"I just wanted more": Hereditary cancer syndromes patients' perspectives on the utility of circulating tumour DNA testing for cancer screening.

Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early. This study aimed to explore patients' perspectives on ctDNA's utility to help inform its clinical adoption and implementation. We conducted a qualitative interpretive description study using semi-structured phone interviews. Participants were purposively sampled adult HCS patients recruited from a Canadian HCS research consortium. Thirty HCS patients were interviewed (n = 19 women, age range 20s-70s, n = 25 were white). Participants were highly concerned about developing cancers, particularly those without reliable screening options for early detection. They "just wanted more" than their current screening strategies. Participants were enthusiastic about ctDNA's potential to be comprehensive (detect multiple cancers), predictive (detect cancers early) and tailored (lead to personalized clinical management). Participants also acknowledged ctDNA's potential limitations, including false positives/negatives risks and experiencing additional anxiety. However, they saw ctDNA's potential benefits outweighing its limitations. In conclusion, participants' belief in ctDNA's potential to improve their care overshadowed its limitations, indicating patients' support for using ctDNA in HCS care.

Theory-based behavior change intervention to increase uptake of risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 pathogenic variant: The PREVENT randomized controlled trial.

OBJECTIVE: To evaluate the effect of a theory-based behavioral intervention delivered by genetic counselors on the uptake of risk-reducing salpingo-oophorectomy (RRSO) at 12 and 24 months by women with a BRCA1 or BRCA2 pathogenic variant (PV) compared to women who received usual care. METHODS: In this two-arm, multi-site randomized controlled trial participants were randomized to receive a theoretically-guided behavioral telephone intervention or usual care. Outcome data were collected at 12 and 24 months. Participants in the usual care arm were offered the intervention after 12 months. RESULTS: Data on 107 participants were included in the analysis. There was no significant difference in the proportion of women who had a RRSO by 1 year (28.6%- intervention; 22.9%- usual care (p = 0.54)). At 1 year, women who received the intervention had significantly lower mean decisional conflict (pinteraction <0.001) and a higher mean knowledge score at one-year compared to usual care (pinteraction <0.001). At 2 years, 53.9% of participants in the intervention arm had RRSO compared to 32.6% in usual care (p = 0.05). CONCLUSIONS: A theory-based behavioral intervention delivered by genetic counselors to women with a BRCA PV who chose not to have the recommended RRSO was effective at reducing decisional conflict and increasing knowledge in women with a BRCA1 or BRCA2 PV.

"I don't need any more unknowns hanging over my head": Views of patients with cancer on variants of uncertain significance and low/moderate risk results from genomic sequencing.

PURPOSE: We sought to explore patient-reported utility of all types of cancer results from genomic sequencing (GS). METHODS: Qualitative study, using semi-structured interviews with patients who underwent GS within a trial. Thematic analysis employing constant comparison was used. Two coders coded transcripts, with use of a third coder to resolve conflicts. RESULTS: 25 patients participated: female (22), >50 years (18), European (12), Ashkenazi Jewish (5), Middle Eastern (3), or other ethnicity (5), with breast cancer history (20). Patients' perceptions of the utility of cancer GS results hinged on whether they triggered clinical action. For example, when patients were enrolled into high-risk breast cancer surveillance programs for low/moderate risk breast cancer genes, they perceived the results to be very "useful" and of moderate-high utility. In contrast, patients receiving low/moderate risk or primary variants of uncertain significance results without clinical action perceived results as "concerning," leading to harms, such as hypervigilance about cancer symptoms. Overall, having supportive relatives or providers enhanced perceptions of utility. CONCLUSION: Patients' perceptions of cancer GS results hinged on whether they triggered clinical management. Consequently, patients who received results without clinical action became hypervigilant, experiencing harms. Our findings call for a need to develop practice interventions to support patients with cancer undergoing GS.

Shared Decision Making in the Care of Patients With Cancer.

