Next-Generation Sequencing in Infectious-Disease Diagnostics: Economic, Regulatory, and Clinical Pathways to Adoption

Next-generation sequencing (NGS) has emerged as a transformative tool for infectious disease diagnosis, offering broad pathogen detection, antimicrobial resistance profiling, and syndromic panel testing. However, widespread clinical adoption remains hindered by insurance reimbursement challenges, high costs, and regulatory barriers. Unlike polymerase chain reaction (PCR), which enjoys well-established Current Procedural Terminology (CPT) codes and reimbursement pathways, many NGS-based tests lack standardized billing mechanisms, discouraging laboratories from integrating NGS into routine diagnostics. This article explores the economic, clinical, and technological considerations of targeted amplicon sequencing (tNGS) versus PCR and whole-genome sequencing (WGS), demonstrating how optimized multiplexing strategies, emerging NGS platforms, and regulatory advancements can enhance feasibility. It is argued that insurance policies must evolve to recognize NGS's superior clinical utility in detecting polymicrobial infections, emerging pathogens, and antimicrobial resistance determinants, ultimately improving patient outcomes and reducing healthcare costs. Current reagent-only costs now average US $65 per microbial genome, US $600 per 30× human genome, and US $130-600 per metagenomic sample when multiplexed; these figures continue to fall with higher multiplexing. To accelerate equitable adoption, we recommend near-term payer coverage pilots for clearly defined clinical indications, dedicated CPT pathways for infectious-disease sequencing (including metagenomic assays), and pragmatic validation frameworks that acknowledge genotype-phenotype limits while leveraging multiplexing and centralized reference workflows.