The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network

PurposeThe goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants.MethodsRoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed.ResultsOf the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052).ConclusionThe real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.     

ORCA,a values-based decision aid for selecting additional findings from genomic sequencing in adults: Efficacy results from a randomized trial

PurposeIndividuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one’s values before making a choice about these additional results.MethodsWe conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone. ORCA is values-focused with a low-literacy design.ResultsIndividuals in both arms had informed values-choice congruence (75% and 73% in the decision aid and web-based groups, respectively; odds ratio [OR] = 1.10, 95% CI = 0.58-2.08). Most participants had adequate knowledge (79% and 76% in the decision aid and web-based groups, respectively; OR = 1.20, 95% CI = 0.61-2.34), with no significant difference between groups. Most had information-seeking values (97% and 98% in the decision aid and web-based groups, respectively; OR = 0.59, 95% CI = 0.10-3.61) and chose to receive additional findings.ConclusionThe ORCA decision aid did not significantly improve informed values-choice congruence over web-based information in this cohort of adults deciding about genomic results. Both web-based approaches may be effective for adults to decide about receiving medically actionable additional results.     

Self-management for pulmonary fibrosis: Insights from people living with the disease and healthcare professionals

ObjectivePeople with pulmonary fibrosis (PF) consider self-management essential for maintaining health. This study aims to explore the needs and expectations of PF self-management from the patient and healthcare professionals (HCPs) perspectives.MethodsSemi-structured interviews were conducted with people with PF and HCPs. Purposive sampling was used to recruit participants. Thematic analysis was performed using the principles of grounded theory.Results18 individuals with PF and 15 HCPs were interviewed. Common self-management components reported included exercise, nutrition, maintaining healthy mind, avoiding infections, recognising deterioration and seeking help, managing symptoms and treatments, social support, and end-of-life planning. Both groups felt that effective self-management required individualised strategies, supports, and reliable information. People with PF identified access to personal health data and self-acceptance as part of self-management. HCPs highlighted the importance of accessible supports and managing patient expectations of disease course and treatments. Some HCPs concerned about missed detection of deterioration and suggested that self-management strategies for PF may differ to other lung diseases.ConclusionThis study identified components important for self-management in PF and provides a basis for designing a PF self-management package. Practice implications: Self-management of PF can be facilitated with individualised support from HCPs and reliable information that is accessible.     

Physicians’ perspectives on receiving unsolicited genomic results

PurposePhysicians increasingly receive genomic test results they did not order, which we term “unsolicited genomic results” (UGRs). We asked physicians how they think such results will affect them and their patients.MethodsSemistructured interviews were conducted with adult and pediatric primary care and subspecialty physicians at four sites affiliated with a large-scale return-of-results project led by the Electronic Medical Records and Genomics (eMERGE) Network. Twenty-five physicians addressed UGRs and (1) perceived need for actionability, (2) impact on patients, (3) health care workflow, (4) return of results process, and (5) responsibility for results.ResultsPhysicians prioritize actionability of UGRs and the need for clear, evidence-based “paths” for action coupled with clinical decision support (CDS). They identified potential harms to patients including anxiety, false reassurance, and clinical disutility. Clinicians worried about anticipated workflow issues including responding to UGRs and unreimbursed time. They disagreed about who was responsible for responding to UGRs.ConclusionThe prospect of receiving UGRs for otherwise healthy patients raises important concerns for physicians. Their responses informed development of an in-depth survey for physicians following return of UGRs. Strategic workflow integration of UGRs will likely be necessary to empower physicians to serve their patients effectively.     

