Genomic sequencing in newborn screening: balancing consent with the right of the asymptomatic at-risk child to be found.

In this paper, we explore key aspects of the complex ethical and legal landscape surrounding consent in the context of incorporating genomic sequencing into existing newborn bloodspot screening programs. In particular, we consider the potential impact of genomic sequencing on the health rights of the child in relation to existing consent practices in newborn screening. We begin with an introduction to newborn screening programs and their population health goals. We then discuss public health ethics as a rationale underpinning newborn screening before turning to consent. We go on to describe seven current research projects on genomic sequencing in newborn screening and then introduce the 'right of the asymptomatic at-risk child to be found' as a useful concept to draw on when considering consent to newborn screening. We draw on this novel right to argue for the adoption of "appropriate consent" when it comes to certain uses of genomics in newborn screening. We contend that, for 'virtual panels' at least, appropriate consent proportionately balances the ongoing universality of newborn screening for important health conditions with an acknowledgement of the complex outcomes that bringing a complicated diagnostic technology into the screening domain will generate.

Unpacking the notion of "serious" genetic conditions: towards implementation in reproductive decision-making?

The notion of a "serious" genetic condition is commonly used in clinical contexts, laws, and policies to define and delineate both the permissibility of and, access to, reproductive genomic technologies. Yet, the notion lacks conceptual and operational clarity, which can lead to its inconsistent appraisal and application. A common understanding of the relevant considerations of "serious" is lacking. This article addresses this conceptual gap. We begin by outlining existing distinctions around the notion of "serious" that will factor into its appraisal and need to be navigated, in the context of prenatal testing and the use of reproductive genomic technologies. These include tensions between clinical care and population health; the impact of categorizing a condition as "serious"; and the role of perception of quality of life. We then propose a set of four core dimensions and four procedural elements that can serve as a conceptual tool to prompt a mapping of the features of seriousness in any given context. Ultimately, consideration of these core dimensions and procedural elements may lead to improvements in the quality and consistency of decision-making where the seriousness of a genetic condition is a pivotal component at both a policy and practice level.

International scope of biomedical research ethics review.

Many countries consider long-term implications for society.

Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Open Data governance at the Canadian Open Neuroscience Platform (CONP): From the Walled Garden to the Arboretum.

Scientific research communities pursue dual imperatives in implementing strategies to share their data. These communities attempt to maximize the accessibility of biomedical data for downstream research use, in furtherance of open science objectives. Simultaneously, such communities safeguard the interests of research participants through data stewardship measures and the integration of suitable risk disclosures to the informed consent process. The Canadian Open Neuroscience Platform (CONP) convened an Ethics and Governance Committee composed of experts in bioethics, neuroethics, and law to develop holistic policy tools, organizational approaches, and technological supports to align the open governance of data with ethical and legal norms. The CONP has adopted novel platform governance methods that favor full data openness, legitimated through the use of robust deidentification processes and informed consent practices. The experience of the CONP is articulated as a potential template for other open science efforts to further build upon. This experience highlights informed consent guidance, deidentification practices, ethicolegal metadata, platform-level norms, and commercialization and publication policies as the principal pillars of a practicable approach to the governance of open data. The governance approach adopted by the CONP stands as a viable model for the broader neuroscience and open science communities to adopt for sharing data in full open access.

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

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

Reconciling the biomedical data commons and the GDPR: three lessons from the EUCAN ELSI collaboratory.

The coming-into-force of the EU General Data Protection Regulation (GDPR) is a watershed moment in the legal recognition of enforceable rights to informational self-determination. The rapid evolution of legal requirements applicable to data use, however, has the potential to outstrip the capabilities of networks of biomedical data users to respond to the shifting norms. It can also delegitimate established institutional bodies that are responsible for assessing and authorising the downstream use of data, including research ethics committees and institutional data custodians. These burdens are especially pronounced for clinical and research networks that are of transnational scale, because the legal compliance burden for outbound international data transfers from the EEA is especially high. Legislatures, courts, and regulators in the EU should therefore implement the following three legal changes. First, the responsibilities of particular actors in a data sharing network should be delimited through the contractual allocation of responsibilities between collaborators. Second, the use of data through secure data processing environments should not trigger the international transfer provisions of the GDPR. Third, the use of federated data analysis methodologies that do not provide analysis nodes or downstream users access to identifiable personal data as part of the outputs of those analyses should not be considered circumstances of joint controllership, nor lead to the users of non-identifiable data to be considered controllers or processors. These small clarifications of, or modifications to, the GDPR would facilitate the exchange of biomedical data amongst clinicians and researchers.

