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Psychiatric genetic counseling (GC) has been associated with patient-reported increases in empowerment (perceived control, emotional regulation, and hope). We sought to evaluate the extent to which patients' psychological state at the time of GC is related to changes in empowerment. Participants with a history of major depressive disorder and/or bipolar disorder that had been refractory to treatment underwent psychiatric GC remotely from 2022 to 2023. GC was performed by four genetic counselors and included discussion of perceived causes of illness, multifactorial inheritance, and protective factors. Empowerment, depression, and anxiety were measured immediately prior to GC via online survey by the GCOS-16, PHQ-9, and GAD-7, respectively. Empowerment was re-assessed 2 weeks later. In total, 66/161 (41.0%) invited individuals completed both the baseline and follow-up surveys. Participants completing both surveys were 54.6% female, 84.8% white, and ranged in age from 22 to 78 years (mean = 54.8 years). Overall, a significant change in mean empowerment was not observed (p = 0.38); however, there were moderating effects by baseline psychological state. A multiple linear regression model incorporating PHQ-9, GAD-7 and baseline GCOS-16 score predicted change in empowerment with a large effect (F = 5.49, R 2  = 0.21, p < 0.01). A higher score on the PHQ-9 was associated with decreases in empowerment from pre to post GC. Higher scores on the GAD-7 and lower baseline GCOS-16 scores were associated with increases in empowerment. Further, two-way ANOVA was conducted to assess change in empowerment between subgroups based on the level of anxiety and depression. Those with low depression and high anxiety reported significant increases in empowerment (F = 6.64, p = 0.01). These findings suggest that psychiatric GC may be especially helpful to individuals experiencing anxiety and low baseline empowerment. Alternative approaches may be needed to best meet the needs of those experiencing significant depression., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Future-oriented emotions are associated with consequential health decision-making, including genomic testing decisions. However, little is known about the relative role of various future-oriented emotions in such decisions. Moreover, most research on predictors of decision making regarding genomic testing is conducted with white participants., Purpose: This study examined the role of future-oriented emotions in decisions to receive genomic testing results in U.S. individuals of African descent., Methods: We analyzed cross-sectional survey data from a genomic sequencing cohort (N = 408). All participants identified as African, African-American, or Afro-Caribbean (Mage = 56.3, 74.7% female). Participants completed measures assessing anticipatory affect (worry about genetic testing results), anticipated distress (feeling devastated if genetic testing showed an increased risk for fatal disease), and anticipated regret (regretting a decision not to learn results). Outcomes were intentions for learning actionable, nonactionable, and carrier results., Results: Anticipated regret was robustly positively associated with intentions to receive actionable (b = 0.28, p < .001), nonactionable (b = 0.39, p < .001), and carrier (b = 0.30, p < .001) results. Anticipated distress was negatively associated with intentions to receive nonactionable results only (b = -0.16, p < .01). Anticipatory negative affect (worry) was not associated with intentions. At higher levels of anticipated regret, anticipated distress was less strongly associated with intentions to receive nonactionable results (b = 0.14, p = .02)., Conclusions: Our results highlight the role of future-oriented emotions in genomic testing among participants who are typically underrepresented in genomic testing studies and behavioral medicine broadly. Future work should examine whether interventions targeting future-oriented emotions such as anticipated regret may have clinically meaningful effects in genetic counseling in similar cohorts., (Published by Oxford University Press on behalf of the Society of Behavioral Medicine 2022.)

Genetic counseling for patients who are pursuing genetic testing in the absence of a medical indication, referred to as elective genomic testing (EGT), is becoming more common. This type of testing has the potential to detect genetic conditions before there is a significant health impact permitting earlier management and/or treatment. Pre- and post-test counseling for EGT is similar to indication-based genetic testing. Both require a complete family and medical history when ordering a test or interpreting a result. However, EGT counseling has some special considerations including greater uncertainties around penetrance and clinical utility and a lack of published guidelines. While certain considerations in the selection of a high-quality genetic testing laboratory are universal, there are some considerations that are unique to the selection of a laboratory performing EGT. This practice resource intends to provide guidance for genetic counselors and other healthcare providers caring for adults seeking pre- or post-test counseling for EGT. Genetic counselors and other genetics trained healthcare providers are the ideal medical professionals to supply accurate information to individuals seeking counseling about EGT enabling them to make informed decisions about testing and follow-up., (© 2023 National Society of Genetic Counselors.)

