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Background and Objective: Wilson statistics describe well the power spectrum of proteins at high frequencies. Therefore, it has found several applications in structural biology, e.g., it is the basis for sharpening steps used in cryogenic electron microscopy (cryo-EM). A recent paper gave the first rigorous proof of Wilson statistics based on a formalism of Wilson's original argument. This new analysis also leads to statistical estimates of the scattering potential of proteins that reveal a correlation between neighboring Fourier coefficients. Here we exploit these estimates to craft a novel prior that can be used for Bayesian inference of molecular structures. Methods: We describe the properties of the prior and the computation of its hyperparameters. We then evaluate the prior on two synthetic linear inverse problems, and compare against a popular prior in cryo-EM reconstruction at a range of SNRs. Results: We show that the new prior effectively suppresses noise and fills-in low SNR regions in the spectral domain. Furthermore, it improves the resolution of estimates on the problems considered for a wide range of SNR and produces Fourier Shell Correlation curves that are insensitive to masking effects. Conclusions: We analyze the assumptions in the model, discuss relations to other regularization strategies, and postulate on potential implications for structure determination in cryo-EM.

Background and Objective: The contrast of cryo-EM images varies from one to another, primarily due to the uneven thickness of the ice layer. This contrast variation can affect the quality of 2-D class averaging, 3-D ab-initio modeling, and 3-D heterogeneity analysis. Contrast estimation is currently performed during 3-D iterative refinement. As a result, the estimates are not available at the earlier computational stages of class averaging and ab-initio modeling. This paper aims to solve the contrast estimation problem directly from the picked particle images in the ab-initio stage, without estimating the 3-D volume, image rotations, or class averages. Methods: The key observation underlying our analysis is that the 2-D covariance matrix of the raw images is related to the covariance of the underlying clean images, the noise variance, and the contrast variability between images. We show that the contrast variability can be derived from the 2-D covariance matrix and we apply the existing Covariance Wiener Filtering (CWF) framework to estimate it. We also demonstrate a modification of CWF to estimate the contrast of individual images. Results: Our method improves the contrast estimation by a large margin, compared to the previous CWF method. Its estimation accuracy is often comparable to that of an oracle that knows the ground truth covariance of the clean images. The more accurate contrast estimation also improves the quality of image restoration as demonstrated in both synthetic and experimental datasets. Conclusions: This paper proposes an effective method for contrast estimation directly from noisy images without using any 3-D volume information. It enables contrast correction in the earlier stage of single particle analysis, and may improve the accuracy of downstream processing.

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 locations and orientations of the target images in the measurement. Our approach uses autocorrelation analysis to estimate rotationally and translationally invariant features of the target image. We demonstrate that, regardless of the level of noise, our technique can be used to recover the target image when the measurement is sufficiently large., Comment: 20 pages, 5 figures

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, then their combination is known as a product manifold. In this paper, we present a new paradigm for non-linear independent component analysis called manifold factorization. Our factorization algorithm is based on spectral graph methods for manifold learning and the separability of the Laplacian operator on product spaces. Recovering the factors of a manifold yields meaningful lower-dimensional representations and provides a new way to focus on particular aspects of the data space while ignoring others. We demonstrate the potential use of our method for an important and challenging problem in structural biology: mapping the motions of proteins and other large molecules using cryo-electron microscopy datasets., Comment: 10 pages, 4 figures

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 angular differences between different particle views. We demonstrate on a synthetic dataset that our method gives superior results compared to an $L_2$ baseline. Furthermore, there is little computational overhead, thanks to the use of a fast linear-time approximation to the Wasserstein-1 metric, also known as the Earthmover's distance., Comment: 11 pages, 5 figures, 1 table

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 microscopy (cryo-EM) at low signal-to-noise ratios. We demonstrate with synthetic numerical experiments that an image can be reconstructed from rotationally and translationally invariant features and show that the reconstruction is robust to noise. These results constitute an important step towards the goal of structure determination of small biomolecules using cryo-EM., Comment: 5 pages, 3 figures

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 compensating for this distortion, the corrupting point spread function, which is termed the contrast transfer function (CTF) in reciprocal space, must be estimated. In this paper, we will present a novel method for CTF estimation. Our method is based on the multi-taper method for power spectral density estimation, which aims to reduce the bias and variance of the estimator. Furthermore, we use known properties of the CTF and of the background of the power spectrum to increase the accuracy of our estimation. We will show that the resulting estimates capture the zero-crossings of the CTF in the low-mid frequency range.