The Deceased, Public Health, and Research: Proposing Legal Reforms.

There is little guidance concerning biomedical research using tissues from deceased individuals. Unique ethical and legal challenges gained visibility during the coronavirus disease 2019 (COVID-19) pandemic, when important studies using genome sequencing required access to biological materials from deceased individuals. These studies proposed to determine whether specific genomic profiles were associated with important disease outcomes. Such research has previously required consent from next-of-kin or other surrogate decision makers. Ethics waivers for such consent vary within Canada. In Ontario, research ethics boards can grant waivers of consent if the Tri-Council Policy Statement-2 conditions are met. These include that the individual is not harmed, that the materials are essential to the research, and that privacy will be protected. Conversely, in Quebec, Civil Code article 22 imposes an obligation on researchers to seek consent from next-of-kin or another surrogate decision maker with no option for waivers. It became evident to researchers that these standards can sometimes impose an impracticable balance of risks and benefits, especially in public health emergencies. We seek to establish why and when consent requirements should be waived for public health and research involving the tissues of deceased individuals.

Canadian Healthcare Professionals' Views and Attitudes toward Risk-Stratified Breast Cancer Screening.

Given the controversy over the effectiveness of age-based breast cancer (BC) screening, offering risk-stratified screening to women may be a way to improve patient outcomes with detection of earlier-stage disease. While this approach seems promising, its integration requires the buy-in of many stakeholders. In this cross-sectional study, we surveyed Canadian healthcare professionals about their views and attitudes toward a risk-stratified BC screening approach. An anonymous online questionnaire was disseminated through Canadian healthcare professional associations between November 2020 and May 2021. Information collected included attitudes toward BC screening recommendations based on individual risk, comfort and perceived readiness related to the possible implementation of this approach. Close to 90% of the 593 respondents agreed with increased frequency and earlier initiation of BC screening for women at high risk. However, only 9% agreed with the idea of not offering BC screening to women at very low risk. Respondents indicated that primary care physicians and nurse practitioners should play a leading role in the risk-stratified BC screening approach. This survey identifies health services and policy enhancements that would be needed to support future implementation of a risk-stratified BC screening approach in healthcare systems in Canada and other countries.

The Canadian Open Neuroscience Platform-An open science framework for the neuroscience community.

The Canadian Open Neuroscience Platform (CONP) takes a multifaceted approach to enabling open neuroscience, aiming to make research, data, and tools accessible to everyone, with the ultimate objective of accelerating discovery. Its core infrastructure is the CONP Portal, a repository with a decentralized design, where datasets and analysis tools across disparate platforms can be browsed, searched, accessed, and shared in accordance with FAIR principles. Another key piece of CONP infrastructure is NeuroLibre, a preprint server capable of creating and hosting executable and fully reproducible scientific publications that embed text, figures, and code. As part of its holistic approach, the CONP has also constructed frameworks and guidance for ethics and data governance, provided support and developed resources to help train the next generation of neuroscientists, and has fostered and grown an engaged community through outreach and communications. In this manuscript, we provide a high-level overview of this multipronged platform and its vision of lowering the barriers to the practice of open neuroscience and yielding the associated benefits for both individual researchers and the wider community.

Regulating cancer risk prediction: legal considerations and stakeholder perspectives on the Canadian context.

