patterns among adolescents resemble the progressive, withdrawal-producing, and dose-dependent … Address correspondence to Amy L. McGuire, JD, PhD, School of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Suite 310D, Houston, TX 77401. E-mail: amcguire{at}bcm.edu

Objectives To describe how linguistic tools used by interpreters during return of genomic sequencing results may have impacted communication with Spanish-speaking families, and to discuss the implications for the role of medical interpreters. Methods Using discourse analysis, we identified and categorized the various ways hospital-based interpreters adapted clinicians’ language in 37 audio-recorded sessions in which Spanish-speaking parents participating in a clinical trial received their child’s genomic sequencing results from English-speaking clinicians. Results We found that interpreters adapted clinicians’ statements using five empathic linguistic tools: contextualization, encouragement, checking comprehension, endearment, and softening. Interpreters used an average of four linguistic tools per session, with contextualization and encouragement being the most frequently used. Conclusions Interpreters used empathic linguistic tools to alter clinicians’ statements when communicating genomic information to Spanish-speaking families. Our findings demonstrate the critical role of interpreters as cultural mediators and facilitators of understanding for Spanish-speaking families. Practice implications This study expands upon the definition of clinical empathy in interpreter-mediated sessions. Our findings suggest that revisions of standards of medical interpretation practice may be warranted regarding interpreters’ ability to adapt clinicians’ language in a culturally sensitive manner during interpretation.

© 2018, American College of Medical Genetics and Genomics. Purpose: Clinical sequencing emerging in health care may result in secondary findings (SFs). Methods: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene–condition pair list; we assessed clinical and psychosocial actions. Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0–$678) and $421 (recommended, range: $141–$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene–condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

Background It has been anticipated that physician and parents will be ill prepared or unprepared for the clinical introduction of genome sequencing, making it ethically disruptive. Procedure As a part of the Baylor Advancing Sequencing in Childhood Cancer Care study, we conducted semistructured interviews with 16 pediatric oncologists and 40 parents of pediatric patients with cancer prior to the return of sequencing results. We elicited expectations and attitudes concerning the impact of sequencing on clinical decision making, clinical utility, and treatment expectations from both groups. Using accepted methods of qualitative research to analyze interview transcripts, we completed a thematic analysis to provide inductive insights into their views of sequencing. Results Our major findings reveal that neither pediatric oncologists nor parents anticipate sequencing to be an ethically disruptive technology, because they expect to be prepared to integrate sequencing results into their existing approaches to learning and using new clinical information for care. Pediatric oncologists do not expect sequencing results to be more complex than other diagnostic information and plan simply to incorporate these data into their evidence-based approach to clinical practice, although they were concerned about impact on parents. For parents, there is an urgency to protect their child's health and in this context they expect genomic information to better prepare them to participate in decisions about their child's care. Conclusions Our data do not support the concern that introducing genome sequencing into childhood cancer care will be ethically disruptive, that is, leave physicians or parents ill prepared or unprepared to make responsible decisions about patient care.

OBJECTIVE A common concern of utilizing prenatal advanced genetic testing is that a result of uncertain clinical significance will increase patient anxiety. However, prenatal ultrasound may also yield findings of uncertain significance, such as 'soft markers' for fetal aneuploidy, or findings with variable prognosis, such as mild ventriculomegaly. In this study we compared risk perception following uncertain test results from each modality. METHODS A single survey with repeated measures design was administered to 133 pregnant women. It included 'intolerance of uncertainty' questions, two hypothetical scenarios involving prenatal ultrasound or advanced genetic testing, and response questions. The primary outcome was risk perception score. RESULTS Risk perception did not vary significantly between ultrasound and genetic scenarios (p = 0.17). The genetic scenario scored a higher accuracy (p = 0.04) but lower sense of empowerment (p = 0.01). Furthermore, patients were more likely to seek additional testing after an ultrasound than after genetic testing (p = 0.05). There were no differences in other secondary outcomes including perception of life-altering consequences and hypothetical worry, anxiety, confusion, or medical care decisions. CONCLUSIONS Our data suggest that uncertain findings on prenatal genetic testing do not elicit a higher perception of risk or anxiety when compared to ultrasound findings of comparable uncertainty. © 2015 John Wiley & Sons, Ltd.

