Publications by authors named "Raymond H Kim"

108 Publications

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

Eur J Hum Genet 2021 Mar 29. Epub 2021 Mar 29.

University of Toronto, Toronto, Canada.

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.
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http://dx.doi.org/10.1038/s41431-021-00876-zDOI Listing
March 2021

Sensitization to implant components is associated withjoint replacement failure; Identification and revision to non-allergenic hardware improves outcomes.

J Allergy Clin Immunol Pract 2021 Mar 17. Epub 2021 Mar 17.

Associate Professor, Division of Environmental & Occupational Health Sciences, Department of Medicine, National Jewish Health, 1400 Jackson St, Denver, CO 80206; Division of Environmental & Occupational Health, University of Colorado School of Medicine, School of Public Health, 13001 E 17th Place, Mail Stop B119, Aurora, CO 80045. Electronic address:

Background: Over 90% of 1 million yearly US joint replacements are highly successful. Nonetheless, 10% do poorly, attributed to infection or mechanical issues. Many implant components are sensitizers, and sensitization could also contribute to implant failure.

Objective: Determine the prevalence of implant sensitization in joint failure patients, their clinical characteristics, and implant revision outcomes. We hypothesized that sensitized patients should improve when revised with non-'allergenic' materials.

Methods: We prospectively enrolled n=105 joint failure patients referred by their orthopedic surgeon who had already excluded infection or mechanical causes. Patients provided informed consent, completed a history & physical exam, patch testing to metals and bone cement, and a Nickel lymphocyte proliferation test (Ni-LPT). A study coordinator was able to contact 64% (n=67) 9-12 months later to evaluate outcomes.

Results: 59% were sensitized to an implant component: 32% to metal and 37% to bone cement. The Ni-LPT was 60% sensitive and 96% specific in diagnosing nickel sensitization. Most sensitized subjects reported no or uncertain histories of reactions to the specific material(s). Implant sensitized patients were younger, reported previous eczema, joint itching, and implant loosening. 9-12 months later, most patients with a revised implant ('revised') described significant improvement (16/22 revised for sensitization, p=0.0003, vs. 9/13 revised without sensitization, p=0.047) compared to patients without implant revision). All revised patients with sensitization used components to which they were not sensitized. Pain (p=0.001), swelling (p=0.035), and instability (p=0.006) were significantly reduced in the revised sensitized group.

Conclusions: Sensitization to implant components is an important cause of unexplained joint replacement failure. Joint revisions based on sensitization information resulted in significant improvements.
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http://dx.doi.org/10.1016/j.jaip.2020.12.068DOI Listing
March 2021

Can variant negative be high-grade serous ovarian carcinoma? A case series.

Gynecol Oncol Rep 2021 May 12;36:100729. Epub 2021 Feb 12.

Division of Medical Oncology & Hematology, Bras Family Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1Z5, Canada.

• variant negative high-grade serous ovarian cancer is rare and can still show p53 abnormal immunohistochemistry.•Diagnostic and therapeutic considerations include pathologic, molecular and clinical domains.•Genetic reassessment through more comprehensive assays should be considered to ensure no missed rare or complex variants.•Presence of mutations can occur in variant high-grade serous ovarian cancer.
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http://dx.doi.org/10.1016/j.gore.2021.100729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910505PMC
May 2021

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

Genet Med 2021 Mar 2. Epub 2021 Mar 2.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1038/s41436-021-01112-1DOI Listing
March 2021

Outpatient Total Joint Arthroplasty: The New Reality.

J Arthroplasty 2021 Feb 12. Epub 2021 Feb 12.

Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL.

As perioperative protocols have improved, there has been a reduction in the rates of key complications after hip and knee arthroplasty. Likewise, as we have been able to make patients more comfortable postoperatively, hospital length of stay has decreased and in some centers, hip and knee arthroplasty is now routinely performed as an outpatient. While the number of surgeons offering this option and patients choosing to have procedures performed as an outpatient grows, many questions revolve around this movement. This article will review the data supporting outpatient arthroplasty, the business and legal aspects involved, if surgeons can align with their hospital to offer these services, and how tightly knit and highly organized teams are key to the success of safely offering hip and knee arthroplasty on an outpatient basis.
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http://dx.doi.org/10.1016/j.arth.2021.02.030DOI Listing
February 2021

Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages.

Sci Rep 2021 Feb 25;11(1):4723. Epub 2021 Feb 25.

Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1Apoe). After 21 weeks of atherogenic diet, Dj1 Apoemice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.
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http://dx.doi.org/10.1038/s41598-021-84063-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907332PMC
February 2021

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

Gynecol Oncol 2021 Apr 19;161(1):221-227. Epub 2021 Jan 19.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network/Sinai Health Systems, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC).

Methods: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases.

Results: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes.

Conclusions: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.002DOI Listing
April 2021

Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences.

Front Genet 2020 15;11:957. Epub 2020 Sep 15.

Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF ( = 175) or related CHD. We adapted a burden test originally developed for variants to assess ultra-rare variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets and for multiple testing. For truncating variants, the gene burden test confirmed significant burden in (Bonferroni corrected -value < 0.01). For missense variants, burden in achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni corrected -value = 0.004), and showed enrichment for variants affecting the extracellular domain, especially those disrupting cysteine residues forming disulfide bonds (OR = 39.8 vs. gnomAD). Individuals with ultra-rare missense variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in CHD had more modest statistical support in gene burden tests. Gene-set burden tests for truncating variants identified a cluster of pathways corresponding to VEGF signaling ( = 0%), and of mouse phenotypes corresponding to abnormal vasculature ( = 0.8%); these suggested additional candidate genes not previously identified (e.g., and ). Results for the most promising genes were driven by the TOF subset of the cohort. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF, accounting for 11-14% of individuals in the TOF cohort. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether or inherited, contribute to the genetic etiopathogenesis of a complex disorder.
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http://dx.doi.org/10.3389/fgene.2020.00957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522597PMC
September 2020

Early-onset renal cell carcinoma in harmatoma tumour syndrome.

NPJ Genom Med 2020 29;5:40. Epub 2020 Sep 29.

Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH USA.

Individuals with PTEN hamartoma tumour syndrome (PHTS), including Cowden syndrome (CS), are susceptible to multiple benign hamartomas and an increased risk of cancer, particularly breast, endometrial, and thyroid. As a result, individuals undergo enhanced surveillance for early detection of these cancers. However, less commonly occurring cancers, such as colorectal and kidney, have insufficient guidelines for early detection. Currently, screening for kidney cancer via renal ultrasound begins at 40 years of age, because there were only rare cases of elevated risk in prospective series under 40. There have, however, been accumulating reports of kidney cancer in individuals with CS in their 30s, illustrating a need to lower the age of surveillance. We present additional evidence of renal cell carcinoma in two individuals with CS in their early twenties, and propose a reassessment of the abdominal surveillance in patients with PHTS. We propose biannual screening for kidney cancer beginning at 20 years of age.
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http://dx.doi.org/10.1038/s41525-020-00148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525494PMC
September 2020

Stay at home: implementation and impact of virtualising cancer genetic services during COVID-19.

J Med Genet 2020 Oct 16. Epub 2020 Oct 16.

Familial Cancer Clinic, University Health Network, Toronto, Ontario, Canada

The COVID-19 pandemic has led to the rapid adoption of virtual clinic processes and healthcare delivery. Herein, we examine the impact of virtualising genetics services at Canada's largest cancer centre. A retrospective review was conducted to evaluate relevant metrics during the 12 weeks prior to and during virtual care, including referral and clinic volumes, patient wait times and genetic testing uptake. The number of appointments and new patients seen were maintained during virtual care. Likewise, there was a significant increase in the number of patients offered testing during virtual care who did not provide a blood sample (176/180 (97.7%) vs 180/243 (74.1%); p<0.001), and a longer median time from the date of pretest genetic counselling to the date a sample was given (0 vs 11 days; p<0.001). Referral volumes significantly decreased during virtual care (35 vs 22; p<0.001), which was accompanied by a decreased median wait time for first appointment (55 days vs 30 days; p<0.001). The rapid virtualisation of cancer genetic services allowed the genetics clinic to navigate the COVID-19 pandemic without compromising clinical volumes or access to genetic testing. There was a decrease in referral volumes and uptake of genetic testing, which may be attributable to pandemic-related clinical restrictions.
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http://dx.doi.org/10.1136/jmedgenet-2020-107418DOI Listing
October 2020

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Blood Adv 2020 10;4(19):4873-4886

Section of Hematology/Oncology and Center for Clinical Cancer Genetics and.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.
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http://dx.doi.org/10.1182/bloodadvances.2020001721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556157PMC
October 2020

Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program.

Mol Oncol 2021 01 22;15(1):80-90. Epub 2020 Oct 22.

Laboratory Medicine Program, Division of Clinical Laboratory Genetics, University Health Network, Toronto, Canada.

