Public attitudes towards genomic data sharing: results from a provincial online survey in Canada.

BACKGROUND: While genomic data sharing can facilitate important health research and discovery benefits, these must be balanced against potential privacy risks and harms to individuals. Understanding public attitudes and perspectives on data sharing is important given these potential risks and to inform genomic research and policy that aligns with public preferences and needs. METHODS: A cross sectional online survey measured attitudes towards genomic data sharing among members of the general public in an Eastern Canadian province. RESULTS: Results showed a moderate comfort level with sharing genomic data, usually into restricted scientific databases with controlled access. Much lower comfort levels were observed for sharing data into open or publicly accessible databases. While respondents largely approved of sharing genomic data for health research permitted by a research ethics board, many general public members were concerned with who would have access to their data, with higher rates of approval for access from clinical or academic actors, but much more limited approval of access from commercial entities or governments. Prior knowledge about sequencing and about research ethics boards were both related to data sharing attitudes. CONCLUSIONS: With evolving regulations and guidelines for genomics research and data sharing, it is important to consider the perspectives of participants most impacted by these changes. Participant information materials and informed consent documents must be explicit about the safeguards in place to protect genomic data and the policies governing the sharing of data. Increased public awareness of the role of research ethics boards and of the need for genomic data sharing more broadly is also needed.

Public interest in unexpected genomic findings: a survey study identifying aspects of sequencing attitudes that influence preferences.

We describe public preferences for unexpected genomic findings and explore predictors of preferences using an online survey in an Eastern Canadian province. Items measuring attitudes toward features of unexpected findings and genomic sequencing concerns were entered in logistic regression models predicting interest in unexpected findings. Very high levels of interest were observed in unexpected findings for treatable disorders and carrier results, with lesser interest in unexpected findings for non-treatable disorders and unclassified variants. Respondents who endorsed items measuring features of patient control and choice over their genomic data and testing options were 3-5 times more likely to be very interested in receiving unexpected findings. Respondents with high genomic sequencing concerns were less interested in the return of any unexpected result. Self-reported history of a genetic condition was significantly related to interest in receiving most categories of unexpected genomic information, while prior use of direct-to-consumer testing was significantly related only to interest in the return of unexpected genomic findings for disorders not currently treatable. Findings highlight the need for specific elements of information and transparency regarding the return of unexpected findings and can inform the development of patient-centered materials and return of results policies.

Psychological Distress and Quality of Life in Participants Undergoing Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy Caused by TMEM43 p.S358L: Is It Time to Offer Population-Based Genetic Screening?

PURPOSE: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy. This pilot study explored the acceptability among subjects to TMEM43 p.S358L population-based genetic screening (PBGS) in this Canadian province. METHODS: A prospective cohort study assessed attitudes, psychological distress, and health-related quality of life (QOL) in unselected individuals who underwent genetic screening for the TMEM43 p.S358L variant. Participants (n = 73) were recruited via advertisements and completed 2 surveys at baseline, 6 months, and 1 year which measured health-related QOL (SF-36v2) and psychological distress (Impact of Events Scale). RESULTS: No variant-positive carriers were identified. Of those screened through a telephone questionnaire, >95% felt positive about population-genetic screening for TMEM43 p.S358L, though 68% reported some degree of anxiety after seeing the advertisement. There were no significant changes in health-related QOL or psychological distress scores over the study period. CONCLUSION: Despite some initial anxiety, we show support for PBGS among research subjects who screened negative for the TMEM43 p.S358L variant in NL. These findings have implications for future PBGS programs in the province.

Identifying Aspects of Public Attitudes Toward Whole Genome Sequencing to Inform the Integration of Genomics into Care.

INTRODUCTION: The growth of global sequencing initiatives and commercial genomic test offerings suggests the public will increasingly be confronted with decisions about sequencing. Understanding public attitudes can assist efforts to integrate sequencing into care and inform the development of public education and outreach strategies. METHODS: A 48-item online survey was advertised on Facebook in Eastern Canada and hosted on SurveyMonkey in late 2018. The survey measured public interest in whole genome sequencing and attitudes toward various aspects of sequencing using vignettes, scaled, and open-ended items. RESULTS: While interest in sequencing was high, critical attitudes were observed. In particular, items measuring features of patient control and choice regarding genomic data were strongly endorsed by respondents. Majority wanted to specify upfront how their data could be used, retain the ability to withdraw their sample at a later date, sign a written consent form, and speak to a genetic counselor prior to sequencing. Concerns about privacy and unauthorized access to data were frequently observed. Education level was the sociodemographic variable most often related to attitude statements such that those with higher levels of education generally displayed more critical attitudes. CONCLUSIONS: Attitudes identified here could be used to inform the development of implementation strategies for genomic medicine. Findings suggest health systems must address patient concerns about privacy, consent practices, and the strong desire to control what happens to their genomic data through public outreach and education. Specific oversight procedures and policies that are clearly communicated to the public will be required.

