Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach

PurposePatients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.MethodsWe explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.ResultsUnderrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus’s ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners.ConclusionA notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.     

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research

PurposeThis study aimed to understand broad data sharing decisions among predominantly underserved families participating in genomic research.MethodsDrawing on clinic observations, semistructured interviews, and survey data from prenatal and pediatric families enrolled in a genomic medicine study focused on historically underserved and underrepresented populations, this paper expands empirical evidence regarding genomic data sharing communication and decision-making.ResultsOne-third of parents declined to share family data, and pediatric participants were significantly more likely to decline than prenatal participants. The pediatric population was significantly more socioeconomically disadvantaged and more likely to require interpreters. Opt-in was tied to altruism and participants’ perception that data sharing was inherent to research participation. Opt-out was associated with privacy concerns and influenced by clinical staff’s presentation of data handling procedures. The ability of participants to make informed choices during enrollment about data sharing was weakened by suboptimal circumstances, which was revealed by poor understanding of data sharing in follow-up interviews as well as discrepancies between expressed participant desires and official recorded choices.ConclusionThese empirical data suggest that the context within which informed consent process is conducted in clinical genomics may be inadequate for respecting participants’ values and preferences and does not support informed decision-making processes.     

Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited

PurposeExome sequencing (ES) is being adopted for neurodevelopmental disorders in pediatric patients. However, little is known about current coverage policies or the evidence cited supporting these policies. Our study is the first in-depth review of private payer ES coverage policies for pediatric patients with neurodevelopmental disorders.MethodsWe reviewed private payer coverage policies and examined evidence cited in the policies of the 15 largest payers in 2017, and trends in coverage policies and evidence cited (2015–2017) for the five largest payers.ResultsThere were four relevant policies (N = 5 payers) in 2015 and 13 policies (N = 15 payers) in 2017. In 2015, no payer covered ES, but by 2017, three payers from the original registry payers did. In 2017, 8 of the 15 payers covered ES. We found variations in the number and types of evidence cited. Positive coverage policies tended to include a larger number and range of citations.ConclusionWe conclude that more systematic assessment of evidence cited in coverage policies can provide a greater understanding of coverage policies and how evidence is used. Such assessments could facilitate the ability of researchers to provide the needed evidence, and the ability of clinicians to provide the most appropriate testing for patients.     

Responsibility,culpability, and parental views on genomic testing for seriously ill children

PurposeWe describe parental perceptions of and experiences with genomic sequencing (GS) in the care of seriously ill children. Understanding parents’ perspectives is vital for clinicians caring for children, given the uptake of genomic technologies into clinical practice.MethodsLongitudinal, semistructured interviews were conducted with parents of pediatric cancer patients who underwent exome sequencing (ES) as a part of the BASIC3 study. Interviews were conducted at baseline, one to eight months after results disclosure, and approximately one year after disclosure. Using thematic qualitative analysis, parent interviews were coded with both inductive and deductive approaches.ResultsBefore receiving genomic information, parents indicated that they saw ES as something responsible parents would agree to if their child had cancer. Some parents talked about the possibility of sequencing affecting feelings of culpability for their child’s cancer, worrying that they passed on a cancer-causing gene or made parenting decisions that caused the disease. However, after receiving their child’s ES results many reported feeling relieved of guilt and worry, and felt they had fulfilled parental duties by agreeing to ES for their child.ConclusionThese results reveal a layer of meaning that parents associate with GS that may inform clinicians’ approach to care.     

Where should my baby sleep: a qualitative study of African American infant sleep location decisions

BackgroundAfrican American infants are at higher risk for sudden infant death syndrome (SIDS) and accidental suffocation than other infants and are up to 4 times more likely to bedshare with their parents.ObjectiveTo investigate, using qualitative methods, factors influencing African American parents’ decisions regarding infant sleep location (room location and sleep surface).MethodsEighty-three mothers participated in focus groups or individual interviews. Questions probed reasons for infant sleep location decisions and influences on decision making.ResultsMost of the mothers in this study slept in the same room as their infant. Reasons for roomsharing included space, convenience, and safety. Mothers largely decided on infant sleep surface because of space for/availability of crib, comfort, convenience, and safety. Both roomsharing and bedsharing were often chosen to make feeding and checking on the infant more convenient. Mothers who chose not to bedshare cited privacy, concern that the infant would become attached to the parents’ bed, and fears about suffocation. Mothers who chose to bedshare often cited the ability to maintain vigilance while asleep. Low-income mothers also used bedsharing as a defense against environmental dangers.ConclusionAfrican American mothers in this study viewed both roomsharing and bedsharing as strategies to keep their infants safe. Efforts to encourage roomsharing without bed-sharing must address parental concerns about space for/ availability of a crib, convenience, infant and parent comfort, and infant safety.     