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.
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http://dx.doi.org/10.1002/1878-0261.12817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782089PMC
January 2021

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

Hum Genet 2021 Mar 6;140(3):493-504. Epub 2020 Sep 6.

St. Michael's Hospital, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1007/s00439-020-02220-9DOI Listing
March 2021

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

Cancer 2020 Nov 18;126(22):4886-4894. Epub 2020 Aug 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
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http://dx.doi.org/10.1002/cncr.33144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693219PMC
November 2020

Year 1: Experiences of a tertiary cancer centre following implementation of reflex BRCA1 and BRCA2 tumor testing for all high-grade serous ovarian cancers in a universal healthcare system.

Gynecol Oncol 2020 09 14;158(3):747-753. Epub 2020 Jul 14.

Lawrence S Bloomberg Faculty of Nursing, University of Toronto, 155 College Street, Toronto, ON M5T 1P8, Canada; Women's College Research Institute, 72 Grenville Street, Toronto, ON M5S 1B2, Canada.

Objective: This study compares the rate and time to genetic referral, and patient uptake of germline genetic services, before and after implementation of reflex BRCA1/2 tumor testing for high-grade serous ovarian cancer (HGSOC) in a universal healthcare system.

Methods: A retrospective chart review of HSGOC patients diagnosed in the year before (PRE) and after (POST) implementation of reflex BRCA1/2 tumor testing was conducted. Clinical information (date/age at diagnosis, personal/family history of breast/ovarian cancer, cancer stage, primary treatment, tumor results) and dates of genetics referral, counseling, and germline testing were obtained. Incident rate ratios (IRR) and 95% CI were calculated using negative binomial regression. Time to referral was evaluated using Kaplan-Meier survival analysis. Fisher Exact tests were used to evaluate uptake of genetic services.

Results: 175 HGSOC patients were identified (81 PRE; 94 POST). Post-implementation of tumor testing, there was a higher rate of genetics referral (12.88 versus 7.10/1000 person-days; IRR = 1.60, 95% CI: 1.07-2.42) and a shorter median time from diagnosis to referral (59 days PRE, 33 days POST; p = .04). In the POST cohort, most patients were referred prior to receiving their tumor results (n = 63/77; 81.8%). Once referred, most patients attended genetic counseling (94.5% PRE, 97.6% POST; p = .418) and pursue germline testing (98.6% PRE; 100% POST; p = .455).

Conclusions: Following implementation of reflex BRCA1/2 tumor testing for HGSOC, significant improvements to the rate and time to genetics referral were identified. Additional studies are needed to evaluate physician referral practices and the long-term impact of reflex tumor testing.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.507DOI Listing
September 2020

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

J Med Genet 2021 Apr 24;58(4):275-283. Epub 2020 Jun 24.

Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada

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.
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http://dx.doi.org/10.1136/jmedgenet-2020-106936DOI Listing
April 2021

Quality of life drives patients' preferences for secondary findings from genomic sequencing.

Eur J Hum Genet 2020 09 18;28(9):1178-1186. Epub 2020 May 18.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

There is growing impetus to include measures of personal utility, the nonmedical value of information, in addition to clinical utility in health technology assessment (HTA) of genomic tests such as genomic sequencing (GS). However, personal utility and clinical utility are challenging to define and measure. This study aimed to explore what drives patients' preferences for hypothetically learning medically actionable and non-medically actionable secondary findings (SF), capturing clinical and personal utility; this may inform development of measures to evaluate patient outcomes following return of SF. Semi-structured interviews were conducted with adults with a personal or family cancer history participating in a trial of a decision aid for selection of SF from genomic sequencing (GS) ( www.GenomicsADvISER.com ). Interviews were analyzed thematically using constant comparison. Preserving health-related and non-health-related quality of life was an overarching motivator for both learning and not learning SF. Some participants perceived that learning SF would help them "have a good quality of life" through informing actions to maintain physical health or leading to psychological benefits such as emotional preparation for disease. Other participants preferred not to learn SF because results "could ruin your quality of life," such as by causing negative psychological impacts. Measuring health-related and non-health-related quality of life may capture outcomes related to clinical and personal utility of GS and SF, which have previously been challenging to measure. Without appropriate measures, generating and synthesizing evidence to evaluate genomic technologies such as GS will continue to be a challenge, and will undervalue potential benefits of GS and SF.
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http://dx.doi.org/10.1038/s41431-020-0640-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609335PMC
September 2020

Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs.

