Amit Singer

• PhD
• Professor at Princeton University

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 posi...

Nuclear Magnetic Resonance (NMR) Spectroscopy is the second most used technique (after X-ray crystallography) for structural determination of proteins. A computational challenge in this technique involves solving a discrete optimization problem that assigns the resonance frequency to each atom in the protein. This paper introduces LIAN (LInear prog...

We consider the multi-target detection problem of estimating a two-dimensional target image from a large noisy measurement image that contains many randomly rotated and translated copies of the target image. Motivated by single-particle cryo-electron microscopy, we focus on the low signal-to-noise regime, where it is difficult to estimate the locat...

Manifold learning methods play a prominent role in nonlinear dimensionality reduction and other tasks involving high-dimensional data sets with low intrinsic dimensionality. Many of these methods are graph-based: they associate a vertex with each data point and a weighted edge with each pair. Existing theory shows that the Laplacian matrix of the g...

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 th...

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...

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 noi...

We consider the multi-target detection problem of estimating a two-dimensional target image from a large noisy measurement image that contains many randomly rotated and translated copies of the target image. Motivated by single-particle cryo-electron microscopy, we focus on the low signal-to-noise regime, where it is difficult to estimate the locat...

We propose a method to reconstruct the 3-D molecular structure from micrographs collected at just one sample tilt angle in the random conical tilt scheme in cryo-electron microscopy. Our method uses autocorrelation analysis on the micrographs to estimate features of the molecule which are invariant under certain nuisance parameters such as the posi...

Manifold learning methods play a prominent role in nonlinear dimensionality reduction and other tasks involving high-dimensional data sets with low intrinsic dimensionality. Many of these methods are graph-based: they associate a vertex with each data point and a weighted edge between each pair of close points. Existing theory shows, under certain...

Motivated by the 2D class averaging problem in single-particle cryo-electron microscopy (cryo-EM), we present a k-means algorithm based on a rotationally-invariant Wasserstein metric for images. Unlike existing methods that are based on Euclidean ($L_2$) distances, we prove that the Wasserstein metric better accommodates for the out-of-plane angula...

We consider problems of dimensionality reduction and learning data representations for continuous spaces with two or more independent degrees of freedom. Such problems occur, for example, when observing shapes with several components that move independently. Mathematically, if the parameter space of each continuous independent motion is a manifold,...

We target the problem of estimating the center of mass of noisy 2-D images. We assume that the noise dominates the image, and thus many standard approaches are vulnerable to estimation errors. Our approach uses a surrogate function to the geometric median, which is a robust estimator of the center of mass. We mathematically analyze cases in which t...

Nuclear Magnetic Resonance (NMR) Spectroscopy is the second most used technique (after X-ray crystallography) for structural determination of proteins. A computational challenge in this technique involves solving a discrete optimization problem that assigns the resonance frequency to each atom in the protein. This paper introduces LIAN (LInear prog...

Single-particle electron cryomicroscopy (cryo-EM) is an increasingly popular technique for elucidating the three-dimensional (3D) structure of proteins and other biologically significant complexes at near-atomic resolution. It is an imaging method that does not require crystallization and can capture molecules in their native states. In single-part...

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...

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...

In this paper, we propose a novel approach for manifold learning that combines the Earthmover's distance (EMD) with the diffusion maps method for dimensionality reduction. We demonstrate the potential benefits of this approach for learning shape spaces of proteins and other flexible macromolecules using a simulated dataset of 3-D density maps that...

Single-particle reconstruction in cryo-electron microscopy (cryo-EM) is an increasingly popular technique for determining the 3D structure of a molecule from several noisy 2D projections images taken at unknown viewing angles. Most reconstruction algorithms require a low-resolution initialization for the 3D structure, which is the goal of ab initio...

Single-particle electron cryomicroscopy (cryo-EM) is an increasingly popular technique for elucidating the three-dimensional structure of proteins and other biologically significant complexes at near-atomic resolution. It is an imaging method that does not require crystallization and can capture molecules in their native states. In single-particle...

