Next-generation sequencing at scale: Guided variant assessment
Genetic analysis requires taking the massive number of variants found in a next-generation sequencing (NGS) sample and bringing it down to a set of relevant candidates for further study. This is a potentially time-consuming process that can be made easier with the appropriate genetic analysis technology. Tools like variant management software can simplify and even automate much of the variant filtration process. That saves valuable time for both patients awaiting results and labs with increasing next-generation sequencing test volume.
The next step, interpreting the relevant variants, is a step that cannot be easily automated. Support for the classification of a variant of uncertain significance can be drawn from several sources, ranging from major research publications to the recent work of other laboratories. Evidence needs to be documented and weighted for significance, and made readily accessible to others who might contribute to the interpretation process. Obviously, the expertise of the geneticist or other lab personnel is indispensable.
Bringing order to the elements of variant interpretation
All that said, the complexity of variant assessment can still be made more efficient with technological tools. Corralling the bits of research, notes and other information used to build a case for variant classification can produce a jumble whether analysts use notebooks or virtual files. Workflow tools or databases not built for the elements of genetic analysis are not much of an improvement over sticky notes and binder clips.
A variant management tool designed to accommodate the process of variant assessment for next-generation sequencing results could keep all those pieces orderly, visible and easy to access. (The screenshot below shows one example of how this could look.) But tidiness is not the only advantage, or the most important one. Beyond providing an organized virtual workspace, a specially-designed variant assessment tool has the potential to help users make meaningful assertions with the evidence they’ve amassed, supporting and streamlining this critical step in genetic analysis.
Intelligently guided variant assessment
By way of example, imagine an analyst carefully building the evidence for a variant. A lab could draw from a variety of sources networked through the assessment tool’s information library, such as ClinVar, COSMIC, OMIM, and/or ExAC. Molecular diagnostic laboratories with data-sharing capabilities could also share clinically-validated variant interpretations directly, using de-identified data, to provide even more current information.
An intelligent tool, however, could go beyond just providing a database and actually help begin the process of applying evidence to rules. If that analyst’s chosen assertion methodology were the guidelines from the American College of Medical Genetics and Genomics, those ACMG rules would be pre-configured in the assessment tool. At the point of analysis, the system could then generate and satisfy some rules on a provisional basis, to reduce the time and effort of the analyst, who could then assess, add necessary evidence or interpretations, and finalize them. A more flexible tool could even allow for multiple assertion methods, to be selected on a case-by-case basis, including those from the College of American Pathologists or custom methods from that lab.
As the analyst begins to compile evidence, the tool would automatically calculate an overall score according to ACMG rules regarding strong, moderate or supporting evidence. In the example above, the different assertion method rules are highlighted on the bar so it’s easy to see how an assessment is progressing. When the evidence compilation is complete, a suggested calculated classification on the spectrum from benign to pathogenic would be proposed, though the analyst naturally has the option to make adjustments and attach his or her own notes or other supporting documents to explain the final interpretation.
Maximizing the promise of precision medicine
There’s no way around all of the intellectual labor of variant assessment, but the data, research and methods for assessment can be organized in a way that makes laboratory personnel’s labor more efficient. Not only does that lead to the capacity for greater lab volume of next-gen sequencing tests, it also helps ensure the accuracy and uniformity critical to clinically applied genetics. This accuracy and consistency may in fact be stipulated in future lab certification guidelines, rendering a variant assessment tool such as the one discussed here, even more valuable.
To learn more about the role of genetic informatics in making molecular diagnostics scalable, download our white paper, Molecular Diagnostics for Healthcare Facilities: How to Start and Scale an Efficient Testing Program.
About the author
Sr. Director Product Management and Marketing, Sunquest Mitogen
After cutting his teeth on the Human Genome Project, Nabil was hooked on genetics. Sixteen years later, his passion remains focused on enabling technologies to bring precision medicine to mainstream medicine.