Linear mixed-effect models provide a natural baseline for estimating disease progression using longitudinal data. They provide interpretable models at the cost of modeling assumptions on the progression profiles and their variability across subjects. A significant improvement is to embed the data in a Riemannian manifold and learn patient-specific trajectories distributed around a central geodesic. A few interpretable parameters characterize subject trajectories at the cost of a prior choice of the metric, which determines the shape of the trajectories. We extend this approach by learning the metric from the data allowing more flexibility while keeping the interpretability. Specifically, we learn the metric as the push-forward of the Euclidean metric by a diffeomorphism. This diffeomorphism is estimated iteratively as the composition of radial basis functions belonging to a reproducible kernel Hilbert space. The metric update allows us to improve the forecasting of imaging and clinical biomarkers in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our results compare favorably to the 56 methods benchmarked in the TADPOLE challenge.

Gaussian graphical models (GGM) are often used to describe the conditional correlations between the components of a random vector. In this article, we compare two families of GGM inference methods: the nodewise approach and the penalised likelihood maximisation. We demonstrate on synthetic data that, when the sample size is small, the two methods produce graphs with either too few or too many edges when compared to the real one. As a result, we propose a composite procedure that explores a family of graphs with a nodewise numerical scheme and selects a candidate among them with an overall likelihood criterion. We demonstrate that, when the number of observations is small, this selection method yields graphs closer to the truth and corresponding to distributions with better KL divergence with regards to the real distribution than the other two. Finally, we show the interest of our algorithm on two concrete cases: first on brain imaging data, then on biological nephrology data. In both cases our results are more in line with current knowledge in each field.

Numerous machine learning (ML) approaches have been proposed for automatic classification of Alzheimer's disease (AD) from brain imaging data. In particular, over 30 papers have proposed to use convolutional neural networks (CNN) for AD classification from anatomical MRI. However, the classification performance is difficult to compare across studies due to variations in components such as participant selection, image preprocessing or validation procedure. Moreover, these studies are hardly reproducible because their frameworks are not publicly accessible and because implementation details are lacking. Lastly, some of these papers may report a biased performance due to inadequate or unclear validation or model selection procedures. In the present work, we aim to address these limitations through three main contributions. First, we performed a systematic literature review. We identified four main types of approaches: i) 2D slice-level, ii) 3D patch-level, iii) ROI-based and iv) 3D subject-level CNN. Moreover, we found that more than half of the surveyed papers may have suffered from data leakage and thus reported biased performance. Our second contribution is the extension of our open-source framework for classification of AD using CNN and T1-weighted MRI. The framework comprises previously developed tools to automatically convert ADNI, AIBL and OASIS data into the BIDS standard, and a modular set of image preprocessing procedures, classification architectures and evaluation procedures dedicated to deep learning. Finally, we used this framework to rigorously compare different CNN architectures. The data was split into training/validation/test sets at the very beginning and only the training/validation sets were used for model selection. To avoid any overfitting, the test sets were left untouched until the end of the peer-review process. Overall, the different 3D approaches (3D-subject, 3D-ROI, 3D-patch) achieved similar performances while that of the 2D slice approach was lower. Of note, the different CNN approaches did not perform better than a SVM with voxel-based features. The different approaches generalized well to similar populations but not to datasets with different inclusion criteria or demographical characteristics. All the code of the framework and the experiments is publicly available: general-purpose tools have been integrated into the Clinica software (www.clinica.run) and the paper-specific code is available at: https://github.com/aramis-lab/AD-DL.

