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We present a fast and numerically accurate method for expanding digitized L x L images representing functions on [-1,1]² supported on the disk {x ∈ R²:|x|<1} in the harmonics (Dirichlet Laplacian eigenfunctions) on the disk. Our method, which we refer to as the Fast Disk Harmonics Transform (FDHT), runs in O(L² log L) operations. This basis is also known as the Fourier-Bessel basis, and it has several computational advantages: it is orthogonal, ordered by frequency, and steerable in the sense that images expanded in the basis can be rotated by applying a diagonal transform to the coefficients. Moreover, we show that convolution with radial functions can also be efficiently computed by applying a diagonal transform to the coefficients. [ABSTRACT FROM AUTHOR]

The number of noisy images required for molecular reconstruction in single-particle cryoelectron microscopy (cryo-EM) is governed by the autocorrelations of the observed, randomly oriented, noisy projection images. In this work, we consider the effect of imposing sparsity priors on the molecule. We use techniques from signal processing, optimization, and applied algebraic geometry to obtain theoretical and computational contributions for this challenging nonlinear inverse problem with sparsity constraints. We prove that molecular structures modeled as sums of Gaussians are uniquely determined by the second-order autocorrelation of their projection images, implying that the sample complexity is proportional to the square of the variance of the noise. This theory improves upon the nonsparse case, where the third-order autocorrelation is required for uniformly oriented particle images and the sample complexity scales with the cube of the noise variance. Furthermore, we build a computational framework to reconstruct molecular structures which are sparse in the wavelet basis. This method combines the sparse representation for the molecule with projection-based techniques used for phase retrieval in X-ray crystallography. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Principal component analysis (PCA) plays an important role in the analysis of cryo-electron microscopy (cryo-EM) images for various tasks such as classification, denoising, compression, and ab initio modeling. We introduce a fast method for estimating a compressed representation of the 2-D covariance matrix of noisy cryo-EM projection images affected by radial point spread functions that enables fast PCA computation. Our method is based on a new algorithm for expanding images in the Fourier–Bessel basis (the harmonics on the disk), which provides a convenient way to handle the effect of the contrast transfer functions. For N images of size L×L, our method has time complexity O(NL³+L4) and space complexity O (NL²+L³) . In contrast to previous work, these complexities are independent of the number of different contrast transfer functions of the images. We demonstrate our approach on synthetic and experimental data and show acceleration by factors of up to two orders of magnitude. [ABSTRACT FROM AUTHOR]

A method is proposed to reconstruct the 3D molecular structure from micrographs collected at just one sample tilt angle in the random conical tilt scheme in cryo‐electron microscopy. The method uses autocorrelation analysis on the micrographs to estimate features of the molecule which are invariant under certain nuisance parameters such as the positions of molecular projections in the micrographs. This enables the molecular structure to be reconstructed directly from micrographs, completely circumventing the need for particle picking. Reconstructions are demonstrated with simulated data and the effect of the missing‐cone region is investigated. These results show promise to reduce the size limit for single‐particle reconstruction in cryo‐electron microscopy. [ABSTRACT FROM AUTHOR]

The article explains a newly developed graph Laplacian-based algorithm, which is used for the tomographic reconstruction of the planar object from its unknown random projections in different directions. The algorithm is shown to be extremely useful for the formation of various biological proteins by using the cryo-electron microscopy.

We study super-resolution multi-reference alignment, the problem of estimating a signal from many circularly shifted, down-sampled and noisy observations. We focus on the low SNR regime, and show that a signal in |${\mathbb{R}}^M$| is uniquely determined when the number |$L$| of samples per observation is of the order of the square root of the signal's length (⁠|$L=O(\sqrt{M})$|⁠). Phrased more informally, one can square the resolution. This result holds if the number of observations is proportional to |$1/\textrm{SNR}^3$|⁠. In contrast, with fewer observations recovery is impossible even when the observations are not down-sampled (⁠|$L=M$|⁠). The analysis combines tools from statistical signal processing and invariant theory. We design an expectation-maximization algorithm and demonstrate that it can super-resolve the signal in challenging SNR regimes. [ABSTRACT FROM AUTHOR]

