Exome Sequencing in the Diagnostic Pathway for Suspected Rare Genetic Diseases: Does the Order of Testing Affect its...

Patients with suspected rare diseases often experience lengthy and uncertain diagnostic pathways. This study aimed to estimate the cost-effectiveness of exome sequencing (ES) in different positions in the diagnostic pathway for patients suspected of having a rare genetic disease.

Data collected retrospectively from 305 patients suspected of having a rare genetic disease (RGD), who received clinical-grade ES and participated in the Canadian multicentre Care4Rare-SOLVE study, informed a discrete event simulation of the diagnostic pathway. We distinguished between tests that can lead to the diagnosis of a specific RGD ('indicator tests') and more routine non-RGD diagnostic tests ('non-indicator tests'). Five strategies were considered: no-ES, and ES as 1st, 2nd, 3rd, or 4th test (Tier 1, Tier 2, Tier 3, and Tier 4, respectively), where ES was the final test in the diagnostic pathway if included. Outcomes included the diagnostic yield, time-to-diagnosis, time on the diagnostic pathway, and test costs for each strategy. The cost-effectiveness analysis from a Canadian healthcare system perspective was conducted with diagnostic yield as the primary outcome of interest. Probabilistic analyses and expert-defined scenario analyses quantified uncertainty.

Implementing ES increases the diagnostic yield by 16 percentage points from 20% with no-ES to 36%. Exome sequencing, as the first test (Tier 1), resulted in the shortest time to a diagnosis and the lowest testing cost. Mean testing costs per patient were CAD4347 (95% CI 3925, 4788) for no-ES, CAD2458 (95% CI 2406, 2512) for Tier 1, CAD3851 (95% CI 3684, 4021) for Tier 2, CAD5246 (95% CI 4956, 5551) for Tier 3 and CAD6422 (95% CI 5954, 6909) for Tier 4, with Tier 1 having the highest diagnostic yield at the lowest cost. The scenario analyses yielded results consistent with those of the base case.

Implementing ES to diagnose patients suspected of having a RGD can result in a higher diagnostic yield. Although a limitation of our study was that the yield for the non-ES indicator tests was estimated using expert opinion due to a lack of available data, the results underscore the value of ES as a first-line diagnostic test, offering reduced time to diagnosis and lower overall testing costs.