Further validation of the Perceptions of Uncertainties in Genome Sequencing scale among patients with cancer undergoing tumor sequencing.

It is important to understand how individuals perceive uncertainties and the consequent impact on their psychological well-being and health behavior. The Perceptions of Uncertainties in Genome Sequencing (PUGS) scale measures clinical, affective, and evaluative uncertainties about information from sequencing. The PUGS scale has been shown to be valid and reliable among individuals receiving results about their genomes. This study assessed whether its validity generalized to patients with cancer undergoing tumor sequencing. Exploratory factor analysis (EFA) was conducted on data from the Molecular Screening and Therapeutics Program (n = 310) to identify a measurement model. Confirmatory factor analysis (CFA) was used to determine the adequacy of the resulting fit. EFA identified the same three-factor structure reported previously. CFA confirmed that the measurement model yielded a good fit (χ2 /df = 3.72, CFI = 0.96, SRMR = 0.05, and RMSEA = 0.09) and satisfied convergent and discriminant validity. These findings provide further evidence of the validity and reliability of the PUGS scale in measuring three types of uncertainty. Continued application will facilitate an evidence-based approach to intervention and enhance understanding of what it is like to receive results. In turn, this will improve clinical outcomes as undergoing sequencing becomes an increasingly common experience.

Perceptions of uncertainties about carrier results identified by exome sequencing in a randomized controlled trial.

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.

Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.

While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings.

Outcomes of Counseling after Education about Carrier Results: A Randomized Controlled Trial.

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.

Barriers and facilitators to clinical trial participation among parents of children with pediatric neuromuscular disorders.

BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics. These parents ( N = 203) completed a questionnaire including assessments of barriers and facilitators to clinical trial participation, parents' interest in trial participation, and their perceptions of others' views about participation in a clinical trial. RESULTS: Trial interest in participating parents was high (64% combined group). The most highly endorsed barrier to participation was the possibility of receiving placebo, followed by not having enough information on risks and trial procedures. Compared to parents of children with Duchenne or Becker muscular dystrophy, parents of children with spinal muscular atrophy endorsed significantly more information and knowledge barriers. The greatest facilitators of participation were (1) confidence in improving disease understanding and (2) guarantee to receive the treatment after a successful trial. A logistic regression model, χ2 (4, n = 188) = 80.64, p < .001, indicated that higher perceived barriers and more frequent trial communication by the provider were associated with lower interest, while positive trial perceptions by the child's providers and concordance in trial perceptions among those close to the decision-maker were associated with higher interest. CONCLUSION: We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents' informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools.

Social comparisons and quality of life following a prostate cancer diagnosis.

PURPOSE: The objective was to explore the relationships among cognitive appraisals of prostate cancer (challenge, threat, and harm/loss), social comparisons, and quality of life in men previously diagnosed. Design, Sample, & Methods: Men who had participated in prostate cancer support groups completed a cross-sectional questionnaire (N = 189). Multivariable linear regression was used to evaluate social comparisons as mediators of quality of life while controlling for uncertainty and optimism. FINDINGS: Positive and negative social comparisons were parallel mediators of the relationships between challenge or threat appraisals and quality of life, while only negative social comparisons mediated the relationship between harm/loss appraisals and quality of life. CONCLUSIONS: These findings demonstrate the importance of social comparisons in accounting for the effect of cognitive appraisals of prostate cancer on quality of life among men in support groups. Implications for Psychosocial Providers: Interventions to improve quality of life could address reduction of maladaptive comparisons, a strategy that could be tailored based on the patient's appraisal of prostate cancer.

Web Platform vs In-Person Genetic Counselor for Return of Carrier Results From Exome Sequencing: A Randomized Clinical Trial.

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.

A Systematic Review of Randomized Controlled Trials to Assess Outcomes of Genetic Counseling.

