Variant classification changes over time in the clinical molecular diagnostic laboratory setting.

BACKGROUND: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario. METHODS: DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category). RESULTS: Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%). CONCLUSIONS: The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.

Genetics providers' perspectives on the use of digital tools in clinical practice.

PURPOSE: Digital tools are increasingly incorporated into genetics practice to address challenges with the current model of care. Yet, genetics providers' perspectives on digital tool use are not well characterized. METHODS: Genetics providers across Canada were recruited. Semistructured interviews were conducted to ascertain their perspectives on digital tool use and the clinical practice factors that might inform digital tool integration. A qualitative interpretive description approach was used for analysis. RESULTS: Thirty-three genetics providers across 5 provinces were interviewed. Participants had favorable attitudes toward digital tool use. They were open to using digital tools in the pretest phase of the genetic testing pathway and for some posttest tasks or in a hybrid model of care. Participants expressed that digital tools could enhance efficiency and allow providers to spend more time practicing at the top of scope. Providers also described the need for careful consideration of the potential impact of digitalization on the clinician-patient dynamic, access to and equity of care, and unintended digital burden on providers. CONCLUSION: Genetics providers considered digital tools to represent a viable solution for improving access, efficiency, and quality of care in genetics practice. Successful use of digital tools in practice will require careful consideration of their potential unintended impacts.

Eliciting parental preferences and values for the return of additional findings from genomic sequencing.

Health economic evidence is needed to inform the design of high-value and cost-effective processes for returning genomic results from analyses for additional findings (AF). This study reports the results of a discrete-choice experiment designed to elicit preferences for the process of returning AF results from the perspective of parents of children with rare conditions and to estimate the value placed on AF analysis. Overall, 94 parents recruited within the Australian Genomics and Melbourne Genomics programmes participated in the survey, providing preferences in a total of 1128 choice scenarios. Statistically significant preferences were identified for the opportunity to change the choices made about AF; receiving positive AF in person from a genetic counsellor; timely access to a medical specialist and high-quality online resources; receiving automatic updates through a secure online portal if new information becomes available; and lower costs. For AF uptake rates ranging between 50-95%, the mean per person value from AF analysis was estimated at AU$450-$1700 (US$300-$1140). The findings enable the design of a value-maximising process of analysis for AF in rare-disease genomic sequencing.

A proposal for an inclusive working definition of genetic discrimination to promote a more coherent debate.

Genetic discrimination is an evolving phenomenon that impacts fundamental human rights such as dignity, justice and equity. Although, in the past, various definitions to better conceptualize genetic discrimination have been proposed, these have been unable to capture several key facets of the phenomenon. In this Perspective, we explore definitions of genetic discrimination across disciplines, consider criticisms of such definitions and show how other forms of discrimination and stigmatization can compound genetic discrimination in a way that affects individuals, groups and systems. We propose a nuanced and inclusive definition of genetic discrimination, which reflects its multifaceted impact that should remain relevant in the face of an evolving social context and advancing science. We argue that our definition should be adopted as a guiding academic framework to facilitate scientific and policy discussions about genetic discrimination and support the development of laws and industry policies seeking to address the phenomenon.

"I Just Assumed This Was Already Being Done": Canadian Patient Preferences for Enhanced Data Sharing for Precision Oncology.

PURPOSE: In Canada, health data are siloed, slowing bioinnovation and evidence generation for personalized cancer care. Secured data-sharing platforms (SDSPs) can enable data analysis across silos through rapid concatenation across trial and real-world settings and timely researcher access. To motivate patient participation and trust in research, it is critical to ensure that SDSP design and oversight align with patients' values and address their concerns. We sought to qualitatively characterize patient preferences for the design of a pan-Canadian SDSP. METHODS: Between January 2022 and July 2023, we conducted pan-Canadian virtual focus groups with individuals who had a personal history of cancer. Following each focus group, participants were invited to provide feedback on early-phase analysis results via a member-checking survey. Three trained qualitative researchers analyzed data using thematic analysis. RESULTS: Twenty-eight individuals participated across five focus groups. Four focus groups were conducted in English and one in French. Thematic analysis generated two major and five minor themes. Analytic themes spanned personal and population implications of data sharing and willingness to manage perceived risks. Participants were supportive of increasing access to health data for precision oncology research, while voicing concerns about unintended data use, reidentification, and inequitable access to costly therapeutics. To mitigate perceived risks, participants highlighted the value of data access oversight and governance and informational transparency. CONCLUSION: Strategies for secured data sharing should anticipate and mitigate the risks that patients perceive. Participants supported enhancing timely research capability while ensuring safeguards to protect patient autonomy and privacy. Our study informs the development of data-governance and data-sharing frameworks that integrate real-world and trial data, informed by evidence from direct patient input.

Prospective cohort study of genomic newborn screening: BabyScreen+ pilot study protocol.

INTRODUCTION: Newborn bloodspot screening (NBS) is a highly successful public health programme that uses biochemical and other assays to screen for severe but treatable childhood-onset conditions. Introducing genomic sequencing into NBS programmes increases the range of detectable conditions but raises practical and ethical issues. Evidence from prospectively ascertained cohorts is required to guide policy and future implementation. This study aims to develop, implement and evaluate a genomic NBS (gNBS) pilot programme. METHODS AND ANALYSIS: The BabyScreen+ study will pilot gNBS in three phases. In the preimplementation phase, study materials, including education resources, decision support and data collection tools, will be designed. Focus groups and key informant interviews will also be undertaken to inform delivery of the study and future gNBS programmes. During the implementation phase, we will prospectively recruit birth parents in Victoria, Australia, to screen 1000 newborns for over 600 severe, treatable, childhood-onset conditions. Clinically accredited whole genome sequencing will be performed following standard NBS using the same sample. High chance results will be returned by genetic healthcare professionals, with follow-on genetic and other confirmatory testing and referral to specialist services as required. The postimplementation phase will evaluate the feasibility of gNBS as the primary aim, and assess ethical, implementation, psychosocial and health economic factors to inform future service delivery. ETHICS AND DISSEMINATION: This project received ethics approval from the Royal Children's Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023, HREC/90929/RCHM-2022 and HREC/91392/RCHM-2022. Findings will be disseminated to policy-makers, and through peer-reviewed journals and conferences.