Risk prediction models hold great promise to reduce the impact of cancer in society through advanced warning of risk and improved preventative modalities. These models are evolving and becoming more complex, increasingly integrating genetic screening data and polygenic risk scores as well as calculating risk for multiple types of a disease. However, unclear regulatory compliance requirements applicable to these models raise significant legal uncertainty and new questions about the regulation of medical devices. This paper aims to address these novel regulatory questions by presenting an initial assessment of the legal status likely applicable to risk prediction models in Canada, using the CanRisk tool for breast and ovarian cancer as an exemplar. Legal analysis is supplemented with qualitative perspectives from expert stakeholders regarding the accessibility and compliance challenges of the Canadian regulatory framework. While the paper focuses on the Canadian context, it also refers to European and U.S. regulations in this domain to contrast them. Legal analysis and stakeholder perspectives highlight the need to clarify and update the Canadian regulatory framework for Software as a Medical Device as it applies to risk prediction models. Findings demonstrate how normative guidance perceived as convoluted, contradictory or overly burdensome can discourage innovation, compliance, and ultimately, implementation. This contribution aims to initiate discussion about a more optimal legal framework for risk prediction models as they continue to evolve and are increasingly integrated into landscape for public health.

Perceptions and Usability of PREVENTION: A Breast Cancer Risk Assessment e-Platform.

BACKGROUND: The PREVENTION e-platform was developed to provide accessible and evidence-based health information tailored to different Breast Cancer (BC) risk levels. The demonstration study objectives were to (1) assess the usability and perceived impact of PREVENTION on women with assigned hypothetical BC risk levels (i.e., near population, intermediate or high) and (2) explore perceptions and recommendations for e-platform improvement. METHODS: Thirty women with no history of cancer were recruited through social media, commercial centers, health clinics, and community settings in Montreal, Qc, Canada. Participants accessed e-platform content tailored to their assigned hypothetical BC risk level, and then completed study e-questionnaires including the user Mobile Application Rating Scale (uMARS), an e-platform quality scale (i.e., in terms of engagement, functionality, aesthetics, and information). A subsample (n = 18) was randomly selected for an individual follow-up semi-structured interview. RESULTS: The e-platform overall quality was high, with mean M = 4.01 (out of 5) and SD = 0.50. A total of 87% (n = 26) agreed or strongly agreed that PREVENTION increased their knowledge and awareness of BC risk, and 80% would recommend it to others while reporting likelihood of following lifestyle recommendations to decrease their BC risk. Follow up interviews indicated that participants perceived the e-platform as a trusted source of BC information and a promising means to connect with peers. They also reported that while the e-platform was easy to navigate, improvements were needed for connectivity, visuals, and the organization of scientific resources. CONCLUSION: Preliminary findings support PREVENTION as a promising means to provide personalized BC information and support. Efforts are underway to further refine the platform, assess its impact in larger samples and gather feedback from BC specialists.

Concordance of International Regulation of Pediatric Health Research.

OBJECTIVE: To assess the comparability of international ethics principles and practices used in regulating pediatric research as a first step in determining whether reciprocal deference for international ethics review is feasible. Prior studies by the authors focused on other aspects of international health research, such as biobanks and direct-to-participant genomic research. The unique nature of pediatric research and its distinctive regulation by many countries warranted a separate study. STUDY DESIGN: A representative sample of 21 countries was selected, with geographical, ethnic, cultural, political, and economic diversity. A leading expert on pediatric research ethics and law was selected to summarize the ethics review of pediatric research in each country. To ensure the comparability of the responses, a 5-part summary of pediatric research ethics principles in the US was developed by the investigators and distributed to all country representatives. The international experts were asked to assess and describe whether principles in their country and the US were congruent. Results were obtained and compiled in the spring and summer of 2022. RESULTS: Some of the countries varied in their conceptualization or description of one or more ethical principles for pediatric research, but overall, the countries in the study demonstrated a fundamental concordance. CONCLUSIONS: Similar regulation of pediatric research in 21 countries suggests that international reciprocity is a viable strategy.

Data and Tools Integration in the Canadian Open Neuroscience Platform.