There is an urgent need for consistent data sharing policies that promote the advancement of science while respecting the values and interests of those providing their genetic data for research. Responding to the article of Jalayne J. Arias, Genevieve Pham-Kanter, and Eric G. Campbell, 'The Growth and Gaps of Genetic Data Sharing Policies in the United States', this commentary further explores the challenges of human subjects' protection in existing data sharing policies. We will elaborate on the need for data sharing policies to accommodate variation in individual and group preferences around data sharing and privacy concerns by comparing our previously published data on patients' and parents' consent to data sharing and attitudes about privacy to data from focus groups with HIV-positive, underserved individuals who were asked about their willingness to participate in genetic research and share their data broadly. These studies support the observation of Arias, Pham-Kanter, and Campbell that researchers, and funding agencies will need to balance the privacy interests of groups as well as individuals in future genomic data sharing policies.

In the pediatric clinical setting, the parent/guardian will almost always be the authorized representative and designated recipient of clinical and research results, making the issue of to whom results should be returned in the pediatric setting less complex than in adult settings. It is also clear that, in genomic research related to pediatric diseases such as cancer, results may be of considerable clinical, ethical, and personal significance for parents in a number of ways, including a genomic explanation of the origin of their child’s cancer, implications for the genetic testing and medical care of other siblings and of the parents themselves, and reproductive planning with regard to the recurrence risk for future children to have an increased risk of cancer. However, what remains unclear is which results should be disclosed, and under what circumstances, to parents of deceased children.

Aim: Identify solutions to the most important policy barriers to the clinical adoption of next-generation sequencing. Materials & methods: Four-round modified policy Delphi with a multistakeholder panel of 48 experts. The panel deliberated policy solutions to (previously reported) challenges deemed most important to address. Results: The group advocated using consensus panels to promote consistency in payer policies and to standardize test reporting, and favored making genomic data-sharing a condition of regulatory clearance, certification, or accreditation processes. They were split on the role of US FDA. Conclusion: Panelists found common ground on solutions for health plan coverage policy consistency, data-sharing, and standardizing reporting, but were sharply divided on the role of the FDA in mitigating risks to patients.

BACKGROUND: Clinical genome and exome sequencing (CGES) are being used in an expanding range of clinical settings. Most approaches to offering patients choices about learning CGES results classify results according to expert definitions of clinical actionability. Little is known about how patients conceptualize different categories of CGES results. METHODS: The MedSeq Project is a randomized controlled trial studying the use of whole-genome sequencing (WGS) in primary care and cardiology. We surveyed 202 patient-participants about different kinds of WGS results and conducted qualitative interviews with 49 of these participants. Interview data was analyzed both inductively and deductively using thematic content analysis. RESULTS: Participants demonstrated high levels of study understanding and genetic literacy. A small majority of participants wanted to learn all of their WGS results (n=123, 61%). Qualitative data provided a deeper understanding of participants’ perspectives about different types of WGS results. Participants did not have the same views about which WGS results would be actionable or upsetting to learn. They conceptualized variants of uncertain significance (VUS) in a variety of different ways. Many participants expressed optimism that the uncertainty associated with VUS results could be reduced over time. CONCLUSIONS: Proposals to determine which WGS /CGES results to disclose by soliciting patient preferences may fail to appreciate the complex ways patients think about disease and the information WGS/CGES can produce. Our findings challenge prevailing methods of facilitating patient choice and assessing the benefits and harms related to the return of WGS/CGES results, which mostly rely on expert definitions of clinical utility to categorize the kinds of results patients can learn.

National and international public–private partnerships, consortia, and government initiatives are underway to collect and share genomic, personal, and healthcare data on a massive scale. Ideally, these efforts will contribute to the creation of a medical information commons (MIC), a comprehensive data resource that is widely available for both research and clinical uses. Stakeholder participation is essential in clarifying goals, deepening understanding of areas of complexity, and addressing long-standing policy concerns such as privacy and security and data ownership. This article describes eight core principles proposed by a diverse group of expert stakeholders to guide the formation of a successful, sustainable MIC. These principles promote formation of an ethically sound, inclusive, participant-centric MIC and provide a framework for advancing the policy response to data-sharing opportunities and challenges.

PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was $5,098 in cardiology settings and $5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = -$1,560, 95% confidence interval -$7,558 to $3,866, p = 0.36; primary care: difference = $681, 95% confidence interval -$884 to $2,171, p = 0.70). Scenario analyses showed the cost reduction of omitting or limiting the types of secondary findings was less than $69 and $182 per patient in cardiology and primary care, respectively.ConclusionShort-term costs of WGS were driven by the costs of sequencing and interpretation rather than downstream health care. Disclosing additional types of secondary findings has a limited cost impact following disclosure.

BACKGROUND: Genomics will play an increasingly prominent role in clinical medicine. OBJECTIVE: To describe how primary care physicians (PCPs) discuss and make clinical recommendations about genome sequencing results. DESIGN: Qualitative analysis. PARTICIPANTS: PCPs and their generally healthy patients undergoing genome sequencing. APPROACH: Patients received clinical genome reports that included four categories of results: monogenic disease risk variants (if present), carrier status, five pharmacogenetics results, and polygenic risk estimates for eight cardiometabolic traits. Patients’ office visits with their PCPs were audio-recorded, and summative content analysis was used to describe how PCPs discussed genomic results. KEY RESULTS: For each genomic result discussed in 48 PCP–patient visits, we identified a “take-home” message (recommendation), categorized as continuing current management, further treatment, further evaluation, behavior change, remembering for future care, or sharing with family members. We analyzed how PCPs came to each recommendation by identifying 1) how they described the risk or importance of the given result and 2) the rationale they gave for translating that risk into a specific recommendation. Quantitative analysis showed that continuing current management was the most commonly coded recommendation across results overall (492/749, 66%) and for each individual result type except monogenic disease risk results. Pharmacogenetics was the most common result type to prompt a recommendation to remember for future care (94/119, 79%); carrier status was the most common type prompting a recommendation to share with family members (45/54, 83%); and polygenic results were the most common type prompting a behavior change recommendation (55/58, 95%). One-fifth of recommendation codes associated with monogenic results were for further evaluation (6/24, 25%). Rationales for these recommendations included patient context, family context, and scientific/clinical limitations of sequencing. CONCLUSIONS: PCPs distinguish substantive differences among categories of genome sequencing results and use clinical judgment to justify continuing current management in generally healthy patients with genomic results. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-017-4295-4) contains supplementary material, which is available to authorized users.

The ubiquity of DNA sequencing and the advent of medical imaging, electronic health records, and “omics” technologies have produced a deluge of data. Making meaning of those data—creating scientific knowledge and useful clinical information—will vastly exceed the capacity of even the largest institutions. Data must be shared to achieve the promises of genomic science and precision medicine.

An ongoing legal challenge to the business model of Myriad Genetics highlights how recent policy developments have contributed to a collision between individual interests in access to personal health data and commercial interests in trade secrecy. Following a landmark ruling by the U.S. Supreme Court invalidating its patents on BRCA1/2 genetic variants ( 1 ), which increase the risk of female breast and ovarian cancer, Myriad now faces efforts to dismantle the proprietary database of variants and their clinical interpretation that it began developing when it was the exclusive provider of BRCA1/2 tests. Although the competing claims that anchor this dispute are hard to reconcile, we see room for legal compromise and opportunity for policy innovations to incentivize companies to invest in test development while ensuring that their findings can be used by others.

Background The importance of health privacy protections in the era of the “Facebook Generation” has been called into question. The ease with which younger people share personal information about themselves has led to the assumption that they are less concerned than older generations about the privacy of their information, including health information. We explored whether survey respondents’ views toward health privacy suggest that efforts to strengthen privacy protections as health information is moved online are unnecessary. Methods Using Amazon’s Mechanical Turk (MTurk), which is well-known for recruitment for survey research, we distributed a 45-item survey to individuals in the U.S. to assess their perspectives toward privacy and security of online and health information, social media behaviors, use of health and fitness devices, and demographic information. Results 1310 participants (mean age: 36 years, 50% female, 78% non-Hispanic white, 54% college graduates or higher) were categorized by generations: Millennials, Generation X, and Baby Boomers. In multivariate regression models, we found that generational cohort was an independent predictor of level of concern about privacy and security of both online and health information. Younger generations were significantly less likely to be concerned than older generations (all P < 0.05). Time spent online and social media use were not predictors of level of concern about privacy or security of online or health information (all P > 0.05). Limitations This study is limited by the non-representativeness of our sample. Conclusions Though Millennials reported lower levels of concern about privacy and security, this was not related to internet or social media behaviors, and majorities within all generations reported concern about both the privacy and security of their health information. Thus, there is no intergenerational imperative to relax privacy and security standards, and it would be advisable to take privacy and security of health information more seriously.

