Background: Laboratory sample transport in low and middle income countries is constrained by poor roads, difficult geographical terrain, and insecurity. This often leads to delayed laboratory diagnostic turn-around times, and hampers epidemic control or patient treatment efforts. While unmanned aerial systems (UAS), commonly known as drones, may mitigate some of these transportation constraints, their cost-effectiveness relative to land-based transportation systems is unclear. Methods: We compared the costs and cost-effectiveness of UAS versus motorcycles in Liberia for laboratory sample transportation under routine and public health emergency conditions. We modeled three UAS systems with operational ranges of 30 km, 65 km, and 100 km, and compared them to an established motorcycle transport system. We included personnel, equipment, maintenance, and training costs, and conducted univariate and probabilistic sensitivity analyses for equipment operational lifespans, operational range, and accident/failure rates. Findings: Under the routine scenario, the per sample transport costs are $0·65 ($0·10:$2·85) for motorcycles and $0·82 ($0·66:$5·05) for UAS. Per sample costs under the emergency scenario are $24·06 ($21·14:$28·20) for motorcycles and $34·09 ($26·70: $127·40) for UAS. Motorcycles are more cost-effective than UAS under most scenarios with the exception of 100 km range aircraft with operational lifespans of more than 3,000 hours and prices less than $15,000. Interpretation: Given the current level of technology, purchase prices, equipment lifespans, and operational flying ranges, UAS are less cost-effective than motorcycles for routine transport of laboratory samples in Liberia. Field studies are needed to generate evidence on UAS lifespan, failure rates and performance under various weather conditions and payloads. Funding: The authors received no financial support for the research, authorship, and publication of this paper. Declaration of Interest: The authors of this paper declare no financial conflicts of interest. Ethical Approval: We did not seek IRB approval consistent with Human Research Protection Policy {45CFR46.101(b)(4)}.
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