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 20...

Motivated by the structure reconstruction problem in single-particle cryo-electron microscopy, we consider the multi-target detection model, where multiple copies of a target signal occur at unknown locations in a long measurement, further corrupted by additive Gaussian noise. At low noise levels, one can easily detect the signal occurrences and es...

When using an electron microscope for imaging of particles embedded in vitreous ice, the recorded image, or micrograph, is a significantly degraded version of the tomographic projection of the sample. Apart from noise, the image is affected by the optical configuration of the microscope. This transformation is typically modeled as a convolution wit...

Cryo-electron microscopy (cryo-EM), the subject of the 2017 Nobel Prize in Chemistry, is a technology for obtaining 3D reconstructions of macromolecules from many noisy 2D projections of instances of these macromolecules, whose orientations and positions are unknown. These molecules are not rigid objects, but flexible objects involved in dynamical...

We introduce a framework for recovering an image from its rotationally and translationally invariant features based on autocorrelation analysis. This work is an instance of the multi-target detection statistical model, which is mainly used to study the mathematical and computational properties of single-particle reconstruction using cryo-electron m...

Single-particle electron cryomicroscopy is an essential tool for high-resolution 3D reconstruction of proteins and other biological macromolecules. An important challenge in cryo-EM is the reconstruction of non-rigid molecules with parts that move and deform. Traditional reconstruction methods fail in these cases, resulting in smeared reconstructio...

In this paper, we propose a novel approach for manifold learning that combines the Earthmover's distance (EMD) with the diffusion maps method for dimensionality reduction. We demonstrate the potential benefits of this approach for learning shape spaces of proteins and other flexible macromolecules using a simulated dataset of 3-D density maps that...

Motivated by the task of 2-D 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...

When using an electron microscope for imaging of particles embedded in vitreous ice, the objective lens will inevitably corrupt the projection images. This corruption manifests as a band-pass filter on the micrograph. In addition, it causes the phase of several frequency bands to be flipped and distorts frequency bands. As a precursor to compensati...

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 new exciting developments, cryo-EM was selected by Nature Methods as Method of the Year 2015, and the Nobel Prize in Chemistry 2017 was...

Single-particle reconstruction in cryo-electron microscopy (cryo-EM) is an increasingly popular technique for determining the 3-D structure of a molecule from several noisy 2-D projections images taken at unknown viewing angles. Most reconstruction algorithms require a low-resolution initialization for the 3-D structure, which is the goal of ab ini...

Cryo-electron microscopy (cryo-EM), the subject of the 2017 Nobel Prize in Chemistry, is a technology for determining the 3-D structure of macromolecules from many noisy 2-D projections of instances of these macromolecules, whose orientations and positions are unknown. The molecular structures are not rigid objects, but flexible objects involved in...

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 3-D imaging and computer vision. We focus on a regime where the noise level is l...

Single-particle electron cryomicroscopy is an essential tool for high-resolution 3D reconstruction of proteins and other biological macromolecules. An important challenge in cryo-EM is the reconstruction of non-rigid molecules with parts that move and deform. Traditional reconstruction methods fail in these cases, resulting in smeared reconstructio...

We consider the multi-target detection problem of recovering a set of signals that appear multiple times at unknown locations in a noisy measurement. In the low noise regime, one can estimate the signals by first detecting occurrences, then clustering and averaging them. In the high noise regime, however, neither detection nor clustering can be per...

Motivated by the structure reconstruction problem in cryo-electron microscopy, we consider the multi-target detection model, where multiple copies of a target signal occur at unknown locations in a long measurement, further corrupted by additive Gaussian noise. At low noise levels, one can easily detect the signal occurrences and estimate the signa...

