Identifying and evaluating clinical subtypes of Alzheimer's disease in care electronic health records using unsupervised machine learning

BACKGROUND: Alzheimer's disease (AD) is a highly heterogeneous disease with diverse trajectories and outcomes observed in clinical populations. Understanding this heterogeneity can enable better treatment, prognosis and disease management. Studies to date have mainly used imaging or cognition data and have been limited in terms of data breadth and sample size. Here we examine the clinical heterogeneity of Alzheimer's disease patients using electronic health records (EHR) to identify and characterise disease subgroups using multiple clustering methods, identifying clusters which are clinically actionable. METHODS: We identified AD patients in primary care EHR from the Clinical Practice Research Datalink (CPRD) using a previously validated rule-based phenotyping algorithm. We extracted and included a range of comorbidities, symptoms and demographic features as patient features. We evaluated four different clustering methods (k-means, kernel k-means, affinity propagation and latent class analysis) to cluster Alzheimer's disease patients. We compared clusters on clinically relevant outcomes and evaluated each method using measures of cluster structure, stability, efficiency of outcome prediction and replicability in external data sets. RESULTS: We identified 7,913 AD patients, with a mean age of 82 and 66.2% female. We included 21 features in our analysis. We observed 5, 2, 5 and 6 clusters in k-means, kernel k-means, affinity propagation and latent class analysis respectively. K-means was found to produce the most consistent results based on four evaluative measures. We discovered a consistent cluster found in three of the four methods composed of predominantly female, younger disease onset (43% between ages 42-73) diagnosed with depression and anxiety, with a quicker rate of progression compared to the average across other clusters. CONCLUSION: Each clustering approach produced substantially different clusters and K-Means performed the best out of the four methods based on the four evaluative criteria. However, the consistent appearance of one particular cluster across three of the four methods potentially suggests the presence of a distinct disease subtype that merits further exploration. Our study underlines the variability of the results obtained from different clustering approaches and the importance of systematically evaluating different approaches for identifying disease subtypes in complex EHR

ND-Track: Tractography utilising parametric models of white matter fibre orientation dispersion

This work develops a tractography algorithm to leverage fibre dispersion estimates derived from fitting parametric models of orientation dispersion to diffusion data. Tractography techniques are powerful tools to probe white matter (WM) connectivity non-invasively. Most current techniques follow a small number of discrete directions per voxel to identify WM connections. This approach addresses the limitation of traditional DTI-based tractography for regions with crossing fibres. However, it remains an oversimplification for regions with fanning and bending configurations, where the underlying fibre orientation distributions are continuous rather than discrete [2]. Following only a discrete set of directions in this case misrepresents the underlying anatomy and is likely to result in false negative connectivity estimates. Recent parameterized models of fibre dispersion represent such sub-voxel fibre architecture more realistically and provide more accurate estimates of dispersion than non-parametric techniques such as spherical deconvolution, which are vulnerable to noise [3]. Here, we present a new tractography algorithm, hereby referred to as ND-Track (Neurite Dispersion Tracking), that leverages directional information gathered from parametric models of dispersion. We investigate the advantages of tracking with dispersion measures on a simple phantom and in in-vivo data, tracking through the coronal radiata, a region known to exhibit a significant degree of fibre dispersion. We further demonstrate that this approach does not compromise the tracking of the WM pathways for which the standard technique works well

Imaging plus X: multimodal models of neurodegenerative disease

PURPOSE OF REVIEW: This article argues that the time is approaching for data-driven disease modelling to take centre stage in the study and management of neurodegenerative disease. The snowstorm of data now available to the clinician defies qualitative evaluation; the heterogeneity of data types complicates integration through traditional statistical methods; and the large datasets becoming available remain far from the big-data sizes necessary for fully data-driven machine-learning approaches. The recent emergence of data-driven disease progression models provides a balance between imposed knowledge of disease features and patterns learned from data. The resulting models are both predictive of disease progression in individual patients and informative in terms of revealing underlying biological patterns. RECENT FINDINGS: Largely inspired by observational models, data-driven disease progression models have emerged in the last few years as a feasible means for understanding the development of neurodegenerative diseases. These models have revealed insights into frontotemporal dementia, Huntington's disease, multiple sclerosis, Parkinson's disease and other conditions. For example, event-based models have revealed finer graded understanding of progression patterns; self-modelling regression and differential equation models have provided data-driven biomarker trajectories; spatiotemporal models have shown that brain shape changes, for example of the hippocampus, can occur before detectable neurodegeneration; and network models have provided some support for prion-like mechanistic hypotheses of disease propagation. The most mature results are in sporadic Alzheimer's disease, in large part because of the availability of the Alzheimer's disease neuroimaging initiative dataset. Results generally support the prevailing amyloid-led hypothetical model of Alzheimer's disease, while revealing finer detail and insight into disease progression. SUMMARY: The emerging field of disease progression modelling provides a natural mechanism to integrate different kinds of information, for example from imaging, serum and cerebrospinal fluid markers and cognitive tests, to obtain new insights into progressive diseases. Such insights include fine-grained longitudinal patterns of neurodegeneration, from early stages, and the heterogeneity of these trajectories over the population. More pragmatically, such models enable finer precision in patient staging and stratification, prediction of progression rates and earlier and better identification of at-risk individuals. We argue that this will make disease progression modelling invaluable for recruitment and end-points in future clinical trials, potentially ameliorating the high failure rate in trials of, e.g., Alzheimer's disease therapies. We review the state of the art in these techniques and discuss the future steps required to translate the ideas to front-line application.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Optimising oscillating waveform-shape for pore size sensitivity in diffusion-weighted MR

