ABSTRACT
Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (â¼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
Subject(s)
Breast Neoplasms/diagnosis , Genetic Testing/statistics & numerical data , Hearing Loss/diagnosis , Metabolic Diseases/diagnosis , Oculocerebrorenal Syndrome/diagnosis , Ovarian Neoplasms/diagnosis , Breast Neoplasms/genetics , Child, Preschool , Female , Genome, Human , Hearing Loss/genetics , Heterozygote , Humans , Infant , Infant, Newborn , Male , Metabolic Diseases/genetics , Neonatal Screening , North Carolina , Oculocerebrorenal Syndrome/genetics , Ovarian Neoplasms/genetics , Public Health/methods , Exome SequencingABSTRACT
PURPOSE: People undergoing diagnostic genome-scale sequencing are expected to have better psychological outcomes when they can incorporate and act on accurate, relevant knowledge that supports informed decision making. METHODS: This longitudinal study used data from the North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing Study (NCGENES) of diagnostic exome sequencing to evaluate associations between factual genomic knowledge (measured with the University of North Carolina Genomic Knowledge Scale at three assessments from baseline to after return of results) and sequencing outcomes that reflected participants' perceived understanding of the study and sequencing, regret for joining the study, and responses to learning sequencing results. It also investigated differences in genomic knowledge associated with subgroups differing in race/ethnicity, income, education, health literacy, English proficiency, and prior genetic testing. RESULTS: Multivariate models revealed higher genomic knowledge at baseline for non-Hispanic Whites and those with higher income, education, and health literacy (p values < 0.001). These subgroup differences persisted across study assessments despite a general increase in knowledge among all groups. Greater baseline genomic knowledge was associated with lower test-related distress (p = 0.047) and greater perceived understanding of diagnostic genomic sequencing (p values 0.04 to <0.001). CONCLUSION: Findings extend understanding of the role of genomic knowledge in psychological outcomes of diagnostic exome sequencing, providing guidance for additional research and interventions.
Subject(s)
Decision Making , Exome Sequencing/methods , Genomics/education , Adult , Aged , Female , Health Knowledge, Attitudes, Practice/ethnology , Health Literacy , Humans , Longitudinal Studies , Male , Middle Aged , Socioeconomic FactorsABSTRACT
OBJECTIVE: This study aimed to understand parental decisions, perspectives, values, and beliefs on next generation sequencing in the newborn period (NGS-NBS) to inform the development of a decision aid to support parental decision making in the North Carolina Newborn Exome Sequencing for Universal Screening study. METHODS: We conducted dyadic interviews with 66 current or expectant parents (33 couples) to understand overall decisions about NGS-NBS and reasons for and against learning NGS-NBS results differing by age of onset and medical actionability. Audio recordings were transcribed, coded, and analyzed using qualitative framework analyses. RESULTS: Favorable views of NGS-NBS included benefits of early intervention, preparedness, child autonomy, and altruism. Unfavorable views were the potential negative effects from early intervention, psychosocial harm, and religious beliefs. Parents universally reported quality of life as important. CONCLUSION: Interviews elucidated what is important in deciding to have NGS-NBS. Understanding parental perspectives, values, and beliefs and integrating evidence-based findings into a parent-centric decision aid provides value and support in making decisions related to NGS-NBS, where there is no clear course of action.