We consider the multi-target detection problem of recovering a set of signals that appear multiple times at unknown locations in a noisy measurement. In the low noise regime, one can estimate the signals by first detecting occurrences, then clustering and averaging them. In the high noise regime however, neither detection nor clustering can be perf...

In photon-limited imaging, the pixel intensities are affected by photon count noise. Many applications, such as 3-D reconstruction using correlation analysis in X-ray free electron laser (XFEL) single molecule imaging, require an accurate estimation of the covariance of the underlying 2-D clean images. Accurate estimation of the covariance from low...

Motivated by the task of $2$-D 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...

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method for 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 locatio...

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method for 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 locatio...

The matching problem between two adjacency matrices can be formulated as the NP-hard quadratic assignment problem (QAP). Previous work on semidefinite programming (SDP) relaxations to the QAP have produced solutions that are often tight in practice, but such SDPs typically scale badly, involving matrix variables of dimension $n^2$ where n is the nu...

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method for biological macromolecules. Cryo-EM was selected by Nature Methods as Method of the Year 2015, large scale investments in cryo-EM facilities are being made all over the world, and the Nobel Priz...

Particle picking is a crucial first step in the computational pipeline of single-particle cryo-electron microscopy (cryo-EM). Selecting particles from the micrographs is difficult especially for small particles with low contrast. As high-resolution reconstruction typically requires hundreds of thousands of particles, manually picking that many part...

Particle picking is a crucial first step in the computational pipeline of single-particle cryo-electron microscopy (cryo-EM). Selecting particles from the micrographs is difficult especially for small particles with low contrast. As high-resolution reconstruction typically requires hundreds of thousands of particles, manually picking that many part...

We analyze the problem of estimating a signal from multiple measurements on a $\mbox{group action channel}$ that linearly transforms a signal by a random group action followed by a fixed projection and additive Gaussian noise. This channel is motivated by applications such as multi-reference alignment and cryo-electron microscopy. We focus on the l...

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. Typi...

In cryo-electron microscopy, the 3D electric potentials of an ensemble of molecules are projected along arbitrary viewing directions to yield noisy 2D 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...

Single-Particle Reconstruction (SPR) in Cryo-Electron Microscopy (cryo-EM) is the task of estimating the 3D structure of a molecule from a set of noisy 2D projections, taken from unknown viewing directions. Many algorithms for SPR start from an initial reference molecule, and alternate between refining the estimated viewing angles given the molecul...

Multireference alignment refers to the problem of estimating a signal from its circularly translated copies in the presence of noise. Previous papers showed that if the translations are drawn from the uniform distribution, then the sample complexity of the problem scales as $1/\operatorname{SNR}^3$ in the low SNR regime. In this work, we show that...

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 sign...

Multireference alignment (MRA) is the problem of estimating a signal from many noisy and cyclically shifted copies of itself. In this paper, we consider an extension called heterogeneous MRA, where $K$ signals must be estimated, and each observation comes from one of those signals, unknown to us. This is a simplified model for the heterogeneity pro...

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...

Illustration of the image preprocessing steps applied on the nuclei channel. The first line shows images resulting from rotation and centering steps. The second line shows images resulting from intensity renormalization. The third line shows images resulting from contrast increase. The first two columns show early and later stages from movie frames...

Values of the parameters for intensity renormalization and contrast increase for each of the experimental datasets (S1 Text). (PDF)

Distribution of the datasets into labeled and unlabeled sets depending on the modality. We refer to Ω(m) as the set of labeled datapoints, while Ω(m)¯ is the set of unlabeled data points for the mth modality. (PDF)

Affinity matrix W = (wi,j) obtained by comparing images as described by equation (6) in S1 Text is shown as a heatmap. The white squares identify each of the 11 datasets. The first 7 correspond to live movies, the last 4 correspond to the datasets of fixed images. (TIF)

Low-dimensional embedding of the 11 datasets obtained by diffusion maps. Each dot is a point and each color is a different dataset. The top left panel shows the points obtained by embedding the points in the first three diffusion map coordinates. The top right panel shows the data points in the plane formed by the first two diffusion map coordinate...