Purpose: People report experiencing value from learning genomic results even in the absence of clinically actionable information. Such personal utility has emerged as a key concept in genomic medicine. The lack of a validated patient-reported outcome measure of personal utility has impeded the ability to assess this concept among those receiving genomic results and evaluate the patient-perceived value of genomics. We aimed to construct and psychometrically evaluate a scale to measure personal utility of genomic results-the Personal Utility (PrU) scale., Methods: We used an evidence-based, operational definition of personal utility, with data from a systematic literature review and Delphi survey to build a novel scale. After piloting with 24 adults, the PrU was administered to healthy adults in a Clinical Sequencing Evidence-Generating Research Consortium study after receiving results. We investigated the responses using exploratory factor analysis., Results: The exploratory factor analysis (N = 841 participants) resulted in a 3-factor solution, accounting for 74% of the variance in items: (1) self-knowledge (α = 0.92), (2) reproductive planning (α = 0.89), and (3) practical benefits (α = 0.91)., Conclusion: Our findings support the use of the 3-factor PrU to assess personal utility of genomic results. Validation of the PrU in other samples will be important for more wide-spread application., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Introduction: Early adopters play a critical role in the diffusion of medical innovations by spreading awareness, increasing acceptability, and driving demand. Understanding the role of race in the context of other characteristics of potential early adopters can shed light on disparities seen in the early implementation of genomic medicine. We aimed to understand the association between self-identified race and individual experience with genetic testing outside of the research context., Methods: We assessed factors associated with the odds of having ever received genetic testing prior to enrollment in a genomic sequencing study among 674 self-identified white and 407 self-identified African, African American, or Afro-Caribbean ("Black") individuals., Results: Controlling for individual determinants of healthcare use (demographics, personality traits, knowledge and attitudes, and health status), identifying as Black was associated with lower odds of prior genetic testing (OR = 0.43, 95% CI [0.27-0.68], p &lt; 0.001). In contrast, self-identified race was not associated with the use of non-genetic clinical screening tests (e.g., echocardiogram, colonoscopy). Black and white individuals were similar on self-reported personality traits tied to early adoption but differed by sociodemographic and resource facilitators of early adoption., Conclusion: Persistent racial disparities among early adopters may represent especially-entrenched disparities in access to and knowledge of genomic technologies in clinical settings., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: The American College of Medical Genetics and Genomics (ACMG) recommends the return of pathogenic and likely pathogenic (P/LP) secondary findings from exome and genome sequencing. The latest version (ACMG secondary finding [SF] v3.0) includes 14 additional genes. We interrogated the ClinSeq cohort for variants in these genes to determine the additional yield in unselected individuals., Methods: Exome data from 1473 individuals (60% White, 34% African American or Black, 6% other) were analyzed. We restricted our analyses to coding variants; +1,+2,-1, and -2 splice site variants; and the pathogenic GAA variant, NM&#95;000152.5:c.-32-13T>G. Variants were assessed with slightly modified ACMG/Association of Molecular Pathology guidelines., Results: A total of 25 P/LP variants were identified. In total, 7 individuals had P/LP variants in genes recommended for return of heterozygous variants, namely HNF1A (1), PALB2 (3), TMEM127 (1), and TTN (2). In total, 4 individuals had a homozygous variant in a gene recommended for biallelic variant return, namely HFE, NM&#95;000410.3(HFE):c.845G>A p.Cys282Tyr. A total of 17 P/LP variants were identified in the heterozygous state in genes recommended only for biallelic variant reporting and were not returned. The frequency of returnable P/LP variants did not significantly differ by race., Conclusion: Using the ACMG SF v3.0, the returnable P/LP variant frequency increased in the ClinSeq cohort by 22%, from 3.4% (n = 50, ACMG SF v2.0) to 4.1% (n = 61, ACMG SF v3.0)., Competing Interests: Conflict of Interest L.G.B. is an uncompensated advisor for Illumina. All other authors declare no conflicts of interest., (Published by Elsevier Inc.)

Future-oriented emotions such as anticipatory affect (i.e., current affect experienced regarding a potential future outcome) and anticipated affect (i.e., expectations about potential future affect), are uniquely associated with health decision-making (e.g., electing to receive results of genomic testing). This study investigated the degree to which negative anticipated and anticipatory emotions predict health decision making over time, and whether such emotions predict social, emotional, and behavioral responses to anticipated information (e.g., genomic testing results). 461 participants (M age = 63.9, SD = 5.61, 46% female) in a genomic sequencing cohort who elected to receive genomic sequencing (carrier) results were included in the current study. Anticipated and anticipatory affect about sequencing results were assessed at baseline. Psychological and behavioral responses to sequencing results, including participants' reported anxiety, decisional conflict, and distress about sequencing results, whether they shared results with family members, and their intentions to continue learning results in the future, were collected immediately, one month, and/or six months after receiving results. More negative anticipated and anticipatory affect at baseline was significantly and independently associated with lower intentions to continue learning results in the future, as well as higher levels of anxiety and uncertainty at multiple time points after receiving results. Anticipated negative affect was also associated with greater decisional conflict, and anticipatory negative affect was also associated with greater distress after receiving results. Future-oriented emotions may play an important role in decisions that unfold over time, with implications for genomic testing, behavioral medicine, and health decision-making broadly., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Although romantic couple concordance has been demonstrated across a wide array of health behaviors, little research has examined dyadic concordance in health beliefs. This study examined the extent to which cohabitating romantic dyads' attitudes and beliefs coincide (i.e., dyadic concordance) in addition to how well they predict intentions to learn genomic sequencing results. The actor-partner interdependence model was applied to cross-sectional data from 81 dyads in an exome sequencing study who were surveyed about their risk perceptions, worry, information avoidance, attitudes, and intentions toward learning carrier results. Information avoidance tendencies were positively correlated between partners, but there was low concordance on other beliefs. Individuals' attitudes and information avoidance predicted their own intentions to learn results. Additionally, partners' information avoidance tendencies predicted their partner's intentions to learn results. Future research should explore mechanisms through which one's partner's information avoidance may affect one's own intentions and behaviors., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241)., (© 2021 National Society of Genetic Counselors. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction: Ensuring equitable access to health care is a widely agreed-upon goal in medicine, yet access to care is a multidimensional concept that is difficult to measure. Although frameworks exist to evaluate access to care generally, the concept of "access to genomic medicine" is largely unexplored and a clear framework for studying and addressing major dimensions is lacking., Methods: Comprised of seven clinical genomic research projects, the Clinical Sequencing Evidence-Generating Research consortium (CSER) presented opportunities to examine access to genomic medicine across diverse contexts. CSER emphasized engaging historically underrepresented and/or underserved populations. We used descriptive analysis of CSER participant survey data and qualitative case studies to explore anticipated and encountered access barriers and interventions to address them., Results: CSER's enrolled population was largely lower income and racially and ethnically diverse, with many Spanish-preferring individuals. In surveys, less than a fifth (18.7%) of participants reported experiencing barriers to care. However, CSER project case studies revealed a more nuanced picture that highlighted the blurred boundary between access to genomic research and clinical care. Drawing on insights from CSER, we build on an existing framework to characterize the concept and dimensions of access to genomic medicine along with associated measures and improvement strategies., Conclusions: Our findings support adopting a broad conceptualization of access to care encompassing multiple dimensions, using mixed methods to study access issues, and investing in innovative improvement strategies. This conceptualization may inform clinical translation of other cutting-edge technologies and contribute to the promotion of equitable, effective, and efficient access to genomic medicine., Competing Interests: The authors declare no conflict of interest., (© The Association for Clinical and Translational Science 2021.)