Subject(s)
Decision Support Techniques , High-Throughput Nucleotide Sequencing/methods , Neonatal Screening/methods , Parents/psychology , Adult , Family Characteristics , Female , High-Throughput Nucleotide Sequencing/trends , Humans , Infant, Newborn , North Carolina , Qualitative ResearchABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
PURPOSE: Genomic sequencing can reveal variants with limited to no medical actionability. Previous research has assessed individuals' intentions to learn this information, but few report the decisions they made and why. METHODS: The North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) project evaluated adult patients randomized to learn up to six types of non-medically actionable secondary findings (NMASF). We previously found that most participants intended to request NMASF and intentions were strongly predicted by anticipated regret. Here we examine discrepancies between intentions and decisions to request NMASF, hypothesizing that anticipated regret would predict requests but that this association would be mediated by participants' intentions. RESULTS: Of the 76% who expressed intentions to learn results, only 42% made one or more requests. Overall, only 32% of the 155 eligible participants requested NMASF. Analyses support a plausible causal link between anticipated regret, intentions, and requests. CONCLUSIONS: The discordance between participants' expressed intentions and their actions provides insight into factors that influence patients' preferences for genomic information that has little to no actionability. These findings have implications for the timing and methods of eliciting preferences for NMASF and suggest that decisions to learn this information have cognitive and emotional components.
Subject(s)
Incidental Findings , Patient Preference/psychology , Whole Genome Sequencing/ethics , Adult , Aged , Decision Making/ethics , Emotions , Exome , Female , Genetic Testing/ethics , Genomics/methods , Health Knowledge, Attitudes, Practice , Health Personnel , High-Throughput Nucleotide Sequencing/ethics , Humans , Intention , Male , Middle Aged , Patients , Whole Genome Sequencing/methodsABSTRACT
OBJECTIVE: To assess the performance of a standardized, age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening and compare it with the results from other contemporary methods. STUDY DESIGN: The North Carolina Newborn Exome Sequencing for Universal Screening study developed an age-based, semiquantitative metric to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel and other methods to evaluate gene-disease pairs for newborn genomic sequencing. RESULTS: We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the Recommended Uniform Screening Panel core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset. CONCLUSIONS: This study describes a novel method to facilitate decisions about the potential use of genomic sequencing for newborn screening. These categories may assist parents and physicians in making informed decisions about the disclosure of results from voluntary genomic sequencing in children.
Subject(s)
Chromosome Mapping/methods , Genetic Diseases, Inborn/diagnosis , Genetic Testing/methods , Neonatal Screening/methods , Sequence Analysis, DNA/methods , Decision Making, Shared , Female , Genetic Diseases, Inborn/epidemiology , Genome, Human , Humans , Infant, Newborn , Male , North Carolina , Exome SequencingABSTRACT
PurposeApplication of whole-exome and whole-genome sequencing is likely to increase in clinical practice, public health contexts, and research. We investigated how parental preference for acquiring information from genome-scale testing is influenced by the characteristics of non-medically actionable genetic disorders in children, as well as whether the preferences differed by gender and between African-American and white respondents.MethodsWe conducted a Web-based discrete-choice experiment with 1,289 parents of young children. Participants completed "choice tasks" based on pairs of profiles describing sequencing results for hypothetical genetic disorders, selected the profile in each pair that they believed represented the information that would be more important to know, and answered questions that measured their level of distress.ResultsKnowing the likelihood that the disorder would develop given a true-positive test result was most important to parents. Parents showed greater interest in learning sequencing results for disease profiles with more severe manifestations. This was associated with greater distress. Differences by gender and race reflected small differences in magnitude, but not direction.ConclusionParents preferred to learn results about genetic disorders with more severe manifestations, even when this knowledge was associated with increased distress. These results may help clinicians support parental decision making by revealing which types of sequencing results parents are interested in learning.
Subject(s)
Choice Behavior , Decision Making , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Testing , Parents/psychology , Whole Genome Sequencing , Adult , Age of Onset , Child , Female , Genetic Diseases, Inborn/epidemiology , Health Knowledge, Attitudes, Practice , Humans , Male , Phenotype , Surveys and QuestionnairesABSTRACT
PurposeClinical genome sequencing produces uncertain diagnostic results, raising concerns about how to communicate the method's inherent complexities in ways that reduce potential misunderstandings and harm. This study investigates clinicians' communications and patient/participant responses to uncertain diagnostic results arising from a clinical exome sequencing research study, contributing empirical data to the debate surrounding disclosure of uncertain genomic information.MethodsWe investigated the communication and impact of uncertain diagnostic results using ethnographic observations of result disclosures with 21 adults and 11 parents of child patients, followed by two semistructured interviews with these same participants.ResultsParticipants understood their uncertain results in ways that were congruent with clinical geneticists' communications. They followed recommendations for further consultation, although family testing to resolve uncertainty was not always done. Participants were prepared for learning an uncertain result and grasped the key concept that it should not be used to guide health-care or other decisions. They did not express regret for having learned the uncertain result; most regarded it as potentially valuable in the future.ConclusionThis study suggests that uncertain diagnostic results from genome sequencing can be relayed to patients in ways they can understand and consistent with providers' interpretations, without causing undue harm.
