Principles and Recommendations for Standardizing the Use of the Next-Generation Sequencing Variant File in Clinical Settings

Abstract

A national workgroup convened by the Centers for Disease Control and Prevention identified principles and made recommendations for standardizing the description of sequence data contained within the variant file generated during the course of clinical next-generation sequence analysis for diagnosing human heritable conditions. The specifications for variant files were initially developed to be flexible with regard to content representation to support a variety of research applications. This flexibility permits variation with regard to how sequence findings are described and this depends, in part, on the conventions used. For clinical laboratory testing, this poses a problem because these differences can compromise the capability to compare sequence findings among laboratories to confirm results and to query databases to identify clinically relevant variants. To provide for a more consistent representation of sequence findings described within variant files, the workgroup made several recommendations that considered alignment to a common reference sequence, variant caller settings, use of genomic coordinates, and gene and variant naming conventions. These recommendations were considered with regard to the existing variant file specifications presently used in the clinical setting. Adoption of these recommendations is anticipated to reduce the potential for ambiguity in describing sequence findings and facilitate the sharing of genomic data among clinical laboratories and other entities.

Clinical Genome Data Model (cGDM) provides Interactive Clinical Decision Support for Precision Medicine

“…When conducting bioinformatics analyses, there is no requirement for unification among the processes, since the internal consistency within each process guarantees scientific rigour. Moreover, the flexible data specifications used in the bioinformatics field have the advantage of supporting various research applications 7 , but that advantage becomes an obstacle to data integration for comprehensive clinical decision making. In addition, relevant external knowledge, tools, platforms, and analytical techniques cannot be unified because they are still under development.…”

“…Here, we define a genomic test as a series of team-based information production processes, in which the meaning of the information is expanded, represented, and reproduced by reference to an external knowledge base, rather than through direct extraction of inherent information. Despite the invariant nature of a personal genome, genomic information presented to a clinician may vary according to specific processing protocols adopted 7,25,26,41 . This variability raises reliability issues for the use of genomic test results as clinical evidence 42 .…”

“…First, a mismatch exists between the structure of genomic and clinical data. Genomic data based on next-generation sequencing (NGS) technology is stored as a number of file types at various stages of the bioinformatics analysis, with flexible file specifications to accommodate the broad range of research interests in bioinformatics 7 . Raw genomic data can contain up to several tens of gigabytes of sequence information, each stored as a long string of data, and therefore cannot be used directly in this form in clinical practice without further processing.…”

Clinical Implementation and Validation of Automated Human Genome Variation Society (HGVS) Nomenclature System for Next-Generation Sequencing–Based Assays for Cancer

“…1 This is further complicated by the fact that variant representation in the genomic coordinate space follows the most 5 0 orientation (left-alignment), resulting in inconsistent variant nomenclature when converted from genomic to coding DNA space. 13 Variants that pose such conversion challenges were included in the validation cohort. Although a large number of variants included in the cohort were clinically important, intronic and splice site variants for which it is technically difficult to generate the HGVS nomenclature were also included.…”

Analysis and Annotation of Whole‐Genome or Whole‐Exome Sequencing Derived Variants for Clinical Diagnosis

“…In the clinic, the process is an end‐to‐end process that is fixed and not subject to any alteration until the next validated release (Richards et al., ). A number of reviews on the strengths, challenges, and limitations and for current progress on clinical interpretation practices have been written (Bowdin et al., ; Gargis et al., ; Lubin et al., ; O'Daniel et al., ; O'Daniel et al., ).…”