Results:
Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57; 0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29) and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of US$15 000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: US$15 848/diagnosis) followed by WES (ICER: US$34 500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: US$15 336/diagnosis); although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: US$18 385/diagnosis). Although the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.