Subject(s)
Data Accuracy , Genetic Association Studies/standards , Uncertainty , Adult , Aged , Aged, 80 and over , Communication , Exome , Female , Genetic Association Studies/methods , Genetic Counseling , Genetic Testing/standards , Humans , Male , Middle Aged , Patient Participation , Referral and Consultation , Exome Sequencing , Young AdultABSTRACT
PURPOSE: In a diagnostic exome sequencing study (the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing project, NCGENES), we investigated adult patients' intentions to request six categories of secondary findings (SFs) with low or no medical actionability and correlates of their intentions. METHODS: At enrollment, eligible participants (n = 152) completed measures assessing their sociodemographic, clinical, and literacy-related characteristics. Prior to and during an in-person diagnostic result disclosure visit, they received education about categories of SFs they could request. Immediately after receiving education at the visit, participants completed measures of intention to learn SFs, interest in each category, and anticipated regret for learning and not learning each category. RESULTS: Seventy-eight percent of participants intended to learn at least some SFs. Logistic regressions examined their intention to learn any or all of these findings (versus none) and interest in each of the six individual categories (yes/no). Results revealed little association between intentions and sociodemographic, clinical, or literacy-related factors. Across outcomes, participants who anticipated regret for learning SFs reported weaker intention to learn them (odds ratios (ORs) from 0.47 to 0.71), and participants who anticipated regret for not learning these findings reported stronger intention to learn them (OR 1.61-2.22). CONCLUSION: Intentions to request SFs with low or no medical actionability may be strongly influenced by participants' desire to avoid regret.
Subject(s)
Health Knowledge, Attitudes, Practice , Incidental Findings , Patient Participation/psychology , Adult , Disclosure , Emotions , Female , Genomics , Health Behavior , Humans , Intention , Male , Middle Aged , Research , Exome SequencingABSTRACT
PURPOSE: There is debate within the genetics community about the optimal term to describe genetic variants unrelated to the test indication but potentially important for health. Given the lack of consensus and the importance of adopting terminology that promotes effective clinical communication, we sought the opinion of clinical genetics patients. METHODS: Surveys and focus groups with two patient populations were conducted. Eighty-eight survey participants were asked to rank four terms according to how well each describes results unrelated to the test indication: incidental findings, secondary findings, additional findings, and ancillary findings. Participants in six focus groups were guided through a free-thought exercise to describe the desired attributes of such a term and then asked to formulate the best term to represent this concept. RESULTS: The term additional findings had the most first-choice rankings by survey participants, followed by secondary findings, incidental findings, and ancillary findings. Most focus group participants preferred the term additional findings; they also gave reasons why other terms were not optimal. CONCLUSION: Additional findings was preferred because it was more neutral and accessible than other terms currently in use. Patient perceptions and comprehension will be framed by the terminology used by healthcare providers. Thus, patient opinions should be considered by medical genetics professionals.Genet Med 19 2, 176-181.
Subject(s)
Genome, Human/genetics , Incidental Findings , Surveys and Questionnaires , Terminology as Topic , Adolescent , Adult , Attitude , Female , Humans , Male , Middle Aged , Patient Preference , Sequence Analysis, DNAABSTRACT
PURPOSE: As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis. METHODS: We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15. RESULTS: The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test). CONCLUSION: Gene-disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467-475.