An increasing number of individuals are being recruited to whole genome sequencing (WGS) research. When asked hypothetically, the majority of the public express willingness to participate in this type of research, yet little is known about how many individuals will actually consent to research participation or what they perceive the risks to be. The MedSeq Project is a clinical trial exploring WGS in clinical care. We documented primary reason(s) for declining participation and reviewed audio-recorded informed consent sessions to identify participants’ concerns. Of 514 individuals recruited, 173 (34%) actively declined, 205 (40%) enrolled, and the remaining 136 (26%) were ineligible, unresponsive or waitlisted. Although the majority of active decliners cited logistical barriers, 40% cited risks related to the ethical, legal, and social implications (ELSI) of WGS research. Participants similarly discussed ELSI-related concerns but felt the potential benefits of participation outweighed the risks. Findings provide insight into the perspectives of potential WGS research participants and identify potential barriers to participation.

Aim: Identify the behavioral challenges to the use of genome sequencing (GS) in a clinical setting. Materials & methods: We observed how general internists and nongenetic specialists delivered GS results to patients enrolled in the MedSeq Project. Using transcripts of such disclosure interactions, we made qualitative observations of communication behaviors that could limit the usefulness of GS results until reaching the point of thematic saturation. Results: Findings included confusion regarding genomic terminology, difficulty with the volume or complexity of information and difficulties communicating complex risk information to patients. We observed a broad dismissal of clinical value of GS by some physicians and sometimes ineffective communication regarding health behavior change. Conclusion: Overcoming these behavioral challenges is necessary to make full use of clinical GS results.

© 2017 by the American Academy of Pediatrics. The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genomescale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Thousands of patents have been awarded that claim human gene sequences and their uses, and some have been challenged in court. In a recent high-profile case, Association for Molecular Pathology, et al. v. Myriad Genetics, Inc., et al., the US Supreme Court ruled that genes are natural occurring substances and therefore not patentable through 'composition of matter' claims. The consequences of this ruling will extend well beyond ending Myriad's monopoly over BRCA testing and may affect similar monopolies of other commercial laboratories for tests involving other genes. It could also simplify intellectual property issues surrounding genome-wide clinical sequencing, which can generate results for genes covered by intellectual property. Non-invasive prenatal testing (NIPT) for common aneuploidies using cell-free fetal (cff) DNA in maternal blood is currently offered through commercial laboratories and is also the subject of ongoing patent litigation. The recent Supreme Court decision in the Myriad case has already been invoked by a lower district court in NIPT litigation and resulted in invalidation of primary claims in a patent on currently marketed cffDNA-based testing for chromosomal aneuploidies.

OBJECTIVE: In the United States, data from federally funded genomics studies are stored in national databases, which may be accessible to anyone online (public release) or only to qualified researchers (restricted release). The availability of such data exposes participants to privacy risk and limits the ability to withdraw from research. This exposure is especially challenging for pediatric participants, who are enrolled in studies with parental permission. The current study examines genomic research participants’ attitudes to explore differences in data sharing (DS) preferences between parents of pediatric patients and adult patients. METHODS: A total of 113 parents of pediatric patients and 196 adult participants from 6 genomics studies were randomly assigned to 3 experimental consent forms. Participants were invited to a follow-up structured interview exploring DS preferences, study understanding, and attitudes. Descriptive analyses and regression models were built on responses. RESULTS: Most parents (73.5%) and adult participants (90.3%) ultimately consented to broad public release. However, parents were significantly more restrictive in their data release decisions, not because of understanding or perceived benefits of participation but rather autonomy and control. Parents want to be more involved in the decision about DS and are significantly more concerned than adult participants about unknown future risks. CONCLUSIONS: Parents have the same altruistic motivations and grasp of genomics studies as adult participants. However, they are more concerned about future risks to their child, which probably motivates them to choose more restrictive DS options, but only when such options are made available.

Genomic researchers increasingly are faced with difficult decisions about whether, under what circumstances, and how to return research results and significant incidental findings to study participants. Many have argued that there is an ethical—maybe even a legal—obligation to disclose significant findings under some circumstances. At the international level, over the last decade there has begun to emerge a clear legal obligation to return significant findings discovered during the course of research. However, there is no explicit legal duty to disclose in the United States. This creates legal uncertainty that may lead to unmanaged variation in practice and poor quality care. This article discusses liability risks associated with the disclosure of significant research findings for investigators in the United States.