Genes (Basel) 2020 04 2;11(4). Epub 2020 Apr 2.

Department of Pathology, University College London Cancer Institute, Bloomsbury, London WC1E 6BT, UK.

The Genomics of Malignant Peripheral Nerve Sheath Tumor (GeM) Consortium is an international collaboration focusing on multi-omic analysis of malignant peripheral nerve sheath tumors (MPNSTs), the most aggressive tumor associated with neurofibromatosis type 1 (NF1). Here we present a summary of current knowledge gaps, a description of our consortium and the cohort we have assembled, and an overview of our plans for multi-omic analysis of these tumors. We propose that our analysis will lead to a better understanding of the order and timing of genetic events related to MPNST initiation and progression. Our ten institutions have assembled 96 fresh frozen NF1-related (63%) and sporadic MPNST specimens from 86 subjects with corresponding clinical and pathological data. Clinical data have been collected as part of the International MPNST Registry. We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling. In addition, we will perform multiregional analysis and temporal sampling, with the same methodologies, on a subset of nine subjects with NF1-related MPNSTs to assess tumor heterogeneity and cancer evolution. Subsequent multi-omic analyses of additional archival specimens will include deep exome sequencing (500×) and high density copy number arrays for both validation of results based on fresh frozen tumors, and to assess further tumor heterogeneity and evolution. Digital pathology images are being collected in a cloud-based platform for consensus review. The result of these efforts will be the largest MPNST multi-omic dataset with correlated clinical and pathological information ever assembled.
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http://dx.doi.org/10.3390/genes11040387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231181PMC
April 2020

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.

Genet Med 2020 06 10;22(6):1015-1024. Epub 2020 Feb 10.

Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.

Purpose: This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.

Methods: We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.

Results: In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.

Conclusion: This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.
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http://dx.doi.org/10.1038/s41436-020-0757-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272322PMC
June 2020

Effectiveness of the Genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial.

Genet Med 2020 04 11;22(4):727-735. Epub 2019 Dec 11.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Purpose: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone.

Methods: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session.

Results: Participants (n = 133) were predominantly White/European (74%), female (90%), and ≥50 years old (60%). Decisional conflict (mean difference 0.05; P = 0.60), preparation for decision-making (0.17; P = 0.95), satisfaction with decision (-2.18; P = 0.06), anxiety (0.72; P = 0.56), and knowledge of sequencing limitations (0.14; P = 0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P < 0.001) and sequencing benefits (0.97; P = 0.01), and significantly shorter counseling time (24.40 minutes less; P < 0.001) CONCLUSIONS: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.
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http://dx.doi.org/10.1038/s41436-019-0702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425118PMC
April 2020

Standard operating procedure for curation and clinical interpretation of variants in cancer.

Genome Med 2019 11 29;11(1):76. Epub 2019 Nov 29.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretation of Variants in Cancer - www.civicdb.org) is a fully open, free-to-use cancer variant interpretation knowledgebase that incorporates highly detailed curation of evidence obtained from peer-reviewed publications and meeting abstracts, and currently holds over 6300 Evidence Items for over 2300 variants derived from over 400 genes. CIViC has seen increased adoption by, and also undertaken collaboration with, a wide range of users and organizations involved in research. To enhance CIViC's clinical value, regular submission to the ClinVar database and pursuit of other regulatory approvals is necessary. For this reason, a formal peer reviewed curation guideline and discussion of the underlying principles of curation is needed. We present here the CIViC knowledge model, standard operating procedures (SOP) for variant curation, and detailed examples to support community-driven curation of cancer variants.
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http://dx.doi.org/10.1186/s13073-019-0687-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883603PMC
November 2019

Return of genetic and genomic research findings: experience of a pediatric biorepository.

BMC Med Genomics 2019 11 27;12(1):173. Epub 2019 Nov 27.

Division of Cardiology, Labatt Family Heart Centre, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Background: Assess process, uptake, validity and resource needs for return of actionable research findings to biobank participants.

Methods: Participants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor. Action taken following receipt of this information was reviewed.

Results: Genetic data was generated in 1963 of 7408 participants. Fifty-nine new findings were presented to the RRR committee; 20 (34%) were deemed reportable. Twelve were returned to the physician, of which 7 were disclosed to participants (median time to disclosure, 192 days). Seven findings were returned to the research genetic counselor; all have been disclosed (median time to disclosure, 19 days). Twelve families (86%) opted for referral to clinical genetics after disclosure of findings; 7 results have been validated, 5 results are pending. Average cost of return and disclosure per reportable finding incurred by the research program was $750 when utilizing a research genetic counselor; clinical costs associated with return were not included.

