CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

Online Knowledge Translation Program Involving Video Games and University Student-Led Tutorials About Cannabis and Psychosis for Black Youth: Mixed Method Feasibility Study.

BACKGROUND: We have piloted a new online knowledge translation (KT) program created to educate youth about cannabis effects, which uniquely focuses on mental health risks for Black youth. Youth are generally unaware of the research linking underage usage and the risk of psychosis. Youth from some Black racialized communities in Ontario may be disproportionately affected and in need of this knowledge. OBJECTIVE: Because very little is known about the acceptability and feasibility of programs educating Black youth about cannabis and psychosis risk, we evaluated this KT program, which consists of tutorials facilitated by university students and video games. METHODS: This mixed methods pilot study evaluates the transfer of knowledge about cannabis and psychosis risk before and after the online KT program and, at the same time, explores participant satisfaction with the program and views about underage use. Eligible participants were youth 16-19 years of age of Black African or Caribbean descent. Trained undergraduate students from McMaster University administered a quiz (psychosis and cannabis test; PCT) to evaluate knowledge before and after the KT program. After playing the psychoeducational video games, participants attended two tutorial group sessions led by undergraduate students. The undergraduate students facilitated the online tutorials about cannabis and psychosis. The tutorials augmented the educational content embedded within the gameplay: participants discussed what they learned from the video games and their understanding of psychosis and the effects of cannabis. In addition, undergraduate students qualitatively analyzed the tutorial discussions for themes, and the prequiz and postquiz scores were analyzed for significant differences in scores. RESULTS: A total of 9 Black youth were recruited and completed this pilot study. The mean PCT scores were 5.67 (SD 1.7) and 7.78 (SD 1.8) before and after the KT program, respectively. There was a significant improvement in scores (P<.05) post-KT program. Thematic analysis of the facilitated tutorials revealed three major themes: video game satisfaction, marijuana and psychosis literacy, and help-seeking awareness. Overall, participants showed an increased awareness and understanding of the subject matter after the gameplay and tutorial intervention. CONCLUSIONS: When supplemented with tutorial sessions, the Back to Reality Series shows promise for addressing the gap in knowledge about cannabis and psychosis, and the results provide preliminary evidence that the games appeal to Black youth.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.