Clinically Responsive Genomic Analysis Pipelines: Elements to Improve Detection Rate and Efficiency

J Mol Diagn. 2021 Jul;23(7):894-905. doi: 10.1016/j.jmoldx.2021.04.007. Epub 2021 May 5.


Massively parallel sequencing has markedly improved mendelian diagnostic rates. This study assessed the effects of custom alterations to a diagnostic genomic bioinformatic pipeline in response to clinical need and derived practice recommendations relative to diagnostic rates and efficiency. The Genomic Annotation and Interpretation Application (GAIA) bioinformatics pipeline was designed to detect panel, exome, and genome sample integrity and prioritize gene variants in mendelian disorders. Reanalysis of selected negative cases was performed after improvements to the pipeline. GAIA improvements and their effect on sensitivity are described, including addition of a PubMed search for gene-disease associations not in the Online Mendelian Inheritance of Man database, inclusion of a process for calling low-quality variants (known as QPatch), and gene symbol nomenclature consistency checking. The new pipeline increased the diagnostic rate and reduced staff costs, resulting in a saving of US$844.34 per additional diagnosis. Recommendations for genomic analysis pipeline requirements are summarized. Clinically responsive bioinformatics pipeline improvements increase diagnostic sensitivity and increase cost-effectiveness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cost-Benefit Analysis
  • Exome
  • Exome Sequencing / economics
  • Exome Sequencing / methods*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Testing / economics
  • Genetic Testing / methods*
  • Genome, Human
  • Genomics / economics
  • Genomics / methods*
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing / economics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • INDEL Mutation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Sensitivity and Specificity