Increasing inclusivity in precision medicine research: Views of deaf and hard of hearing individuals

PurposeDeaf/hard of hearing (HoH) individuals can benefit from precision medicine research (PMR) but are underrepresented in mainstream health research and may experience barriers to participation. Understanding their views and concerns about PMR can inform processes to foster inclusion in future studies and reduce health disparities.MethodsWe administered an online disability-accessible survey to explore perceptions of PMR among, inter alia, deaf/HoH individuals. Questions included willingness to participate, interest in results, and barriers and facilitators to participation. Analyses describe results for participants who self-identified their primary condition as being deaf/HoH and compared results for key demographic characteristics.ResultsA total of 267 deaf/HoH participants completed the survey. Interest in PMR was high, although many reported inaccessible facilities and information about medical research; 51% reported that communication with health professionals is a barrier. Concerns about harm, lack of access to benefits, misinformed allocation decisions, and limited disability-relevant knowledge among researchers and health care providers were significant. Differences across racial, ethnic, and sex groups were observed and are discussed.ConclusionStrategies to remove barriers to participation of deaf/HoH individuals in PMR are suggested. Distrust is a major challenge for cohort diversity, and research is needed to identify measures to increase the trustworthiness of PMR endeavors.     

Perspectives of US private payers on insurance coverage for pediatric and prenatal exome sequencing: Results of a study from the Program in Prenatal and Pediatric Genomic Sequencing (P3EGS)

PurposeExome sequencing (ES) has the potential to improve management of congenital anomalies and neurodevelopmental disorders in fetuses, infants, and children. US payers are key stakeholders in patient access to ES. We examined how payers view insurance coverage and clinical utility of pediatric and prenatal ES.MethodsWe employed the framework approach of qualitative research to conduct this study. The study cohort represented 14 payers collectively covering 170,000,000 enrollees.ResultsSeventy-one percent of payers covered pediatric ES despite perceived insufficient evidence because they saw merit in available interventions or in ending the diagnostic odyssey. None covered prenatal ES, because they saw no merit. For pediatric ES, 50% agreed with expanded aspects of clinical utility (e.g., information utility), and 21% considered them sufficient for coverage. For prenatal ES, payers saw little utility until in utero interventions become available.ConclusionThe perceived merit of ES is becoming a factor in payers’ coverage for serious diseases with available interventions, even when evidence is perceived insufficient. Payers’ views on ES’s clinical utility are expanding to include informational utility, aligning with the views of patients and other stakeholders. Our findings inform clinical research, patient advocacy, and policy-making, allowing them to be more relevant to payers.     

Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy

PurposeWe evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.MethodsWe identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis.ResultsWe reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%.ConclusionWe propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.     

To share or not to share: A randomized trial of consent for data sharing in genome research

PurposeDespite growing concerns toward maintaining participants' privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. Our purpose was to assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing.MethodsA single-blinded, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas, between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n = 110; binary, n = 103; and tiered, n = 110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation.ResultsBefore debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns.ConclusionOur findings indicate that most participants are willing to publicly release their genomic data; however, a significant portion prefers restricted release. These results suggest discordance between existing data sharing policies and participants' judgments and desires.     

Motivations and barriers to pursue cancer genomic testing: A systematic review

ObjectivesSingle-gene testing is associated with psycho-social challenges for cancer patients. Genomic testing may amplify these. The aim of this study was to understand patients’ motivations and barriers to pursue cancer genomic testing, to enable healthcare providers to support their patients throughout the testing process and interpretation of test results.MethodsFive databases were searched for original peer reviewed research articles published between January 2001 and September 2018 addressing motivation for genomic cancer testing. QualSyst was used to assess quality.Results182 studies were identified and 17 were included for review. Studies were heterogenous. Both somatic and germline testing were included, and 14 studies used hypothetical scenarios. 3249 participants were analyzed, aged 18 to 94. Most were female and white. The most common diagnoses were breast, ovarian, lung and colorectal cancer. Interest in testing was high. Motivations included ability to predict cancer risk, inform disease management, benefit families, and understand cancer. Barriers included concerns about cost, privacy/confidentiality, clinical utility, and psychological harm.ConclusionsDespite concerns, consumers are interested in cancer genomic testing if it can provide actionable results for themselves and their families.Practice ImplicationsProviders must manage understanding and expectations of testing and translate genetic information into health-promoting behaviours.     