Shared decision making (SDM) is a method of care that is suitable for the care of patients with cancer. It involves a collaborative conversation seeking to respond sensibly to the problematic situation of the patient, cocreating a plan of care that makes sense intellectually, practically, and emotionally. Genetic testing to identify whether a patient has a hereditary cancer syndrome represents a prime example of the importance for SDM in oncology. SDM is important for genetic testing because not only results affect current cancer treatment, cancer surveillance, and care of relatives but also these tests generate both complex results and psychological concerns. SDM conversations should take place without interruptions, disruptions, or hurry and be supported, where available, by tools that assist in conveying the relevant evidence and in supporting plan development. Examples of these tools include treatment SDM encounter aids and the Genetics Adviser. Patients are expected to play a key role in making decisions and implementing plans of care, but several evolving challenges related to the unfettered access to information and expertise of varying trustworthiness and complexity in between interactions with clinicians can both support and complicate this role. SDM should result in a plan of care that is maximally responsive to the biology and biography of each patient, maximally supportive of each patient's goals and priorities, and minimally disruptive of their lives and loves.

A model for the return and referral of all clinically significant secondary findings of genomic sequencing.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS. As part of a randomised controlled trial evaluating the outcomes and costs of disclosing all clinically significant SFs from GS, we consulted genetics and primary care experts to determine a feasible workflow to manage SFs. Consensus was sought to determine appropriate clinical recommendations for each category of SF and which clinician specialist would provide follow-up care. We developed a communication and referral plan for each category of SFs. This involved referrals to specialised clinics, such as an Adult Genetics clinic, for highly penetrant medically actionable findings. Common and non-urgent SFs, such as pharmacogenomics and carrier status results for non-family planning participants, were directed back to the family physician (FP). SF results and recommendations were communicated directly to participants to respect autonomy and to their FPs to support follow-up of SFs. We describe a model for the return and referral of all clinically significant SFs to facilitate the utility of GS and promote the health benefits of SFs. This may serve as a model for others returning GS results transitioning participants from research to clinical settings.

Great expectations: patients' preferences for clinically significant results from genomic sequencing.

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50 years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG's recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences.

How do members of the public expect to use variants of uncertain significance in their health care? A population-based survey.

PURPOSE: Genomic sequencing can generate complex results, including variants of uncertain significance (VUS). In general, VUS should not inform clinical decision-making. This study aimed to assess the public's expected management of VUS. METHODS: An online, hypothetical survey was conducted among members of the Canadian public preceded by an educational video. Participants were randomized to 1 of 2 arms, VUS or pathogenic variant in a colorectal cancer gene, and asked which types of health services they expected to use for this result. Expected health service use was compared between randomization arms, and associations between participants' sociodemographic characteristics, attitudes, and medical history were explored. RESULTS: Among 1003 respondents (completion rate 60%), more participants expected to use each type of health service for a pathogenic variant than for a VUS. However, a considerable proportion of participants expected to request monitoring (73.4%) and consult health care providers (60.9%) for a VUS. There was evidence to support associations between expectation to use health services for a VUS with family history of genetic disease, family history of cancer, education, and attitudes toward health care and technology. CONCLUSION: Many participants expected to use health services for a VUS in a colorectal cancer predisposition gene, suggesting a potential disconnect between patients' expectations for VUS management and guideline-recommended care.

From the patient to the population: Use of genomics for population screening.

Genomic medicine is expanding from a focus on diagnosis at the patient level to prevention at the population level given the ongoing under-ascertainment of high-risk and actionable genetic conditions using current strategies, particularly hereditary breast and ovarian cancer (HBOC), Lynch Syndrome (LS) and familial hypercholesterolemia (FH). The availability of large-scale next-generation sequencing strategies and preventive options for these conditions makes it increasingly feasible to screen pre-symptomatic individuals through public health-based approaches, rather than restricting testing to high-risk groups. This raises anew, and with urgency, questions about the limits of screening as well as the moral authority and capacity to screen for genetic conditions at a population level. We aimed to answer some of these critical questions by using the WHO Wilson and Jungner criteria to guide a synthesis of current evidence on population genomic screening for HBOC, LS, and FH.

A comprehensive genomic reporting structure for communicating all clinically significant primary and secondary findings.

Genomic sequencing (GS) can reveal secondary findings (SFs), findings unrelated to the reason for testing, that can be overwhelming to both patients and providers. An effective approach for communicating all clinically significant primary and secondary GS results is needed to effectively manage this large volume of results. The aim of this study was to develop a comprehensive approach to communicate all clinically significant primary and SF results. A genomic test report with accompanying patient and provider letters were developed in three phases: review of current clinical reporting practices, consulting with genetic and non-genetics experts, and iterative refinement through circulation to key stakeholders. The genomic test report and consultation letters present a myriad of clinically relevant GS results in distinct, tabulated sections, including primary (cancer) and secondary findings, with in-depth details of each finding generated from exome sequencing. They provide detailed variant and disease information, personal and familial risk assessments, clinical management details, and additional resources to help support providers and patients with implementing healthcare recommendations related to their GS results. The report and consultation letters represent a comprehensive approach to communicate all clinically significant SFs to patients and providers, facilitating clinical management of GS results.

