Clinical NGS software exhibits higher consistency than human NGS variant interpretation

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Significant efforts are being made to standardize the interpretation of NGS somatic variants between clinical laboratories. A new study suggests clinical decision support software will be key.

GenQA conducts blind study to assess variant classifications between labs and software

QCI Interpret is a clinical decision support software that enables pathologists to identify biologically and clinically relevant oncology-related variants. The application draws on a large knowledgebase of curated information, coupled with an expert interpretation service to classify variant pathogenicity and actionability based on the ACMG and AMP guidelines.

To validate the accuracy and consistency of QCI Interpret’s somatic variant classification, GenQA, an external quality assessment organization, designed and executed a study published in the Journal of Molecular Pathology that compared the use of QCI Interpret to internal variant interpretation methods of 8 laboratories who regularly perform next-generation sequencing of oncology samples.

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Each lab was assigned a set of 5 or 10 VCF files to analyze using their current analysis methods and an additional set of files to analyze using QCI Interpret.
Analysis was limited to genes listed in the Illumina TruSight Oncology 500 assay.
The 8 labs were asked to determine which variants they would report and what “Tier” would be assigned to each variant, as described by AMP/ASCO/CAP in Li et al. 2017 (1).

Comparing QCI Interpret to human variant asessments

GenQA collected and analyzed the data from the 8 laboratories. The variants reported and classified using QCI Interpret were compared to the variants reported and classified using independent methods. Conflicts were resolved using a panel of experts.

A total of 77 VCFs containing 217,718 variants were collected and analyzed.

91%

QCI Interpret's automated somatic NGS variant assessment demonstrated 91% concordance with human expert classifications.

28%

In contrast, 41/149 variants (28%) reflected discrepancy among human reviewers. The expert panel was unable to reach resolution on 8 variants.

19%

The rate of disagreement among laboratories and the expert panel was 19% greater than the disagreement between QCI Interpret and expert assessment.

"QCI Interpret can help to reliably streamline and standardize somatic variant interpretation and address the high degree of variability among experts in somatic clinical interpretation. It provides consistency in interpretation, which exceeds the consistency among variant scientists."

- Fairley et al. (2022), Journal of Molecular Pathology

Read the white paper from the article in the Journal of Molecular Pathology

Learn more about the study, including the sources of discrepancies and methods of variant analysis

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References

Li et al (2017). Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. The Journal of molecular diagnostics : JMD, 19(1), 4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002