Genomics researchers are increasingly interested in what constitutes effective engagement of individuals from underrepresented groups. This is critical for longitudinal projects needed to inform the implementation of precision medicine. Return of results is one opportunity for engagement. The aims of this study were to determine participant perspectives on optimal engagement strategies and priorities for return of results and the extent to which focus groups were an effective modality for gathering input on these topics. We conducted six professionally moderated focus groups with 49 participants in a genomics research study. Transcripts from audio-recorded sessions were coded by two researchers and themes were discussed with the wider research team. All groups raised the issue of mistrust. Individuals participated nonetheless to contribute their perspectives and benefit their community. Many group members preferred engagement modalities that are offered to all participants and allow them to share the nuances of their perspectives over the use of participant representatives and surveys. All groups created a consensus ranking for result return priorities. Results for life-threatening conditions were the highest priority to return, followed by those related to treatable conditions that affect physical or mental health. We advocate for engagement strategies that reach as many participants as possible and allow them to share their perspectives in detail. Such strategies are valued by participants, can be effective for developing return of results policies, and may help institutions become more trustworthy., (Published by Elsevier Inc.)

Background and Objectives: Next generation sequencing (NGS) has promising applications in transfusion medicine. Exome sequencing (ES) is increasingly used in the clinical setting, and blood group interpretation is an additional value that could be extracted from existing data sets. We provide the first release of an open-source software tailored for this purpose and describe its validation with three blood group systems., Materials and Methods: The DTM-Tools algorithm was designed and used to analyse 1018 ES NGS files from the ClinSeq ® cohort. Predictions were correlated with serology for 5 antigens in a subset of 108 blood samples. Discrepancies were investigated with alternative phenotyping and genotyping methods, including a long-read NGS platform., Results: Of 116 genomic variants queried, those corresponding to 18 known KEL, FY and JK alleles were identified in this cohort. 596 additional exonic variants were identified KEL, ACKR1 and SLC14A1, including 58 predicted frameshifts. Software predictions were validated by serology in 108 participants; one case in the FY blood group and three cases in the JK blood group were discrepant. Investigation revealed that these discrepancies resulted from (1) clerical error, (2) serologic failure to detect weak antigenic expression and (3) a frameshift variant absent in blood group databases., Conclusion: DTM-Tools can be employed for rapid Kell, Duffy and Kidd blood group antigen prediction from existing ES data sets; for discrepancies detected in the validation data set, software predictions proved accurate. DTM-Tools is open-source and in continuous development., (© 2020 International Society of Blood Transfusion.)

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility., Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls., Design: We compared patients with HA to control women., Setting: The study was conducted at secondary referral centers., Patients and Other Participants: Women with HA (n = 106) and control women (ClinSeq study; n = 468)., Interventions: We performed exome sequencing in all patients and controls., Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests., Results: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%)., Conclusions: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

The concept of therapeutic alliance is central to genetic counseling as the mechanism through which the outcomes of empowerment and effective coping are likely to be achieved. To date, there have been no published systematic assessments of the therapeutic relationship in genetic counseling. We adapted a previously validated measure of the therapeutic alliance to genetic counseling and assessed its reliability and validity. Participants were enrolled in a clinical genomic study where they were randomized to receive education about carrier results via a Web platform or via a genetic counselor and then further randomized to receive genetic counseling (without additional education) or not. We rated the therapeutic alliance from audio recordings of 120 genetic counseling sessions. We modified the observer version of the Working Alliance Inventory (WAI-O), initially designed to assess therapeutic relationships in psychotherapy. We examined internal consistency reliability by calculating Cronbach's alpha and inter-rater reliability through both percent agreement and Gwet's alternative agreement coefficient (AC). Regression analyses were used to evaluate the relationship of WAI-O scores with session length and with the designation of the session as one in which prior education was delivered by the genetic counselor or not. The adapted scale had high-reliability characteristics with agreement of 88%-93%, Gwet's AC of 0.84-0.90, and Cronbach's alpha of 0.89-0.93 for the three WAI-O subscales (bonds, goals, and tasks). Although there was no difference in alliance based on whether prior education was provided by the genetic counselor, the total WAI-O score significantly increased with increasing session length (beta =0.667, p<.001), providing preliminary evidence of construct validity. The WAI-O that we have adapted can be used reliably with two independent raters to assess the therapeutic alliance in studies of genetic counseling. The initial evidence for construct validity is promising and should be reassessed in future genetic counseling studies using the WAI-O., (© 2021 National Society of Genetic Counselors.)

Rationale: Individuals who choose to obtain genetic information may learn that their genetic profile confers health risks to themselves or offspring. Individuals may react more negatively to this information when personal attitudes, perceived norms, and/or the decision to receive results conflict with one another., Objective: We predicted that holding more negative attitudes (personal evaluations) or injunctive norms (perceptions of others' approval) toward obtaining genetic test results would prospectively predict greater conflict about the decision to undergo sequencing and less disclosure of sequencing results to family members. We also expected attitudes and norms to interact, such that attitudes would be negatively associated with decisional conflict and positively associated with disclosure when injunctive norms were positive, but weakly associated with outcomes when injunctive norms were negative., Method: Participants (N=312) were enrolled in a genomic sequencing trial focused on identifying carrier genetic variants, reflecting a variant that might affect their biological children's or grandchildren's health. Participants reported attitudes and injunctive norms, underwent sequencing, and later received results indicating carrier status for at least one variant. Decisional conflict was assessed at immediate post-test, and 1- and 6-month follow-ups. Disclosure of results to children and siblings were assessed at 1 and 6 months., Results: In structural equation models with covariates, attitudes were negatively associated with post-test and 1-month decisional conflict. Injunctive norms were negatively associated with decisional conflict at 1 and 6 months and positively associated with disclosure to children and siblings at 1 month. The significant attitudes by injunctive norms interaction predicting post-test decisional conflict supported lower decisional conflict when attitudes, norms, and the decision to receive results were all aligned. Exploratory analyses supported indirect effects of attitudes and norms on 6-month sibling disclosure via 1- month decisional conflict., Conclusion: Results support roles of psychosocial factors in decisional conflict and disclosure after receiving sequencing results., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

