Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method to resolve biological macromolecules. In a cryo-EM experiment, the microscope produces images called micrographs. Projections of the molecule of interest are embedded in the micrographs at unknown locations, and under unknown viewing directions. Standard imaging techniques first locate these projections (detection) and then reconstruct the 3-D structure from them. Unfortunately, high noise levels hinder detection. When reliable detection is rendered impossible, the standard techniques fail. This is a problem, especially for small molecules. In this paper, we pursue a radically different approach: we contend that the structure could, in principle, be reconstructed directly from the micrographs, without intermediate detection. The aim is to bring small molecules within reach for cryo-EM. To this end, we design an autocorrelation analysis technique that allows one to go directly from the micrographs to the sought structures. This involves only one pass over the micrographs, allowing online, streaming processing for large experiments. We show numerical results and discuss challenges that lay ahead to turn this proof-of-concept into a complementary approach to state-of-the-art algorithms.

We study the dihedral multi-reference alignment problem of estimating the orbit of a signal from multiple noisy observations of the signal, acted on by random elements of the dihedral group. We show that if the group elements are drawn from a generic distribution, the orbit of a generic signal is uniquely determined from the second moment of the observations. This implies that the optimal estimation rate in the high noise regime is proportional to the square of the variance of the noise. This is the first result of this type for multi-reference alignment over a non-abelian group with a non-uniform distribution of group elements. Based on tools from invariant theory and algebraic geometry, we also delineate conditions for unique orbit recovery for multi-reference alignment models over finite groups (namely, when the dihedral group is replaced by a general finite group) when the group elements are drawn from a generic distribution. Finally, we design and study numerically three computational frameworks for estimating the signal based on group synchronization, expectation-maximization, and the method of moments.

This paper studies the related problems of prediction, covariance estimation, and principal component analysis for the spiked covariance model with heteroscedastic noise. We consider an estimator of the principal components based on whitening the noise, and we derive optimal singular value and eigenvalue shrinkers for use with these estimated principal components. Underlying these methods are new asymptotic results for the high-dimensional spiked model with heteroscedastic noise, and consistent estimators for the relevant population parameters. We extend previous analysis on out-of-sample prediction to the setting of predictors with whitening. We demonstrate certain advantages of noise whitening. Specifically, we show that in a certain asymptotic regime, optimal singular value shrinkage with whitening converges to the best linear predictor, whereas without whitening it converges to a suboptimal linear predictor. We prove that for generic signals, whitening improves estimation of the principal components, and increases a natural signal-to-noise ratio of the observations. We also show that for rank one signals, our estimated principal components achieve the asymptotic minimax rate.

In the multireference alignment model, a signal is observed by the action of a random circular translation and the addition of Gaussian noise. The goal is to recover the signal’s orbit by accessing multiple independent observations. Of particular interest is the sample complexity, i.e., the number of observations/samples needed in terms of the signal-to-noise ratio (SNR) (the signal energy divided by the noise variance) in order to drive the mean-square error to zero. Previous work showed that if the translations are drawn from the uniform distribution, then, in the low SNR regime, the sample complexity of the problem scales as$\omega (1/ \mathrm {SNR}^{3})$. In this paper, using a generalization of the Chapman–Robbins bound for orbits and expansions of the$\chi ^{2}$divergence at low SNR, we show that in the same regime the sample complexity for any aperiodic translation distribution scales as$\omega (1/ \mathrm {SNR}^{2})$. This rate is achieved by a simple spectral algorithm. We propose two additional algorithms based on non-convex optimization and expectation–maximization. We also draw a connection between the multireference alignment problem and the spiked covariance model.