Monitoring the emergence and spread of novel human pathogens in tropical regions is a central public health concern. Metagenomic analysis enables more systemic viral detection of both known and novel viral pathogens [42] and can be employed as diagnostic supplements to pathogen detection as part of public health monitoring systems and epidemiologic surveys [9] [10] [11] [12] [15] [16] [17] 19, 21, 23] . Despite the headway, metagenomic virus detection studies will have to confront several remaining difficulties concerning diagnostic accuracy. Foremost concerns include enhancing the sensitivity and specificity of deep sequencing-based diagnostic methods and re-evaluating the evidence for disease causality in light of increasingly sensitive nucleic acid detection and pathogen discovery methods. The former will require improved strategies to biochemically enrich and computationally identify viral sequences while reducing host background sequences. The latter will require a cautious reconsideration of criteria used to establish causal links between microbes and disease, as well as extensive case-by-case follow-up studies employing classical laboratory methods, such as serological analysis and cell culture amplification. It is important to highlight that observing viral sequence in sequencing data is insufficient to establish the role of a virus in disease causality. Like other detection strategies, deep sequencing will serve to inform secondary tests, including seroconversion assays, further nucleic acid testing, cell culture amplification, and additional investigations into plausible disease mechanisms.