Low-Dose Tomography of Random Fields and the Problem of Continuous Heterogeneity

TL;DR

This paper develops a nonparametric method for estimating structural variability in biological samples from low-dose tomography data, enabling accurate heterogeneity analysis with minimal projections.

Contribution

It introduces a novel functional data analysis approach for cryo-EM heterogeneity, with theoretical guarantees and efficient computational algorithms.

Findings

Consistent estimation with as few as two projections per individual.

Derivation of uniform convergence rates for the estimation process.

Successful demonstration through simulation experiments.

Abstract

We consider the problem of nonparametric estimation of the conformational variability in a population of related structures, based on low-dose tomography of a random sample of representative individuals. In this context, each individual represents a random perturbation of a common template and is imaged noisily and discretely at but a few projection angles. Such problems arise in the cryo Electron Microscopy of structurally heterogeneous biological macromolecules. We model the population as a random field, whose mean captures the typical structure, and whose covariance reflects the heterogeneity. We show that consistent estimation is achievable with as few as two projections per individual, and derive uniform convergence rates reflecting how the various parameters of the problem affect statistical efficiency, and their trade-offs. Our analysis formulates the domain of the forward operator to be a reproducing kernel Hilbert space, where we establish representer and Mercer theorems tailored to question at hand. This allows us to exploit pooling estimation strategies central to functional data analysis, illustrating their versatility in a novel context. We provide an efficient computational implementation using tensorized Krylov methods and demonstrate the performance of our methodology by way of simulation.