We consider the two-dimensional multi-target detection (MTD) problem of estimating a target image from a noisy measurement that contains multiple copies of the image, each randomly rotated and translated. The MTD model serves as a mathematical abstraction of the structure reconstruction problem in single-particle cryo-electron microscopy, the chief motivation of this study. We focus on high noise regimes, where accurate detection of image occurrences within a measurement is impossible. To estimate the image, we develop an expectation-maximization framework that aims to maximize an approximation of the likelihood function. We demonstrate image recovery in highly noisy environments, and show that our framework outperforms the previously studied autocorrelation analysis in a wide range of parameters. [ABSTRACT FROM AUTHOR]

We consider the problem of estimating a cloud of points from numerous noisy observations of that cloud after unknown rotations and possibly reflections. This is an instance of the general problem of estimation under group action, originally inspired by applications in three-dimensional imaging and computer vision. We focus on a regime where the noise level is larger than the magnitude of the signal, so much so that the rotations cannot be estimated reliably. We propose a simple and efficient procedure based on invariant polynomials (effectively: the Gram matrices) to recover the signal, and we assess it against fundamental limits of the problem that we derive. We show our approach adapts to the noise level and is statistically optimal (up to constants) for both the low and high noise regimes. In studying the variance of our estimator, we encounter the question of the sensivity of a type of thin Cholesky factorization, for which we provide an improved bound which may be of independent interest. [ABSTRACT FROM AUTHOR]

We target the problem of estimating the center of mass of objects in noisy two-dimensional images. We assume that the noise dominates the image, and thus many standard approaches are vulnerable to estimation errors, e.g., the direct computation of the center of mass and the geometric median which is a robust alternative to the center of mass. In this paper, we define a novel surrogate function to the center of mass. We present a mathematical and numerical analysis of our method and show that it outperforms existing methods for estimating the center of mass of an object in various realistic scenarios. As a case study, we apply our centering method to data from singleparticle cryo-electron microscopy (cryo-EM), where the goal is to reconstruct the three-dimensional structure of macromolecules. We show how to apply our approach for a better translational alignment of molecule images picked from experimental data. In this way, we facilitate the succeeding steps of reconstruction and streamline the entire cryo-EM pipeline, saving computational time and supporting resolution enhancement. [ABSTRACT FROM AUTHOR]

In photon-limited imaging, the pixel intensities are affected by photon count noise. Many applications require an accurate estimation of the covariance of the underlying 2-D clean images. For example, in X-ray free electron laser (XFEL) single molecule imaging, the covariance matrix of 2-D diffraction images is used to reconstruct the 3-D molecular structure. Accurate estimation of the covariance from low-photon-count images must take into account that pixel intensities are Poisson distributed, hence the classical sample covariance estimator is highly biased. Moreover, in single molecule imaging, including in-plane rotated copies of all images could further improve the accuracy of covariance estimation. In this paper we introduce an efficient and accurate algorithm for covariance matrix estimation of count noise 2-D images, including their uniform planar rotations and possibly reflections. Our procedure, steerable $e$ PCA, combines in a novel way two recently introduced innovations. The first is a methodology for principal component analysis (PCA) for Poisson distributions, and more generally, exponential family distributions, called $e$ PCA. The second is steerable PCA, a fast and accurate procedure for including all planar rotations when performing PCA. The resulting principal components are invariant to the rotation and reflection of the input images. We demonstrate the efficiency and accuracy of steerable $e$ PCA in numerical experiments involving simulated XFEL datasets and rotated face images from Yale Face Database B. [ABSTRACT FROM AUTHOR]

