International policies guiding the selection, analysis, and clinical management of secondary findings from genomic sequencing: A systematic review.

Secondary findings (SFs) from genomic sequencing can have significant impacts on patient health, yet existing practices guiding their clinical investigation are inconsistent. We systematically reviewed existing SFs policies to identify variations and gaps in guidance. We cataloged and appraised international policies from academic databases (n = 5, inception-02/2022) and international human genetic societies (n = 64; inception-05/2022), across the continuum of SFs selection, analysis, and clinical management. We assessed quality using AGREE-II and interpreted results using qualitative description. Of the 63 SFs policies identified, most pertained to clinical management of SFs (98%; n = 62; primarily consent and disclosure), some guided SFs analysis (60%; n = 38), while fewer mentioned SFs selection (48%; n = 30). Overall, policies recommend (1) identifying clinically actionable, pathogenic variants with high positive predictive values for disease (selection), (2) bioinformatically filtering variants using evidence-informed gene lists (analysis), and (3) discussing with affected individuals the SFs identified, their penetrance, expressivity, medical implications, and management (clinical management). Best practices for SFs variant analysis, clinical validation, and follow-up (i.e., surveillance, treatment, etc.) were minimally described. Upon quality assessment, policies were highly rated for scope and clarity (median score, 69) but were limited by their rigor and applicability (median scores, 27 and 25). Our review represents a comprehensive international synthesis of policy guiding SFs across the continuum of selection, analysis, and clinical management. Our synthesis will help providers navigate critical decision points in SFs investigation, although significant work is needed to address gaps in SFs analysis, clinical validation, and follow-up processes and to support evidence-based practice.

Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal.

Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered to research participants in order to demonstrate respect for autonomy, reciprocity, and participant interests in health and privacy. Some recommendations go further and support offering a wider range of findings, including those that are not immediately actionable. In addition, entities covered by the US Health Insurance Portability and Accountability Act (HIPAA) may be required to provide a participant's raw genomic data on request. Despite these widely endorsed guidelines and requirements, the implementation of return of genomic results and data by researchers remains uneven. This article analyzes the ethical and legal foundations for researcher duties to offer adult participants their interpreted results and raw data as the new normal in genomic research.

The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

The incidental thyroid nodule.

Incidental thyroid nodules that are found on an imaging study performed for reasons other than thyroid pathology represent a common scenario encountered by health care providers. The initial workup for these nodules comprises a thorough history and physical examination, thyroid function tests, a dedicated thyroid ultrasound, and fine-needle aspiration of any suspicious lesions. Management ranges from observation and reassurance to surgical resection and depends on the cytologic diagnosis. In cases of cytologically indeterminate or discordant nodules, surgical excision (lobectomy) offers a definitive diagnosis, although molecular testing or a reasonable period of observation may be useful as less invasive adjuncts. CA Cancer J Clin 2018;68:97-105. © 2018 American Cancer Society.

Decision-Making for Preventive Interventions in Asymptomatic Patients.

The decision to treat an incidental finding in an asymptomatic patient results from careful risk-benefit consideration and is often challenging. One of the main aspects is after how many years the group who underwent the intervention and faced the immediate treatment complications will gain a treatment benefit over the conservatively managed group, which maintains a lower but ongoing risk. We identify a common error in decision-making. We illustrate how a risk-based approach using the classical break-even point at the Kaplan-Meier curves can be misleading and advocate for using an outcome-based approach, counting the cumulative number of lost quality-adjusted life years instead. In clinical practice, we often add together the yearly risk of the natural course up to the time point where the number equals the risk of the intervention and assume that the patient will benefit from an intervention beyond this point in time. It corresponds to the crossing of the Kaplan-Meier curves. However, because treatment-related poor outcome occurs at the time of the intervention, while the poor outcome in the conservative group occurs over a given time period, the true benefit of retaining more quality-adjusted life years in the interventional group emerges at a much later time. To avoid overtreatment of patients with asymptomatic diseases, decision-making should be outcome-based with counting the cumulative loss of quality-adjusted life years, rather than risk-based, comparing the interventional risk with the ongoing yearly risk of the natural course.

The chloroplast genome of Chrozophora sabulosa Kar. & Kir. and its exploration in the evolutionary position uncertainty of genus Chrozophora.

