A major interest in longitudinal neuroimaging studies involves investigating voxel-level neuroplasticity due to treatment and other factors across visits. However, traditional voxel-wise methods are beset with several pitfalls, which can compromise the accuracy of these approaches. We propose a novel Bayesian tensor response regression approach for longitudinal imaging data, which pools information across spatially-distributed voxels to infer significant changes while adjusting for covariates. The proposed method, which is implemented using Markov chain Monte Carlo (MCMC) sampling, utilizes low-rank decomposition to reduce dimensionality and preserve spatial configurations of voxels when estimating coefficients. It also enables feature selection via joint credible regions which respect the shape of the posterior distributions for more accurate inference. In addition to group level inferences, the method is able to infer individual-level neuroplasticity, allowing for examination of personalized disease or recovery trajectories. The advantages of the proposed approach in terms of prediction and feature selection over voxel-wise regression are highlighted via extensive simulation studies. Subsequently, we apply the approach to a longitudinal Aphasia dataset consisting of task functional MRI images from a group of subjects who were administered either a control intervention or intention treatment at baseline and were followed up over subsequent visits. Our analysis revealed that while the control therapy showed long-term increases in brain activity, the intention treatment produced predominantly short-term changes, both of which were concentrated in distinct localized regions. In contrast, the voxel-wise regression failed to detect any significant neuroplasticity after multiplicity adjustments, which is biologically implausible and implies lack of power.
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Prediction models are popular in medical research and practice. By predicting an outcome of interest for specific patients, these models may help inform difficult treatment decisions, and are often hailed as the poster children for personalized, data-driven healthcare. We show however, that using prediction models for decision making can lead to harmful decisions, even when the predictions exhibit good discrimination after deployment. These models are harmful self-fulfilling prophecies: their deployment harms a group of patients but the worse outcome of these patients does not invalidate the predictive power of the model. Our main result is a formal characterization of a set of such prediction models. Next we show that models that are well calibrated before and after deployment are useless for decision making as they made no change in the data distribution. These results point to the need to revise standard practices for validation, deployment and evaluation of prediction models that are used in medical decisions.
Quadratization of polynomial and nonpolynomial systems of ordinary differential equations is advantageous in a variety of disciplines, such as systems theory, fluid mechanics, chemical reaction modeling and mathematical analysis. A quadratization reveals new variables and structures of a model, which may be easier to analyze, simulate, control, and provides a convenient parametrization for learning. This paper presents novel theory, algorithms and software capabilities for quadratization of non-autonomous ODEs. We provide existence results, depending on the regularity of the input function, for cases when a quadratic-bilinear system can be obtained through quadratization. We further develop existence results and an algorithm that generalizes the process of quadratization for systems with arbitrary dimension that retain the nonlinear structure when the dimension grows. For such systems, we provide dimension-agnostic quadratization. An example is semi-discretized PDEs, where the nonlinear terms remain symbolically identical when the discretization size increases. As an important aspect for practical adoption of this research, we extended the capabilities of the QBee software towards both non-autonomous systems of ODEs and ODEs with arbitrary dimension. We present several examples of ODEs that were previously reported in the literature, and where our new algorithms find quadratized ODE systems with lower dimension than the previously reported lifting transformations. We further highlight an important area of quadratization: reduced-order model learning. This area can benefit significantly from working in the optimal lifting variables, where quadratic models provide a direct parametrization of the model that also avoids additional hyperreduction for the nonlinear terms. A solar wind example highlights these advantages.
While many phenomena in physics and engineering are formally high-dimensional, their long-time dynamics often live on a lower-dimensional manifold. The present work introduces an autoencoder framework that combines implicit regularization with internal linear layers and $L_2$ regularization (weight decay) to automatically estimate the underlying dimensionality of a data set, produce an orthogonal manifold coordinate system, and provide the mapping functions between the ambient space and manifold space, allowing for out-of-sample projections. We validate our framework's ability to estimate the manifold dimension for a series of datasets from dynamical systems of varying complexities and compare to other state-of-the-art estimators. We analyze the training dynamics of the network to glean insight into the mechanism of low-rank learning and find that collectively each of the implicit regularizing layers compound the low-rank representation and even self-correct during training. Analysis of gradient descent dynamics for this architecture in the linear case reveals the role of the internal linear layers in leading to faster decay of a "collective weight variable" incorporating all layers, and the role of weight decay in breaking degeneracies and thus driving convergence along directions in which no decay would occur in its absence. We show that this framework can be naturally extended for applications of state-space modeling and forecasting by generating a data-driven dynamic model of a spatiotemporally chaotic partial differential equation using only the manifold coordinates. Finally, we demonstrate that our framework is robust to hyperparameter choices.
We present a finite element approach for diffusion problems with thermal fluctuations based on a fluctuating hydrodynamics model. The governing transport equations are stochastic partial differential equations with a fluctuating forcing term. We propose a discrete formulation of the stochastic forcing term that has the correct covariance matrix up to a standard discretization error. Furthermore, to obtain a numerical solution with spatial correlations that converge to those of the continuum equation, we derive a linear mapping to transform the finite element solution into an equivalent discrete solution that is free from the artificial correlations introduced by the spatial discretization. The method is validated by applying it to two diffusion problems: a second-order diffusion equation and a fourth-order diffusion equation. The theoretical (continuum) solution to the first case presents spatially decorrelated fluctuations, while the second case presents fluctuations correlated over a finite length. In both cases, the numerical solution presents a structure factor that approximates well the continuum one.