Frequency and spectrum of actionable pathogenic secondary findings in 196 Korean exomes

PurposeOne of the biggest challenges of exome and genome sequencing in the era of genomic medicine is the identification and reporting of secondary findings. In this study we investigated the frequency and spectrum of actionable pathogenic secondary findings in Korean exomes.MethodsData from 196 Korean exomes were screened for variants from a list of 56 genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return of secondary findings. Identified variants were classified according to the evidence-based guidelines reached by a joint consensus of the ACMG and the Association for Molecular Pathology.ResultsAmong the 196 exomes, which were from 100 healthy controls and 96 patients with suspected genetic disorders, 11 variants in 13 individuals were found to be pathogenic or likely pathogenic. We estimated that the frequency of actionable pathogenic secondary findings was 7% for the control subjects (7/100) and 6% for the patients with disease (6/96). For one autosomal-recessive disease, four individuals exhibited either one pathogenic or one likely pathogenic variant of the MUTYH gene, leading to a carrier frequency of 2% (4/196).ConclusionSecondary findings are not uncommon in Korean exomes.     

Disclosure of genetic information to family members: a systematic review of normative documents

PurposeFindings from genomic sequencing can have important implications for patients and family members. Yet, when a patient does not consent to the disclosure of genetic information to relatives, it is unclear how health-care professionals (HCPs) should balance their responsibilities toward patients and their family members and whether breaches in confidentiality are warranted.MethodsWe conducted a systematic review of normative documents to understand how HCPs should discuss and facilitate family disclosure, and what should be done in cases where the patient does not consent to disclosure.ResultsWe analyzed 35 documents from advisory committees at the national, European, and international level. We identified discrepancies regarding the recommended role of HCPs in disclosure. While almost all normative documents supported the disclosure of genetic information without patient consent in limited conditions, the conditions for disclosure were often not well defined. Documents provided varying degrees of information regarding what actions HCPs must take in such situations.ConclusionOur findings present concerns regarding the ability of these normative documents to guide HCPs’ decision making around the disclosure of genetic information to family members. Clearer guidance outlining the responsibilities and acceptability of disclosure is necessary to facilitate disclosure of genetic information to family members.     

Barriers and facilitators to discussing HPV with head and neck cancer patients: A qualitative study using the theoretical domains framework

ObjectiveThe incidence of human papillomavirus-associated head and neck cancers (HPV-HNC) is increasing worldwide. Research in other clinical contexts has shown that healthcare professionals (HCPs) can find discussing HPV with patients challenging. However, limited research has been conducted in HNC. This study aimed to investigate barriers and facilitators to, discussing HPV among HCPs caring for patients with HNC in Ireland.MethodsSemi-structured telephone/face-to-face interviews were conducted with HCPs. Barriers and facilitators to discussing HPV with patients were identified using the Theoretical Domains Framework (TDF).Results20 HCPs (8 clinicians, 3 nurses, 9 allied healthcare professionals) were interviewed. Barriers to discussing HPV included professionals' lack of HPV knowledge, difficulties in talking about sexual issues with patients and lack of privacy to discuss HPV in busy clinic settings. Facilitators included increasing public and patient awareness of the link between HPV and HNC and professional education and skills development.ConclusionsThis is the first theoretically informed study to identify barriers and facilitators to discussing HPV with HNC patients. HCPs consider HPV discussions to be an essential part of HNC patient care.Practice implicationsUnderstanding the issues associated with patient-provider HPV communication will help develop effective interventions to support HCPs in their HPV discussions.     

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals

PurposeTo measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.MethodsWe used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.ResultsOne in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.ConclusionMedically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.     

Prospective,phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield

PurposeTo investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria.MethodsIntensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team.ResultsA genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies.ConclusionPhenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.     

Identifying rare,medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls

PurposeTo evaluate the effectiveness and specificity of population-based genomic screening in Alabama.MethodsThe Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results.ResultsAmong 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants.ConclusionIn AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.     

