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A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data.

ABSTRACT: Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services.

SUBMITTER: Stark Z

PROVIDER: S-EPMC5643958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This paper proposes a task-driven computational framework for assessing diffusion MRI experimental designs which, rather than relying on parameter-estimation metrics, directly measures quantitative task performance. Traditional computational experimental design (CED) methods may be ill-suited to experimental tasks, such as clinical classification, where outcome does not depend on parameter-estimation accuracy or precision alone. Current assessment metrics evaluate experiments' ability to faithfully recover microstructural parameters rather than their task performance. The method we propose addresses this shortcoming. For a given MRI experimental design (protocol, parameter-estimation method, model, etc.), experiments are simulated start-to-finish and task performance is computed from receiver operating characteristic (ROC) curves and associated summary metrics (e.g. area under the curve (AUC)). Two experiments were performed: first, a validation of the pipeline's task performance predictions against clinical results, comparing in-silico predictions to real-world ROC/AUC; and second, a demonstration of the pipeline's advantages over traditional CED approaches, using two simulated clinical classification tasks. Comparison with clinical datasets validates our method's predictions of (a) the qualitative form of ROC curves, (b) the relative task performance of different experimental designs, and (c) the absolute performance (AUC) of each experimental design. Furthermore, we show that our method outperforms traditional task-agnostic assessment methods, enabling improved, more useful experimental design. Our pipeline produces accurate, quantitative predictions of real-world task performance. Compared to current approaches, such task-driven assessment is more likely to identify experimental designs that perform well in practice. Our method is not limited to diffusion MRI; the pipeline generalises to any task-based quantitative MRI application, and provides the foundation for developing future task-driven end-to end CED frameworks.

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A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data.

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