Color scheme used to color the final movie. (PDF)

Detailed description of the semi-supervised learning framework and its applications to the illustrative example and the experimental datasets. (PDF)

Detailed description of the supplementary software and the supplementary files. (PDF)

K-fold cross validation on the illustrative example. A) Setting with K = 5, there are 120 labeled points and the number of unlabeled points varies from 0 to 300. B) The normalized absolute error as a function of the number of unlabeled points. There are 100 repetitions for each number of unlabeled data points. (TIF)

Normalized Absolute Error obtained by K-fold cross-validation for each modality of each dataset. In each case, we performed 10 repetitions, where the labeled samples are distributed randomly among the K bins, and the 309 unlabeled data points are chosen randomly. The error is then averaged over 10 repetitions. More details about the Normalized Abso...

We consider the linearly transformed spiked model, where observations $Y_i$ are noisy linear transforms of unobserved signals of interest $X_i$: \begin{align*} Y_i = A_i X_i + \varepsilon_i, \end{align*} for $i=1,\ldots,n$. The transform matrices $A_i$ are also observed. We model $X_i$ as random vectors lying on an unknown low-dimensional space. Ho...

We consider the linearly transformed spiked model, where observations $Y_i$ are noisy linear transforms of unobserved signals of interest $X_i$: \begin{align*} Y_i = A_i X_i + \varepsilon_i, \end{align*} for $i=1,\ldots,n$. The transform matrices $A_i$ are also observed. We model $X_i$ as random vectors lying on an unknown low-dimensional space. Ho...

The growing role of data-driven approaches to scientific discovery has unveiled a large class of models that involve latent transformations with a rigid algebraic constraint. Among them, multi-reference alignment (MRA) is a simple model that captures fundamental aspects of the statistical and algorithmic challenges arising from this new paradigm. I...

We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program (SDP). However, often the NOE distance restraints a...

Power spectrum estimation is an important tool in many applications, such as the whitening of noise. The popular multitaper method enjoys significant success, but fails for short signals with few samples. We propose a statistical model where a signal is given by a random linear combination of fixed, yet unknown, stochastic sources. Given multiple s...

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...

The Boolean multireference alignment problem consists in recovering a Boolean signal from multiple shifted and noisy observations. In this paper we obtain an expression for the error exponent of the maximum A posteriori decoder. This expression is used to characterize the number of measurements needed for signal recovery in the low SNR regime, in t...

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 di...

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 di...

The missing phase problem in X-ray crystallography is commonly solved using the technique of molecular replacement, which borrows phases from a previously solved homologous structure, and appends them to the measured Fourier magnitudes of the diffraction patterns of the unknown structure. More recently, molecular replacement has been proposed for s...

Single particle cryo-electron microscopy (EM) is an increasingly popular method for determining the 3-D structure of macromolecules from noisy 2-D images of single macromolecules whose orientations and positions are random and unknown. One of the great opportunities in cryo-EM is to recover the structure of macromolecules in heterogeneous samples,...

Single particle reconstruction (SPR) from cryo-electron microscopy (EM) is a technique in which the 3D structure of a molecule needs to be determined from its contrast transfer function (CTF) affected, noisy 2D projection images taken at unknown viewing directions. One of the main challenges in cryo-EM is the typically low signal to noise ratio (SN...

The matching problem between two adjacency matrices can be formulated as the NP-hard quadratic assignment problem (QAP). Previous work on semidefinite programming (SDP) relaxations to the QAP have produced solutions that are often tight in practice, but such SDPs typically scale badly, involving matrix variables of dimension $n^2$ where n is the nu...

Power spectrum estimation is an important tool in many applications, such as the whitening of noise. The popular multitaper method enjoys significant success, but fails for short signals with few samples. We propose a statistical model where a signal is given by a random linear combination of fixed, yet unknown, stochastic sources. Given multiple s...