"Doctors shouldn't have to cheat the system": Clinicians' real-world experiences of the utility of genomic sequencing.

PURPOSE: Emerging genetic tests such as genomic sequencing (GS) can generate a broad range of benefits, but funding criteria only prioritize diagnosis and clinical management. There is limited evidence on all types of benefits obtained from GS in practice. We aimed to explore real-world experiences of Canadian clinicians across specialties on the full range of benefits obtained from the results from GS. METHODS: We conducted a qualitative study using semistructured interviews with Canadian clinicians. Transcripts were thematically analyzed using constant comparison. RESULTS: In total, 25 clinicians participated, including 12 geneticists, 7 genetic counselors, 4 oncologists, 1 neurologist, and 1 family physician. Although diagnoses and management were the most valued benefits of GS, clinicians also prioritized nontraditional utility, such as access to community supports. However, clinicians felt "restricted" by funding bodies, which only approved funding when GS would inform diagnoses and management. Consequently, clinicians sought ways to "cheat the system" to access GS (eg, research testing) but acknowledged workarounds were burdensome, drove inequity, and undermined patient care. CONCLUSION: Current governance structures undervalue real-world benefits of GS leading clinicians to adopt workarounds, which jeopardize patient care. These results support calls for the expansion of the definition of clinical utility and research to quantify the additional benefits.

"Game Changer": Health Professionals' Views on the Clinical Utility of Circulating Tumor DNA Testing in Hereditary Cancer Syndrome Management.

BACKGROUND: We explored health professionals' views on the utility of circulating tumor DNA (ctDNA) testing in hereditary cancer syndrome (HCS) management. MATERIALS AND METHODS: A qualitative interpretive description study was conducted, using semi-structured interviews with professionals across Canada. Thematic analysis employing constant comparison was used for analysis. 2 investigators coded each transcript. Differences were reconciled through discussion and the codebook was modified as new codes and themes emerged from the data. RESULTS: Thirty-five professionals participated and included genetic counselors (n = 12), geneticists (n = 9), oncologists (n = 4), family doctors (n = 3), lab directors and scientists (n = 3), a health-system decision maker, a surgeon, a pathologist, and a nurse. Professionals described ctDNA as "transformative" and a "game-changer". However, they were divided on its use in HCS management, with some being optimistic (optimists) while others were hesitant (pessimists). Differences were driven by views on 3 factors: (1) clinical utility, (2) ctDNA's role in cancer screening, and (3) ctDNA's invasiveness. Optimists anticipated ctDNA testing would have clinical utility for HCS patients, its role would be akin to a diagnostic test and would be less invasive than standard screening (eg imaging). Pessimistic participants felt ctDNA testing would add limited utility; it would effectively be another screening test in the pathway, likely triggering additional investigations downstream, thereby increasing invasiveness. CONCLUSIONS: Providers anticipated ctDNA testing will transform early cancer detection for HCS families. However, the contrasting positions on ctDNA's role in the care pathway raise potential practice variations, highlighting a need to develop evidence to support clinical implementation and guidelines to standardize adoption.

Genetics Adviser: a protocol for a mixed-methods randomised controlled trial evaluating a digital platform for genetics service delivery.

INTRODUCTION: The high demand for genetic tests and limited supply of genetics professionals has created a need for alternative service delivery models. Digital tools are increasingly being used to support multiple points in the genetic testing journey; however, none are transferable across multiple clinical specialties and settings nor do they encompass the entire trajectory of the journey. We aim to evaluate the effectiveness of the Genetics Adviser, an interactive, patient-facing, online digital health tool that delivers pre-test counselling, provides support during the waiting period for results, and returns results with post-test counselling, encompassing the entire patient genetic testing journey. METHODS AND ANALYSIS: We will compare the Genetics Adviser paired with a brief genetic counselling session to genetic counselling alone in a randomised controlled trial. One hundred and forty patients who previously received uninformative genetic test results for their personal and family history of cancer will be recruited from familial cancer clinics in Toronto and offered all clinically significant results from genomic sequencing. Participants randomised into the intervention arm will use the Genetics Adviser to learn about genomic sequencing, receive pre-test counselling, support during the waiting period and results, supplemented with brief counselling from a genetic counsellor. Participants in the control arm will receive standard pre-test and post-test counselling for genomic sequencing from a genetic counsellor. Our primary outcome is decisional conflict following pre-test counselling from the Genetics Adviser+genetic counsellor or counsellor alone. Secondary outcomes include: knowledge, satisfaction with decision-making, anxiety, quality of life, psychological impact of results, empowerment, acceptability and economic impact for patients and the health system. A subset of patients will be interviewed to assess user experience. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System (REB#20-035). Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04725565.

