This presentation from Broad Clinical Labs details their efforts to integrate rapid whole-genome sequencing (rWGS) into practical clinical applications, specifically for critically ill neonates in the intensive care unit (NICU). Leveraging a collaboration with Roche Sequencing and their Nanopore and Expandimer sequencer (SBX chemistry), the Broad team established and optimized a high-speed, high-accuracy workflow. They demonstrated the system's ability to reliably detect causative small variants, copy number variations, and repeat expansions in patient cell lines and previously diagnosed clinical samples. Through iterative process improvements, they achieved impressive turnaround times, performing trio sequencing (three genomes) from DNA input to variant calls in as little as 7 hours and 8 minutes with consistent >30x coverage. The successfully generated data was also integrated into a clinical tertiary analysis platform, demonstrating effective variant prioritization. The presentation concludes by outlining future work with Roche to further refine bioinformatics, automate workflows, expand tertiary analysis integration, and ultimately implement rWGS for routine patient care within a single day.
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0:06 Clinical Application Focus: Broad Clinical Labs (part of the Broad Institute) is focused on translating advanced genomic technologies into practical clinical applications, particularly rapid whole-genome sequencing.
0:26 Broad Institute's Role: As a major U.S. sequencing center, Broad serves as a "proving ground" for new technologies, engaging with vendors early in their development, and contributes significantly to public genomic data resources.
1:51 Roche Collaboration: A key partnership involves the Roche Nanopore and Expandimer sequencer (SBX chemistry), which demonstrated initial impressive claims for accuracy, speed, and scalability.
3:31 NICU Rapid Genome Application: The primary clinical focus for this technology is rapid whole-genome sequencing (rWGS) in Neonatal Intensive Care Units (NICU), where early diagnosis is critical for patient management, despite current "rapid" tests still taking days to a week.
5:22 Workflow Speed Optimization: After receiving the system in January, the team quickly established a workflow, initially achieving 3-sample runs from DNA to variant calls in 12 hours and 10 minutes.
6:09 High Performance Metrics: The system demonstrated strong performance, with good quality scores and effective detection of Single Nucleotide Variants (SMVs) and indels, even in challenging regions like homopolymers and extreme GC content.
6:25 Causative Variant Detection: Across various patient cell lines and previously diagnosed clinical samples (including inborn errors of metabolism, large copy number events, and repeat expansions), the system consistently detected causative variants.
7:32 Single-Sample Speed Breakthrough: Optimized single-sample rWGS achieved a turnaround time of 6 hours and 25 minutes, with further improvements reported by Roche reaching 4 hours and 25 minutes.
8:08 Trio Sample Optimization (Clinical Utility): Recognizing the clinical importance of trio sequencing (mom, dad, proband) for variant interpretation, the team optimized 3-sample runs to 8 hours and 2 minutes, later refining it to a consistent 7 hours and 8 minutes, all with >30x coverage.
11:39 Tertiary Analysis Integration: Data from the sequencing was successfully loaded into Broad Clinical Labs' clinical tertiary analysis platform (Fabric Genomics), demonstrating effective prioritization of causative variants.
14:11 Future Collaboration Goals: Ongoing work with Roche aims to further optimize bioinformatics for complex variants, streamline and automate workflows, expand integration with various tertiary analysis platforms, and validate an end-to-end process to implement routine, single-day rWGS for patient care.
15:35 Acknowledging Teamwork: The speaker credits the significant contributions of their Broad team and highlights the exceptional, "startup-like" partnership with the Roche sequencing team.