Subject(s)
Genetic Diseases, Inborn/diagnosis , Genetic Testing , Genome, Human , High-Throughput Nucleotide Sequencing/methods , Chromosome Mapping , Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/pathology , Genomics , Humans , Incidental FindingsABSTRACT
As the use of genomic technology has expanded in research and clinical settings, issues surrounding informed consent for genome and exome sequencing have surfaced. Despite the importance of informed consent, little is known about the specific challenges that professionals encounter when consenting patients or research participants for genomic sequencing. We interviewed 29 genetic counselors and research coordinators with considerable experience obtaining informed consent for genomic sequencing to understand their experiences and perspectives. As part of this interview, 24 interviewees discussed an informed consent case they found particularly memorable or challenging. We analyzed these case examples to determine the primary issue or challenge represented by each case. Challenges fell into two domains: participant understanding, and facilitating decisions about testing or research participation. Challenges related to participant understanding included varying levels of general and genomic literacy, difficulty managing participant expectations, and contextual factors that impeded participant understanding. Challenges related to facilitating decision-making included complicated family dynamics such as disagreement or coercion, situations in which it was unclear whether sequencing research would be a good use of participant time or resources, and situations in which the professional experienced disagreement or discomfort with participant decisions. The issues highlighted in these case examples are instructive in preparing genetics professionals to obtain informed consent for genomic sequencing.
Subject(s)
Genetic Counseling/methods , Genome, Human , Informed Consent , Professional Role , Professional-Family Relations , Decision Making , Genetic Testing , HumansABSTRACT
Despite the increased utilization of genome and exome sequencing, little is known about the actual content and process of informed consent for sequencing. We addressed this by interviewing 29 genetic counselors and research coordinators experienced in obtaining informed consent for sequencing in research and clinical settings. Interviews focused on the process and content of informed consent; patients/participants' common questions, concerns and misperceptions; and challenges to obtaining informed consent. Content analysis of transcribed interviews revealed that the main challenges to obtaining consent related to the broad scope and uncertainty of results, and patient/participants' unrealistic expectations about the likely number and utility of results. Interviewees modified their approach to sessions according to contextual issues surrounding the indication for testing, type of patient, and timing of testing. With experience, most interviewees structured sessions to place less emphasis on standard elements in the consent form and technological aspects of sequencing. They instead focused on addressing misperceptions and helping patients/participants develop realistic expectations about the types and implications of possible results, including secondary findings. These findings suggest that informed consent sessions should focus on key issues that may be misunderstood by patients/participants. Future research should address the extent to which various stakeholders agree on key elements of informed consent.
Subject(s)
Genome, Human , Informed Consent , Sequence Analysis, DNA/methods , Health Personnel , Humans , PerceptionABSTRACT
Erratum to: J Genet Counsel DOI 10.1007/s10897-014-9804-6. Grant support from the Clinical Sequencing Exploratory Research program of the National Human Genome Research Institute was awarded to James P. Evans, Jonathan S. Berg, and Gail E. Henderson for the NCGENES Study (NIH #U01 HG006487). The authors and publisher regret the omission from the original article.
ABSTRACT
Next generation genomic sequencing technologies (including whole genome or whole exome sequencing) are being increasingly applied to clinical care. Yet, the breadth and complexity of sequencing information raise questions about how best to communicate and return sequencing information to patients and families in ways that facilitate comprehension and optimal health decisions. Obtaining answers to such questions will require multidisciplinary research. In this paper, we focus on how psychological science research can address questions related to clinical genomic sequencing by explaining emotional, cognitive, and behavioral processes in response to different types of genomic sequencing information (e.g., diagnostic results and incidental findings). We highlight examples of psychological science that can be applied to genetic counseling research to inform the following questions: (1) What factors influence patients' and providers' informational needs for developing an accurate understanding of what genomic sequencing results do and do not mean?; (2) How and by whom should genomic sequencing results be communicated to patients and their family members?; and (3) How do patients and their families respond to uncertainties related to genomic information?