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 dynamical processes. The different conformations are exhibited by different instances of the macromolecule observed in a cryo-EM experiment, each of which is recorded as a particle image. The range of conformations and the conformation of each particle are not known a priori; one of the great promises of cryo-EM is to map this conformation space. Remarkable progress has been made in determining rigid structures from homogeneous samples of molecules in spite of the unknown orientation of each particle image and significant progress has been made in recovering a few distinct states from mixtures of rather distinct conformations, but more complex heterogeneous samples remain a major challenge. We introduce the ``hyper-molecule'' framework for modeling structures across different states of heterogeneous molecules, including continuums of states. The key idea behind this framework is representing heterogeneous macromolecules as high-dimensional objects, with the additional dimensions representing the conformation space. This idea is then refined to model properties such as localized heterogeneity. In addition, we introduce an algorithmic framework for recovering such maps of heterogeneous objects from experimental data using a Bayesian formulation of the problem and Markov chain Monte Carlo (MCMC) algorithms to address the computational challenges in recovering these high dimensional hyper-molecules. We demonstrate these ideas in a prototype applied to synthetic data.

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-photon count images must take into account that pixel intensities are Poisson distributed, hence the classical sample covariance estimator is sub-optimal. 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 for 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 Yale B face data.

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 particles is often too time-consuming. While semi-automated particle picking is currently a popular approach, it may suffer from introducing manual bias into the selection process. In addition, semi-automated particle picking is still somewhat time-consuming. This paper presents the APPLE (Automatic Particle Picking with Low user Effort) picker, a simple and novel approach for fast, accurate, and fully automatic particle picking. While our approach was inspired by template matching, it is completely template-free. This approach is evaluated on publicly available datasets containing micrographs of $\beta$-galactosidase and keyhole limpet hemocyanin projections., Comment: 18 pages, 14 figures

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 solving the missing orthogonal matrices problem arising in Kam's autocorrelation analysis for single particle reconstruction using X-ray free electron lasers and cryo-EM. In classical molecular replacement, it is common to estimate the magnitudes of the unknown structure as twice the measured magnitudes minus the magnitudes of the homologous structure, a procedure known as `twicing'. Mathematically, this is equivalent to finding an unbiased estimator for a complex-valued scalar. We generalize this scheme for the case of estimating real or complex valued matrices arising in single particle autocorrelation analysis. We name this approach "Anisotropic Twicing" because unlike the scalar case, the unbiased estimator is not obtained by a simple magnitude isotropic correction. We compare the performance of the least squares, twicing and anisotropic twicing estimators on synthetic and experimental datasets. We demonstrate 3D homology modeling in cryo-EM directly from experimental data without iterative refinement or class averaging, for the first time.

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, where multiple types or multiple conformations are mixed together. Indeed, in recent years, many tools have been introduced for the analysis of multiple discrete classes of molecules mixed together in a cryo-EM experiment. However, many interesting structures have a continuum of conformations which do not fit discrete models nicely; the analysis of such continuously heterogeneous models has remained a more elusive goal. In this manuscript, we propose to represent heterogeneous molecules and similar structures as higher dimensional objects. We generalize the basic operations used in many existing reconstruction algorithms, making our approach generic in the sense that, in principle, existing algorithms can be adapted to reconstruct those higher dimensional objects. As proof of concept, we present a prototype of a new algorithm which we use to solve simulated reconstruction problems.

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 images has rank 6. Moreover, this matrix forms the symmetric part of a rank 3 matrix whose factors relate directly to the corresponding camera matrices. We use this new characterization to produce better estimations of fundamental matrices by optimizing an L1-cost function using Iterative Re-weighted Least Squares and Alternate Direction Method of Multiplier. We further show that this procedure can improve the recovery of camera locations, particularly in multi-view settings in which fewer images are available.