Attitudes,knowledge and practice behaviours of oncology health care professionals towards lesbian,gay, bisexual,transgender, queer and intersex (LGBTQI) patients and their carers: A mixed-methods study

ObjectiveThere is growing recognition that health care professionals (HCPs) and policy makers are insufficiently equipped to provide culturally competent care to lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI) cancer patients and their families. We examined HCP attitudes, knowledge, and practices regarding LGBTQI cancer care using a mixed-methods research design.MethodSurveys were completed by 357 oncology HCPs in nursing (40%), medical (24%), allied health (19%), and clinical leadership roles (11%); 48 of the surveyed HCPs were interviewed.ResultsMost HCPs reported being comfortable treating LGBTQI patients, but reported low levels of confidence and knowledge and systemic barriers to LGBTQI cancer care. Most wanted more education and training, particularly on trans and gender-diverse people (TGD) and those born with intersex variations.ConclusionEducation of HCPs and health system changes are required to overcome barriers to the provision of culturally competent cancer care for LGBTQI patients.Practice implicationsThese findings reinforce the need for inclusion of LGBTQI content in HCP education and professional training curricula, and institutional support for LGBTQI-inclusive practice behaviours. This includes administrative and visual cues to signal safety of LGBTQI patients within cancer care, facilitating inclusive environments, and the provision of tailored patient-centred care.     

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

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

Patient experiences with gene panels based on exome sequencing in clinical diagnostics: high acceptance and low distress

The Radboud University Medical Center was among the first to implement two‐step exome sequencing in clinical genetic diagnostics. This study is the first to evaluate patient experiences with gene panels based on exome sequencing, using quantified psychological variables: acceptance, psychological distress, expectations of heredity and unsolicited findings. Between August 2011 and July 2012, 177 patients diagnosed with early‐onset colorectal/kidney cancer, deafness, blindness or movement disorder consented to diagnostic exome sequencing offered by clinical geneticists. Baseline questionnaires were sent to 141 adults, returned by 111 with median age of 49 [22–79] years and positive family history in 81%. Follow‐up included 91 responders at median 4 [2–22] weeks after results from known gene panels per diagnosis group; exome‐wide analysis is ongoing. Confirmed or possibly pathogenic mutations were found in 31% with one unsolicited finding (oncogenetic panel). Most patients (92%) were satisfied. There were no significant changes in heredity‐specific distress (18% at baseline, 17% at follow‐up) and expectations of heredity. Fewer patients expected unsolicited findings at follow‐up (29% vs 18%, p = 0.01). Satisfaction and distress were equal in those with vs without mutations. In conclusion, most adults accepted and were satisfied with gene panels based on diagnostic exome sequencing, few reporting distress.     

Genomic sequencing identifies secondary findings in a cohort of parent study participants

PurposeClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.MethodsExome/genome sequencing and analysis of 789 “unaffected” parents was performed.ResultsPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the American College of Medical Genetics and Genomics. These 25 individuals self-reported either relevant clinical diagnoses (5); relevant family history or symptoms (13); or no relevant family history, symptoms, or clinical diagnoses (7). A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate pairs (n = 365) to identify cases in which both parents were carriers for the same recessive disease, yielding three such cases (0.8%), two of which had children with the relevant recessive disease. Four participants had two findings (one carrier and one noncarrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.ConclusionWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design and implementation of research and clinical sequencing efforts to identify such findings.     

Psychiatric genomics researchers’ perspectives on best practices for returning results to individual participants

PurposeLarge-scale array-based and sequencing studies have advanced our understanding of the genetic architecture of psychiatric disorders, but also increased the potential to generate an exponentially larger amount of clinically relevant findings. As genomic testing becomes more widespread in psychiatry research, urgency grows to establish best practices for offering return of results (RoR) to individuals at risk or diagnosed with a psychiatric disorder.MethodsWe interviewed an international sample (n = 39) of psychiatric genetics researchers to examine conceptualizations of “best practices” for RoR to individual research participants.ResultsWhile the vast majority of researchers do not offer RoR, most believed medically actionable findings (85%) and clinically valid but non–medically actionable findings (54%) should be offered. Researchers identified three main areas for improvement: interfacing with individual participants; interdisciplinary training, guidance, and integration; and quality planning and resource allocation for returning results.ConclusionThere are significant gaps between researchers’ visions for “best” versus “actual” RoR practices. While researchers call for participant-centered practices, including consent practices that consider any special needs of participants with psychiatric disorders, return of individually meaningful results, and effective follow-up and provisions for treatment, the current reality is that consent and RoR practices lack standardized and evidence-based norms.     