Factors associated with the time to complete clinical exome sequencing in a pediatric patient population

PurposeExome sequencing (ES) is becoming increasingly important for diagnosing rare genetic disorders. Patients and clinicians face several barriers when attempting to obtain ES. This study is aimed to describe factors associated with a longer time interval between provider recommendation of testing and sample collection for ES.MethodsA retrospective chart review was conducted for insurance-authorized, completed pediatric ES in which initial requests were reviewed by Stanford’s Genetic Testing Optimization Service between November 2018 and December 2019. Regression analysis was used to determine the association between the geocoded median household income and 3 different time point intervals defined as time to test, insurance decision, and scheduling/consent.ResultsOf the 281 charts reviewed, 115 cases were included in the final cohort. The average time from provider preauthorization request to sample collection took 104.4 days, and income was negatively correlated with the length of the insurance decision interval.ConclusionPediatric patients undergo a lengthy, uncertain process when attempting to obtain ES, some of which is associated with income. More research and clinician interventions are required to clarify specific socioeconomic factors that influence the ability to obtain timely ES and develop optimal protocols.     

Perspectives of Australian adults about protecting the privacy of their health information in statistical databases

ObjectivesThe aim of this study was to discover the public's attitude and views towards privacy in health care. This is a part of a larger project which aims to gain an insight into what kind of privacy is needed and develop technical measures to provide such privacy.MethodsThe study was a two-stage process which combined qualitative and quantitative research. Stage One of the study comprised arranging and facilitating focus groups while in Stage Two we conducted a social survey.MeasurementsWe measured attitudes towards privacy, medical research and consent; privacy concern about sharing one's health information for research; privacy concern about the possibility that some specific information from medical records could be linked to the patient's name in a situation that was not related to medical treatment.ResultsThe results of the study revealed both great support for medical research (98%), and concern about privacy of health information (66%). Participants prefer to be asked for their permission before their health information is used for any purpose other than medical treatment (92%), and they would like to know the organisation and details of the research before allowing the use of their health records (83%). Age, level of education, place of birth and employment status are most strongly associated with privacy concerns. The study showed that there are some particularly sensitive issues and there is a concern (42–60%) about any possibility of linking these kinds of data to the patient's name in a situation that is not related to medical treatment. Such issues include sexually transmitted diseases, abortions and infertility, family medical history/genetic disorders, mental illness, drug/alcohol related incidents, lists of previous operations/procedures/dates and current medications.ConclusionsParticipants believe they should be asked for permission before their health information is used for any purpose other than medical treatment. However, consent and privacy concerns are not necessary related.Assuring individuals that their personal health information is de-identified reduces their concern about the necessity of consent for releasing health information for research purposes, but many people are not aware that removing their names and other direct identifiers from medical records does not guarantee full privacy protection for their health information. Privacy concerns decrease as extra security measures are introduced to protect privacy. Therefore, instead of “tailoring concern” as proposed by Willison [1] we suggest improving privacy protection of personal information by introducing additional security measures in data publishing.     

A curated gene list for reporting results of newborn genomic sequencing

PurposeGenomic 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.MethodsTo 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.ResultsHere, 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.ConclusionOur 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     

Quantifying family dissemination and identifying barriers to communication of risk information in Australian BRCA families

PurposeRecommendations for BRCA1 and BRCA2 mutation carriers to disseminate information to at-risk relatives pose significant challenges. This study aimed to quantify family dissemination, to explain the differences between fully informed families (all relatives informed verbally or in writing) and partially informed families (at least one relative uninformed), and to identify dissemination barriers.MethodsBRCA1 and BRCA2 mutation carriers identified from four Australian hospitals (n=671) were invited to participate in the study. Distress was measured at consent using the Kessler psychological distress scale (K10). A structured telephone interview was used to assess the informed status of relatives, geographical location of relatives, and dissemination barriers. Family dissemination was quantified, and fully versus partially informed family differences were examined. Dissemination barriers were thematically coded and counted.ResultsA total of 165 families participated. Information had been disseminated to 81.1% of relatives. At least one relative had not been informed in 52.7% of families, 4.3% were first-degree relatives, 27.0% were second-degree relatives, and 62.0% were cousins. Partially informed families were significantly larger than fully informed families, had fewer relatives living in close proximity, and exhibited higher levels of distress. The most commonly recorded barrier to dissemination was loss of contact.ConclusionLarger, geographically diverse families have greater difficulty disseminating BRCA mutation risk information to all relatives. Understanding these challenges can inform future initiatives for communication, follow-up and support.     