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 three main stages of (1) extraction of features in images (e.g., points of interest, lines, etc.) and matching these features between images, (2) camera motion estimation (e.g., using relative pairwise camera positions estimated from the extracted features), and (3) recovery of the $3$D 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 (2) and (3). 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 $3$D 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 (1) above), various recent methods for handling ambiguities in $3$D scenes, SfM techniques involving relatively uncommon camera models and image features, and popular sources of data and SfM software., Comment: 40 pages, 16 figures; Updated title and abstract

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 (SNR) of the acquired images. 2D classification of images, followed by class averaging, improves the SNR of the resulting averages, and is used for selecting particles from micrographs and for inspecting the particle images. We introduce a new affinity measure, akin to the Mahalanobis distance, to compare cryo-EM images belonging to different defocus groups. The new similarity measure is employed to detect similar images, thereby leading to an improved algorithm for class averaging. We evaluate the performance of the proposed class averaging procedure on synthetic datasets, obtaining state of the art classification., Comment: Final version accepted to the 14th IEEE International Symposium on Biomedical Imaging (ISBI 2017)

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 reconstruction of molecules from images in heterogeneous Cryo-EM experiments are based on iterative approximations of the molecules in a non-convex optimization that is prone to reaching suboptimal local minima. Other algorithms require an alignment in order to perform classification, or vice versa. The recently introduced Non-Unique Games framework provides a representation theoretic approach to studying problems of alignment over compact groups, and offers convex relaxations for alignment problems which are formulated as semidefinite programs (SDPs) with certificates of global optimality under certain circumstances. In this manuscript, we propose to extend Non-Unique Games to the problem of simultaneous alignment and classification with the goal of simultaneously classifying Cryo-EM images and aligning them within their respective classes. Our proposed approach can also be extended to the case of continuous heterogeneity.

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 image restoration method which we call `Covariance Wiener Filtering' (CWF). In CWF, the covariance matrix of the projection images is used within the classical Wiener filtering framework for solving the image restoration deconvolution problem. Our estimation procedure for the covariance matrix is new and successfully corrects for the CTF. We demonstrate the efficacy of CWF by applying it to restore both simulated and experimental cryo-EM images. Results with experimental datasets demonstrate that CWF provides a good way to evaluate the particle images and to see what the dataset contains even without 2D classification and averaging., Comment: Revision for JSB

Let $\mathcal{G}$ be a compact group and let $f_{ij} \in L^2(\mathcal{G})$. We define the Non-Unique Games (NUG) problem as finding $g_1,\dots,g_n \in \mathcal{G}$ to minimize $\sum_{i,j=1}^n f_{ij} \left( g_i g_j^{-1}\right)$. We devise a relaxation of the NUG problem to a semidefinite program (SDP) by taking the Fourier transform of $f_{ij}$ over $\mathcal{G}$, which can then be solved efficiently. 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 in cryo-Electron Microscopy.

Classifying structural variability in noisy projections of biological macromolecules is a central problem in Cryo-EM. In this work, we build on a previous method for estimating the covariance matrix of the three-dimensional structure present in the molecules being imaged. Our proposed method allows for incorporation of contrast transfer function and non-uniform distribution of viewing angles, making it more suitable for real-world data. We evaluate its performance on a synthetic dataset and an experimental dataset obtained by imaging a 70S ribosome complex.

Cryo-electron microscopy nowadays often requires the analysis of hundreds of thousands of 2D images as large as a few hundred pixels in each direction. Here we introduce an algorithm that efficiently and accurately performs principal component analysis (PCA) for a large set of two-dimensional images, and, for each image, the set of its uniform rotations in the plane and their reflections. For a dataset consisting of $n$ images of size $L \times L$ pixels, the computational complexity of our algorithm is $O(nL^3 + L^4)$, while existing algorithms take $O(nL^4)$. The new algorithm computes the expansion coefficients of the images in a Fourier-Bessel basis efficiently using the non-uniform fast Fourier transform. We compare the accuracy and efficiency of the new algorithm with traditional PCA and existing algorithms for steerable PCA.

