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

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

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

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.

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

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

Assessment of the Implementation of Pharmacogenomic Testing in a Pediatric Tertiary Care Setting.

Importance: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions. Objectives: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting. Design, Setting, and Participants: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research. Exposures: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines. Main Outcomes and Measures: The number of patients for whom PGx test results warranted deviation from standard dosing regimens. Results: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile. Conclusions and Relevance: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

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.

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.

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

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.

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

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.

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.

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.

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

Introduction: In the past 5 years, multi-gene panels have replaced the practice of BRCA1 and BRCA2 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. Areas covered: 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. Expert opinion: 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. BRCA1 and BRCA2, TP53). 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.

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of BRCA1/2-related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline BRCA1/2 testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for BRCA1/2-associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.

Assessment of Knee Kinematics in Older Adults Using High-Speed Stereo Radiography.

PURPOSE: Quantification of knee motion is essential for assessment of pathologic joint function, such as tracking osteoarthritis progression and evaluating outcomes after conservative or surgical treatment, including total knee arthroplasty. Our purpose was to establish a useful baseline for the kinematic envelope of knee motion in healthy older adults performing movements of daily living. METHODS: A high-speed stereo radiography system was used to measure the three-dimensional tibiofemoral kinematics of eight healthy people over 55 yr of age (4 women/4 men; age, 61.7 ± 5.4 yr; body mass, 74.6 ± 7.7 kg; body mass index, 26.7 ± 4.4 kg·m; height, 168.2 ± 13.7 cm) during seated knee extension, level walking, pivoting, and step descent. RESULTS: Internal-external and varus-valgus rotation and anterior-posterior range of motion through stance in normal walking averaged 3.6° ± 1.1°, 2.3° ± 0.6°, and 3.4 ± 1.57 mm, respectively. Average range of motion across subjects was greater during the step-down in both internal-external rotation (average, 6.5° ± 3.1°) and anterior-posterior translation (average, 4.5 ± 1.1). Average internal-external range of motion increased to 13.5° ± 3.6° during pivoting. Range of motion of the knee in varus-valgus rotation was nearly the same for each subject across activities, rarely exceeding 6°. CONCLUSIONS: Pivoting and step descending during walking had greater internal-external rotation and anterior-posterior translation than normal gait. Internal-external rotation and anterior-posterior translation were shown to have greater activity dependence, whereas varus-valgus rotation was consistent across activities. These results were similar to prior measurements in younger cohorts, though a trend toward reduced range of motion in the older adults was observed.

Structured assessment and followup for patients with hereditary kidney tumour syndromes.

INTRODUCTION: Optimal clinical assessment and subsequent followup of patients with or suspected of having a hereditary renal cell carcinoma syndrome (hRCC) is not standardized and practice varies widely. We propose protocols to optimize these processes in patients with hRCC to encourage a more uniform approach to management that can then be evaluated. METHODS: A review of the literature, including existing guidelines, was carried out for the years 1985-2015. Expert consensus was used to define recommendations for initial assessment and followup. RESULTS: Recommendations for newly diagnosed patients' assessment and optimal ages to initiate followup protocols for von Hippel Lindau disease (VHL), hereditary papillary renal cancer (HPRC), hereditary leiomyomatosis with renal cell carcinoma (HLRCC), Birt-Hogg-Dubé syndrome (BHD), familial paraganglioma-pheochromocytoma syndromes (PGL-PCC), and tuberous sclerosis (TSC) are proposed. CONCLUSIONS: Our proposed consensus for structured assessment and followup is intended as a roadmap for the care of patients with hRCC to guide healthcare providers. Although the list of syndromes included is not exhaustive, the document serves as a starting point for future updates.

Is socioeconomic status a risk factor for stiffness after total knee arthroplasty? A multicenter case-control study.

Socioeconomic factors may play a role in the development of arthrofibrosis following total knee arthroplasty. Using manipulation following total knee arthroplasty as a surrogate for stiffness, this multicenter case-control study found that African American and young patients (<45 years of age) had twice the odds for manipulation compared with Caucasian and older-age patients.