Chrozophora sabulosa Kar. & Kir. is a biennial herbaceous plant that belongs to the Euphorbiaceae family and has medicinal properties. This research aimed to identify the genetic characteristics and phylogenetic position of the Chrozophora genus within the Euphorbiaceae family. The evolutionary position of the Chrozophora genus was previously unknown due to insufficient research. Therefore, to determine the evolutionary link between C. sabulosa and other related species, we conducted a study using the NGS Illumina platform to sequence the C. sabulosa chloroplast (cp.) genome. The study results showed that the genome was 156,488 bp in length. It had a quadripartite structure consisting of two inverted repeats (IRb and IRa) of 24,649-bp, separated by an 87,696-bp LSC region and a 19,494-bp SSC region. The CP genome contained 113 unique genes, including four rRNA genes, 30 tRNA genes, and 79 CDS genes. In the second copy of the inverted repeat, there were 18 duplicated genes. The C. sabulosa lacks the petD, petB, rpl2, and rps16 intron. The analysis of simple sequence repeats (SSRs) revealed 93 SSR loci of 22 types and 78 oligonucleotide repeats of four kinds. The phylogenetic investigation showed that the Chrozophora genus evolved paraphyletically from other members of the Euphorbiaceae family. To support the phylogenetic findings, we selected species from the Euphorbiaceae and Phyllanthaceae families to compare with C. sabulosa for Ks and Ka substitution rates, InDels investigation, IR contraction and expansion, and SNPs analysis. The results of these comparative studies align with the phylogenetic findings. We identified six highly polymorphic regions shared by both families, which could be used as molecular identifiers for the Chrozophora genus (rpl33-rps18, rps18-rpl20, rps15-ycf1, ndhG-ndhI, psaI-ycf4, petA-psbJ). The cp. genome sequence of C. sabulosa reveals the evolution of plastid sequences in Chrozophora species. This is the first time the cp. genome of a Chrozophora genus has been sequenced, serving as a foundation for future sequencing of other species within the Chrozophoreae tribe and facilitating in-depth taxonomic research. The results of this research will also aid in identifying new Chrozophora species.

Association of race with incidence, characteristics, and mortality from incidental prostate cancer: Analysis of two North American contemporary cohorts.

BACKGROUND: Non-Hispanic Black (NHB) men are at higher risk both for incidence and mortality from prostate cancer (PCa) compared to Non-Hispanic White (NHW) men, but these findings arise from biopsy-detected PCa reports. We aimed to compare the incidence, subsequent management and cancer-specific mortality (CSM) of incidental PCa among NHB and NHW men, using two different North American cohorts. METHODS: The Surveillance, Epidemiology and End-Result (SEER: 2004-2017) and our institutional Henry Ford Health (HFH: 1995-2022) databases were queried to identify men diagnosed with incidental PCa. Cumulative incidence estimates were used to calculate CSM differences between NHB and NHW men. Competing-risk multivariable regression analysis tested the impact of race on CSM, after accounting for all available covariates. RESULTS: A total of 418 and 6,124 incidental PCa cases were recorded in HFH and SEER database respectively. No pathological differences were observed between NHB and NHW men in both the cohorts, except for prostate-specific antigen (PSA) value at diagnosis, which was higher in NHB men. At 10-years, the CSM rates were 5.5% vs 7.2% in our cohort and 8.6% vs 10.3% in the SEER cohort for NHW and NHB men, respectively (all Gray's test p-value > 0.05). At multivariable, race was not an independent predictor of CSM in our HFH cohort (HR: 1.46, 95% CI: 0.57-3.71, p = 0.6). In the SEER cohort, NHB men were 34% less likely to die from PCa from 1 year to the next (95% CI: 0.49-0.90, p = 0.008), when compared with NHW men. CONCLUSIONS: In the comparison of incidental PCa findings between NHB and NHW men, both groups had similar pathological characteristic and survival outcomes. These findings are different from the 'conventional' screening-detected PCa and suggest that racial differences have minimal to no adverse effects on PCa-specific mortality after incidental diagnosis.

Risk of Hepatocellular Carcinoma in Subcentimeter Liver Nodules Identified on Surveillance Ultrasound: A Systematic Review.