In single particle reconstruction (SPR) from cryo-electron microscopy (cryo-EM), the 3D structure of a molecule needs to be determined from its 2D projection images taken at unknown viewing directions. Zvi Kam showed already in 1980 that the autocorrelation function of the 3D molecule over the rotation group SO(3) can be estimated from 2D projection images whose viewing directions are uniformly distributed over the sphere. The autocorrelation function determines the expansion coefficients of the 3D molecule in spherical harmonics up to an orthogonal matrix of size $(2l+1)\times (2l+1)$ for each $l=0,1,2,...$. In this paper we show how techniques for solving the phase retrieval problem in X-ray crystallography can be modified for the cryo-EM setup for retrieving the missing orthogonal matrices. Specifically, we present two new approaches that we term Orthogonal Extension and Orthogonal Replacement, in which the main algorithmic components are the singular value decomposition and semidefinite programming. We demonstrate the utility of these approaches through numerical experiments on simulated data., Comment: Modified introduction and summary. Accepted to the IEEE International Symposium on Biomedical Imaging

$3$D structure recovery from a collection of $2$D images requires the estimation of the camera locations and orientations, i.e. the camera motion. For large, irregular collections of images, existing methods for the location estimation part, which can be formulated as the inverse problem of estimating $n$ locations $\mathbf{t}_1, \mathbf{t}_2, \ldots, \mathbf{t}_n$ in $\mathbb{R}^3$ from noisy measurements of a subset of the pairwise directions $\frac{\mathbf{t}_i - \mathbf{t}_j}{\|\mathbf{t}_i - \mathbf{t}_j\|}$, are sensitive to outliers in direction measurements. In this paper, we firstly provide a complete characterization of well-posed instances of the location estimation problem, by presenting its relation to the existing theory of parallel rigidity. For robust estimation of camera locations, we introduce a two-step approach, comprised of a pairwise direction estimation method robust to outliers in point correspondences between image pairs, and a convex program to maintain robustness to outlier directions. In the presence of partially corrupted measurements, we empirically demonstrate that our convex formulation can even recover the locations exactly. Lastly, we demonstrate the utility of our formulations through experiments on Internet photo collections., Comment: 10 pages, 6 figures, 3 tables

We study the inverse problem of estimating n locations $t_1, ..., t_n$ (up to global scale, translation and negation) in $R^d$ from noisy measurements of a subset of the (unsigned) pairwise lines that connect them, that is, from noisy measurements of $\pm (t_i - t_j)/\|t_i - t_j\|$ for some pairs (i,j) (where the signs are unknown). This problem is at the core of the structure from motion (SfM) problem in computer vision, where the $t_i$'s represent camera locations in $R^3$. The noiseless version of the problem, with exact line measurements, has been considered previously under the general title of parallel rigidity theory, mainly in order to characterize the conditions for unique realization of locations. For noisy pairwise line measurements, current methods tend to produce spurious solutions that are clustered around a few locations. This sensitivity of the location estimates is a well-known problem in SfM, especially for large, irregular collections of images. In this paper we introduce a semidefinite programming (SDP) formulation, specially tailored to overcome the clustering phenomenon. We further identify the implications of parallel rigidity theory for the location estimation problem to be well-posed, and prove exact (in the noiseless case) and stable location recovery results. We also formulate an alternating direction method to solve the resulting semidefinite program, and provide a distributed version of our formulation for large numbers of locations. Specifically for the camera location estimation problem, we formulate a pairwise line estimation method based on robust camera orientation and subspace estimation. Lastly, we demonstrate the utility of our algorithm through experiments on real images., Comment: 40 pages, 12 figures, 6 tables; notation and some unclear parts updated, some typos corrected