A review of the key issues associated with the commercialization of biobanks Timothy Caulfield∗, Sarah Burningham, Yann Joly, ZubinMaster, Mahsa Shabani, Pascal Borry, Allan Becker, Michael Burgess, Kathryn Calder, Christine Critchley, Kelly Edwards, Stephanie M. Fullerton, Herbert Gottweis, Robyn Hyde-Lay, Judy Illes, Rosario Isasi, Kazuto Kato, Jane Kaye, Bartha Knoppers, John Lynch, AmyMcGuire, Eric Meslin, Dianne Nicol, Kieran O’Doherty, Ubaka Ogbogu, Margaret Otlowski, Daryl Pullman, Nola Ries, Chris Scott, Malcolm Sears, HelenWallace andMa’n H. Zawati†

Brain implants are being trialled for their potential to ameliorate treatment-resistant conditions or to restore function. However, there are no clear guidelines for continued access to brain implants for trial participants whose symptoms improve with these devices.

Genomic sequencing technologies have facilitated the unbiased examination of cancer genomes, allowing rational prioritization of candidate genes and pathways for biological study and clinical application. Clinical experience with these methods as “precision oncology” strategies for children with central nervous system (CNS) tumors remains unproven. Over the past several years, a number of pilot studies of precision oncology have provided early clues regarding the feasibility, clinical utility, and limitations of genome-scale testing, emphasizing the critical importance of both tumor and germline results for patient care. These studies provide a foundation for incorporation of genomic testing into prospective clinical trials utilizing biomarker-driven treatment assignments in the care of pediatric cancer patients. To more rigorously compare the diagnostic utility of clinical genomic tests, the Texas KidsCanSeq study, an NHGRI and NCI-funded Clinical Sequencing Evidence Generating Research (CSER) Program project, was activated in June 2018. This study, which will enroll 1100 patients from six Texas institutions, aims to compare the diagnostic yield of targeted panel testing (comprehensive pediatric cancer-focused DNA and RNA panels utilized clinically at Texas Children’s Cancer Center) versus more extensive genomic testing (exome sequencing, transcriptome sequencing, copy number array) of formalin-fixed paraffin-embedded tumor and blood samples. Additionally, study oncologists are being surveyed regarding the downstream implications of these tests on decision-making related to the use of molecularly targeted therapies and/or enrollment on clinical trials. Early examples of CNS tumor cases with clinically-actionable mutations include two patients with midline high grade glioma (HGG) harboring activating PIK3CA mutations (15 year old male with thalamic HGG and PIK3CA p.Glu542Lys; 7 year old female with pontine HGG and PIK3CA p.Glu545Gly) that are potentially targetable by PI3K inhibitors or combined PI3K/MTOR inhibitors. These cases highlight the potential utility of molecular testing of pediatric CNS tumors for identification of novel therapies and relevant clinical trials.

In 1996, President Clinton offered a promissory vision for human genetics when he said: “I think it won't be too many years before parents will be able to go home from the hospital with their newborn babies with a genetic map in their hands that will tell them, here's what your child's future will likely be like.”The rapid evolution of genetic sequencing technologies has advanced that vision. In October 2006, the cost of sequencing an entire human genome was $10.4 million; by 2014 the cost had decreased a thousand fold. The term next generation sequencing (NGS) describes a variety of laboratory methods that allow efficient determination of the precise order of nucleotides in a DNA sequence. The papers in this issue of the Journal of Law, Medicine & Ethics focus on “clinical NGS,” which refers to rapid DNA sequencing using second-, third- and fourth-generation sequencing technologies to perform genome-wide sequencing of multiple genes or alleles for clinical prognostic, diagnostic, and therapeutic purposes.

Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research.We surveyed corresponding authors of genome-wide association studies, identified through the National Human Genome Research Institute's Catalog of Published Genome-Wide Association Studies, to describe the experiences and attitudes of these stakeholders.Of 357 corresponding authors, 200 (56%) responded. One hundred twenty-six (63%) had been responsible for primary data and sample collection, whereas 74 (37%) had performed secondary analyses. Only 7 (4%) had returned individual results within their index genome-wide association studies. Most (69%) believed that return of results to individual participants was warranted under at least some circumstances. Most respondents identified a desire to benefit participants' health (63%) and respect for participants' desire for information (57%) as major motivations for returning results. Most also identified uncertain clinical utility (76%), the possibility that participants will misunderstand results (74%), the potential for emotional harm (61%), the need to ensure access to trained clinicians (59%), and the potential for loss of confidentiality (51%) as major barriers to return of results.Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances.

