A fully-automated event-based variant prioritizing solution to the CAGI5 intellectual disability gene panel challenge

Abstract

Recent applications of gene panel sequencing analysis have significantly helped with identifying genetic causes for inherited diseases. However, large amounts of candidate variants remain a major challenge for prioritizing, often requiring arbitrary cutoffs in multiple steps. In addition, existing tools often prioritize a list of promising candidates that require much manual work to evaluate. To this end, we designed an automated, basically cutoff-free scoring scheme named Context and Hereditary Event based Scoring Scheme (CHESS), that scores all possible inheritance events in each gene, by taking into consideration phenotypes, genotypes, and how the manual prioritization works. We applied CHESS to the Critical Assessment of Genome Interpretation 5 intellectual disability panel challenge, to assign clinical phenotypes to patients based on gene panel sequencing data. Through this blind testing, CHESS proved to be a leading and useful tool for genetic diagnosis in a research setting. Further analyses showed that precise phenotype terms played an important role in variant prioritization and that multiple etiologies may exist for some patients. CHESS also successfully identified many of the causal, putative and contributing variants. In the postchallenge analysis, we showed that our best submission performed slightly better than the predictions made by a state-of-the-art tool. We believe that CHESS can provide aid to this and many other diagnostic scenarios.

Keywords: gene panel sequencing; genetic diagnosis; intellectual disability; variant prioritization.

FIGURE 1

The workflow for predictions made by CHESS. The left half of this figure shows the scheme of the solution to the CAGI intellectual disability gene panel challenge. The right half of this figure shows the process of input data preparation and the CHESS scoring steps (the box by dotted line). CAGI, Critical Assessment of Genome Interpretation; CHESS, Context and Hereditary Event based Scoring Scheme

FIGURE 2

The ROC curves of the three submissions. The light blue line represents CHESS “Medium Stringent”; the dark blue line represents CHESS “stringent”; the orange line represents CHESS “less stringent”. CHESS, Context and Hereditary Event based Scoring Scheme; ROC, receiver operating characteristic

FIGURE 3

(a) Comparisons of prediction performances (quantified by AUCs) of CHESS “less stringent” versus “random median.” “Random median” refers to the median value of 1,000 times randomizations. The randomization was done by shuffling of case IDs. Performances for all seven disease terms as well as the term “ataxia” are shown here. (b) The distribution of phenotype match scores of all the genes in the gene panel, for each of the seven disease terms as well as the additional term “ataxia.” AUCs, areas under the ROC curve; CHESS, Context and Hereditary Event based Scoring Scheme

FIGURE 4

Comparisons of prediction performances (quantified by AUCs) of CHESS “less stringent” versus Exomiser “Top 2”. Performances for all seven disease terms are shown here. AUCs, areas under the ROC curve; CHESS, Context and Hereditary Event based Scoring Scheme