Motivated by the task of 2D classification in single particle reconstruction by cryo-electron microscopy (cryo-EM), we consider the problem of heterogeneous multireference alignment of images. In this problem, the goal is to estimate a (typically small) set of target images from a (typically large) collection of observations. Each observation is a rotated, noisy version of one of the target images. For each individual observation, neither the rotation nor which target image has been rotated are known. As the noise level in cryo-EM data is high, clustering the observations and estimating individual rotations is challenging. We propose a framework to estimate the target images directly from the observations, completely bypassing the need to cluster or register the images. The framework consists of two steps. First, we estimate rotation-invariant features of the images, such as the bispectrum. These features can be estimated to any desired accuracy, at any noise level, provided sufficiently many observations are collected. Then, we estimate the images from the invariant features. Numerical experiments on synthetic cryo-EM datasets demonstrate the effectiveness of the method. Ultimately, we outline future developments required to apply this method to experimental data. [ABSTRACT FROM AUTHOR]

Let be a compact group and let. We define the non-unique games (NUG) problem as finding to minimize. We introduce a convex relaxation of the NUG problem to a semidefinite program (SDP) by taking the Fourier transform of fij over. The NUG framework can be seen as a generalization of the little Grothendieck problem over the orthogonal group and the unique games problem and includes many practically relevant problems, such as the maximum likelihood estimator to registering bandlimited functions over the unit sphere in d-dimensions and orientation estimation of noisy cryo-electron microscopy (cryo-EM) projection images. We implement an SDP solver for the NUG cryo-EM problem using the alternating direction method of multipliers (ADMM). Numerical study with synthetic datasets indicate that while our ADMM solver is slower than existing methods, it can estimate the rotations more accurately, especially at low signal-to-noise ratio (SNR). [ABSTRACT FROM AUTHOR]

In recent years, an abundance of new molecular structures have been elucidated using cryo-electron microscopy (cryo-EM), largely due to advances in hardware technology and data processing techniques. Owing to these exciting new developments, cryo-EM was selected by Nature Methods as the "Method of the Year 2015," and the Nobel Prize in Chemistry 2017 was awarded to three pioneers in the cryo-EM field: Jacques Dubochet, Joachim Frank, and Richard Henderson "for developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution" [93]. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In cryo-electron microscopy, the three-dimensional (3D) electric potentials of an ensemble of molecules are projected along arbitrary viewing directions to yield noisy two-dimensional images. The volume maps representing these potentials typically exhibit a great deal of structural variability, which is described by their 3D covariance matrix. Typically, this covariance matrix is approximately low rank and can be used to cluster the volumes or estimate the intrinsic geometry of the conformation space. We formulate the estimation of this covariance matrix as a linear inverse problem, yielding a consistent least-squares estimator. For n images of size N-by-N pixels, we propose an algorithm for calculating this covariance estimator with computational complexity O(nN4 + p √κN6 logN), where the condition number κ is empirically in the range 10{200. Its efficiency relies on the observation that the normal equations are equivalent to a deconvolution problem in six dimensions. This is then solved by the conjugate gradient method with an appropriate circulant preconditioner. The result is the first computationally efficient algorithm for consistent estimation of the 3D covariance from noisy projections. It also compares favorably in runtime with respect to previously proposed nonconsistent estimators. Motivated by the recent success of eigenvalue shrinkage procedures for high-dimensional covariance matrix estimation, we incorporate a shrinkage procedure that improves accuracy at lower signal-to-noise ratios. We evaluate our methods on simulated datasets and achieve classification results comparable to state-of-the-art methods in shorter running time. We also present results on clustering volumes in an experimental dataset, illustrating the power of the proposed algorithm for practical determination of structural variability. [ABSTRACT FROM AUTHOR]

