Clinical utility of exome sequencing: Post-exome testing decision changes in the management of children with suspected rare genetic disease.

Abstract

This study investigates a previously unquantified aspect of health economic evaluations of exome sequencing (ES): post-ES testing decision change (P-TDC), a measure of clinical utility that captures how ES influences downstream decisions regarding ordering and avoiding tests. A decision analytic simulation model was developed for 523 pediatric patients with suspected rare genetic diseases, simulating 4 strategies (ES positioned from first to fourth in the diagnostic testing sequence). The primary outcome was P-TDC, defined as the proportion of patients whose diagnostic tests were influenced (ordered or avoided) by ES. Cost-effectiveness was evaluated alongside costs modeled from the Canadian healthcare perspective in 2023 Canadian dollars. Using ES as a first-tier test produced the highest P-TDC, 0.94 (95% CI: 0.8-1.00), and the lowest cost, $3414 (95% CI: $3296-$3540), compared with lower P-TDC and higher costs when ES was delayed (fourth-tier: lowest P-TDC = 0.71 [95% CI: 0.62-0.80], highest cost = $10,026 [95% CI: $9,400-$10,745]). Diagnostic yield remained constant across strategies (0.34), whereas time to diagnosis increased from 1.63 to 3.57 years across the second through fourth tiers. Early ES reduces costs, accelerates diagnosis, and most strongly influences clinical decision-making. P-TDC offers a practical, quantifiable measure of clinical utility for genomic economic evaluations.