INTRODUCTION: Guidelines recommend that subcentimeter nodules on ultrasound be followed with short-interval surveillance ultrasound given assumed low risk of hepatocellular carcinoma (HCC) and suboptimal diagnostic imaging performance in lesions < 1cm. We performed a systematic review to estimate HCC risk among patients with cirrhosis and subcentimeter nodules detected on ultrasound. METHODS: We systematically searched Ovid MEDLINE and EMBASE databases for relevant articles published between January 2005 and July 2024. A random-effects model was used to calculate the pooled proportion of incident HCC. RESULTS: We identified 9 eligible studies, of which 5 provided both lesion- and patient-level data (n=354 patients), 2 patient-level alone (n=888 patients), and 2 lesion-level alone (n=69 lesions). The pooled proportion of incident HCC was 31.9% (95%CI: 8.7-69.7%) on a lesion-level and 21.3% (95%CI: 6.0-53.6%) on a patient-level; however, pooled estimates were limited by high heterogeneity (I2 >90%). Among two studies with study periods post-dating 2015, HCC developed in only ∼5% of patients during a median follow-up of 2 years. Risk factors associated with incident HCC were older age, male sex, elevated AFP levels, thrombocytopenia, and Child Pugh B cirrhosis. Limitations of studies included small sample sizes, selection bias, ascertainment bias for HCC, and failure to report factors associated with HCC. CONCLUSION: Up to one-fifth of patients with subcentimeter nodules may develop HCC, although contemporary cohorts report a substantially lower risk. Older patients and those with elevated AFP levels or poorer liver function are at greatest risk of HCC, highlighting an unmet need for better risk stratification models.

Clinical implications of non-breast cancer related findings on FDG-PET/CT scan prior to neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: Breast cancer (BC) patients undergoing FDG-PET/CT scans for neoadjuvant chemotherapy (NAC) may have additional non-BC related findings. The aim of this study is to describe the clinical implications of these findings. METHODS: We included BC patients who underwent an FDG-PET/CT scan in our institute between 2011-2020 prior to NAC. We focused on patients with an additional non-BC related finding (i.e. BC metastases were excluded) for which diagnostic work-up was performed. Information about the diagnostic work-up and the clinical consequences was retrospectively gathered. A revision of all FDG-PET/CT scans was conducted by an independent physician to assess the suspicion level of the additional findings. RESULTS: Of the 1337 patients who underwent FDG-PET/CT, 202 patients (15%) had an non-BC related additional finding for which diagnostic work-up was conducted, resulting in 318 examinations during the first year. The non-BC related findings were mostly detected in the endocrine region (26%), gastro-intestinal region (16%), or the lungs (15%). Seventeen patients (17/202: 8%, 17/1337: 1.3%) had a second primary malignancy. Only 8 patients (8/202: 4%, 8/1337: 0.6%) had a finding that was considered more prognosis-determining than their BC disease. When revising all FDG-PET/CT scans, 57 (202/57: 28%) of the patients had an additional finding categorized as low suspicious, suggesting no indication for diagnostic work-up. CONCLUSION: FDG-PET/CT scans used for dissemination imaging in BC patients detect a high number of non-BC related additional findings, often clinically irrelevant and causing a large amount of unnecessary work-up. However, in 8% of the patients undergoing diagnostic work-up for an additional finding, a second primary malignancy was detected, warranting diagnostic attention in selected patients.

Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants.

PURPOSE: Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of a large pediatric cohort at the Center for Applied Genomics at The Children's Hospital of Philadelphia. METHODS: We systematically identified pathogenic (P) and likely pathogenic (LP) variants in established disease-causing genes, adhering to ACMG v3.2 secondary finding guidelines and beyond. For non-ACMG SFs, akin to incidental findings in clinical settings, we utilized a set of criteria focusing on pediatric onset, high penetrance, moderate to severe phenotypes, and the clinical actionability of the variants. This criteria-based approach was applied rather than using a fixed gene list to ensure that the variants identified are likely to affect participant health significantly. To identify and categorize these variants, we used a clinical-grade variant classification standard per ACMG/AMP recommendations; additionally, we conducted a detailed literature search to ensure a comprehensive exploration of potential SFs relevant to pediatric participants. RESULTS: We report a distinctive distribution of 1464 P/LP SF variants in 16,713 participants. There were 427 unique variants in ACMG genes and 265 in non-ACMG genes. The most frequently mutated genes among the ACMG and non-ACMG gene lists were TTR(41.6%) and CHEK2 (7.16%), respectively. Overall, variants of possible medical importance were found in 8.76% of participants in both ACMG (5.81%) and non-ACMG (2.95%) genes. CONCLUSION: Our study revealed that 8.76% of a large, multiethnic pediatric cohort carried actionable secondary genetic findings, with 5.81% in ACMG genes and 2.95% in non-ACMG genes. These findings emphasize the importance of including diverse populations in genetic research to ensure that all groups benefit from early identification of disease risks. Our results provide a foundation for expanding the ACMG gene list and improving clinical care through early interventions.

Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Implementing evidence-based assertions of clinical actionability in the context of secondary findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Additional findings from the 100,000 Genomes Project: A qualitative study of recipient perspectives.