Widening the lens of actionability: A qualitative study of primary care providers' views and experiences of managing secondary genomic findings.

Most secondary genomic findings (SFs) fall in the scope of primary care practice. However, primary care providers' (PCPs) capacity to manage these findings is not well understood. We explored PCPs' views and experiences of managing SFs through a qualitative study. PCPs participated in semi-structured interviews about SFs from a patient in their practice or a hypothetical patient. The interpretive descriptive methodology was used to analyze transcripts thematically through constant comparison. Fifteen family physicians from Ontario, Canada participated (ten females; 6-40 years in practice across community and academic settings). PCPs made sense of SFs through the lens of actionability: they actively looked for clinical relevance by considering a wide range of immediate and future actions, including referrals, genetic testing, screening, lifestyle changes, counseling about family planning, informing family members, future medication choice, increased vigilance/surveillance, and managing results in the electronic medical record. PCPs saw clinical actionability as the main benefit mitigating the potential harms of learning SFs, namely patient anxiety and unnecessary investigations. PCPs conceptualized actionability more broadly than it is traditionally defined in medical genetics. Further research will be needed to determine if PCPs' emphasis on actionability conflicts with patients' expectations of SFs and if it leads to overutilization of healthcare resources.

Challenges and practical solutions for managing secondary genomic findings in primary care.

Primary care providers will increasingly be tasked with managing most secondary findings from genomic sequencing, but literature exploring their capacity to manage findings beyond conventional genetic testing is limited. This study aimed to explore primary care providers' challenges and potential solutions for managing secondary findings. Providers were recruited in two groups. Group 1 providers had a patient in their practice who received secondary findings and all potential group 1 providers were invited to participate. Group 2 providers were provided with the secondary findings of a hypothetical patient and were purposefully sampled for maximal variation in sex, practice setting, and geographic location. Providers were interviewed about their challenges and solutions managing secondary findings from a patient in their practice or a hypothetical patient. Using interpretive description methodology, transcripts were analysed thematically complemented by constant comparison. Out of the fifty-five providers invited, 15 family physicians participated across community and academic settings in Ontario, Canada (range 6-40 years in practice; 10/15 female). Providers described a responsibility to manage secondary findings, but limited capacity for this, describing practice, knowledge, and technical challenges. Providers expressed concern that compared to other incidental findings, secondary genomic findings might be reported directly to patients and result in longer-term anxiety. Potential solutions were a structured letter with categorized results and summary tables highlighting key secondary findings with follow-up recommendations and resources, as well as electronic medical records (EMRs) that store and integrate genomic information for prescribing or referrals. These solutions were deemed essential to address knowledge and technical challenges faced by primary care physicians and ultimately promote clinical utility of secondary findings.

Patient and public preferences for being recontacted with updated genomic results: a mixed methods study.

Variants of uncertain significance (VUS) are frequently reclassified but recontacting patients with updated results poses significant resource challenges. We aimed to characterize public and patient preferences for being recontacted with updated results. A discrete choice experiment (DCE) was administered to representative samples of the Canadian public and cancer patients. DCE attributes were uncertainty, cost, recontact modality, choice of results, and actionability. DCE data were analyzed using a mixed logit model and by calculating willingness to pay (WTP) for types of recontact. Qualitative interviews exploring recontact preferences were analyzed thematically. DCE response rate was 60% (n = 1003, 50% cancer patient participants). 31 participants were interviewed (11 cancer patients). Interviews revealed that participants expected to be recontacted. Quantitatively, preferences for how to be recontacted varied based on certainty of results. For certain results, WTP was highest for being recontacted by a doctor with updates ($1075, 95% CI: $845, $1305) and for contacting a doctor to request updates ($1038, 95% CI: $820, $1256). For VUS results, WTP was highest for an online database ($1735, 95% CI: $1224, $2247) and for contacting a doctor ($1705, 95% CI: $1102, $2307). Qualitative data revealed that preferences for provider-mediated recontact were influenced by trust in healthcare providers. Preferences for a database were influenced by lack of trust in providers and desire for control. Patients and public participants support an online database (e.g. patient portal) to recontact for VUS, improving feasibility, and provider-mediated recontact for certain results, consistent with usual care.