Public engagement with genomic medicine: a summary of town hall discussions.

Engaging with the public for their input about genomic medicine is critical before it is implemented into routine healthcare practice. In order to inform discussion and planning for the introduction of genome sequencing into clinical care in an Eastern Canadian province, we implemented a program of public engagement activities. Here, we report a qualitative summary of two town hall discussions utilizing a hybrid information-consultation approach with 20 residents of the province of Newfoundland and Labrador, Canada. Discussion revealed largely positive attitudes towards genomic medicine; however, critical reflection around informed consent models, the return of sequencing findings, and access to qualified healthcare professionals revealed numerous public concerns. Public support will be important to realize the potential benefits of genomics and precision medicine to health outcomes. Our findings highlight public concerns that must be addressed in educational and informed consent documents related to sequencing. Town hall attendees endorsed ongoing public education and awareness-building initiatives which could help foster transparency and trust as genomics is integrated into healthcare systems.

Public interest in whole genome sequencing and information needs: an online survey study.

Aim: To survey the general public about whole genome sequencing interest, including pharmacogenomic testing, and to identify information important for sequencing decisions. Patients & methods: An online survey of 901 members of the general public in an eastern Canadian province. Results: Interest in whole genome sequencing, including pharmacogenomic testing, was high with few differences among demographic variables. Issues identified as very important to sequencing decisions included familial implications of testing, whether treatment was available for conditions tested and knowing who could access genomic information. Most respondents would value support when interpreting sequencing results. Conclusion: Findings reveal the kind of information and support users of sequencing services would value and could inform the implementation of sequencing into care in ways that accord with public preferences and needs.

What is in a Name? Parent, Professional and Policy-Maker Conceptions of Consent-Related Language in the Context of Newborn Screening.

Newborn bloodspot screening programs are some of the longest running population screening programs internationally. Debate continues regarding the need for parents to give consent to having their child screened. Little attention has been paid to how meanings of consent-related terminology vary among stakeholders and the implications of this for practice. We undertook semi-structured interviews with parents (n = 32), healthcare professionals (n = 19) and policy decision makers (n = 17) in two Canadian provinces. Conceptions of consent-related terms revolved around seven factors within two broad domains, decision-making and information attainment. Decision-making comprised: parent decision authority; voluntariness; parent engagement with decision-making; and the process of enacting choice. Information ascertainment comprised: professional responsibilities (including disclosure of information and time to review); parent responsibilities; and the need for discussion and understanding prior to a decision. Our findings indicate that consent-related terms are variously understood, with substantive implications for practice. We suggest that consent procedures should be explained descriptively, regardless of approach, so there are clear indications of what is expected of parents and healthcare professionals. Support systems are required both to meet the educational needs of parents and families and to support healthcare professionals in delivering information in a manner in keeping with parent needs.

Universal tumor screening for Lynch syndrome: Perceptions of Canadian pathologists and genetic counselors of barriers and facilitators.

BACKGROUND: People at risk of developing hereditary cancers associated with Lynch Syndrome (LS) can be identified through universal screening of colorectal tumors. However, tumor screening practices are variable across Canada and few studies explore the perspectives of genetic counselors and pathologists about tumor screening. This study was conducted to better understand the barriers and facilitators of implementing universal tumor screening in health centers across Canada. METHODS: An online survey about tumor screening programs was administered to genetic counselors and pathologists across Canada through communication channels of professional organizations. It was hosted on SurveyMonkey and accessible from October 2016 to March 2017. RESULTS: Barriers to tumor screening included a lack of sustainable resources, including funding and genetic counselors. Respondents strongly identified the need for a coordinated, interdisciplinary approach to program planning with the "right people at the table." Respondents currently with a screening program provided advice such as carefully designing the program structure, developing patient and family follow-up protocols, and ensuring adequate resources (funding, staff, training for providers) were available prior to program initiation. CONCLUSION: There is no national approach to universal tumor screening in Canada. However, future efforts can be informed by the experiences of those centers that have already created a universal tumor screening program for LS. These data suggest the need for an interdisciplinary approach, initial and sustained funding, and careful advanced planning of program structures and policies.

Universal tumor screening for Lynch syndrome: perspectives of Canadian pathologists and genetic counselors.

