Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for pediatric diagnostic testing.

INTRODUCTION: Measuring effects of genomic sequencing (GS) on patients and families is critical for translational research. We aimed to develop and validate an instrument to assess parents' perceived utility of pediatric diagnostic GS. METHODS: Informed by a five-domain conceptual model, the study comprised five steps: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Parents of pediatric patients who had received results of clinically indicated GS participated in structured cognitive interviews and two rounds of surveys. After eliminating items based on theory and quantitative performance, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments. RESULTS: We derived the 21-item Pediatric Diagnostic version of the GENEtic Utility (GENE-U) scale, which has a two-factor structure that includes an Informational Utility subscale (16 items, α = 0.91) and an Emotional Utility subscale (5 items, α = 0.71). Scores can be summed to calculate a Total scale score (α = 0.87). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS, and the Emotional Utility subscale was moderately associated with psychosocial impact and depression and anxiety. DISCUSSION: The Pediatric Diagnostic GENE-U scale demonstrated good psychometric performance in this initial evaluation and could be a useful tool for translational genomics researchers, warranting additional validation.

Parents' decision-making regarding whether to receive adult-onset only genetic findings for their children: Findings from the BabySeq Project.

PURPOSE: Most professional guidelines recommend against genetic screening for adult-onset only (AO) conditions until adulthood, yet others argue that there may be benefit to disclosing such results. We explored parents' decision-making on this issue in the BabySeq Project, a clinical trial of newborn genomic sequencing. METHODS: We conducted interviews with parents (N = 24) who were given the option to receive actionable AO results for their children. Interviews explored parents' motivations to receive and reasons to decline AO genetic disease risk information, their decision-making process, and their suggestions for supporting parents in making this decision. RESULTS: Parents noted several motivations to receive and reasons to decline AO results. Most commonly, parents cited early intervention/surveillance (n = 11), implications for family health (n = 7), and the ability to prepare (n = 6) as motivations to receive these results. The most common reasons to decline were protection of the child's future autonomy (n = 4), negative effect on parenting (n = 3), and anxiety about future disease (n = 3). Parents identified a number of ways to support parents in making this decision. CONCLUSION: Results show considerations to better support parental decision-making that aligns with their values when offering AO genetic information because it is more commonly integrated into pediatric clinical care.

Researchers' Ethical Concerns About Using Adaptive Deep Brain Stimulation for Enhancement.

The capacity of next-generation closed-loop or adaptive deep brain stimulation devices (aDBS) to read (measure neural activity) and write (stimulate brain regions or circuits) shows great potential to effectively manage movement, seizure, and psychiatric disorders, and also raises the possibility of using aDBS to electively (non-therapeutically) modulate mood, cognition, and prosociality. What separates aDBS from most neurotechnologies (e.g. transcranial stimulation) currently used for enhancement is that aDBS remains an invasive, surgically-implanted technology with a risk-benefit ratio significantly different when applied to diseased versus non-diseased individuals. Despite a large discourse about the ethics of enhancement, no empirical studies yet examine perspectives on enhancement from within the aDBS research community. We interviewed 23 aDBS researchers about their attitudes toward expanding aDBS use for enhancement. A thematic content analysis revealed that researchers share ethical concerns related to (1) safety and security; (2) enhancement as unnecessary, unnatural or aberrant; and (3) fairness, equality, and distributive justice. Most (70%) researchers felt that enhancement applications for DBS will eventually be technically feasible and that attempts to develop such applications for DBS are already happening (particularly for military purposes). However, researchers unanimously (100%) felt that DBS ideally should not be considered for enhancement until researchers better understand brain target localization and functioning. While many researchers acknowledged controversies highlighted by scholars and ethicists, such as potential impacts on personhood, authenticity, autonomy and privacy, their ethical concerns reflect considerations of both gravity and perceived near-term likelihood.

Parental Attitudes Toward Standard Newborn Screening and Newborn Genomic Sequencing: Findings From the BabySeq Study.