Conclusions: Return of actionable research findings was faster if disclosed directly to the participant by a research genetic counselor. There was a high acceptability amongst participants for receiving the findings, for referral to clinical genetics, and for clinical validation of research findings, with all referred cases being clinically confirmed.
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http://dx.doi.org/10.1186/s12920-019-0618-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882371PMC
November 2019

Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial.

BMJ Open 2019 10 7;9(10):e031092. Epub 2019 Oct 7.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

Introduction: Genomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to the return of incidental results, which refer to genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance. High-quality evidence evaluating health outcomes and costs of receiving incidental results is critical for the adoption of genomic sequencing into clinical care and to understand the unintended consequences of adoption of genomic sequencing. We aim to evaluate the health outcomes and costs of receiving incidental results for patients undergoing genomic sequencing.

Methods And Analysis: We will compare health outcomes and costs of receiving, versus not receiving, incidental results for adult patients with cancer undergoing genomic sequencing in a mixed-methods randomised controlled trial. Two hundred and sixty patients who have previously undergone first or second-tier genetic testing for cancer and received uninformative results will be recruited from familial cancer clinics in Toronto, Ontario. Participants in both arms will receive cancer-related results. Participants in the intervention arm have the option to receive incidental results. Our primary outcome is psychological distress at 2 weeks following return of results. Secondary outcomes include behavioural consequences, clinical and personal utility assessed over the 12 months after results are returned and health service use and costs at 12 months and 5 years. A subset of participants and providers will complete qualitative interviews about utility of incidental results.

Ethics And Dissemination: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System that provides ethical review and oversight for multiple sites participating in the same clinical trial in Ontario.Results from the trial will be shared through stakeholder workshops, national and international conferences, and peer-reviewed journals.

Trial Registration Number: NCT03597165.
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http://dx.doi.org/10.1136/bmjopen-2019-031092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797333PMC
October 2019

Co-occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes.

Endocrinol Diabetes Metab 2019 Oct 8;2(4):e00092. Epub 2019 Sep 8.

Division of Endocrinology and Metabolism Department of Medicine University Health Network University of Toronto Toronto Ontario Canada.

Objective: Age-standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours.

Design And Patients: A retrospective chart review (2007-2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next-generation sequencing panel.

Results: Mean age was 61.4 years (35-85) at breast cancer diagnosis and 63.4 years (51-89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of and one patient was found to harbour a pathogenic variant in and a variant of unknown significance (VUS) in . A second patient was found to harbour a pathogenic variant in . A third patient was found to carry a pathogenic variant in as well as a VUS in and . Another patient was found to harbour a VUS in . One patient was found to carry a pathogenic variant in .

Conclusion: The first cases of a , an and a pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond , have important implications for cancer surveillance.
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http://dx.doi.org/10.1002/edm2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775469PMC
October 2019

An update on genetic risk assessment and prevention: the role of genetic testing panels in breast cancer.

Expert Rev Anticancer Ther 2019 09 7;19(9):787-801. Epub 2019 Sep 7.

Familial Cancer Clinic, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto , Toronto , Canada.

: In the past 5 years, multi-gene panels have replaced the practice of and genetic testing in cases of suspected inherited breast cancer susceptibility. A variety of genes have been included on these panels without certainty of their clinical utility. Pertinent current and historical literature was reviewed to provide an up-to-date snapshot of the changing landscape of the use of gene panel tests in the context of breast cancer. : Following a recent review of the evidence, 10 genes have been found to have definitive evidence of increased breast cancer risk with variable penetrance. Here, we review the recent changes to the practice of multi-gene panel use in breast cancer diagnoses, including an update on next generation sequencing, alternative models of genetic testing, considerations when ordering these panel tests, and recommendations for management in identified carriers for a variety of genes. A comparison of screening recommendations and carrier frequencies from recent studies is also explored. Lastly, we consider what the future of hereditary oncologic genetic testing holds. : The transition to multi-gene panels in breast cancer patients has improved the likelihood of capturing a rare variant in a well-established gene associated with hereditary breast cancer (e.g. ). There is also an increase in the likelihood of uncovering an uncertain result. This could be in the form of a variant of uncertain significance, or a pathogenic variant in a gene with questionable breast cancer risk-association. Concurrently, a changing landscape of who orders genetic tests will improve access to genetic testing. This pervasiveness of genetic testing must be accompanied with increased genetic literacy in all health-care providers, and access to support from genetics professionals for management of patients and at-risk family members.
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http://dx.doi.org/10.1080/14737140.2019.1659730DOI Listing
September 2019

Evidence of small-fiber neuropathy in neurofibromatosis type 1.