We introduce a new rotationally invariant viewing angle classification method for identifying, among a large number of Cryo-EM projection images, similar views without prior knowledge of the molecule. Our rotationally invariant features are based on the bispectrum. Each image is denoised and compressed using steerable principal component analysis (PCA) such that rotating an image is equivalent to phase shifting the expansion coefficients. Thus we are able to extend the theory of bispectrum of 1D periodic signals to 2D images. The randomized PCA algorithm is then used to efficiently reduce the dimensionality of the bispectrum coefficients, enabling fast computation of the similarity between any pair of images. The nearest neighbors provide an initial classification of similar viewing angles. In this way, rotational alignment is only performed for images with their nearest neighbors. The initial nearest neighbor classification and alignment are further improved by a new classification method called vector diffusion maps. Our pipeline for viewing angle classification and alignment is experimentally shown to be faster and more accurate than reference-free alignment with rotationally invariant K-means clustering, MSA/MRA 2D classification, and their modern approximations.

Consider $N$ points in $\mathbb{R}^d$ and $M$ local coordinate systems that are related through unknown rigid transforms. For each point we are given (possibly noisy) measurements of its local coordinates in some of the coordinate systems. Alternatively, for each coordinate system, we observe the coordinates of a subset of the points. The problem of estimating the global coordinates of the $N$ points (up to a rigid transform) from such measurements comes up in distributed approaches to molecular conformation and sensor network localization, and also in computer vision and graphics. The least-squares formulation of this problem, though non-convex, has a well known closed-form solution when $M=2$ (based on the singular value decomposition). However, no closed form solution is known for $M\geq 3$. In this paper, we demonstrate how the least-squares formulation can be relaxed into a convex program, namely a semidefinite program (SDP). By setting up connections between the uniqueness of this SDP and results from rigidity theory, we prove conditions for exact and stable recovery for the SDP relaxation. In particular, we prove that the SDP relaxation can guarantee recovery under more adversarial conditions compared to earlier proposed spectral relaxations, and derive error bounds for the registration error incurred by the SDP relaxation. We also present results of numerical experiments on simulated data to confirm the theoretical findings. We empirically demonstrate that (a) unlike the spectral relaxation, the relaxation gap is mostly zero for the semidefinite program (i.e., we are able to solve the original non-convex least-squares problem) up to a certain noise threshold, and (b) the semidefinite program performs significantly better than spectral and manifold-optimization methods, particularly at large noise levels., Comment: 33 pages, 12 figures. To appear in SIAM Journal on Optimization

It was recently demonstrated in [Chaudhury et al.,Non-Local Euclidean Medians,2012] that the denoising performance of Non-Local Means (NLM) can be improved at large noise levels by replacing the mean by the robust Euclidean median. Numerical experiments on synthetic and natural images showed that the latter consistently performed better than NLM beyond a certain noise level, and significantly so for images with sharp edges. The Euclidean mean and median can be put into a common regression (on the patch space) framework, in which the l_2 norm of the residuals is considered in the former, while the l_1 norm is considered in the latter. The natural question then is what happens if we consider l_p (0

We present an efficient and accurate algorithm for principal component analysis (PCA) of a large set of two dimensional images, and, for each image, the set of its uniform rotations in the plane and its reflection. The algorithm starts by expanding each image, originally given on a Cartesian grid, in the Fourier-Bessel basis for the disk. Because the images are bandlimited in the Fourier domain, we use a sampling criterion to truncate the Fourier-Bessel expansion such that the maximum amount of information is preserved without the effect of aliasing. The constructed covariance matrix is invariant to rotation and reflection and has a special block diagonal structure. PCA is efficiently done for each block separately. This Fourier-Bessel based PCA detects more meaningful eigenimages and has improved denoising capability compared to traditional PCA for a finite number of noisy images., Comment: 7 pages

In this letter, we note that the denoising performance of Non-Local Means (NLM) at large noise levels can be improved by replacing the mean by the Euclidean median. We call this new denoising algorithm the Non-Local Euclidean Medians (NLEM). At the heart of NLEM is the observation that the median is more robust to outliers than the mean. In particular, we provide a simple geometric insight that explains why NLEM performs better than NLM in the vicinity of edges, particularly at large noise levels. NLEM can be efficiently implemented using iteratively reweighted least squares, and its computational complexity is comparable to that of NLM. We provide some preliminary results to study the proposed algorithm and to compare it with NLM., Comment: 6 figures, 1 table