The clinical utility of exome and genome sequencing across clinical indications: a systematic review.

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37-70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4-100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time.Prospero registration CRD42019094101.

The role of digital tools in the delivery of genomic medicine: enhancing patient-centered care.

PURPOSE: Alternative models of genetic counseling are needed to meet the rising demand for genomic sequencing. Digital tools have been proposed as a method to augment traditional counseling and reduce burden on professionals; however, their role in delivery of genetic counseling is not established. This study explored the role of the Genomics ADvISER, a digital decision aid, in delivery of genomic counseling. METHODS: We performed secondary analysis of 52 pretest genetic counseling sessions that were conducted over the course of a randomized controlled trial evaluating the effectiveness of the Genomics ADvISER. As part of the trial, participants were randomized to receive standard counseling or use the tool and then speak with a counselor. A qualitative interpretive description approach using thematic analysis and constant comparison was used for analysis. RESULTS: In the delivery of genomic counseling, the Genomics ADvISER contributed to enhancing counseling by (1) promoting informed dialogue, (2) facilitating preference-sensitive deliberation, and (3) deepening personalization of decisions, all of which represent fundamental principles of patient-centered care: providing clear high-quality information, respecting patients' values, preferences, and expressed needs, and providing emotional support. CONCLUSION: This study demonstrates that our digital tool contributed to enhancing patient-centered care in the delivery of genomic counseling.

Effect of genetics clinical decision support tools on health-care providers' decision making: a mixed-methods systematic review.

PURPOSE: Patient care involving genetics is challenging for nongenetics health-care providers. Clinical decision support (CDS) tools are a potential solution because they provide patient-specific risk assessments and/or management recommendations. This systematic review synthesized evidence on whether using CDS tools resulted in appropriate changes in genetics-related patient management made by nongenetics health-care providers. METHODS: A comprehensive search in MEDLINE, Embase, and CINAHL yielded 2,239 unique articles. Two independent reviewers screened abstracts and full texts for quantitative, qualitative, and mixed-methods articles on management changes by nongenetics clinicians using a CDS tool as part of patient care. Effect sizes were calculated for quantitative studies and all articles were analyzed together using narrative synthesis. Twenty articles were included. RESULTS: In 12/16 quantitative studies, CDS tools slightly increased appropriate changes in management, but study design appeared to affect the statistical significance of the effect. The qualitative data in the four remaining studies reaffirmed that CDS tools facilitated management decisions but raised questions about their effect on patient outcomes. CONCLUSION: Our review assessed clinical utility of CDS tools, finding that they slightly increase appropriate management changes by nongenetics providers. Future studies on CDS tools should explicitly evaluate decision making and patient outcomes.

Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study.

BACKGROUND: Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology. METHODS: Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing. RESULTS: Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results. CONCLUSIONS: This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.

Beyond medically actionable results: an analytical pipeline for decreasing the burden of returning all clinically significant secondary findings.

Genomic sequencing advances have increased the potential to identify secondary findings (SFs). Current guidelines recommend the analysis of 59 medically actionable genes; however, patient preferences indicate interest in learning a broader group of SFs. We aimed to develop an analytical pipeline for the efficient analysis and return of all clinically significant SFs. We developed a pipeline consisting of comprehensive gene lists for five categories of SFs and filtration parameters for prioritization of variants in each category. We applied the pipeline to 42 exomes to assess feasibility and efficiency. Comprehensive lists of clinically significant SF genes were curated for each category: (1) 90 medically actionable genes and 28 pharmacogenomic variants; (2) 17 common disease risk variants; (3) 3166 Mendelian disease genes, (4) 7 early onset neurodegenerative disorder genes; (5) 688 carrier status results. Analysis of 42 exomes using our pipeline resulted in a significant decrease (> 98%) in variants compared to the raw analysis (13,036.56 ± 59.72 raw variants/exome vs 161.32 ± 7.68 filtered variants/exome), and aided in time and costs savings for the overall analysis process. Our pipeline represents a critical step in overcoming the analytic challenge associated with returning all clinically relevant SFs to allow for its routine implementation in clinical practice.