PURPOSE: Participants in the 100,000 Genomes Project, a clinical/research initiative delivered through the UK National Health Service, were offered screening for "additional findings" (AFs): pathogenic/likely pathogenic secondary findings in genes associated with familial hypercholesterolemia or a cancer predisposition syndrome. Understanding the psychological and behavioral responses to secondary findings can inform the clinical utility of a search and disclose policy. METHODS: Thirty-two adult AF recipients took part in semi-structured interviews analyzed using deductive and inductive thematic analysis. RESULTS: Five themes were constructed: cognitive responses to an AF, emotional and psychological responses, personal control, perceived risk of AF-associated disease, and family implications. Many participants had misunderstood or incompletely remembered consent for AFs, and most were surprised or shocked to receive an AF. Although many ultimately appreciated knowing about the risk conferred, some struggled to make sense of their disease risk, which complicated decision making about risk management, particularly for women with a BRCA AF. Recipients sought control through seeking clinical evaluation and information, and informing relatives. Difficulties with conceptualizing risk and lack of AF-associated disease family history meant that some hesitated to inform relatives. CONCLUSION: Genome sequencing programs offering secondary findings require attention to consent processes. Post-disclosure care should aim to promote recipients' perceived personal control.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Decision making for health-related research outcomes that alter diagnosis: A model from paediatric brain tumours.

AIMS: The question of how to handle clinically actionable outcomes from retrospective research studies is poorly explored. In neuropathology, this problem is exacerbated by ongoing refinement in tumour classification. We sought to establish a disclosure threshold for potential revised diagnoses as determined by the neuro-oncology speciality. METHODS: As part of a previous research study, the diagnoses of 73 archival paediatric brain tumour samples were reclassified according to the WHO 2016 guidelines. To determine the disclosure threshold and clinical actionability of pathology-related findings, we conducted a result-evaluation approach within the ethical framework of BRAIN UK using a surrogate clinical multidisciplinary team (MDT) of neuro-oncology specialists. RESULTS: The MDT identified key determinants impacting decision-making, including anticipated changes to patient management, time elapsed since initial diagnosis, likelihood of the patient being alive and absence of additional samples since cohort inception. Ultimately, none of our research findings were considered clinically actionable, largely due to the cohort's historic archival and high-risk nature. From this experience, we developed a decision-making framework to determine if research findings indicating a change in diagnosis require reporting to the relevant clinical teams. CONCLUSIONS: Ethical issues relating to the use of archival tissue for research and the potential to identify actionable findings must be carefully considered. We have established a structured framework to assess the actionability of research data relating to patient diagnosis. While our specific findings are most applicable to the pathology of poor prognostic brain tumour groups in children, the model can be adapted to a range of disease settings, for example, other diseases where research is dependent on retrospective tissue cohorts, and research findings may have implications for patients and families, such as other tumour types, epilepsy-related pathology, genetic disorders and degenerative diseases.

Outcomes of hybrid surgical ablation and concomitant left atrial appendage exclusion in long-standing persistent atrial fibrillation.

INTRODUCTION: Management of patients with long-standing persistent atrial fibrillation (LSPAF) presents a clinical challenge. Hybrid convergent ablation has been shown to have superior efficacy compared to endocardial-only ablation. However, data on concomitant left atrial appendage (LAA) management along with hybrid ablation is sparse. METHODS: We aimed to evaluate the effectiveness of concomitant hybrid convergent ablation and LAA clipping in patients with LSPAF. We conducted a retrospective analysis of all patients with LSPAF who underwent hybrid surgical ablation with LAA clipping at our institution. The primary endpoint was a recurrence of atrial arrhythmias at 12 months. Further, the durability of surgical left atrial posterior wall ablation was examined during the endocardial catheter ablation using standing electrophysiological criteria. RESULTS: A total of 79 patients were included. Mean age was 63.5 ± 9.6 years, and 71% were males. LAA clipping was performed in 99% of patients. The mean time between the surgical and endocardial stages of the procedure was 2.6 ± 1.7 months. Persistent posterior wall activity was observed in 34.2% (n = 27/79) patients during the endocardial phase of the procedure. Cardiac implantable electronic device was used in 74% of patients for monitoring of recurrence of atrial fibrillation (AF). The primary effectiveness of AF freedom at 12 months was 73.8% (45/61). Over a 12-month follow-up period, 11.4% (9/79) of patients required repeat catheter ablation, of which 88.9% (8/9) had evidence of persistent posterior wall activity. CONCLUSION: Concomitant hybrid convergent ablation and LAA exclusion with an atrial clip provides reasonable long-term AF-free survival in patients with LSPAF. Persistent posterior wall activity is seen commonly in patients presenting with recurrent AF following hybrid convergent AF ablation.