Standardized benchmarking methods and tools are essential to robust accuracy assessment of NGS variant calling. Benchmarking variant calls requires careful attention to definitions of performance metrics, sophisticated comparison approaches, and stratification by variant type and genome context. To address these needs, the Global Alliance for Genomics and Health (GA4GH) Benchmarking Team convened representatives from sequencing technology developers, government agencies, academic bioinformatics researchers, clinical laboratories, and commercial technology and bioinformatics developers for whom benchmarking variant calls is essential to their work. This team addressed challenges in (1) matching variant calls with different representations, (2) defining standard performance metrics, (3) enabling stratification of performance by variant type and genome context, and (4) developing and describing limitations of high-confidence calls and regions that can be used as “truth”. Our methods are publicly available on GitHub (https://github.com/ga4gh/benchmarking-tools) and in a web-based app on precisionFDA, which allow users to compare their variant calls against truth sets and to obtain a standardized report on their variant calling performance. Our methods have been piloted in the precisionFDA variant calling challenges to identify the best-in-class variant calling methods within high-confidence regions. Finally, we recommend a set of best practices for using our tools and critically evaluating the results.

Background Clinical interpretation of genetic variants in the context of the patient’s phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation. Methods We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole-genome or whole-exome sequencing (WGS, WES). We replicated our analyses in a separate cohort of 60 cases collected from five academic medical centers. For comparison, we also analyzed these cases with current state-of-the-art variant prioritization tools. Included in the comparisons were trio, duo, and singleton cases. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted from clinical notes by two means: manually and using an automated clinical natural language processing (CNLP) tool. Finally, 14 previously unsolved cases were reanalyzed. Results GEM ranked over 90% of the causal genes among the top or second candidate and prioritized for review a median of 3 candidate genes per case, using either manually curated or CNLP-derived phenotype descriptions. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top candidate and in 19/20 within the top five, irrespective of whether SV calls were provided or inferred ab initio by GEM using its own internal SV detection algorithm. GEM showed similar performance in absence of parental genotypes. Analysis of 14 previously unsolved cases resulted in a novel finding for one case, candidates ultimately not advanced upon manual review for 3 cases, and no new findings for 10 cases. Conclusions GEM enabled diagnostic interpretation inclusive of all variant types through automated nomination of a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing cost and expediting case review.

A new study highlights the biases and inaccuracies of polygenic risk scores (PRS) when predicting disease risk in individuals from populations other than those used in their derivation. The design bias of workhorse tools used for research, particularly genotyping arrays, contributes to these distortions. To avoid further inequities in health outcomes, the inclusion of diverse populations in research, unbiased genotyping, and methods of bias reduction in PRS are critical.

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The COVID-19 pandemic brought a new set of unprecedented challenges not only for healthcare, education, and everyday jobs but also in terms of academic conferences. In this study, we investigate the effect of the broad adoption of virtual platforms for academic conferences as a response to COVID-19 restrictions. We show that virtual platforms enable higher participation from underrepresented minority groups, increased inclusion, and broader geographic distribution. We also discuss emerging challenges associated with the virtual conference format resulting in a decreased engagement of social activities, limited possibilities of cross-fertilization between participants, and reduced peer-to-peer interactions. Lastly, we conclude that a novel comprehensive approach needs to be adopted by the conference organizers to ensure increased accessibility, diversity, and inclusivity of post-pandemic conferences. Our findings provide evidence favoring a hybrid format for future conferences, marrying the strength of both in-person and virtual platforms.

Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed interpretation by comprehensively evaluating genetic variants for pathogenicity in the context of the growing knowledge of genetic disease. We assess the diagnostic performance of GEM, a new, AI-based, clinical decision support tool, compared with expert manual interpretation. We benchmarked GEM in a retrospective cohort of 119 probands, mostly NICU infants, diagnosed with rare genetic diseases, who received whole genome sequencing (WGS) at Rady Children's Hospital. We also performed a replication study in a separate cohort of 60 cases diagnosed at five additional academic medical centers. For comparison, we also analyzed these cases with commonly used variant prioritization tools (Phevor, Exomiser, and VAAST). Included in the comparisons were WGS and whole exome sequencing (WES) as trios, duos, and singletons. Variants underpinning diagnoses spanned diverse modes of inheritance and types, including structural variants (SVs). Patient phenotypes were extracted either manually or by automated clinical natural language processing (CNLP) from clinical notes. Finally, 14 previously unsolved cases were re-analyzed. GEM ranked >90% of causal genes among the top or second candidate, using manually curated or CNLP derived phenotypes, and prioritized a median of 3 genes for review per case. Ranking of trios and duos was unchanged when analyzed as singletons. In 17 of 20 cases with diagnostic SVs, GEM identified the causal SVs as the top or second candidate irrespective of whether SV calls where provided or inferred ab initio by GEM when absent. Analysis of 14 previously unsolved cases provided novel findings in one, candidates ultimately not advanced in 3, and no new findings in 10, demonstrating the utility of GEM for reanalysis. GEM enables automated diagnostic interpretation of WES and WGS for all types of variants, including SVs, nominating a very short list of candidate genes and disorders for final review and reporting. In combination with deep phenotyping by CNLP, GEM enables substantial automation of genetic disease diagnosis, potentially decreasing the cost and speeding case review.

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Purpose: Prior research in the molecular correlates of disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity have typically used self-reported or observed categories, which can be missing or inaccurate. Furthermore, race and ethnicity do not always capture genetic similarity well, particularly in admixed populations. To overcome these limitations, we examined associations of CRC tumor molecular profiles with genetic ancestry. Experimental Design: Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8,454 CRC patients. Genetic ancestry proportions were estimated for five continental groups, Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS), using ancestry informative markers. We assessed association of genetic ancestry proportions and genetic ancestry-imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in expression profiles, including consensus molecular subtypes (CMS). Results: Increased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the non-Hispanic Black category were associated with higher than expected CMS3, while patients in the Hispanic/Latino category had higher indeterminate CMS. Conclusions: Use of genetic ancestry enables identification of molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity, and suggests that subtype classifications such as CMS may benefit from more diversity in representation.