Introduction: With increasing utility and decreasing cost of genomic sequencing, augmentation of standard newborn screening (NBS) programs with newborn genomic sequencing (nGS) has been proposed. Before nGS can be integrated into newborn screening, parents' perspectives must be better understood. Objective: Using data from surveys administered to parents of healthy newborns who were enrolled in the BabySeq Project, a randomized clinical trial of nGS alongside NBS, this paper reports parents' attitudes regarding population-based NBS and nGS assessed 3 months after results disclosure. Methods: Parental attitudes regarding whether all newborns should receive, and whether informed consent should be required for, NBS and nGS, as well as whether nGS should be mandated were assessed using 5-point scales from strongly disagree (=1) to strongly agree (=5). Parents' interest in receiving types of results from nGS was assessed on a 5-point scale from not at all interested (=1) to very interested (=5). Survey responses were analyzed using Fisher's exact tests, paired t-tests, and repeated measures ANOVA. Results: At 3 months post-disclosure, 248 parents of 174 healthy newborns submitted a survey. Support for every newborn receiving standard NBS (mean 4.67) was higher than that for every newborn receiving nGS (mean 3.60; p < 0.001). Support for required informed consent for NBS (mean 3.44) was lower than that for nGS (mean 4.27, p < 0.001). Parents' attitudes toward NBS and nGS were not significantly associated with self-reported political orientation. If hypothetically receiving nGS outside of the BabySeq Project, most parents reported being very interested in receiving information on their baby's risk of developing a disease in childhood that can be prevented, treated, or cured (86.8%) and their risk of developing a disease during adulthood that can be prevented, treated, or cured (84.6%). Discussion: Parents' opinions are crucial to inform design and delivery of public health programs, as the success of the program hinges on parents' trust and participation. To accommodate parents' preferences without affecting the current high participation rates in NBS, an optional add-on consent to nGS in addition to NBS may be a feasible approach. Trial Registration ClinicalTrials.gov Identifier: NCT02422511.

Perceived Utility of Genomic Sequencing: Qualitative Analysis and Synthesis of a Conceptual Model to Inform Patient-Centered Instrument Development.

BACKGROUND AND OBJECTIVES: Successful clinical integration of genomic sequencing (GS) requires evidence of its utility. While GS potentially has benefits (utilities) or harms (disutilities) across multiple domains of life for both patients and their families, there is as yet no empirically informed conceptual model of these effects. Our objective was to develop an empirically informed conceptual model of perceived utility of GS that captures utilities and disutilities for patients and their families across diverse backgrounds. METHODS: We took a patient-centered approach, in which we began with a review of existing literature followed by collection of primary interview data. We conducted semi-structured interviews to explore types of utility in a clinically and sociopolitically diverse sample of 60 adults from seven Clinical Sequencing Evidence-Generating Research (CSER) consortium projects. Interviewees had either personally received, or were parents of a child who had received, GS results. Qualitative data were analyzed using thematic analysis. Findings from interviews were integrated with existing literature on clinical and personal utility to form the basis of an initial conceptual model that was refined based on expert review and feedback. RESULTS: Five key utility types that have been previously identified in qualitative literature held up as primary domains of utility and disutility in our diverse sample. Interview data were used to specify and organize subdomains of an initial conceptual model. After expert refinement, the five primary domains included in the final model are clinical, emotional, behavioral, cognitive, and social, and several subdomains are specified within each. CONCLUSION: We present an empirically informed conceptual model of perceived utility of GS. This model can be used to guide development of instruments for patient-centered outcome measurement that capture the range of relevant utilities and disutilities and inform clinical implementation of GS.

Challenges to Building a Gene Variant Commons to Assess Hereditary Cancer Risk: Results of a Modified Policy Delphi Panel Deliberation.

Understanding the clinical significance of variants associated with hereditary cancer risk requires access to a pooled data resource or network of resources-a "cancer gene variant commons"-incorporating representative, well-characterized genetic data, metadata, and, for some purposes, pathways to case-level data. Several initiatives have invested significant resources into collecting and sharing cancer gene variant data, but further progress hinges on identifying and addressing unresolved policy issues. This commentary provides insights from a modified policy Delphi process involving experts from a range of stakeholder groups involved in the data-sharing ecosystem. In particular, we describe policy issues and options generated by Delphi participants in five domains critical to the development of an effective cancer gene variant commons: incentives, financial sustainability, privacy and security, equity, and data quality. Our intention is to stimulate wider discussion and lay a foundation for further work evaluating policy options more in-depth and mapping them to those who have the power to bring about change. Addressing issues in these five domains will contribute to a cancer gene variant commons that supports better care for at-risk and affected patients, empowers patient communities, and advances research on hereditary cancers.

