Mastermind: A Comprehensive Genomic Association Search Engine for Empirical Evidence Curation and Genetic Variant Interpretation

Abstract

Design and interpretation of genome sequencing assays in clinical diagnostics and research labs is complicated by an inability to identify information from the medical literature and related databases quickly, comprehensively and reproducibly. This challenge is compounded by the complexity and heterogeneity of nomenclatures used to describe diseases, genes and genetic variants. Mastermind is a widely-used bioinformatic platform of genomic associations that has indexed more than 7.5 M full-text articles and 2.5 M supplemental datasets. It has automatically identified, disambiguated and annotated >6.1 M genetic variants and identified >50 K disease-gene associations. Here, we describe how Mastermind improves the sensitivity and reproducibility of clinical variant interpretation and produces comprehensive genomic landscapes of genetic variants driving pharmaceutical research. We demonstrate an alarmingly high degree of heterogeneity across commercially available panels for hereditary cancer that is resolved by evidence from Mastermind. We further examined the sensitivity of Mastermind for variant interpretation by examining 108 clinically-encountered variants and comparing the results to alternate methods. Mastermind demonstrated a sensitivity of 98.4% compared to 4.4, 45.6, and 37.4% for alternatives PubMed, Google Scholar, and ClinVar, respectively, and a specificity of 98.5% compared to 45.1, 57.6, and 68.8% as well as an increase in content yield of 22.6-, 2.2-, and 2.6-fold. When curated for clinical significance, Mastermind identified more than 4.9-fold more pathogenic variants than ClinVar for representative genes. For structural variants, we compared Mastermind's ability to sensitively identify evidence for 10 representative disease-causing CNVs versus results identified in PubMed, as well as its ability to identify evidence for fusion events compared to COSMIC. Mastermind demonstrated a 4.0- to 43.9-fold increase in references for specific CNVs compared to PubMed, as well as 5.4-fold more fusion genes when compared with COSMIC's curated database. Additionally, Mastermind produced an 8.0-fold increase in reference citations for fusion events common to Mastermind and outside databases. Taken together, these results demonstrate the utility and superiority of Mastermind in terms of both sensitivity and specificity of automated results for clinical diagnostic variant interpretation for multiple genetic variant types and highlight the potential benefit in informing pharmaceutical research.

Keywords: copy number variant; gene fusions; genome sequence analysis; oncology; rare disease; variant interpretation and classification.

FIGURE 1

Commercially available hereditary cancer panels show significant discrepancies. (A) Comparison of the genes targeted by Fulgent’s Full Comprehensive Cancer Panel (123 total genes), Ambry Genetics’ CustomNext-Cancer (68 total genes), and Centogene’s CentoCancer^® (56 total genes). 48 genes were found to be on all 3 panels. (B) Comparison of the genes targeted by Ambry Genetics’ CustomNext-Cancer (68 total genes), Centogene’s CentoCancer^® (56 total genes), and GeneDx’s Comprehensive Common Cancer Panel (46 total genes). 40 genes were found to be on all three panels. (C) Comparison of the genes targeted by Centogene’s CentoCancer^® (56 total genes), GeneDx’s Comprehensive Common Cancer Panel (46 total genes), and Otogenetics’ Comprehensive Inherited Cancer Panel (39 total genes). 27 genes were found to be on all three panels. (D) Comparison of the genes targeted by Counsyl’s Reliant^TM Cancer Screen (expanded panel; 36 total genes), Quest diagnostics’ MYvantage^® Hereditary Comprehensive Cancer Panel (34 total genes), and Color Genomics’ Hereditary Cancer Test (30 total genes). 27 genes were found to be on all three panels.

FIGURE 2

Representative screenshot of the Mastermind software interface. A representative screenshot depicting the results of a typical Mastermind variant search including the variant landscape for all variants in the searched for gene (upper left), the literature landscape results for the searched for variant (upper right; size of each icon reflects the relevance of the reference to the searched for content including categorized keywords) as well as context for the mention of the relevant search terms in the text of the specified reference (lower right).

FIGURE 3

Mastermind identifies a significant number of additional fusion gene partners than COSMIC. The number of unique fusion partners identified by Mastermind (blue) compared to results for those same genes identified in COSMIC (pink) from among genes routinely commercially tested for fusion events using the Illumina TruSight RNA fusion Sequencing Panel.