Preferences of biobank participants for receiving actionable genomic test results: results of a recontacting study

PurposeWe sought to determine preferences of biobank participants whose samples were tested for clinically actionable variants but did not respond to an initial invitation to receive results.MethodsWe recontacted a subsample of participants in the Kaiser Permanente Washington/University of Washington site of the Electronic Medical Records and Genomics (eMERGE3) Network. The subsample had provided broad consent for their samples to be used for research but had not responded to one initial mailed invitation to receive their results. We sent a letter from the principal investigators with phone outreach. If no contact was made, we sent a certified letter stating our assumption that participant had actively refused. We collected reasons for declining.ResultsWe recontacted 123 participants. Response rate was 70.7% (n = 87). Of these, 62 (71.3%) declined the offer of returned results and 25 (28.7%) consented. The most common reasons provided for refusal included not wanting to know (n = 22) and concerns about insurability (n = 28).ConclusionEfforts to recontact biobank participants can yield high response. Though active refusal upon recontact was common, our data do not support assuming initial nonresponse to be refusal. Future research can work toward best practices for reconsenting, especially when clinically actionable results are possible.     

The cost-effectiveness of returning incidental findings from next-generation genomic sequencing

PurposeThe American College of Medical Genetics and Genomics (ACMG) recommended that clinical laboratories performing next-generation sequencing analyze and return pathogenic variants for 56 specific genes it considered medically actionable. Our objective was to evaluate the clinical and economic impact of returning these results.MethodsWe developed a decision-analytic policy model to project the quality-adjusted life-years and lifetime costs associated with returning ACMG-recommended incidental findings in three hypothetical cohorts of 10,000 patients.ResultsReturning incidental findings to cardiomyopathy patients, colorectal cancer patients, or healthy individuals would increase costs by $896,000, $2.9 million, and $3.9 million, respectively, and would increase quality-adjusted life-years by 20, 25.4, and 67 years, respectively, for incremental cost-effectiveness ratios of $44,800, $115,020, and $58,600, respectively. In probabilistic analyses, returning incidental findings cost less than $100,000/quality-adjusted life-year gained in 85, 28, and 91%, respectively, of simulations. Assuming next-generation sequencing costs $500, the incremental cost-effectiveness ratio for primary screening of healthy individuals was $133,400 (<$100,000/quality-adjusted life-year gained in 10% of simulations). Results were sensitive to the cohort age and assumptions about gene penetrance.ConclusionReturning incidental findings is likely cost-effective for certain patient populations. Screening of generally healthy individuals is likely not cost-effective based on current data, unless next-generation sequencing costs less than $500.Genet Med 17 7, 587–595.     

Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing

PurposeElectronic health records (EHRs) and their associated decision support tools are potentially important means of disseminating a patient’s pharmacogenomic profile to his or her health-care providers. We sought to create a proof-of-concept decision support alert system generated from pharmacogenomic incidental findings from exome sequencing.MethodsA pipeline for alerts from exome sequencing tests was created for patients in the New EXome Technology in (NEXT) Medicine study at the University of Washington. Decision support rules using discrete, machine-readable incidental finding results were programmed into a commercial EHR rules engine. An evaluation plan to monitor the alerts in real medical interactions was established.ResultsAlerts were created for 48 actionable pharmacogenomic variants in 11 genes and were launched on 24 September 2014 for University of Washington inpatient care. Of the 94 participants enrolled in the NEXT Medicine study, 49 had one or more pharmacogenomic variants identified for return.ConclusionReflections on the process reveal that while incidental findings can be used to generate decision support alerts, substantial resources are required to ensure that each alert is consistent with rapidly evolving pharmacogenomic literature and is customized to fit in the clinical workflow unique to each incidental finding.Genet Med17 11, 939–942.