Universal screening of all newly diagnosed colorectal cancer tumors can identify individuals at high risk for Lynch syndrome (LS), a hereditary cancer syndrome predisposing carriers to increased risk of colorectal, endometrial, and other cancers. To inform planning of a universal tumor screening program for LS in our jurisdiction, we undertook online surveys of Canadian pathologists and genetic counselors to describe existing tumor screening programs. Online surveys were hosted on SurveyMonkey between October 2016 and March 2017. Fifty-three pathologists and 66 genetic counselors completed surveys (total n = 119). While attitudes towards tumor screening were positive, considerable variability was observed in the existence of tumor screening, test ordering criteria, and practices. Most respondents indicated consent was not obtained for tumor screening nor were educational materials provided to patients; however, opting out of additional mutation testing in the event of a positive tumor screen was endorsed. Results add to the growing literature on providers' perspectives on population-based tumor screening programs and inform ways to offer these. Findings highlight the need to develop methods of patient education that allow meaningful opt-out decisions. The variability we observed also suggests the need for national standards and guidance on tumor screening for LS.

Surgical treatment choices for breast cancer in Newfoundland and Labrador: a retrospective cohort study.

BACKGROUND: Mastectomy is often chosen by women for treatment of breast cancer, even when breast-conserving surgery (BCS) is an option. Newfoundland and Labrador has a high mastectomy rate. We documented the number of breast cancers over a given period in the province and their related surgical treatments, and explored the impact of several variables on surgical choice. METHODS: A retrospective cohort design linked diagnosis data from the Newfoundland and Labrador tumour registry to surgery data from the Canadian Institute for Health Information Discharge Abstract Database. Data were extracted for all women aged 19 years or more in whom breast cancer was diagnosed in 2009-2014. RESULTS: A total of 2346 cases of breast cancer with a linked surgical procedure were included. Most operations (1605 [68.4%]) were mastectomy procedures, with the remainder being BCS. Logistic regression analysis revealed that women were 1.82 times (95% confidence interval [CI] 1.64-2.02) more likely to have mastectomy for each unit of stage increase from 0 to IV and 1.15 times (95% CI 1.11-1.21) more likely for each unit of driving time increase. CONCLUSION: Tumour stage and driving time to a radiation facility significantly predicted Newfoundland and Labrador women's surgical treatment choices for breast cancer. Notably, mastectomy was the favoured choice across all age groups, tumour stages and geographical regions of the province. We hope that these results will galvanize efforts to better understand local surgical practices and assist in improving the quality of surgical care of women with breast cancer.

CONTEXTE: Les femmes atteintes d'un cancer du sein optent souvent pour la mastectomie, même lorsque la chirurgie mammaire conservatrice (CMC) est possible. Considérant que la province de Terre-Neuve-et-Labrador enregistre des taux de mastectomie élevés, nous y avons recensé durant une période donnée les cas de cancer du sein et les traitements chirurgicaux associés, et avons étudié l'influence de plusieurs variables sur le choix d'intervention. MÉTHODES: Suivant un modèle de cohorte rétrospective, nous avons apparié les données diagnostiques du registre des cancers de Terre-Neuve-et-Labrador aux données chirurgicales correspondantes de la Base de données sur les congés des patients de l'Institut canadien d'information sur la santé. Nous avons extrait les données de toutes les femmes de 19 ans et plus qui ont reçu un diagnostic de cancer du sein entre 2009 et 2014. RÉSULTATS: Nous avons retenu 2346 cas de cancer du sein avec prise en charge chirurgicale. La majorité des interventions (1605, ou 68,4 %) étaient des mastectomies; les autres étaient des CMC. Une analyse de régression logistique a révélé qu'avec chaque augmentation unitaire du stade (de 0 à 4), les femmes devenaient 1,82 fois plus susceptibles d'opter pour la mastectomie (intervalle de confiance [IC] de 95 % 1,64 à 2,02), et 1,15 fois plus susceptibles de le faire avec chaque augmentation unitaire du temps de conduite (IC de 95 % 1,11 à 1,21). CONCLUSION: Le stade de la tumeur et le temps nécessaire pour se rendre dans un établissement de radiothérapie étaient des facteurs prédictifs significatifs du choix de traitement chirurgical du cancer du sein chez les femmes de Terre-Neuve-et-Labrador. Fait intéressant : tous les groupes, quels que soient leur âge, le stade de leur tumeur et leur région de la province, avaient une préférence pour la mastectomie. Nous espérons que ces résultats mèneront à d'autres analyses des pratiques chirurgicales locales et contribueront à améliorer la qualité de la prise en charge chirurgicale des femmes atteintes d'un cancer du sein.