A systematic literature review of individuals’ perspectives on broad consent and data sharing in the United States

PurposeIn 2011, an Advanced Notice of Proposed Rulemaking proposed that de-identified human data and specimens be included in biobanks only if patients provide consent. The National Institutes of Health Genomic Data Sharing policy went into effect in 2015, requiring broad consent from almost all research participants.MethodsWe conducted a systematic literature review of attitudes toward biobanking, broad consent, and data sharing. Bibliographic databases included MEDLINE, Web of Science, EthxWeb, and GenETHX. Study screening was conducted using DistillerSR.ResultsThe final 48 studies included surveys (n = 23), focus groups (n = 8), mixed methods (n = 14), interviews (n = 1), and consent form analyses (n = 2). Study quality was characterized as good (n = 19), fair (n = 27), and poor (n = 2). Although many participants objected, broad consent was often preferred over tiered or study-specific consent, particularly when broad consent was the only option, samples were de-identified, logistics of biobanks were communicated, and privacy was addressed. Willingness for data to be shared was high, but it was lower among individuals from under-represented minorities, individuals with privacy and confidentiality concerns, and when pharmaceutical companies had access to data.ConclusionsAdditional research is needed to understand factors affecting willingness to give broad consent for biobank research and data sharing in order to address concerns to enhance acceptability.     

Breast cancer polygenic risk scores: a 12-month prospective study of patient reported outcomes and risk management behavior

PurposeTo prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer polygenic risk score (PRS).MethodsWomen either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene were invited to receive their PRS. All participants completed a questionnaire at study enrollment. Receivers completed questionnaires at two weeks and 12 months after receiving their PRS, and decliners a second questionnaire at 12 months post study enrollment.ResultsOf the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing–specific distress, perceived risk, decisional regret, and less genetic testing–positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current Australian guidelines of breast cancer risk management. Reasons for declining PRS included being unable to attend the appointment in person and concerns over potential emotional response.ConclusionThe outcomes of the study provide insight into women’s responses to receiving PRS and highlight the issues that need to be addressed in the associated model of genetic counseling.     

Motivations,concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project

Whole exome/genome sequencing (WES/WGS) is increasingly offered to ostensibly healthy individuals. Understanding the motivations and concerns of research participants seeking out personal WGS and their preferences regarding return-of-results and data sharing will help optimize protocols for WES/WGS. Baseline interviews including both qualitative and quantitative components were conducted with research participants (n=35) in the HealthSeq project, a longitudinal cohort study of individuals receiving personal WGS results. Data sharing preferences were recorded during informed consent. In the qualitative interview component, the dominant motivations that emerged were obtaining personal disease risk information, satisfying curiosity, contributing to research, self-exploration and interest in ancestry, and the dominant concern was the potential psychological impact of the results. In the quantitative component, 57% endorsed concerns about privacy. Most wanted to receive all personal WGS results (94%) and their raw data (89%); a third (37%) consented to having their data shared to the Database of Genotypes and Phenotypes (dbGaP). Early adopters of personal WGS in the HealthSeq project express a variety of health- and non-health-related motivations. Almost all want all available findings, while also expressing concerns about the psychological impact and privacy of their results.     

Determinants of enrollment in a preventive HIV vaccine trial: hypothetical versus actual willingness and barriers to participation

OBJECTIVE: To compare hypothetical and actual willingness to enroll in a preventive HIV vaccine trial and identify factors affecting enrollment. METHODS: Participants previously enrolled in an HIV vaccine preparedness study (VPS) in 8 US cities were invited to be screened for a phase 2 HIV vaccine trial. Demographic and risk characteristics of those enrolling, ineligible, and refusing enrollment were compared using the chi2 or Fisher exact test. Multivariable logistic models were used to identify independent predictors of refusal. RESULTS: Of 2531 high-risk HIV-uninfected former VPS participants contacted for the vaccine trial, 13% enrolled, 34% were ineligible, and 53% refused enrollment. Only 20% of those stating hypothetical willingness during the VPS actually enrolled in this vaccine trial. In multivariate analysis, refusal was higher among African Americans and lower in persons >40 years of age, those attending college, and those with > or =5 partners in the prior 6 months. All racial ethnic groups cited concerns about vaccine-induced seropositivity; African Americans also cited mistrust of government and safety concerns as barriers to enrollment. CONCLUSIONS: Steps can be taken to minimize potential social harms and to mobilize diverse communities to enroll in trials. Statements of hypothetical willingness to participate in future trials may overestimate true enrollment.