How individuals perceive uncertainties in sequencing results may affect their clinical utility. The purpose of this study was to explore perceptions of uncertainties in carrier results and how they relate to psychological well-being and health behavior. Post-reproductive adults (N = 462) were randomized to receive carrier results from sequencing through either a web platform or a genetic counselor. On average, participants received two results. Group differences in affective, evaluative, and clinical uncertainties were assessed from baseline to 1 and 6 months; associations with test-specific distress and communication of results were assessed at 6 months. Reductions in affective uncertainty (∆x̅ = 0.78, 95% CI: 0.53, 1.02) and evaluative uncertainty (∆x̅ = 0.69, 95% CI: 0.51, 0.87) followed receipt of results regardless of randomization arm at 1 month. Participants in the web platform arm reported greater clinical uncertainty than those in the genetic counselor arm at 1 and 6 months; this was corroborated by the 1,230 questions asked of the genetic counselor and residual questions reported by those randomized to the web platform. Evaluative uncertainty was associated with a lower likelihood of communicating results to health care providers. Clinical uncertainty was associated with a lower likelihood of communicating results to children. Learning one's carrier results may reduce perceptions of uncertainties, though web-based return may lead to less reduction in clinical uncertainty in the short term. These findings warrant reinforcement of clinical implications to minimize residual questions and promote appropriate health behavior (communicating results to at-risk relatives in the case of carrier results), especially when testing alternative delivery models., (© Society of Behavioral Medicine 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We examined the role of ethnic identity (which measures the degree to which individuals identify with their ethnic group) in beliefs about, and intentions to learn, genomic results., Methods: A longitudinal cohort was recruited to implement genome sequencing among healthy participants self-identifying as African, African American, or Afro-Caribbean, 40-65 years old (n = 408). Before receiving genomic results, participants completed a survey assessing social and behavioral constructs related to health, genomics, and ethnic identity., Results: Ethnic identity was positively correlated with perceived value of genomic results and expected benefits from genomic research participation. Among participants with stronger ethnic identity, cognitive beliefs (perceived value of results [b = 0.63, 95% confidence interval: 0.29, 0.98, p < 0.001] and expected benefits from genomic research participation [b = 0.32, 95% confidence interval: 0.12, 0.53, p = 0.002]) were associated with intentions to receive results. Among those with weaker ethnic identity, there was no such association., Conclusion: Individuals with stronger ethnic identity seem to attend more to cognitive beliefs such as the value of genomic results when deliberating receipt of results compared with those with weaker ethnic identity. Understanding ethnic identity variation and its influence on genome sequencing perceptions and intentions can inform future research opportunities using ethnic identity to explore specific practical, clinical questions.

Purpose: Racial minority populations are underrepresented in genomics research. This study enrolled African-descended individuals in a sequencing study and reported their characteristics., Methods: We purposively recruited 467 individuals self-identified as African, African American, or Afro-Caribbean to the ClinSeq ® study and surveyed them about knowledge, motivations, expectations, and traits. Summary statistics were calculated and compared with data from the study's original cohort, which was primarily White and self-referred., Results: Recruitment took five years and 83% of enrollees completed the survey. Participants had modest knowledge about benefits and limitations of sequencing (x̅s = 5.1, ranges: 0-10), and less than the original cohort (x̅ = 7.5 and 7.7, respectively). Common motivations to enroll were learning information relevant to personal health (49%) or family members' health (33%), and most had realistic expectations of sequencing. Like the original cohort, they had high levels of optimism, openness, and resilience., Conclusion: Early adopters may have relatively consistent personality traits irrespective of majority/minority status and recruitment methods, but high levels of genomics knowledge are not universal. Research should determine whether recruitment and consent procedures provide adequate education to promote informed choices and realistic expectations, which are vital to ethical research and increasing genomics research participation in underrepresented communities.

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.

Exome and genome sequencing (EGS) are increasingly the genetic testing modalities of choice among researchers owing to their ready availability, low cost, and large data output. Recruitment of larger, more diverse cohorts into long-term studies with extensive data collection is fundamental to the success of EGS research and to the widespread benefit of genomic medicine to various populations. Effective engagement will be critical to meeting this demand. The Diffusion of Innovation (DOI) model provides a framework for how new technologies are adopted in communities, including antecedents of an individual's decision to adopt the technology, how the technology's attributes influence its acceptability, the predictors of sustained use of that technology, and its diffusion through society. We apply the DOI model to frame participant engagement in EGS research and to guide the proposal of potential strategies that aim to overcome forecasted challenges. Finally, we suggest a variety of ways genetic counselors can apply their skills and training to the development and implementation of these strategies., (© Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Studies on returning variants of uncertain significance (VUS) results have predominantly included patients with a personal or family history of cancer and cancer-associated gene VUS. This study examined health behaviors among participants with cardiomyopathy-associated gene VUS, but without a personal history of cardiomyopathy., Methods: Sixty-eight eligible participants without apparent cardiomyopathy but with VUS in cardiomyopathy-associated genes completed a survey of health behaviors, disclosure, distress, uncertainty, positive experiences, decisional conflict, and perceived value. The medical records of participants who reported cardiac testing because of their VUS were reviewed for testing indication(s)., Results: Two participants had cardiac testing due to their VUS alone. Four had cardiac testing because of their VUS and other clinical indications. Twelve changed health behaviors, including one participant who was subsequently diagnosed with cardiomyopathy. Distress, uncertainty, and decisional conflict were low (means = 1.2, 4.2, and 24.5 (scale ranges = 0-30, 0-45, and 15-75), respectively), and positive experiences and perceived value were moderate (means = 12.4 and 14.4 (scale ranges = 0-20 and 4-20), respectively). Greater perceived value was associated with greater likelihood to engage in health behaviors (P = 0.04)., Conclusion: Positive VUS results can be returned to apparently unaffected individuals with modest use of healthcare resources, minimal behavioral changes, and favorable psychological reactions.