With the advancements in precision medicine and health care reform, it is critical that genetic counseling practice respond to emerging evidence to maximize client benefit. The objective of this review was to synthesize evidence on outcomes from randomized controlled trials (RCTs) of genetic counseling to inform clinical practice. Seven databases were searched in conducting this review. Studies were selected for inclusion if they were: (a) RCTs published from 1990 to 2015, and (b) assessed a direct outcome of genetic counseling. Extracted data included study population, aims, and outcomes. Risk of bias was evaluated using the Cochrane Handbook for Systematic Reviews of Interventions guidelines. A review of 1654 abstracts identified 58 publications of 54 unique RCTs that met inclusion criteria, the vast majority of which were conducted in cancer genetic counseling setting. Twenty-seven publications assessed 'enhancements' to genetic counseling, and 31 publications compared delivery modes. The methodological rigor varied considerably, highlighting the need for attention to quality criteria in RCT design. While most studies assessed several client outcomes hypothesized to be affected by genetic counseling (e.g., psychological wellbeing, knowledge, perceived risk, patient satisfaction), disparate validated and reliable scales and other assessments were often used to evaluate the same outcome(s). This limits opportunity to compare findings across studies. While RCTs of genetic counseling demonstrate enhanced client outcomes in a number of studies and pave the way to evidence-based practice, the heterogeneity of the research questions suggest an important need for more complementary studies with consistent outcome assessments.

A taxonomy of medical uncertainties in clinical genome sequencing.

PURPOSE: Clinical next-generation sequencing (CNGS) is introducing new opportunities and challenges into the practice of medicine. Simultaneously, these technologies are generating uncertainties of an unprecedented scale that laboratories, clinicians, and patients are required to address and manage. We describe in this report the conceptual design of a new taxonomy of uncertainties around the use of CNGS in health care. METHODS: Interviews to delineate the dimensions of uncertainty in CNGS were conducted with genomics experts and themes were extracted in order to expand on a previously published three-dimensional taxonomy of medical uncertainty. In parallel, we developed an interactive website to disseminate the CNGS taxonomy to researchers and engage them in its continued refinement. RESULTS: The proposed taxonomy divides uncertainty along three axes-source, issue, and locus-and further discriminates the uncertainties into five layers with multiple domains. Using a hypothetical clinical example, we illustrate how the taxonomy can be applied to findings from CNGS and used to guide stakeholders through interpretation and implementation of variant results. CONCLUSION: The utility of the proposed taxonomy lies in promoting consistency in describing dimensions of uncertainty in publications and presentations, to facilitate research design and management of the uncertainties inherent in the implementation of CNGS.Genet Med advance online publication 19 January 2017.

Engagement and communication among participants in the ClinSeq Genomic Sequencing Study.

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.

Family functioning mediates adaptation in caregivers of individuals with Rett syndrome.

OBJECTIVE: The objective of this study was to investigate factors related to family functioning and adaptation in caregivers of individuals with Rett syndrome (RS). METHODS: A cross-sectional quantitative survey explored the relationships between demographics, parental self-efficacy, coping methods, family functioning and adaptation. A forward-backward, step-wise model selection procedure was used to evaluate variables associated with both family functioning and adaptation. Analyses also explored family functioning as a mediator of the relationship between other variables and adaptation. RESULTS: Bivariate analyses (N=400) revealed that greater parental self-efficacy, a greater proportion of problem-focused coping, and a lesser proportion of emotion-focused coping were associated with more effective family functioning. In addition, these key variables were significantly associated with greater adaptation, as was family functioning, while controlling for confounders. Finally, regression analyses suggest family functioning as a mediator of the relationships between three variables (parental self-efficacy, problem-focused coping, and emotion-focused coping) with adaptation. CONCLUSION: This study demonstrates the potentially predictive roles of expectations and coping methods and the mediator role of family functioning in adaptation among caregivers of individuals with RS, a chronic developmental disorder. PRACTICE IMPLICATIONS: A potential target for intervention is strengthening of caregiver competence in the parenting role to enhance caregiver adaptation.