Optimising the shape of a generalised gradient waveform (GEN) in diffusion-weighted MR has been shown to, in theory, greatly increase sensitivity to pore size. The broad class of optimised shapes takes simple oscillatory forms. To speed up convergence of the optimisation, improve computation times and make the waveforms more practical, here we explore various oscillatory waveforms constructed from trapezoidal and sinusoidal shapes and compare their performance with the optimised GEN waveform. The oscillating waveforms are optimised to maximise sensitivity to parameters, such as axon radius, intra-cellular volume fraction and diffusion constants, of a simple white matter model. Simulation experiments find that all oscillating waveforms we tried perform significantly better than the original generalised waveform due to the improved convergence of the optimisation. Differences among the oscillating shapes however are very small and although a truncated sinusoidal waveform consistently gives the lowest cost function, no significant difference in the estimated model parameters was found. Therefore the simplest choice, i.e. the trapezoidal parametrisation, seems sufficient for most practical purposes

Degenerative Adversarial NeuroImage Nets: Generating Images that Mimic Disease Progression

Simulating images representative of neurodegenerative diseases is important for predicting patient outcomes and for validation of computational models of disease progression. This capability is valuable for secondary prevention clinical trials where outcomes and screening criteria involve neuroimaging. Traditional computational methods are limited by imposing a parametric model for atrophy and are extremely resource-demanding. Recent advances in deep learning have yielded data-driven models for longitudinal studies (e.g., face ageing) that are capable of generating synthetic images in real-time. Similar solutions can be used to model trajectories of atrophy in the brain, although new challenges need to be addressed to ensure accurate disease progression modelling. Here we propose Degenerative Adversarial NeuroImage Net (DaniNet)—a new deep learning approach that learns to emulate the effect of neurodegeneration on MRI by simulating atrophy as a function of ages, and disease progression. DaniNet uses an underlying set of Support Vector Regressors (SVRs) trained to capture the patterns of regional intensity changes that accompany disease progression. DaniNet produces whole output images, consisting of 2D-MRI slices that are constrained to match regional predictions from the SVRs. DaniNet is also able to maintain the unique brain morphology of individuals. Adversarial training ensures realistic brain images and smooth temporal progression. We train our model using 9652 T1-weighted (longitudinal) MRI extracted from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. We perform quantitative and qualitative evaluations on a separate test set of 1283 images (also from ADNI) demonstrating the ability of DaniNet to produce accurate and convincing synthetic images that emulate disease progression

Parametric Probability Distribution Functions for Axon Diameters of Corpus Callosum

Axon diameter is an important neuroanatomical characteristic of the nervous system that alters in the course of neurological disorders such as multiple sclerosis. Axon diameters vary, even within a fiber bundle, and are not normally distributed. An accurate distribution function is therefore beneficial, either to describe axon diameters that are obtained from a direct measurement technique (e.g., microscopy), or to infer them indirectly (e.g., using diffusion-weighted MRI). The gamma distribution is a common choice for this purpose (particularly for the inferential approach) because it resembles the distribution profile of measured axon diameters which has been consistently shown to be non-negative and right-skewed. In this study we compared a wide range of parametric probability distribution functions against empirical data obtained from electron microscopy images. We observed that the gamma distribution fails to accurately describe the main characteristics of the axon diameter distribution, such as location and scale of the mode and the profile of distribution tails. We also found that the generalized extreme value distribution consistently fitted the measured distribution better than other distribution functions. This suggests that there may be distinct subpopulations of axons in the corpus callosum, each with their own distribution profiles. In addition, we observed that several other distributions outperformed the gamma distribution, yet had the same number of unknown parameters; these were the inverse Gaussian, log normal, log logistic and Birnbaum-Saunders distributions

