ECHO: A lightweight tool for inferring missing case counts from pathogen phylogenies

Timed phylogenetic trees express the evolutionary history of a pathogen outbreak in units of time, providing an estimate of the elapsed time across the shared ancestry of a set of taxa. By combining this elapsed time with known information about the epidemiology of a disease, we can relate the total branch length to the total number of cases related to the phylogeny. This gives information about the number of unsequenced cases that are related to the phylogeny. We call these “cryptic” cases. We present ECHO (Estimation of Cryptic Hosts from Outbreak trees), a collection of three lightweight estimators of the number of cryptic cases in a phylogeny. ECHO is agnostic to the form of the sampling process, making it robust to a variety of forms of sampling heterogeneity. We demonstrate ECHO’s baseline accuracy and its robustness to heterogenous sampling frameworks through simulation. Additionally, we apply ECHO to measles virus sequences that were collected during an outbreak in the USA in 2021. ECHO is able to recover the number of cryptic cases with a reasonable degree of accuracy both in simulation and in practice. We discuss the contexts in which ECHO is most applicable, and the interpretation of its estimates.