As genomic researchers are urged to openly share generated sequence data with other researchers, it is important to examine the utility of informed consent documents and processes, particularly as these relate to participants' engagement with and recall of the information presented to them, their objective or subjective understanding of the key elements of genomic research (e.g., data sharing), as well as how these factors influence or mediate the decisions they make. We conducted a randomized trial of three experimental informed consent documents (ICDs) with participants (n = 229) being recruited to genomic research studies; each document afforded varying control over breadth of release of genetic information. Recall and understanding, their impact on data sharing decisions, and comfort in decision making were assessed in a follow-up structured interview. Over 25% did not remember signing an ICD to participate in a genomic study, and the majority (54%) could not correctly identify with whom they had agreed to share their genomic data. However, participants felt that they understood enough to make an informed decision, and lack of recall did not impact final data sharing decisions or satisfaction with participation. These findings raise questions about the types of information participants need in order to provide valid informed consent, and whether subjective understanding and comfort with decision making are sufficient to satisfy the ethical principle of respect for persons.

Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. Here, we present our curated list for 1,514 gene–disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations. Genet Med advance online publication 12 January 2017

Aim: The return of individual genetic research results has been identified as one of the most pressing ethical challenges warranting immediate policy attention. We explored the practices and perspectives of genome-wide association studies (GWAS) investigators on this topic. Materials & methods: Corresponding authors of published GWAS were invited to participate in a semistructured interview. Interviews (n = 35) were transcribed and analyzed using conventional content analysis. Results: Most investigators had not returned GWAS results. Several had experience returning results in the context of linkage/family studies, and many felt that it will become a larger issue in whole-genome/-exome sequencing. Conclusions: Research context and nature of the study are important considerations in the decision to return results. More nuanced ethical guidelines should take these contextual factors into account.

Prospects have never seemed better for a truly global approach to science to improve human health, with leaders of national initiatives laying out their vision of a worldwide network of related projects. An extensive literature addresses obstacles to global genomic data sharing, yet a series of public polls suggests that the scientific community may be overlooking a significant barrier: potential public resistance to data sharing across national borders. In several large United States surveys, university researchers in other countries were deemed the least acceptable group of data users, and a just-completed US survey found a marked increase in privacy and security concerns related to data access by non-US researchers. Furthermore, diminished support for sharing beyond national borders is not unique to the US, although the limited data from outside the US suggest variation across countries as well as demographic groups. Possible sources of resistance include apprehension about privacy and security protections. Strategies for building public support include making the affirmative case for global data sharing, addressing privacy, security, and other legitimate concerns, and investigating public concerns in greater depth.

While the bioethics literature demonstrates that the field has spent substantial time and thought over the last four decades on the goals, methods, and desired outcomes for service and training in bioethics, there has been less progress defining the nature and goals of bioethics research and scholarship. This gap makes it difficult both to describe the breadth and depth of these areas of bioethics and, importantly, to gauge their success. However, the gap also presents us with an opportunity to define this scope of work for ourselves and to help shape the broader conversation about the impact of academic research. Because of growing constraints on academic funding, researchers and scholars in many fields are being asked to demonstrate and also forecast the value and impact of their work. To do that, and also to satisfy ourselves that our work has meaningful effect, we must understand how our work can motivate change and how that change can be meaningfully measured. In a field as diverse as bioethics, the pathways to and metrics of change will likewise be diverse. It is therefore critical that any assessment of the impact of bioethics research and scholarship be informed by an understanding of the nature of the work, its goals, and how those goals can and ought to be furthered. In this paper, we propose a conceptual model that connects individual bioethics projects to the broader goals of scholarship, describing the translation of research and scholarly output into changes in thinking, practice, and policy. One of the key implications of the model is that impact in bioethics is generally the result of a collection of projects rather than of any single piece of research or scholarship. Our goal is to lay the groundwork for a thoroughgoing conversation about bioethics research and scholarship that will advance and shape the important conversation about their impact.