Bayesian Image Quality Transfer with CNNs: Exploring Uncertainty in dMRI Super-Resolution

In this work, we investigate the value of uncertainty modeling in 3D super-resolution with convolutional neural networks (CNNs). Deep learning has shown success in a plethora of medical image transformation problems, such as super-resolution (SR) and image synthesis. However, the highly ill-posed nature of such problems results in inevitable ambiguity in the learning of networks. We propose to account for intrinsic uncertainty through a per-patch heteroscedastic noise model and for parameter uncertainty through approximate Bayesian inference in the form of variational dropout. We show that the combined benefits of both lead to the state-of-the-art performance SR of diffusion MR brain images in terms of errors compared to ground truth. We further show that the reduced error scores produce tangible benefits in downstream tractography. In addition, the probabilistic nature of the methods naturally confers a mechanism to quantify uncertainty over the super-resolved output. We demonstrate through experiments on both healthy and pathological brains the potential utility of such an uncertainty measure in the risk assessment of the super-resolved images for subsequent clinical use.Comment: Accepted paper at MICCAI 201

Double oscillating diffusion encoding and sensitivity to microscopic anisotropy

PURPOSE: To introduce a novel diffusion pulse sequence, namely double oscillating diffusion encoding (DODE), and to investigate whether it adds sensitivity to microscopic diffusion anisotropy (µA) compared to the well-established double diffusion encoding (DDE) methodology. METHODS: We simulate measurements from DODE and DDE sequences for different types of microstructures exhibiting restricted diffusion. First, we compare the effect of varying pulse sequence parameters on the DODE and DDE signal. Then, we analyse the sensitivity of the two sequences to the microstructural parameters (pore diameter and length) which determine µA. Finally, we investigate specificity of measurements to particular substrate configurations. RESULTS: Simulations show that DODE sequences exhibit similar signal dependence on the relative angle between the two gradients as DDE sequences, however, the effect of varying the mixing time is less pronounced. The sensitivity analysis shows that in substrates with elongated pores and various orientations, DODE sequences increase the sensitivity to pore diameter, while DDE sequences are more sensitive to pore length. Moreover, DDE and DODE sequence parameters can be tailored to enhance/suppress the signal from a particular range of substrates. CONCLUSIONS: A combination of DODE and DDE sequences maximize sensitivity to µA, compared to using just the DDE method. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine

Beyond Crossing Fibers: Tractography Exploiting Sub-voxel Fibre Dispersion and Neighbourhood Structure

In this paper we propose a novel algorithm which leverages models of white matter fibre dispersion to improve tractography. Tractography methods exploit directional information from diffusion weighted magnetic resonance (DW-MR) imaging to infer connectivity between different brain regions. Most tractography methods use a single direction (e.g. the principal eigenvector of the diffusion tensor) or a small set of discrete directions (e.g. from the peaks of an orientation distribution function) to guide streamline propagation. This strategy ignores the effects of within-bundle orientation dispersion, which arises from fanning or bending at the sub-voxel scale, and can lead to missing connections. Various recent DW-MR imaging techniques estimate the fibre dispersion in each bundle directly and model it as a continuous distribution. Here we introduce an algorithm to exploit this information to improve tractography. The algorithm further uses a particle filter to probe local neighbourhood structure during streamline propagation. Using information gathered from neighbourhood structure enables the algorithm to resolve ambiguities between converging and diverging fanning structures, which cannot be distinguished from isolated orientation distribution functions. We demonstrate the advantages of the new approach in synthetic experiments and in vivo data. Synthetic experiments demonstrate the effectiveness of the particle filter in gathering and exploiting neighbourhood information in recovering various canonical fibre configurations and experiments with in vivo brain data demonstrate the advantages of utilising dispersion in tractography, providing benefits in practical situations. © 2013 Springer-Verlag

A spatial variation model of white matter microstructure

In this study, we introduce a new technique to model the variation of microstructural parameters across speci c brain regions. We use a simple model of di usion in each voxel, but model the variation of parameters across the region using penalised splines. We t the whole region model directly to the di usion-weighted signals. We test the tech- nique on the mid-sagittal section of the corpus callosum (CC) using a di usion MRI data set with distinct age groups. The method detects di erences and separates the groups