We present the Canadian Open Neuroscience Platform (CONP) portal to answer the research community's need for flexible data sharing resources and provide advanced tools for search and processing infrastructure capacity. This portal differs from previous data sharing projects as it integrates datasets originating from a number of already existing platforms or databases through DataLad, a file level data integrity and access layer. The portal is also an entry point for searching and accessing a large number of standardized and containerized software and links to a computing infrastructure. It leverages community standards to help document and facilitate reuse of both datasets and tools, and already shows a growing community adoption giving access to more than 60 neuroscience datasets and over 70 tools. The CONP portal demonstrates the feasibility and offers a model of a distributed data and tool management system across 17 institutions throughout Canada.

Open Data in the Era of the GDPR: Lessons from the Human Cell Atlas.

The Human Cell Atlas (HCA) is striving to build an open community that is inclusive of all researchers adhering to its principles and as open as possible with respect to data access and use. However, open data sharing can pose certain challenges. For instance, being a global initiative, the HCA must contend with a patchwork of local and regional privacy rules. A notable example is the implementation of the European Union General Data Protection Regulation (GDPR), which caused some concern in the biomedical and genomic data-sharing community. We examine how the HCA's large, international group of researchers is investing tremendous efforts into ensuring appropriate sharing of data. We describe the HCA's objectives and governance, how it defines open data sharing, and ethico-legal challenges encountered early in its development; in particular, we describe the challenges prompted by the GDPR. Finally, we broaden the discussion to address tools and strategies that can be used to address ethical data governance.

Mitochondrial Replacement Therapy: In Whose Interests?

Mitochondrial replacement therapy (MRT), also called nuclear genome transfer and mitochondrial donation, is a new technique that can be used to prevent the transmission of mitochondrial DNA diseases. Apart from the United Kingdom, the first country to approve MRT in 2015, Australia became the second country with a clear regulatory path for the clinical applications of this technique in 2021. The rapidly evolving clinical landscape of MRT makes the elaboration and evaluation of the responsible use of this technology a pressing matter. As jurisdictions with less strict or non-existent reproductive laws are continuing to use MRT in the clinical context, the need to address the underlying ethical issues surrounding MRT's clinical translation is fundamental.

Bridging the European Data Sharing Divide in Genomic Science.

In this viewpoint, we argue for the importance of creating data spaces for genomic research that are detached from contexts in which fundamental rights concerns related to surveillance measures override a purpose-specific balancing of fundamental rights. Genomic research relies on molecular and phenotypic data, on comparing findings within large data sets, on searchable metadata, and on translating research results into a clinical setting. These methods require sensitive genetic and health data to be shared across borders. International data sharing between the European Union (EU) or the European Economic Area and third countries has accordingly become a cornerstone of genomics. The EU General Data Protection Regulation contains rules that accord privileged status to data processing for research purposes to ensure that strict data protection requirements do not impede biomedical research. However, the General Data Protection Regulation rules applicable to international transfers of data accord no such preferential treatment to international data transfers made in the research context. The rules that govern the international transfer of data create considerable barriers to international data sharing because of the cost-intensive procedural and substantive compliance burdens that they impose. For certain jurisdictions and select use cases, there exist practically no lawful mechanisms to enable the international transfer of data because of concerns about the protection of fundamental rights. The proposed solutions further fail to address the need to share large data sets of local and regional cohorts across national borders to enable joint analyses. The European Health Data Space is an emerging federated, EU-wide data infrastructure that is intended to function as an infrastructure bringing together EU health data to improve patient care and enable the secondary use of health-related data for research purposes. Such infrastructure is implementing new institutions to support its functioning and is being implemented in reliance on a new enabling law, the regulation on the European Health Data Space. This innovation provides the opportunity to facilitate EU contribution to international genomic research efforts. The draft regulation for this data space provides for a concept of data infrastructure intended to enable cross-border data exchange and access, including access to genetic and health data for scientific analysis purposes. The draft regulation also provides for obligations of national actors aimed at making data widely available. This effort is laudable. However, in the absence of further, more fundamental changes to the manner in which the EU regulates the secondary use of health data, it is reasonable to believe that EU participation in international genomic research efforts will remain impeded.