We propose a method to learn a distribution of shape trajectories from longitudinal data, i.e. the collection of individual objects repeatedly observed at multiple time-points. The method allows to compute an average spatiotemporal trajectory of shape changes at the group level, and the individual variations of this trajectory both in terms of geometry and time dynamics. First, we formulate a non-linear mixed-effects statistical model as the combination of a generic statistical model for manifold-valued longitudinal data, a deformation model defining shape trajectories via the action of a finite-dimensional set of diffeomorphisms with a manifold structure, and an efficient numerical scheme to compute parallel transport on this manifold. Second, we introduce a MCMC-SAEM algorithm with a specific approach to shape sampling, an adaptive scheme for proposal variances, and a log-likelihood tempering strategy to estimate our model. Third, we validate our algorithm on 2D simulated data, and then estimate a scenario of alteration of the shape of the hippocampus 3D brain structure during the course of Alzheimer's disease. The method shows for instance that hippocampal atrophy progresses more quickly in female subjects, and occurs earlier in APOE4 mutation carriers. We finally illustrate the potential of our method for classifying pathological trajectories versus normal ageing.

Deformations, and diffeormophisms, in particular, have played a tremendous role in the field of statistical shape analysis, as a proxy to measure and interpret differences between similar objects but with different shapes. Diffeomorphisms usually result from the integration of a flow of regular velocity fields, whose parameters have not enabled, so far, a full control of the local behavior of the deformation. In this work, we propose a new mathematical and computational framework, in which these velocity fields are constrained to be built through a combination of local deformation modules with few degrees of freedom. Deformation modules contribute to the global velocity field, and interact with it during integration so that the local modules are transported by the global diffeomorphic deformation under construction. Such modular diffeomorphisms are used to deform shapes and to provide the shape space with a sub-Riemannian metric. We then derive a method to estimate a Fréchet mean from a series of observations, and to decompose the variations in shape observed in the training samples into a set of elementary deformation modules encoding distinctive and interpretable aspects of the shape variability. We show how this approach brings new solutions to long lasting problems in the fields of computer vision and medical image analysis. For instance, the easy implementation of priors in the type of deformations offers a direct control to favor one solution over another in situations where multiple solutions may fit the observations equally well. It allows also the joint optimization of a linear and a nonlinear deformation between shapes, the linear transform simply being a particular type of module. The proposed approach generalizes previous methods for constructing diffeomorphisms and opens up new perspectives in the field of statistical shape analysis.

The brain is composed of several neural circuits which may be seen as anatomical complexes composed of grey matter structures interconnected by white matter tracts. Grey and white matter components may be modeled as 3-D surfaces and curves, respectively. Neurodevelopmental disorders involve morphological and organizational alterations which cannot be jointly captured by usual shape analysis techniques based on single diffeomorphisms. We propose a new deformation scheme, called double diffeomorphism, which is a combination of two diffeomorphisms. The first one captures changes in structural connectivity, whereas the second one recovers the global morphological variations of both grey and white matter structures. This deformation model is integrated into a Bayesian framework for atlas construction. We evaluate it on a data-set of 3-D structures representing the neural circuits of patients with Gilles de la Tourette syndrome (GTS). We show that this approach makes it possible to localise, quantify, and easily visualise the pathological anomalies altering the morphology and organization of the neural circuits. Furthermore, results also indicate that the proposed deformation model better discriminates between controls and GTS patients than a single diffeomorphism.

We propose a generic Bayesian mixed-effects model to estimate the temporal progression of a biological phenomenon from observations obtained at multiple time points for a group of individuals. The progression is modeled by continuous trajectories in the space of measurements. Individual trajectories of progression result from spatiotemporal transformations of an average trajectory. These transformations allow for the quantification of changes in direction and pace at which the trajectories are followed. The framework of Riemannian geometry allows the model to be used with any kind of measurements with smooth constraints. A stochastic version of the Expectation-Maximization algorithm is used to produce maximum a posteriori estimates of the parameters. We evaluated our method using a series of neuropsychological test scores from patients with mild cognitive impairments, later diagnosed with Alzheimer's disease, and simulated evolutions of symmetric positive definite matrices. The data-driven model of impairment of cognitive functions illustrated the variability in the ordering and timing of the decline of these functions in the population. We showed that the estimated spatiotemporal transformations effectively put into correspondence significant events in the progression of individuals.