Muscle Nerve 2019 12 12;60(6):673-678. Epub 2019 Sep 12.

Elisabeth Raab Neurofibromatosis Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Introduction: Large-fiber neuropathy is rare in neurofibromatosis type 1, but small-fiber neuropathy has not been studied.

Methods: Patients with neurofibromatosis type 1 underwent nerve conduction studies for large-fiber assessment. Small-fiber tests included quantitative thermal thresholds, laser Doppler flare imaging, intraepidermal nerve fiber density, and corneal nerve fiber length.

Results: Of the 52 patients enrolled, 31 (60%) were female and the mean age was 33.0 ± 12.3 years. Four (8%) patients had abnormal nerve conduction studies. Small-fiber tests were frequently abnormal: thermal thresholds in 7 (13%); laser Doppler flare imaging in 10 (19%); intraepidermal nerve fiber density in 11 (22%); and corneal nerve fiber length in 27 (52%). The mean corneal nerve fiber length was below normative level (10.1 ± 2.7 mm/mm ).

Discussion: Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients.
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http://dx.doi.org/10.1002/mus.26687DOI Listing
December 2019

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Clin Genet 2019 11 6;96(5):461-467. Epub 2019 Aug 6.

Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.
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http://dx.doi.org/10.1111/cge.13613DOI Listing
November 2019

NF1 Patients Receiving Breast Cancer Screening: Insights from The Ontario High Risk Breast Screening Program.

Cancers (Basel) 2019 May 22;11(5). Epub 2019 May 22.

Familial Breast and Ovarian Cancer Clinic, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada.

Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing breast cancer compared with the general population. Impaired emotional functioning is reported as a comorbidity that may influence the participation of NF1 patients in regular clinical surveillance despite their increased risk of breast and other cancers. Despite emphasis on breast cancer surveillance in women with NF1, the uptake and feasibility of high-risk screening programs in this population remains unclear. A retrospective chart review between 2014-2018 of female NF1 patients seen at the Elizabeth Raab Neurofibromatosis Clinic (ERNC) in Ontario was conducted to examine the uptake of high-risk breast cancer screening, radiologic findings, and breast cancer characteristics. 61 women with pathogenic variants in enrolled in the high-risk Ontario breast screening program (HR-OBSP); 95% completed at least one high-risk breast screening modality, and four were diagnosed with invasive breast cancer. Our findings support the integration of a formal breast screening programs in clinical management of NF1 patients.
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http://dx.doi.org/10.3390/cancers11050707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562659PMC
May 2019

Development of patient "profiles" to tailor counseling for incidental genomic sequencing results.

Eur J Hum Genet 2019 07 8;27(7):1008-1017. Epub 2019 Mar 8.

University of Toronto, Toronto, ON, Canada.

Guidelines recommend that providers engage patients in shared decision-making about receiving incidental results (IR) prior to genomic sequencing (GS), but this can be time-consuming, given the myriad of IR and variation in patients' preferences. We aimed to develop patient profiles to inform pre-test counseling for IR. We conducted semi-structured interviews with participants as a part of a randomized trial of the GenomicsADvISER.com, a decision aid for selecting IR. Interviews explored factors participants considered when deliberating over learning IR. Interviews were analyzed by thematic analysis and constant comparison. Participants were mostly female (28/31) and about half of them were over the age of 50 (16/31). We identified five patient profiles that reflect common contextual factors, attitudes, concerns, and perceived utility of IR. Information Enthusiasts self-identified as "planners" and valued learning most or all IR to enable planning and disease prevention because "knowledge is power". Concerned Individuals defined themselves as "anxious," and were reluctant to learn IR, anticipating negative psychological impacts from IR. Contemplators were discerning about the value and limitations of IR, weighing health benefits with the impacts of not being able to "un-know" information. Individuals of Advanced Life Stage did not consider IR relevant for themselves and primarily considered their implications for family members. Reassurance Seekers were reassured by previous negative genetic test results which shaped their expectations for receiving no IR: "hopefully [GS will] be negative, too. And then I can rest easy". These profiles could inform targeted counseling for IR by providing a framework to address common values, concerns. and misconceptions.
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http://dx.doi.org/10.1038/s41431-019-0352-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777527PMC
July 2019