We consider the problem of estimating a signal from noisy circularly translated versions of itself, called multireference alignment (MRA). One natural approach to MRA could be to estimate the shifts of the observations first, and infer the signal by aligning and averaging the data. In contrast, we consider a method based on estimating the signal directly, using features of the signal that are invariant under translations. Specifically, we estimate the power spectrum and the bispectrum of the signal from the observations. Under mild assumptions, these invariant features contain enough information to infer the signal. In particular, the bispectrum can be used to estimate the Fourier phases. To this end, we propose and analyze a few algorithms. Our main methods consist of nonconvex optimization over the smooth manifold of phases. Empirically, in the absence of noise, these nonconvex algorithms appear to converge to the target signal with random initialization. The algorithms are also robust to noise. We then suggest three additional methods. These methods are based on frequency marching, semidefinite relaxation, and integer programming. The first two methods provably recover the phases exactly in the absence of noise. In the high noise level regime, the invariant features approach for MRA results in stable estimation if the number of measurements scales like the cube of the noise variance, which is the information-theoretic rate. Additionally, it requires only one pass over the data, which is important at low signal-to-noise ratio when the number of observations must be large. [ABSTRACT FROM AUTHOR]

Dynamical processes in biology are studied using an ever-increasing number of techniques, each of which brings out unique features of the system. One of the current challenges is to develop systematic approaches for fusing heterogeneous datasets into an integrated view of multivariable dynamics. We demonstrate that heterogeneous data fusion can be successfully implemented within a semi-supervised learning framework that exploits the intrinsic geometry of high-dimensional datasets. We illustrate our approach using a dataset from studies of pattern formation in Drosophila. The result is a continuous trajectory that reveals the joint dynamics of gene expression, subcellular protein localization, protein phosphorylation, and tissue morphogenesis. Our approach can be readily adapted to other imaging modalities and forms a starting point for further steps of data analytics and modeling of biological dynamics. [ABSTRACT FROM AUTHOR]

The structure from motion (SfM) problem in computer vision is to recover the three-dimensional (3D) structure of a stationary scene from a set of projective measurements, represented as a collection of two-dimensional (2D) images, via estimation of motion of the cameras corresponding to these images. In essence, SfM involves the three main stages of (i) extracting features in images (e.g. points of interest, lines, etc.) and matching these features between images, (ii) camera motion estimation (e.g. using relative pairwise camera positions estimated from the extracted features), and (iii) recovery of the 3D structure using the estimated motion and features (e.g. by minimizing the so-called reprojection error). This survey mainly focuses on relatively recent developments in the literature pertaining to stages (ii) and (iii). More specifically, after touching upon the early factorization-based techniques for motion and structure estimation, we provide a detailed account of some of the recent camera location estimation methods in the literature, followed by discussion of notable techniques for 3D structure recovery. We also cover the basics of the simultaneous localization and mapping (SLAM) problem, which can be viewed as a specific case of the SfM problem. Further, our survey includes a review of the fundamentals of feature extraction and matching (i.e. stage (i) above), various recent methods for handling ambiguities in 3D scenes, SfM techniques involving relatively uncommon camera models and image features, and popular sources of data and SfM software. [ABSTRACT FROM AUTHOR]

Spectral methods that are based on eigenvectors and eigenvalues of discrete graph Laplacians, such as DiffusionMaps and Laplacian Eigenmaps, are often used for manifold learning and nonlinear dimensionality reduction. Itwas previously shown by Belkin&Niyogi (2007, Convergence of Laplacian eigenmaps, vol. 19. Proceedings of the 2006 Conference on Advances in Neural Information Processing Systems. The MIT Press, p. 129.) that the eigenvectors and eigenvalues of the graph Laplacian converge to the eigen-functions and eigenvalues of the Laplace--Beltrami operator of the manifold in the limit of infinitely many data points sampled independently from the uniform distribution over the manifold. Recently, we introduced Vector Diffusion Maps and showed that the connection Laplacian of the tangent bundle of the manifold can be approximated from random samples. In this article, we present a unified framework for approximating other connection Laplacians over the manifold by considering its principle bundle structure. We prove that the eigenvectors and eigenvalues of these Laplacians converge in the limit of infinitely many independent random samples. We generalize the spectral convergence results to the case where the data points are sampled from a non-uniform distribution, and for manifolds with and without boundary. [ABSTRACT FROM AUTHOR]