Background: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed., Methods: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects., Results: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results., Conclusion: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

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., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Clinical and research settings are increasingly incorporating genomic sequencing (GS) technologies. Previous research has explored reasons for declining genetic testing and participation in genetic studies; however, there is a dearth of literature regarding why potential participants decline participation in GS research, and if any of these reasons are unique to GS. This knowledge is essential to promote informed decision-making and identify potential barriers to research participation and clinical implementation. We aggregated data from seven sites across the National Institutes of Health's Clinical Sequencing Exploratory Research (CSER) consortium on each project's procedures for recruitment, and rates of and reasons for decline. Data were analyzed using descriptive statistics. The decline rate for enrollment at the seven CSER sites ranged from 12 to 64% (median 28%) and varied based on age and disease status. Projects differed in their protocols for approaching potential participants and obtaining informed consent. Reasons for declining GS research were reported for 1088 potential participants. Commonly cited reasons were similar to those reported for clinical single gene testing and non-GS genetic research. The most frequently cited reason for decline was study logistics (35%); thus, addressing logistical barriers to enrollment may positively impact GS study recruitment. Privacy and discrimination concerns were cited by 13% of decliners, highlighting the need for researchers and providers to focus educational efforts in this area. The potential psychological burden of pursuing and receiving results from GS and not wanting to receive secondary findings, a concern specific to GS, have been cited as concerns in the literature. A minority of potential participants cited psychological impact (8%) or not wanting to receive secondary findings (2%) as reasons for decline, suggesting that these concerns were not major barriers to participation in these GS studies. Further research is necessary to explore the impact, if any, of different participant groups or study protocols on rates of decline for GS studies. Future studies exploring GS implementation should consider using standardized collection methods to examine reasons for decline in larger populations and more diverse healthcare settings.

Background: Clinical genetic testing for heritable cardiovascular disease has become a widely used tool to aid in the management of patients and their families. A 5-category variant classification system is commonly used for genetic test results, but some laboratories further subclassify variants of uncertain significance. How and whether patients perceive differences among the variant categories or subclassifications of variants of uncertain significance is unknown., Methods: We tested whether participants perceived differences in genetic variant subclassifications on outcomes including risk comprehension, risk perception, worry, perceived uncertainty, and intentions. Order-randomized hypothetical cardiovascular genetic results were given to 289 participants enrolled in a genome sequencing study. Three categories of variants were presented to participants: variants of uncertain significance, possibly pathogenic, and likely pathogenic. Responses to the first variant presented were analyzed in a between-groups analysis, and responses to all 3 variants were analyzed in a within-groups analysis., Results: When presented with all 3 results, participants distinguished among the subclassifications on all outcomes ( P <0.001). When given only a possibly pathogenic result, their risk perceptions were similar to those of variants of uncertain significance, but they were more worried and intended to behave as if they had received a likely pathogenic result. Individuals depended more on their affective responses such as worry when they received only one result ( P <0.05)., Conclusions: Participants are better able to distinguish pathogenicity subclassifications when presented with multiple categories. Individuals who receive a single uncertain result in a cardiovascular disease gene may benefit from interventions to decrease worry, calibrate risk perceptions, and motivate variant-appropriate behaviors., (© 2018 American Heart Association, Inc.)

Objective: Genomic sequencing is becoming increasingly accessible, highlighting the need to understand the social and psychological factors that drive interest in receiving testing results. These decisions may depend on perceived descriptive norms (how most others behave) and injunctive norms (what is approved of by others). We predicted that descriptive norms would be directly associated with intentions to learn genomic sequencing results, whereas injunctive norms would be associated indirectly, via attitudes. These differential associations with intentions versus attitudes were hypothesized to be strongest when individuals held ambivalent attitudes toward obtaining results., Method: Participants enrolled in a genomic sequencing trial (n = 372) reported intentions to learn medically actionable, nonmedically actionable, and carrier sequencing results. Descriptive norms items referenced other study participants. Injunctive norms were analyzed separately for close friends and family members. Attitudes, attitudinal ambivalence, and sociodemographic covariates were also assessed., Results: In structural equation models, both descriptive norms and friend injunctive norms were associated with intentions to receive all sequencing results (ps < .004). Attitudes consistently mediated all friend injunctive norms-intentions associations, but not the descriptive norms-intentions associations. Attitudinal ambivalence moderated the association between friend injunctive norms (p ≤ .001), but not descriptive norms (p = .16), and attitudes. Injunctive norms were significantly associated with attitudes when ambivalence was high, but were unrelated when ambivalence was low. Results replicated for family injunctive norms., Conclusions: Descriptive and injunctive norms play roles in genomic sequencing decisions. Considering mediators and moderators of these processes enhances ability to optimize use of normative information to support informed decision making. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Given familial implications of genetic information, it is important to understand intentions to share carrier results with family members. To our knowledge, no studies among individuals undergoing exome sequencing have used dyadic data analysis to examine the effect of spousal perceptions and beliefs. Survey responses from 136 individuals (68 couples) undergoing exome sequencing in a research study were analyzed using dyadic analysis (the actor-partner interdependence model). Intention to share carrier results with family members was correlated between spouses (ICC = 0.43; 95% CI: 0.21-0.61; p = 0.004), as was worry about risk of a genetic condition in the family (ICC = 0.45; 95% CI: 0.24-0.62; p < 0.001). Perceived value of result and worry about risk of a genetic condition in the family were associated with one's own intentions to share carrier results. However, spousal status on these variables did not explain additional variance in an individual's intentions. Although we found no partner effects on intentions, spouses have comparable intentions to share carrier results, suggesting it may be important to account for non-independence in other research studies.

In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post-reproductive participants from the ClinSeq cohort within a randomized controlled trial. Participants received education and were randomized to receive counseling or not. Primary outcomes included risk worry, test-related positive experiences, attitudes, and decisional conflict. Secondary outcomes were satisfaction, preferences, and counseling value. There were no differences between participants who received counseling and those who did not in the primary outcomes. Participants who received counseling were more satisfied than those who did not (x¯ = 10.2 and 9.5, respectively, p < 0.002, range: 3-12), although overall satisfaction was high. Most participants (92%) randomized to counseling preferred it and valued it because it provided validation of their reactions and an opportunity for interpersonal interaction. Web-based tools address the challenge of returning low-impact results, and these data provide empiric evidence that counseling, although preferred and satisfying, is not critical to achieving desired outcomes., (Published by Elsevier Inc.)

