The impact of next-generation sequencing on diagnosis and management of children with epilepsy: from molecular testing to cost-effectiveness analysis

Tran, Ha Thi Thu (2020) The impact of next-generation sequencing on diagnosis and management of children with epilepsy: from molecular testing to cost-effectiveness analysis. Masters thesis, Memorial University of Newfoundland.

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Abstract

Genetic testing is essential for diagnosis and treatment selection for children with epilepsy. Conventional approaches to genetic testing such as chromosomal microarray (CMA), and single-gene sequencing are time-consuming and expensive. Meanwhile, next-generation sequencing (NGS) allows simultaneous examination of all or most genes, which permits comprehensive and timely diagnosis of genetic etiology. Although NGS methods such as epilepsy panel (EP), whole-exome sequencing (WES), and whole-genome sequencing (WGS) are increasingly used, there is limited evidence about their diagnostic yield, clinical utility, and the cost-effectiveness of NGS-incorporated diagnostic strategies. The goal of this thesis, therefore, is two-fold: first, to conduct a systematic review and a meta-analysis of diagnostic yield and clinical utility of EP, WES, and WGS in comparison with CMA in pediatric epilepsy and second, to evaluate the cost-effectiveness of different NGS-incorporated diagnostic strategies from the health care system’s perspective. A systematic review of PUBMED and EMBASE database identified 56 studies investigating diagnostic yields of EP, WES, WGS, and CMA (Chapter 2). Our random-effects meta-analysis of these 56 studies revealed that diagnostic yield was highest for WGS (0.66; 95% CI 0.00-1.00, two studies, 211 children, I² =99%), followed by WES (0.37; 95% CI 0.30-0.44, eighteen studies, 1322 children, I² =86%), and EP (0.25; 95% CI 0.22-0.28, thirty five studies, 14,265 children, I² =86%). CMA provided the lowest diagnostic yield (0.10; 95% CI 0.07-0.13, seventeen studies, 2,306 children, I² =85%). Clinical utility regarding to clinical management of WES (0.15, 95% CI 0.09-0.22, p=0.15, two studies of 289 children) was higher than that of EP (0.10, 95% CI 0.07-0.13, p<0.01, eleven studies of 11,044 children). Given their high diagnostic yield and clinical utility, NGS should be adopted in routine genetic investigation of pediatric epilepsy. A decision-analytic model was developed to evaluate the cost-effectiveness of EP and WES in diagnosis and clinical management of epilepsy (Chapter 3). All EP and WES-related strategies were more effective than conventional diagnostic strategy. Among all diagnostic strategies, “WES as second-tier test” was the most cost-effective (ICER of 26,070 CAD per QALY). I also found that although the “WES and CMA as first-tier tests” strategy generated the highest QALYs, it was not cost-effective relative to “WES as second-tier test” (ICER > 100,000 CAD per QALY). Given the high cost of WES, “WES and CMA as first-tier tests” could become a cost-effective strategy when cost of WES decreases or the proportion of patients with etiology identified by WES and CMA increases.

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