"There are days I wish it wasn't there, and there's days I realize I'm lucky": A qualitative study of psychological sequelae to the implantable cardioverter defibrillator as a treatment for the prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy caused by a TMEM43 p.S358L mutation is a fully penetrant autosomal dominant cause of sudden cardiac death where prophylactic implantable cardioverter defibrillator therapy significantly reduces mortality by returning lethal cardiac rhythms to normal. This qualitative study assessed the psychological ramifications of the implantable cardioverter defibrillator on recipients, their spouses and their mutation negative siblings. DESIGN: Qualitative interview study. PARTICIPANTS: Twenty-one individuals (nine mutation positive, eight mutation negative and four spouses) from 15 families completed semi-structured interviews. RESULTS: No theoretical assumptions about the data were made: inductive sub-coding was accomplished with the constant comparison method and cohesive themes across all respondent interviews were determined. All interviewees had a family history of sudden cardiac death and appropriate implantable cardioverter defibrillator therapy in themselves or family members. Average length of time with an implantable cardioverter defibrillator was 10 years. Major themes included: (1) acceptance and gratitude, (2) grudging acceptance, (3) psychological effects (on emotional and psychological well-being; functioning of the broader family unit; and relationships), and (4) practical concerns (on clothes, travel, loss of driving licence and the effects of an implantable cardioverter defibrillator discharge). These affected all family members, regardless of mutation status. CONCLUSIONS: Despite the survival advantage of implantable cardioverter defibrillator therapy, the intervention carries psychological and practical burdens for family members from kindreds manifesting p.S358L TMEM43 ARVC that does not appear to dissipate with time. A move towards integrating psychology services with the cardiac genetics clinic for the extended family may provide benefit.

Consent for newborn screening: parents' and health-care professionals' experiences of consent in practice.

Consent processes for newborn bloodspot screening (NBS) are variable, with a lack of descriptive research that depicts how the offer of NBS is made to parents. We explored the experience, in practice, of consent for NBS. Semistructured interviews in two Canadian provinces were held with: (1) parents of children offered NBS (n=32); and (2) health-care professionals involved in the NBS process (n=19). Data on recollections of NBS, including consent processes, were utilized to identify emerging themes using the method of constant comparison. Three themes were relevant to NBS consent: (1) The 'offer' of NBS; (2) content and timing of information provision; and (3) the importance of parental experiences for consent decisions. Recollections of consent for NBS were similar between jurisdictions. Excepting midwives and their patients, NBS was viewed as a routine part of giving birth, with little evidence of an informed consent process. Although most parents were satisfied, all respondents suggested information about NBS be provided long before the birth. Accounts of parents who declined screening highlight the influence of parental experiences with the heel prick process in screening decisions. Findings further our understanding of consent in practice and highlight areas for improvement in parent-provider interactions.

Role of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in regulating mineral homeostasis during fetal development.

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) play complementary and overlapping roles in regulating fetal mineral homeostasis. PTHrP is expressed within the growth plate, directs endochondral bone formation, and determines the fate of chondrocytes before bone formation can be initiated. It is expressed in placenta and is present at high levels in the fetal circulation. It stimulates placental calcium (and possibly magnesium) transfer and raises blood mineral levels above ambient maternal values in order to effect mineralization of the skeleton. It does not upregulate in response to absence of PTH or hypocalcemia, and thus, its secretion may be regulated autonomously or in response to placental signals. PTH is expressed in fetal parathyroids and placenta. Despite circulating at low levels, it has a more dominant effect than PTHrP in regulating the blood calcium and ensuring adequate mineralization of the skeleton. It may also have effects on bone formation in the steps that occur after apoptosis of hypertrophic chondrocytes. Unlike PTHrP, it increases with fetal hypocalcemia, but its secretion is constrained by the calcium-sensing receptor to maintain the adult calcium level, well below what the fetus normally achieves. PTH also stimulates placental calcium transfer, and its absence disrupts placental expression of calciotropic and cation transporter genes.

Parathyroid hormone regulates fetal-placental mineral homeostasis.

Parathyroid hormone (PTH) plays an essential role in regulating calcium and bone homeostasis in the adult, but whether PTH is required at all for regulating fetal-placental mineral homeostasis and skeletal development is uncertain. We hypothesized that despite its low circulating levels during fetal life, PTH plays a critical role in regulating these processes. To address this, we examined two different genetic models of PTH deficiency. Pth null mice have enlarged parathyroids that are incapable of making PTH, whereas Gcm2 null mice lack parathyroids but have PTH that arises from the thymus. Pth nulls served as a model of complete absence of PTH, whereas Gcm2 nulls were a model of severe hypoparathyroidism. We determined that PTH contributes importantly to fetal mineral homeostasis because in its absence a fetal hypoparathyroid phenotype results with hypocalcemia, hypomagnesemia, hyperphosphatemia, low amniotic fluid mineral content, and reduced skeletal mineral content. We also determined that PTH is expressed in the placenta, regulates the placental expression of genes involved in calcium and other solute transfer, and may directly stimulate placental calcium transfer. Although parathyroid hormone-related protein (PTHrP) acts in concert with PTH to regulate fetal mineral homeostasis and placental calcium transfer, unlike PTH, it does not upregulate in response to fetal hypocalcemia.