PurposeCa V 3.2 signaling contributes to nociception, pruritus, gastrointestinal motility, anxiety, and blood pressure homeostasis. This calcium channel, encoded by CACNA1H, overlaps the human tryptase locus, wherein increased TPSAB1 copy number causes hereditary α-tryptasemia. Germ-line CACNA1H variants may contribute to the variable expressivity observed with this genetic trait.MethodsTryptase-encoding sequences at TPSAB1 and TPSB2, and TPSG1 and CACNA1H variants were genotyped in 46 families with hereditary α-tryptasemia syndrome. Electrophysiology was performed on tsA201 HEK cells transfected with wild-type or variant CACNA1H constructs. Effects on clinical phenotypes were interrogated in families with TPSAB1 duplications and in volunteers from the ClinSeq cohort.ResultsThree nonsynonymous variants in CACNA1H (rs3751664, rs58124832, and rs72552056) cosegregated with TPSAB1 duplications in 32/46 families and were confirmed to be in linkage disequilibrium (LD). In vitro, variant Ca V 3.2 had functional effects: reducing current densities, and altering inactivation and deactivation properties. No clinical differences were observed in association with the CACNA1H haplotype.ConclusionA previously unrecognized haplotype containing three functional CACNA1H variants is relatively common among Caucasians, and is frequently coinherited on the same allele as additional TPSAB1 copies. The variant CACNA1H haplotype, which in vitro imparts partial gain of function, does not result in detectable phenotypic differences in the heterozygous state.

PurposeAs genome science advances, people receiving personalized genetic information may receive reinterpretations of pathogenicity. Little is known about responses to adjusted results. We examined how reinterpretations might affect attitudes about genetic testing and intentions to share results with family.MethodsData were collected from high-socioeconomic-status participants (n = 58) in a genome sequencing study. Twenty-nine originally learned they were carriers of Duarte variant galactosemia, based on a variant that was reclassified as benign. Positive testers (n = 19) had a newly identified causative variant and remained carriers. Negative testers (n = 10) learned they were no longer carriers. Twenty-nine controls were carriers for a disease of comparable severity with no reclassification. Participants completed baseline, immediate, and 3-month follow-up surveys.ResultsApproximately 80% of participants demonstrated complete or partially accurate recall of their results and reported positive or neutral reactions to their result and about genetic information more generally. Positive testers reported lower intentions to share the change in their result with family. Controls reported the lowest intentions to learn future results. There were no significant group differences or changes over time in perceived ambiguity or negative emotions.ConclusionThe results suggest that high-socioeconomic-status participants understand reinterpretations conferring a neutral change or a change from carrier to noncarrier status. Participants' responses to changes in carrier results for a low-risk condition indicated minimal adverse effects.

Importance: A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them., Objective: To test whether a web-based platform is noninferior to a genetic counselor for educating patients about their carrier results from exome sequencing., Design, Setting, and Participants: A randomized noninferiority trial conducted in a longitudinal sequencing cohort at the National Institutes of Health from February 5, 2014, to December 16, 2016, was used to compare the web-based platform with a genetic counselor. Among the 571 eligible participants, 1 to 7 heterozygous variants were identified in genes that cause a phenotype that is recessively inherited. Surveys were administered after cohort enrollment, immediately following trial education, and 1 month and 6 months later to primarily healthy postreproductive participants who expressed interest in learning their carrier results. Both intention-to-treat and per-protocol analyses were applied., Interventions: A web-based platform that integrated education on carrier results with personal test results was designed to directly parallel disclosure education by a genetic counselor. The sessions took a mean (SD) time of 21 (10.6), and 27 (9.3) minutes, respectively., Main Outcomes and Measures: The primary outcomes and noninferiority margins (δNI) were knowledge (0 to 8, δNI = -1), test-specific distress (0 to 30, δNI = +1), and decisional conflict (15 to 75, δNI = +6)., Results: After 462 participants (80.9%) provided consent and were randomized, all but 3 participants (n = 459) completed surveys following education and counseling; 398 (86.1%) completed 1-month surveys and 392 (84.8%) completed 6-month surveys. Participants were predominantly well-educated, non-Hispanic white, married parents; mean (SD) age was 63 (63.1) years and 246 (53.6%) were men. The web platform was noninferior to the genetic counselor on outcomes assessed at 1 and 6 months: knowledge (mean group difference, -0.18; lower limit of 97.5% CI, -0.63; δNI = -1), test-specific distress (median group difference, 0; upper limit of 97.5% CI, 0; δNI = +1), and decisional conflict about choosing to learn results (mean group difference, 1.18; upper limit of 97.5% CI, 2.66; δNI = +6). There were no significant differences between the genetic counselors and web-based platform detected between modes of education delivery in disclosure rates to spouses (151 vs 159; relative risk [RR], 1.04; 95% CI, 0.64-1.69; P > .99), children (103 vs 117; RR, 1.07; 95% CI, 0.85-1.36; P = .59), or siblings (91 vs 78; RR, 1.17; 95% CI, 0.94-1.46; P = .18)., Conclusions and Relevance: This trial demonstrates noninferiority of web-based return of carrier results among postreproductive, mostly healthy adults. Replication studies among younger and more diverse populations are needed to establish generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a greater health threat., Trial Registration: clinicaltrials.gov Identifier: NCT00410241.

Caregivers of children with autism spectrum disorder (ASD) may find it difficult to feel a sense of control and to cope with the overall physical and emotional demands of caring for their child. While caregivers are able to successfully cope with a high level of stress, there are limits to their resources and abilities to cope over time. Genetic counselors working with affected families may be able to help parents more effectively manage stress related to the disorder. Few short-term interventions have been reported in genetic counseling yet implementation of evidence-based examples may be achievable. This study aimed to assess the feasibility of a coping effectiveness training (CET) intervention designed to enhance coping self-efficacy (CSE) among caregivers of children with ASD, with the eventual goal of translating this intervention into genetic counseling practice. A randomized treatment-control design was used to investigate the feasibility of an intervention using CET among caregivers of children with ASD. The primary outcome was the feasibility of the intervention; the secondary outcome was improvements in CSE in the intervention group as compared to the control group. Caregivers were recruited and randomized into the treatment (n=15) or control (n=13) groups. Of these, 22 completed the study (retention: 78.6%). The intervention was highly feasible; most caregivers found the CET helpful, practical, useful, and relatively easy to attend. The treatment group demonstrated significantly increased CSE from pre-intervention to post-intervention (p=0.02). Between group differences were not significant when comparing the pre-post changes. We provide preliminary evidence that CET may be beneficial to caregivers of children with ASD. The results of this feasibility study support development of a phase II study of this intervention in a larger cohort, aimed to be implemented into a genetic counseling setting.

