Calibrating variant curation by clinical context based on factors that influence patients' tolerance of uncertainty.

PURPOSE: Shared decision making manages genomic uncertainty by integrating molecular and clinical uncertainties with patient values to craft a person-centered management plan. Laboratories seek genomic report consistency, agnostic to clinical context. Molecular reports often mask laboratory-managed uncertainties from clinical decision making. Better integration of these uncertainty management strategies requires a nuanced understanding of patients' perceptions and reactions to test uncertainties. We explored patients' tolerance to variant uncertainty in 3 parameters: (1) relative causal significance, (2) risk accuracy, and (3) classification validity. METHOD: Deliberative forums were undertaken with 18 patients with predictive testing experience. Uncertainty deliberations were elicited for each parameter. A thematic framework was first developed, and then mapped to whether they justified tolerance to more or less parameter-specific uncertainty. RESULTS: Six identified themes mapped to clinical and personal domains. These domains generated opposing forces when calibrating uncertainty. Personal themes justified tolerance of higher uncertainty and clinical themes lower uncertainty. Decision making in uncertainty focused on reducing management regret. Open communication increased tolerance of classification validity and risk accuracy uncertainty. Using these data, we have developed a nascent clinical algorithm integrating molecular uncertainty with clinical context through a targeted communication framework. CONCLUSION: Maximizing test utility necessitates context-specific recalibration of uncertainty management and communication.

Development of a person-centred digital platform for the long-term support of people living with an adult-onset genetic disease predisposition: a mixed-methods study protocol.

INTRODUCTION: Individuals at an inherited high-risk of developing adult-onset disease, such as breast cancer, are rare in the population. These individuals require lifelong clinical, psychological and reproductive assistance. After a positive germline test result, clinical genetic services provide support and care coordination. However, ongoing systematic clinical follow-up programmes are uncommon. Digital health solutions offer efficient and sustainable ways to deliver affordable and equitable care. This paper outlines the codesign and development of a digital health platform to facilitate long-term clinical and psychological care, and foster self-efficacy in individuals with a genetic disease predisposition. METHODS AND ANALYSIS: We adopt a mixed-methods approach for data gathering and analysis. Data collection is in two phases. In phase 1, 300 individuals with a high-risk genetic predisposition to adult disease will undertake an online survey to assess their use of digital health applications (apps). In phase 2, we will conduct focus groups with 40 individuals with a genetic predisposition to cardiac or cancer syndromes, and 30 clinicians from diverse specialities involved in their care. These focus groups will inform the platform's content, functionality and user interface design, as well as identify the barriers and enablers to the adoption and retention of the platform by all endusers. The focus groups will be audiorecorded and transcribed, and thematic and content data analysis will be undertaken by adopting the Unified Theory of Acceptance and Use of Technology. Descriptive statistics will be calculated from the survey data. Phase 3 will identify the core skillsets for a novel digital health coordinator role. Outcomes from phases 1 and 2 will inform development of the digital platform, which will be user-tested and optimised in phase 4. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/88892/PMCC). Results will be disseminated in academic forums, peer-reviewed publications and used to optimise clinical care.

Heterogeneity in how women value risk-stratified breast screening.

PURPOSE: Risk-stratified screening has potential to improve the cost effectiveness of national breast cancer screening programs. This study aimed to inform a socially acceptable and equitable implementation framework by determining what influences a woman's decision to accept a personalized breast cancer risk assessment and what the relative impact of these key determinants is. METHODS: Multicriteria decision analysis was used to elicit the relative weights for 8 criteria that women reported influenced their decision. Preference heterogeneity was explored through cluster analysis. RESULTS: The 2 criteria valued most by the 347 participants related to program access, "Mode of invitation" and "Testing process". Both criteria significantly influenced participation (P < .001). A total of 73% preferred communication by letter/online. Almost all women preferred a multidisease risk assessment with potential for a familial high-risk result. Four preference-based subgroups were identified. Membership to the largest subgroup was predicted by lower educational attainment, and women in this subgroup were concerned with program access. Higher relative perceived breast cancer risk predicted membership to the smallest subgroup that was focused on test parameters, namely "Scope of test" and "Test specificity". CONCLUSION: Overall, Australian women would accept a personalized multidisease risk assessment, but when aligning with their preferences, it will necessitate a focus on program access and the development of online communication frameworks.

Exploring Implementation of Personal Breast Cancer Risk Assessments.

Personal Breast Cancer (BC) Risk Assessments (PBCRA) have potential to stratify women into clinically-actionable BC risk categories. As this could involve population-wide genomic testing, women's attitudes to PBCRA and views on acceptable implementation platforms must be considered to ensure optimal population participation. We explored these issues with 31 women with different BC risk profiles through semi-structured focus group discussions or interviews. Inductive thematic coding of transcripts was performed. Subsequently, women listed factors that would impact on their decision to participate. Participants' attitudes to PBCRA were positive. Identified themes included that PBCRA acceptance hinges on result actionability. Women value the ability to inform decision-making. Participants reported anxiety, stress, and genetic discrimination as potential barriers. The age at which PBCRA was offered, ease of access, and how results are returned held importance. Most women value the opportunity for PBCRA to inform increased surveillance, while highlighting hesitance to accept reduced surveillance as they find reassurance in regular screening. Women with BRCA pathogenic variants value the potential for PBCRA to identify a lower cancer risk and potentially inform delayed prophylactic surgery. This study highlights complexities in adopting advances in BC early detection, especially for current users who value existing processes as a social good.