Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Finding the right diagnosis for rare genetic diseases (RGDs) can be a long and expensive process. This study looked at how using exome sequencing (ES), a type of advanced genetic testing, in different stages of the diagnostic process affects the overall cost and effectiveness.We examined data from 305 patients suspected of having a RGD who underwent ES as part of a Canadian study. We compared five different testing strategies: no ES, ES as the first test, ES as the second test, ES as the third test, and ES as the fourth and final test. We wanted to see how these strategies impacted the success rate of finding a diagnosis, how quickly patients received their diagnosis, the total time spent on testing, and the expected total testing costs incurred.Our findings showed that using ES early in the diagnostic process significantly improves the chances of finding a diagnosis. Specifically, using ES as the first test led to the highest success rate, finding a diagnosis in 36% of cases compared to 20% when no ES was used. This approach provided the fastest results and was the least expensive. Testing costs were lowest when ES was the first test (CAD2458) and highest when ES was the last test (CAD6422).Overall, starting with ES as the first test is the most cost-effective and efficient strategy for diagnosing RGDs.
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.