Subject(s)
Genetic Counseling/psychology , Genetic Privacy , Psychology, Medical/methods , Sequence Analysis, DNA , Communication , Family/psychology , Genetic Research , Genomics , Humans , Incidental FindingsABSTRACT
The passage of the Genetic Information Non Discrimination Act (GINA) was hailed as a pivotal achievement that was expected to calm the fears of both patients and research participants about the potential misuse of genetic information. However, 6 years later, patient and provider awareness of legal protections at both the federal and state level remains discouragingly low, thereby, limiting their potential effectiveness. The increasing demand for genetic testing will expand the number of individuals and families who could benefit from obtaining accurate information about the privacy and anti-discriminatory protections that GINA and other laws extend. In this paper we describe legal protections that are applicable to individuals seeking genetic counseling, review the literature on patient and provider fears of genetic discrimination and examine their awareness and understandings of existing laws, and summarize how genetic counselors currently discuss genetic discrimination. We then present three genetic counseling cases to illustrate issues of genetic discrimination and provide relevant information on applicable legal protections. Genetic counselors have an unprecedented opportunity, as well as the professional responsibility, to disseminate accurate knowledge about existing legal protections to their patients. They can strengthen their effectiveness in this role by achieving a greater knowledge of current protections including being able to identify specific steps that can help protect genetic information.
Subject(s)
Confidentiality/legislation & jurisprudence , Genetic Counseling/legislation & jurisprudence , Genetic Privacy , Genetic Testing/legislation & jurisprudence , Genetic Research/legislation & jurisprudence , Humans , Public Policy , United StatesABSTRACT
OBJECTIVE: Many people prefer to learn secondary or "additional" findings from genomic sequencing, including findings with limited medical actionability. Research has investigated preferences for and effects of learning such findings, but not psychosocial and behavioral effects of receiving education about them and the option to request them, which could be burdensome or beneficial (e.g., causing choice overload or satisfying strong preferences, respectively). METHODS: 335 adults with suspected genetic disorders who had diagnostic exome sequencing in a research study and were randomized to receive either diagnostic findings only (DF; n = 171) or diagnostic findings plus education about additional genomic findings and the option to request them (DF + EAF; n = 164). Assessments occurred after enrollment (Time 1), after return of diagnostic results and-for DF + EAF-the education under investigation (Time 2), and three and six months later (Times 3, 4). RESULTS: Time 2 test-related distress, test-related uncertainty, and generalized anxiety were lower in the DF + EAF group (ps = 0.025-0.043). There were no other differences. CONCLUSIONS: Findings show limited benefits and no harms of providing education about and the option to learn additional findings with limited medical actionability. PRACTICE IMPLICATIONS: Findings can inform recommendations for returning additional findings from genomic sequencing (e.g., to research participants or after commercial testing).
Subject(s)
Exome , Genomics , Adult , Educational Status , Exome/genetics , Genetic Testing , HumansABSTRACT
This study describes how parents of a child referred for genetic services searched the Internet for information, summarizes how they interpreted and evaluated the information they obtained, and identifies barriers that they encountered. Audio-taped interviews were conducted with 100 ethnically diverse families referred to a pediatric genetics clinic. After transcription, coded text was entered into a software program (QSR N6) for searching and data retrieval. Matrices were created to systematically categorize and compare families' Internet use. Eighty-three percent of families obtained Internet information about the diagnosis, the clinic visit, and/or treatment and services. Those not conducting searches lacked access, Internet experience, or a diagnostic term and had lower incomes and less education, regardless of ethnicity. Families sought information in preparation for the clinic visit but barriers to obtaining and interpreting relevant information were common. Parents' Internet searching experiences illustrate common barriers to obtaining and understanding genetic information. Identifying them can help genetic counselors facilitate parents' searches for relevant information.