Biological causes and impacts of rugged tree landscapes in phylodynamic inference

Phylodynamic analysis has been instrumental in elucidating epidemiological and evolutionary dynamics of pathogens. Bayesian phylodynamics integrates out phylogenetic uncertainty, which is typically substantial in phylodynamic datasets due to limited genetic diversity. Phylodynamic inference does not, however, scale with modern datasets, partly due to difficulties in traversing tree space. Here, we characterize tree space and landscape in phylodynamic inference and assess its impacts on analysis difficulty and key biological estimates. By running extensive Bayesian analyses of 15 classic large phylodynamic datasets and carefully analyzing the posterior samples, we find that the posterior tree landscape is diffuse yet rugged, leading to widespread tree sampling problems that usually stem from sequences in a small part of the tree. We develop clade-specific diagnostics to show that a few sequences--including putative recombinants and recurrent mutants--frequently drive the ruggedness and sampling problems, although existing data-quality tests show limited power to detect them. The sampling problems can significantly impact phylodynamic inferences or distort major biological conclusions; the impact is usually stronger on "local" estimates (e.g., introduction history) associated with particular clades than on "global" parameters (e.g., demographic trajectory) governed by general tree shape. We evaluate existing and newly-developed MCMC diagnostics, and offer strategies for optimizing phylodynamic analysis settings and mitigating sampling problem impacts. Our findings highlight the need and directions to develop efficient traversal over rugged tree landscapes, ultimately advancing scalable and reliable phylodynamics. Significance StatementBayesian phylodynamics is central to epidemiological studies, but exploring the vast and complex tree space is computationally challenging. Phylodynamic datasets comprise many highly similar sequences, sampled through time, creating a uniquely structured landscape of optimal trees. Here, we show that phylodynamic tree landscapes are often highly rugged, with multiple peaks separated by difficult-to-cross valleys. These features lead to widespread sampling problems which are often driven by a few sequences. These problems can significantly impact phylodynamic estimates, especially those associated with particular clades, distorting biological conclusions. We develop diagnostics to identify problematic sequences and provide solutions to mitigate their impacts. We offer strategies to optimize phylodynamic analysis workflows and to develop algorithms for navigating rugged landscapes, thereby advancing infectious disease investigation.