Psychosocial Effect of Newborn Genomic Sequencing on Families in the BabySeq Project: A Randomized Clinical Trial.

Importance: Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. Objective: To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. Design, Setting, and Participants: In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. Intervention: Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). Main Outcomes and Measures: Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents' relationship (Kansas Marital Satisfaction Scale), and parents' psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). Results: A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, -0.18 [0.18]; 10 months, -0.07 [0.20]; joint P = .57) or parents' psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents' relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, -0.19 [0.07]; 3 months, -0.04 [0.07]; and 10 months, -0.01 [0.08]; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. Conclusions and Relevance: In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. Trial Registration: ClinicalTrials.gov Identifier: NCT02422511.

Airmen and health-care providers' attitudes toward the use of genomic sequencing in the US Air Force: findings from the MilSeq Project.

PURPOSE: The use of genomic sequencing (GS) in military settings poses unique considerations, including the potential for GS to impact service members' careers. The MilSeq Project investigated the use of GS in clinical care of active duty Airmen in the United States Air Force (USAF). METHODS: We assessed perceived risks, benefits, and attitudes toward use of GS in the USAF among patient participants (n = 93) and health-care provider participants (HCPs) (n = 12) prior to receiving or disclosing GS results. RESULTS: Participants agreed that there are health benefits associated with GS (90% patients, 75% HCPs), though more HCPs (75%) than patients (40%) agreed that there are risks (p = 0.048). The majority of both groups (67% HCPs, 77% patients) agreed that they trust the USAF with genetic information, but far fewer agreed that genetic information should be used to make decisions about deployment (5% patients, 17% HCPs) or duty assignments (3% patients, 17% HCPs). Despite their hesitancy, patients were supportive of the USAF testing for nondisease traits that could impact their duty performance. Eighty-seven percent of patients did not think their GS results would influence their career. CONCLUSION: Results suggest favorable attitudes toward the use of GS in the USAF when not used for deployment or assignment decisions.

Perceived Benefits, Risks, and Utility of Newborn Genomic Sequencing in the BabySeq Project.

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 price of whole-genome sequencing may be decreasing, but who will be sequenced?

AIM: Since whole-genome sequencing (WGS) information can have positive and negative personal utility for individuals, we examined predictors of willingness to pay (WTP) for WGS. PATIENTS & METHODS: We surveyed two independent populations: adult patients (n = 203) and college seniors (n = 980). Ordinal logistic regression models were used to characterize the relationship between predictors and WTP. RESULTS: Sex, age, education, income, genomic knowledge and knowing someone who had genetic testing or having had genetic testing done personally were associated with significantly higher WTP for WGS. After controlling for income and education, males were willing to pay more for WGS than females. CONCLUSION: Differences in WTP may impact equity, coverage, affordability and access, and should be anticipated by public dialog about related health policy.

Do privacy and security regulations need a status update? Perspectives from an intergenerational survey.

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.

Participants and Study Decliners' Perspectives About the Risks of Participating in a Clinical Trial of Whole Genome Sequencing.

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.

'Someday it will be the norm': physician perspectives on the utility of genome sequencing for patient care in the MedSeq Project.

AIM: To describe practicing physicians' perceived clinical utility of genome sequencing. MATERIALS & METHODS: We conducted a mixed-methods analysis of data from 18 primary care physicians and cardiologists in a study of the clinical integration of whole-genome sequencing. Physicians underwent brief genomics continuing medical education before completing surveys and semi-structured interviews. RESULTS: Physicians described sequencing as currently lacking clinical utility because of its uncertain interpretation and limited impact on clinical decision-making, but they expressed the idea that its clinical integration was inevitable. Potential clinical uses for sequencing included complementing other clinical information, risk stratification, motivating patient behavior change and pharmacogenetics. CONCLUSION: Physicians given genomics continuing medical education use the language of both evidence-based and personalized medicine in describing the utility of genome-wide testing in patient care.

Pediatric data sharing in genomic research: attitudes and preferences of parents.

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.

Returning genetic research results: study type matters.

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.

Participants' recall and understanding of genomic research and large-scale data sharing.

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.

Experiences and attitudes of genome investigators regarding return of individual genetic test results.

PURPOSE: Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research. METHODS: 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. RESULTS: 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. CONCLUSION: Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances.