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The forecasting of disease progression from images is a holy grail for clinical decision making. However, this task is complicated by the inherent high dimensionality, temporal sparsity and sampling irregularity in longitudinal image acquisitions. Existing methods often rely on extracting hand-crafted features and performing time-series analysis in this vector space, leading to a loss of rich spatial information within the images. To overcome these challenges, we introduce ImageFlowNet, a novel framework that learns latent-space flow fields that evolve multiscale representations in joint embedding spaces using neural ODEs and SDEs to model disease progression in the image domain. Notably, ImageFlowNet learns multiscale joint representation spaces by combining cohorts of patients together so that information can be transferred between the patient samples. The dynamics then provide plausible trajectories of progression, with the SDE providing alternative trajectories from the same starting point. We provide theoretical insights that support our formulation of ODEs, and motivate our regularizations involving high-level visual features, latent space organization, and trajectory smoothness. We then demonstrate ImageFlowNet's effectiveness through empirical evaluations on three longitudinal medical image datasets depicting progression in retinal geographic atrophy, multiple sclerosis, and glioblastoma., Comment: Fixed some typos. Merged multibib

The multivariate hypergeometric distribution describes sampling without replacement from a discrete population of elements divided into multiple categories. Addressing a gap in the literature, we tackle the challenge of estimating discrete distributions when both the total population size and the sizes of its constituent categories are unknown. Here, we propose a novel solution using the hypergeometric likelihood to solve this estimation challenge, even in the presence of severe under-sampling. We develop our approach to account for a data generating process where the ground-truth is a mixture of distributions conditional on a continuous latent variable, such as with collaborative filtering, using the variational autoencoder framework. Empirical data simulation demonstrates that our method outperforms other likelihood functions used to model count data, both in terms of accuracy of population size estimate and in its ability to learn an informative latent space. We demonstrate our method's versatility through applications in NLP, by inferring and estimating the complexity of latent vocabularies in text excerpts, and in biology, by accurately recovering the true number of gene transcripts from sparse single-cell genomics data.

Through Diffusion Models (DMs), we have made significant advances in generating high-quality images. Our exploration of these models delves deeply into their core operational principles by systematically investigating key aspects across various DM architectures: i) noise schedules, ii) samplers, and iii) guidance. Our comprehensive examination of these models sheds light on their hidden fundamental mechanisms, revealing the concealed foundational elements that are essential for their effectiveness. Our analyses emphasize the hidden key factors that determine model performance, offering insights that contribute to the advancement of DMs. Past findings show that the configuration of noise schedules, samplers, and guidance is vital to the quality of generated images; however, models reach a stable level of quality across different configurations at a remarkably similar point, revealing that the decisive factors for optimal performance predominantly reside in the diffusion process dynamics and the structural design of the model's network, rather than the specifics of configuration details. Our comparative analysis reveals that Denoising Diffusion Probabilistic Model (DDPM)-based diffusion dynamics consistently outperform the Noise Conditioned Score Network (NCSN)-based ones, not only when evaluated in their original forms but also when continuous through Stochastic Differential Equation (SDE)-based implementations., Comment: 28 pages, 21 figures

Equity is widely held to be fundamental to the ethics of healthcare. In the context of clinical decision-making, it rests on the comparative fidelity of the intelligence -- evidence-based or intuitive -- guiding the management of each individual patient. Though brought to recent attention by the individuating power of contemporary machine learning, such epistemic equity arises in the context of any decision guidance, whether traditional or innovative. Yet no general framework for its quantification, let alone assurance, currently exists. Here we formulate epistemic equity in terms of model fidelity evaluated over learnt multi-dimensional representations of identity crafted to maximise the captured diversity of the population, introducing a comprehensive framework for Representational Ethical Model Calibration. We demonstrate use of the framework on large-scale multimodal data from UK Biobank to derive diverse representations of the population, quantify model performance, and institute responsive remediation. We offer our approach as a principled solution to quantifying and assuring epistemic equity in healthcare, with applications across the research, clinical, and regulatory domains., Comment: 13 pages

Most of the existing deep learning based methods for vessel segmentation neglect two important aspects of retinal vessels, one is the orientation information of vessels, and the other is the contextual information of the whole fundus region. In this paper, we propose a robust Orientation and Context Entangled Network (denoted as OCE-Net), which has the capability of extracting complex orientation and context information of the blood vessels. To achieve complex orientation aware, a Dynamic Complex Orientation Aware Convolution (DCOA Conv) is proposed to extract complex vessels with multiple orientations for improving the vessel continuity. To simultaneously capture the global context information and emphasize the important local information, a Global and Local Fusion Module (GLFM) is developed to simultaneously model the long-range dependency of vessels and focus sufficient attention on local thin vessels. A novel Orientation and Context Entangled Non-local (OCE-NL) module is proposed to entangle the orientation and context information together. In addition, an Unbalanced Attention Refining Module (UARM) is proposed to deal with the unbalanced pixel numbers of background, thick and thin vessels. Extensive experiments were performed on several commonly used datasets (DRIVE, STARE and CHASEDB1) and some more challenging datasets (AV-WIDE, UoA-DR, RFMiD and UK Biobank). The ablation study shows that the proposed method achieves promising performance on maintaining the continuity of thin vessels and the comparative experiments demonstrate that our OCE-Net can achieve state-of-the-art performance on retinal vessel segmentation., Comment: 62 pages, 14 figures

High-quality data accumulation is now becoming ubiquitous in the health domain. There is increasing opportunity to exploit rich data from normal subjects to improve supervised estimators in specific diseases with notorious data scarcity. We demonstrate that low-dimensional embedding spaces can be derived from the UK Biobank population dataset and used to enhance data-scarce prediction of health indicators, lifestyle and demographic characteristics. Phenotype predictions facilitated by Variational Autoencoder manifolds typically scaled better with increasing unlabeled data than dimensionality reduction by PCA or Isomap. Performances gains from semisupervison approaches will probably become an important ingredient for various medical data science applications., Comment: Accepted at NIPS 2017 Workshop on Machine Learning for Health

Identification of disease subtypes and corresponding biomarkers can substantially improve clinical diagnosis and treatment selection. Discovering these subtypes in noisy, high dimensional biomedical data is often impossible for humans and challenging for machines. We introduce a new approach to facilitate the discovery of disease subtypes: Instead of analyzing the original data, we train a diagnostic classifier (healthy vs. diseased) and extract instance-wise explanations for the classifier's decisions. The distribution of instances in the explanation space of our diagnostic classifier amplifies the different reasons for belonging to the same class - resulting in a representation that is uniquely useful for discovering latent subtypes. We compare our ability to recover subtypes via cluster analysis on model explanations to classical cluster analysis on the original data. In multiple datasets with known ground-truth subclasses, most compellingly on UK Biobank brain imaging data and transcriptome data from the Cancer Genome Atlas, we show that cluster analysis on model explanations substantially outperforms the classical approach. While we believe clustering in explanation space to be particularly valuable for inferring disease subtypes, the method is more general and applicable to any kind of sub-type identification.

Functional connectivity fingerprints are among today's best choices to obtain a faithful sampling of an individual's brain and cognition in health and disease. Here we make a case for key advantages of analyzing such connectome profiles using Bayesian analysis strategies. They (i) afford full probability estimates of the studied neurocognitive phenomenon (ii) provide analytical machinery to separate methodological uncertainty and biological variability in a coherent manner (iii) usher towards avenues to go beyond classical null-hypothesis significance testing and (iv) enable estimates of credibility around all model parameters at play and thus enable predictions with uncertainty intervals for single subject. We pick research questions about autism spectrum disorder as a recurring theme to illustrate our methodological arguments.

The last decades saw dramatic progress in brain research. These advances were often buttressed by probing single variables to make circumscribed discoveries, typically through null hypothesis significance testing. New ways for generating massive data fueled tension between the traditional methodology, used to infer statistically relevant effects in carefully-chosen variables, and pattern-learning algorithms, used to identify predictive signatures by searching through abundant information. In this article, we detail the antagonistic philosophies behind two quantitative approaches: certifying robust effects in understandable variables, and evaluating how accurately a built model can forecast future outcomes. We discourage choosing analysis tools via categories like 'statistics' or 'machine learning'. Rather, to establish reproducible knowledge about the brain, we advocate prioritizing tools in view of the core motivation of each quantitative analysis: aiming towards mechanistic insight, or optimizing predictive accuracy.

Since the beginning of the 21st century, the size, breadth, and granularity of data in biology and medicine has grown rapidly. In the example of neuroscience, studies with thousands of subjects are becoming more common, which provide extensive phenotyping on the behavioral, neural, and genomic level with hundreds of variables. The complexity of such big data repositories offer new opportunities and pose new challenges to investigate brain, cognition, and disease. Canonical correlation analysis (CCA) is a prototypical family of methods for wrestling with and harvesting insight from such rich datasets. This doubly-multivariate tool can simultaneously consider two variable sets from different modalities to uncover essential hidden associations. Our primer discusses the rationale, promises, and pitfalls of CCA in biomedicine.

Background: We previously presented GraphVar as a user-friendly MATLAB toolbox for comprehensive graph analyses of functional brain connectivity. Here we introduce a comprehensive extension of the toolbox allowing users to seamlessly explore easily customizable decoding models across functional connectivity measures as well as additional features. New Method: GraphVar 2.0 provides machine learning (ML) model construction, validation and exploration. Machine learning can be performed across any combination of network measures and additional variables, allowing for a flexibility in neuroimaging applications. Results: In addition to previously integrated functionalities, such as network construction and graph-theoretical analyses of brain connectivity with a high-speed general linear model (GLM), users can now perform customizable ML across connectivity matrices, network metrics and additionally imported variables. The new extension also provides parametric and nonparametric testing of classifier and regressor performance, data export, figure generation and high quality export. Comparison with existing methods: Compared to other existing toolboxes, GraphVar 2.0 offers (1) comprehensive customization, (2) an all-in-one user friendly interface, (3) customizable model design and manual hyperparameter entry, (4) interactive results exploration and data export, (5) automated cueing for modelling multiple outcome variables within the same session, (6) an easy to follow introductory review. Conclusions: GraphVar 2.0 allows comprehensive, user-friendly exploration of encoding (GLM) and decoding (ML) modelling approaches on functional connectivity measures making big data neuroscience readily accessible to a broader audience of neuroimaging investigators., Comment: MATLAB, GUI, Toolbox, 11 pages, first two authors contributed equally, , uncorrected proof Journal of Neuroscience Methods, Accepted 1 July 2018

Cognitive neuroscience is enjoying rapid increase in extensive public brain-imaging datasets. It opens the door to large-scale statistical models. Finding a unified perspective for all available data calls for scalable and automated solutions to an old challenge: how to aggregate heterogeneous information on brain function into a universal cognitive system that relates mental operations/cognitive processes/psychological tasks to brain networks? We cast this challenge in a machine-learning approach to predict conditions from statistical brain maps across different studies. For this, we leverage multi-task learning and multi-scale dimension reduction to learn low-dimensional representations of brain images that carry cognitive information and can be robustly associated with psychological stimuli. Our multi-dataset classification model achieves the best prediction performance on several large reference datasets, compared to models without cognitive-aware low-dimension representations, it brings a substantial performance boost to the analysis of small datasets, and can be introspected to identify universal template cognitive concepts., Comment: Advances in Neural Information Processing Systems, Dec 2017, Long Beach, United States. 2017

The nature of mental illness remains a conundrum. Traditional disease categories are increasingly suspected to mis-represent the causes underlying mental disturbance. Yet, psychiatrists and investigators now have an unprecedented opportunity to benefit from complex patterns in brain, behavior, and genes using methods from machine learning (e.g., support vector machines, modern neural-network algorithms, cross-validation procedures). Combining these analysis techniques with a wealth of data from consortia and repositories has the potential to advance a biologically grounded re-definition of major psychiatric disorders. Within the next 10-20 years, incoming patients could be stratified into distinct biological subgroups that cut across classical diagnostic boundaries. In a new era of evidence-based psychiatry tailored to single patients, objectively measurable endophenotypes could allow for individualized prediction of early diagnosis, treatment selection, and dosage adjustment to reduce the burden of disease. This primer aims to introduce clinicians and researchers to the opportunities and challenges in bringing machine intelligence into psychiatric practice.