Accurate estimation of camera matrices is an important step in structure from motion algorithms. In this paper we introduce a novel rank constraint on collections of fundamental matrices in multi-view settings. We show that in general, with the selection of proper scale factors, a matrix formed by stacking fundamental matrices between pairs of imag...

The structure from motion (SfM) problem in computer vision is the problem of recovering the $3$D structure of a stationary scene from a set of projective measurements, represented as a collection of $2$D images, via estimation of motion of the cameras corresponding to these images. In essence, SfM involves the three main stages of (1) extraction of...

The structure from motion (SfM) problem in computer vision is the problem of recovering the three-dimensional ($3$D) structure of a stationary scene from a set of projective measurements, represented as a collection of two-dimensional ($2$D) images, via estimation of motion of the cameras corresponding to these images. In essence, SfM involves the...

The Boolean multireference alignment problem consists in recovering a Boolean signal from multiple shifted and noisy observations. In this paper we obtain an expression for the error exponent of the maximum A posteriori decoder. This expression is used to characterize the number of measurements needed for signal recovery in the low SNR regime, in t...

Suppose we observe data of the form $Y_i = D_i (S_i + \varepsilon_i) \in \mathbb{R}^p$ or $Y_i = D_i S_i + \varepsilon_i \in \mathbb{R}^p$, $i=1,\ldots,n$, where $D_i \in \mathbb{R}^{p\times p}$ are known diagonal matrices, $\varepsilon_i$ are noise, and we wish to perform principal component analysis (PCA) on the unobserved signals $S_i \in \mathb...

Group contraction is an algebraic map that relates two classes of Lie groups by a limiting process. We utilize this notion for the compactification of the class of Cartan motion groups. The compactification process is then applied to reduce a non-compact synchronization problem to a problem where the solution can be obtained by means of a unitary,...

Group contraction is an algebraic map that relates two classes of Lie groups by a limiting process. We utilize this notion for the compactification of the class of Cartan motion groups. The compactification process is then applied to reduce a non-compact synchronization problem to a problem where the solution can be obtained by means of a unitary,...

Many applications involve large collections of high-dimensional datapoints with noisy entries from exponential family distributions. It is of interest to estimate the covariance and principal components of the noiseless distribution. In photon-limited imaging (e.g. XFEL) we want to estimate the covariance of the pixel intensities of 2-D images, whe...

Many applications, such as photon-limited imaging and genomics, involve large datasets with noisy entries from exponential family distributions. It is of interest to estimate the covariance structure and principal components of the noiseless distribution. Principal Component Analysis (PCA), the standard method for this setting, can be inefficient w...

Single particle reconstruction (SPR) from cryo-electron microscopy (EM) is a technique in which the 3D structure of a molecule needs to be determined from its contrast transfer function (CTF) affected, noisy 2D projection images taken at unknown viewing directions. One of the main challenges in cryo-EM is the typically low signal to noise ratio (SN...

One of the difficulties in 3D reconstruction of molecules from images in single particle Cryo-Electron Microscopy (Cryo-EM), in addition to high levels of noise and unknown image orientations, is heterogeneity in samples: in many cases, the samples contain a mixture of molecules, or multiple conformations of one molecule. Many algorithms for the re...

Estimation of the Saupe tensor is central to the determination of molecular structures from residual dipolar couplings (RDC) or chemical shift anisotropies. Assuming a given template structure, the singular value decomposition (SVD) method proposed in Losonczi et al. 1999 has been used traditionally to estimate the Saupe tensor. Despite its simplic...

The problem of image restoration in cryo-EM entails correcting for the effects of the Contrast Transfer Function (CTF) and noise. Popular methods for image restoration include 'phase flipping', which corrects only for the Fourier phases but not amplitudes, and Wiener filtering, which requires the spectral signal to noise ratio. We propose a new ima...