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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.