Supervision is a practice that is utilized by a variety of practitioners to hone their counseling skills. Genetic counselors have embraced the supervision process, and some seek out supervision in a group setting with peers. Researchers have described the structure and content of genetic counseling peer supervision groups, and provided evidence for the benefits of seeking peer supervision. This study aimed to describe the interpersonal aspects of one genetic counseling peer supervision group, including personality traits and group dynamics, and how those factors influenced our experiences within the group. We also describe how the process of evaluating these factors impacted us individually and collectively. There was consensus that the group was a safe and trusting one, which was united by similar goals and mutual respect. Members reported gaining insights about how their own personality functioned within the group milieu, and also how the group setting impacted them. Based on our experiences, we recommend that other peer supervision groups consider similar self-evaluations on a periodic basis, both to enhance group functioning and to allow for increased self-awareness and professional growth.

Purpose: As clinical genome sequencing expand its reach, understanding how individuals engage with this process are of critical importance. In this study, we aimed to describe internal engagement and its correlates among a ClinSeq cohort of adults consented to genome sequencing and receipt of results., Methods: This study was framed using the precaution adoption process model (PAPM), in which knowledge predicts engagement and engagement predicts subsequent behaviors. Prior to receipt of sequencing results, 630 participants in the study completed a baseline survey. Engagement was assessed as the frequency with which participants thought about their participation in ClinSeq since enrollment., Results: Results were consistent with the PAPM: those with higher genomics knowledge reported higher engagement (r = 0.13, P = 0.001) and those who were more engaged reported more frequent communication with their physicians (r = 0.28, P < 0.001) and family members (r = 0.35, P < 0.001) about ClinSeq. Characteristics of those with higher engagement included poorer overall health (r = -0.13, P = 0.002), greater seeking of health information (r = 0.16, P < 0.001), and more recent study enrollment (r = -0.21, P < 0.001)., Conclusion: These data support the importance of internal engagement in communication related to genomic sequencing.Genet Med 19 1, 98-103., Competing Interests: K.L.U., L.K.K., K.L.L., and B.B.B. have no conflicts of interest to declare. L.G.B. is an uncompensated consultant to the Illumina Corporation and receives royalties from the Genentech and Amgen Corporations. G.W.H. is a full-time employee of Next-GxDx.

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Purpose: This study investigated how genome sequencing results affect health behaviors, affect, and communication., Methods: We report on 29 participants who received a sequence result in the ClinSeq study, a cohort of well-educated, postreproductive volunteers. A mixed-methods design was used to explore respondents' use, communication, and perceived utility of results., Results: Most participants (72%) shared their result with at least one health-care provider, and 31% reported subsequent changes in the health care they received. Participants scored high on the Positive Experiences subscale and low on the Distress subscale of a modified version of the Multidimensional Impact of Cancer Risk Assessment. The majority (93%) shared their result with at least one family member. Participants described deriving personal utility from their results., Conclusion: This article is the first to describe research participants' reactions to actionable sequencing results. Our findings suggest clinical and personal benefit from receiving sequencing results, both of which may contribute to improved health for the recipients. Given the participants' largely positive or neutral affective responses and disclosure of their results to physicians and relatives, health-care providers should redirect concern from the potential for distress and attend to motivating patients to follow their medical recommendations.Genet Med 18 6, 577-583.

Many variants that could be returned from genome sequencing may be perceived as ambiguous-lacking reliability, credibility, or adequacy. Little is known about how perceived ambiguity influences thoughts about sequencing results. Participants (n = 494) in an NIH genome sequencing study completed a baseline survey before sequencing results were available. We examined how perceived ambiguity regarding sequencing results and individual differences in medical ambiguity aversion and tolerance for uncertainty were associated with cognitions and intentions concerning sequencing results. Perceiving sequencing results as more ambiguous was associated with less favorable cognitions about results and lower intentions to learn and share results. Among participants low in tolerance for uncertainty or optimism, greater perceived ambiguity was associated with lower intentions to learn results for non-medically actionable diseases; medical ambiguity aversion did not moderate any associations. Results are consistent with the phenomenon of "ambiguity aversion" and may influence whether people learn and communicate genomic information.

Background: Information avoidance is a defensive strategy that undermines receipt of potentially beneficial but threatening health information and may especially occur when threat management resources are unavailable., Purpose: We examined whether individual differences in information avoidance predicted intentions to receive genetic sequencing results for preventable and unpreventable (i.e., more threatening) disease and, secondarily, whether threat management resources of self-affirmation or optimism mitigated any effects., Methods: Participants (N = 493) in an NIH study (ClinSeq®) piloting the use of genome sequencing reported intentions to receive (optional) sequencing results and completed individual difference measures of information avoidance, self-affirmation, and optimism., Results: Information avoidance tendencies corresponded with lower intentions to learn results, particularly for unpreventable diseases. The association was weaker among individuals higher in self-affirmation or optimism, but only for results regarding preventable diseases., Conclusions: Information avoidance tendencies may influence decisions to receive threatening health information; threat management resources hold promise for mitigating this association.

Genome sequencing is a novel clinical tool that has the potential to identify genetic origins of disease. However, the complexities of this new technology are significant and little is known about its integration into clinical care, and its potential adoption by patients. Expectations of its promise for personalized medicine are high and it is important to properly match expectations to the realities of the test. The NIH ClinSeq cohort study pilots the integration of genome sequencing into clinical research and care to assess the technical, medical and socio-behavioral aspects of implementing this technology. Over 950 adults ages 45-65 have been enrolled and clinically phenotyped. As an initial study, we describe the personality traits of ClinSeq participants, and explore how these traits compare to those that characterize early adopters of other new technologies. Our analysis was conducted on responses from 630 members of the cohort who completed a baseline survey on health cognitions, affect, health-related behaviors and personality traits, prior to receipt of any genome sequencing results. The majority of participants were white (90.5%), had at least a college degree (86.5%), and had at least one biological child (74.6%). Members of this ClinSeq sample were found to be high in dispositional optimism and resilience. Their high SES paralleled that of other early adopters of new technology. These attributes may contribute to participants' expectations for favorable outcomes and willingness to take higher risks when compared to the general population. These characteristics may distinguish those who are most likely to pursue genome sequencing and be indicative of their psychological resources to manage returned results.