Fiber bundles stemming from tractography algorithms contain many streamlines. They require therefore a great amount of computer memory and computational resources to be stored, visualised and processed. We propose an approximation scheme for fiber bundles which results in a parsimonious representation of weighted prototypes. Prototypes are chosen among the streamlines and they represent groups of similar streamlines. Their weight is related to the number of approximated streamlines. Both streamlines and prototypes are modelled as weighted currents. This computational model does not need point-to-point correspondences and two streamlines are considered similar if their endpoints are close to each other and if their pathways follow similar trajectories. Moreover, the space of weighted currents is a vector space with a closed-form metric. This permits easy computation of the approximation error and the selection of the prototypes is based on the minimisation of this error. We propose an iterative algorithm which approximates independently and simultaneously all the fascicles of the bundle in a fast and accurate way. We show that the resulting representation preserves the shape of the bundle and it can be used to accurately reconstruct the original structural connectivity. We evaluate our algorithm on bundles obtained from both deterministic and probabilistic tractography algorithms. The resulting approximations use on average only 2% of the original streamlines as prototypes. This drastically reduces the computational burden of the processes where the geometry of the streamlines is considered. We demonstrate its effectiveness using as example the registration between two fiber bundles.

We propose a Bayesian mixed-effects model to learn typical scenarios of changes from longitudinal manifold-valued data, namely repeated measurements of the same objects or individuals at several points in time. The model allows to estimate a group-average trajectory in the space of measurements. Random variations of this trajectory result from spatiotemporal transformations, which allow changes in the direction of the trajectory and in the pace at which trajectories are followed. The use of the tools of Riemannian geometry allows to derive a generic algorithm for any kind of data with smooth constraints, which lie therefore on a Riemannian manifold. Stochastic approximations of the Expectation-Maximization algorithm is used to estimate the model parameters in this highly non-linear setting.The method is used to estimate a data-driven model of the progressive impairments of cognitive functions during the onset of Alzheimer's disease. Experimental results show that the model correctly put into correspondence the age at which each individual was diagnosed with the disease, thus validating the fact that it effectively estimated a normative scenario of disease progression. Random effects provide unique insights into the variations in the ordering and timing of the succession of cognitive impairments across different individuals.

In this paper we introduce a diffeomorphic constraint on the deformations considered in the deformable Bayesian mixed effect template model. Our approach is built on a generic group of diffeomorphisms, which is parameterized by an arbitrary set of control point positions and momentum vectors. This enables us to estimate the optimal positions of control points together with a template image and parameters of the deformation distribution which compose the atlas. We propose to use a stochastic version of the expectation-maximization algorithm where the simulation is performed using the anisotropic Metropolis adjusted Langevin algorithm. We propose also an extension of the model including a sparsity constraint to select an optimal number of control points with relevant positions. Experiments are carried out on the United States Postal Service database, on mandibles of mice, and on three-dimensional murine dendrite spine images.

Cardiac remodelling plays a crucial role in heart diseases. Analyzing how the heart grows and remodels over time can provide precious insights into pathological mechanisms, eventually resulting in quantitative metrics for disease evaluation and therapy planning. This study aims to quantify the regional impacts of valve regurgitation and heart growth upon the end-diastolic right ventricle (RV) in patients with tetralogy of Fallot, a severe congenital heart defect. The ultimate goal is to determine, among clinical variables, predictors for the RV shape from which a statistical model that predicts RV remodelling is built. Our approach relies on a forward model based on currents and a diffeomorphic surface registration algorithm to estimate an unbiased template. Local effects of RV regurgitation upon the RV shape were assessed with Principal Component Analysis (PCA) and cross-sectional multivariate design. A generative 3-D model of RV growth was then estimated using partial least squares (PLS) and canonical correlation analysis (CCA). Applied on a retrospective population of 49 patients, cross-effects between growth and pathology could be identified. Qualitatively, the statistical findings were found realistic by cardiologists. 10-fold cross-validation demonstrated a promising generalization and stability of the growth model. Compared to PCA regression, PLS was more compact, more precise and provided better predictions.