Objective: Dispositional optimism and risk perceptions are each associated with health-related behaviors and decisions and other outcomes, but little research has examined how these constructs interact, particularly in consequential health contexts. The predictive validity of risk perceptions for health-related information seeking and intentions may be improved by examining dispositional optimism as a moderator, and by testing alternate types of risk perceptions, such as comparative and experiential risk., Method: Participants (n = 496) had their genomes sequenced as part of a National Institutes of Health pilot cohort study (ClinSeq®). Participants completed a cross-sectional baseline survey of various types of risk perceptions and intentions to learn genome sequencing results for differing disease risks (e.g., medically actionable, nonmedically actionable, carrier status) and to use this information to change their lifestyle/health behaviors., Results: Risk perceptions (absolute, comparative, and experiential) were largely unassociated with intentions to learn sequencing results. Dispositional optimism and comparative risk perceptions interacted, however, such that individuals higher in optimism reported greater intentions to learn all 3 types of sequencing results when comparative risk was perceived to be higher than when it was perceived to be lower. This interaction was inconsistent for experiential risk and absent for absolute risk. Independent of perceived risk, participants high in dispositional optimism reported greater interest in learning risks for nonmedically actionable disease and carrier status, and greater intentions to use genome information to change their lifestyle/health behaviors., Conclusions: The relationship between risk perceptions and intentions may depend on how risk perceptions are assessed and on degree of optimism., ((c) 2015 APA, all rights reserved.)

Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

One reason for not seeking personally threatening information may be negative current and anticipated affective responses. We examined whether current (e.g., worry) and anticipated negative affect predicted intentions to seek sequencing results in the context of an actual genomic sequencing trial (ClinSeq®; n = 545) and whether spontaneous self-affirmation mitigated any (negative) association between affect and intentions. Anticipated affective response negatively predicted intentions to obtain and share results pertaining to both medically actionable and non-actionable disease, whereas current affect was only a marginal predictor. The negative association between anticipated affect and intentions to obtain results pertaining to non-actionable disease was weaker in individuals who were higher in spontaneous self-affirmation. These results have implications for the understanding of current and anticipated affect, self-affirmation and consequential decision-making and contribute to a growing body of evidence on the role of affect in medical decisions.

Purpose: The scope of uncertainty in genome sequence information has no rival in health-care delivery. We present data from adults participating in a National Institutes of Health study using this technology, in which perceptions of uncertainty are hypothesized to be key in predicting decisions to learn and act on genome health information., Methods: We conducted six professionally moderated focus groups with 39 randomly selected ClinSeq participants varying on whether they had coronary heart disease and had received prior sequence results. We elicited perceptions of the uncertainties associated with genome sequencing using written prompts., Results: Participants perceived uncertainty as a quality of genome information. The majority of participants characterized uncertainty of sequencing information as "changing, fluid, developing, or ground breaking." These responses led to anticipation of more optimistic future outcomes. Fewer participants described uncertainty as "questionable, less accurate, limited, or poorly understood." These perceptions seemed to undermine participants' faith in genome information, leading to feelings of disillusionment., Conclusion: Our findings suggest that perceptions of uncertainty are related to epistemological beliefs that inform expectations for the information. Interventions that promote realistic expectations of genome sequencing may mitigate negative responses to uncertainty.

Purpose: The aim of this study was to explore the implications of sequencing information and stated preferences for return of results among research participants., Methods: Six focus groups were held with 39 ClinSeq participants. The groups included participants who had received results, those who had not, those affected with cardiovascular disease, and healthy adults. Audio recordings of the sessions were transcribed and coded and analyzed for themes., Results: All participants expressed interest in receiving results that are medically actionable, nonactionable, carrier, and less so variants that cannot be interpreted. Most participants preferred to receive results in person, although several endorsed use of Internet-based resources that they could return to. Participants identified benefits for health management along with satisfying curiosity, making scientific contributions, and partnering in research. Value was seen in gaining control over health risks. Concerns were distress and/or fear that may result. Some participants were opposed to or ambivalent about learning certain types of results, particularly those having to do with diseases that were incurable or that might have implications for the health of their children., Conclusion: There was relative enthusiasm about the value of learning sequencing information, yet it was tempered by concern about negative feeling responses and aversion to learning about incurable conditions.

Background: Massively parallel sequencing to identify rare variants is widely practiced in medical research and in the clinic. Genome and exome sequencing can identify the genetic cause of a disease (primary results), but it can also identify pathogenic variants underlying diseases that are not being sought (secondary or incidental results). A major controversy has developed surrounding the return of secondary results to research participants. We have piloted a method to analyze exomes to identify participants at risk for cardiac arrhythmias, cardiomyopathies, or sudden death., Methods and Results: Exome sequencing was performed on 870 participants not selected for arrhythmia, cardiomyopathy, or a family history of sudden death. Exome data from 22 cardiac arrhythmia- and 41 cardiomyopathy-associated genes were analyzed using an algorithm that filtered results on genotype quality, frequency, and database information. We identified 1367 variants in the cardiomyopathy genes and 360 variants in the arrhythmia genes. Six participants had pathogenic variants associated with dilated cardiomyopathy (n=1), hypertrophic cardiomyopathy (n=2), left ventricular noncompaction (n=1), or long-QT syndrome (n=2). Two of these participants had evidence of cardiomyopathy and 1 had left ventricular noncompaction on echocardiogram. Three participants with likely pathogenic variants had prolonged QTc. Family history included unexplained sudden death among relatives., Conclusions: Approximately 0.5% of participants in this study had pathogenic variants in known cardiomyopathy or arrhythmia genes. This high frequency may be due to self-selection, false positives, or underestimation of the prevalence of these conditions. We conclude that clinically important cardiomyopathy and dysrhythmia secondary variants can be identified in unselected exomes.