Dynamic treatment regimes (DTRs) formalize medical decision-making as a sequence of rules for different stages, mapping patient-level information to recommended treatments. In practice, estimating an optimal DTR using observational data from electronic medical record (EMR) databases can be complicated by covariates that are missing not at random (MNAR) due to informative monitoring of patients. Since complete case analysis can result in consistent estimation of outcome model parameters under the assumption of outcome-independent missingness \citep{Yang_Wang_Ding_2019}, Q-learning is a natural approach to accommodating MNAR covariates. However, the backward induction algorithm used in Q-learning can introduce complications, as MNAR covariates at later stages can result in MNAR pseudo-outcomes at earlier stages, leading to suboptimal DTRs, even if outcome variables are fully observed. To address this unique missing data problem in DTR settings, we propose two weighted Q-learning approaches where inverse probability weights for missingness of the pseudo-outcomes are obtained through estimating equations with valid nonresponse instrumental variables or sensitivity analysis. Asymptotic properties of the weighted Q-learning estimators are derived and the finite-sample performance of the proposed methods is evaluated and compared with alternative methods through extensive simulation studies. Using EMR data from the Medical Information Mart for Intensive Care database, we apply the proposed methods to investigate the optimal fluid strategy for sepsis patients in intensive care units.
Understanding whether and how treatment effects vary across subgroups is crucial to inform clinical practice and recommendations. Accordingly, the assessment of heterogeneous treatment effects (HTE) based on pre-specified potential effect modifiers has become a common goal in modern randomized trials. However, when one or more potential effect modifiers are missing, complete-case analysis may lead to bias and under-coverage. While statistical methods for handling missing data have been proposed and compared for individually randomized trials with missing effect modifier data, few guidelines exist for the cluster-randomized setting, where intracluster correlations in the effect modifiers, outcomes, or even missingness mechanisms may introduce further threats to accurate assessment of HTE. In this article, the performance of several missing data methods are compared through a simulation study of cluster-randomized trials with continuous outcome and missing binary effect modifier data, and further illustrated using real data from the Work, Family, and Health Study. Our results suggest that multilevel multiple imputation (MMI) and Bayesian MMI have better performance than other available methods, and that Bayesian MMI has lower bias and closer to nominal coverage than standard MMI when there are model specification or compatibility issues.
In a longitudinal clinical registry, different measurement instruments might have been used for assessing individuals at different time points. To combine them, we investigate deep learning techniques for obtaining a joint latent representation, to which the items of different measurement instruments are mapped. This corresponds to domain adaptation, an established concept in computer science for image data. Using the proposed approach as an example, we evaluate the potential of domain adaptation in a longitudinal cohort setting with a rather small number of time points, motivated by an application with different motor function measurement instruments in a registry of spinal muscular atrophy (SMA) patients. There, we model trajectories in the latent representation by ordinary differential equations (ODEs), where person-specific ODE parameters are inferred from baseline characteristics. The goodness of fit and complexity of the ODE solutions then allows to judge the measurement instrument mappings. We subsequently explore how alignment can be improved by incorporating corresponding penalty terms into model fitting. To systematically investigate the effect of differences between measurement instruments, we consider several scenarios based on modified SMA data, including scenarios where a mapping should be feasible in principle and scenarios where no perfect mapping is available. While misalignment increases in more complex scenarios, some structure is still recovered, even if the availability of measurement instruments depends on patient state. A reasonable mapping is feasible also in the more complex real SMA dataset. These results indicate that domain adaptation might be more generally useful in statistical modeling for longitudinal registry data.
Ductile damage models and cohesive laws incorporate the material plasticity entailing the growth of irrecoverable deformations even after complete failure. This unrealistic growth remains concealed until the unilateral effects arising from the crack closure emerge. We address this issue by proposing a new strategy to cope with the entire process of failure, from the very inception in the form of diffuse damage to the final stage, i.e. the emergence of sharp cracks. To this end, we introduce a new strain field, termed discontinuity strain, to the conventional additive strain decomposition to account for discontinuities in a continuous sense so that the standard principle of virtual work applies. We treat this strain field similar to a strong discontinuity, yet without introducing new kinematic variables and nonlinear boundary conditions. In this paper, we demonstrate the effectiveness of this new strategy at a simple ductile damage constitutive model. The model uses a scalar damage index to control the degradation process. The discontinuity strain field is injected into the strain decomposition if this damage index exceeds a certain threshold. The threshold corresponds to the limit at which the induced imperfections merge and form a discrete crack. With three-point bending tests under pure mode I and mixed-mode conditions, we demonstrate that this augmentation does not show the early crack closure artifact which is wrongly predicted by plastic damage formulations at load reversal. We also use the concrete damaged plasticity model provided in Abaqus commercial finite element program for our comparison. Lastly, a high-intensity low-cycle fatigue test demonstrates the unilateral effects resulting from the complete closure of the induced crack.
We propose an innovative and generic methodology to analyse individual and collective behaviour through individual trajectory data. The work is motivated by the analysis of GPS trajectories of fishing vessels collected from regulatory tracking data in the context of marine biodiversity conservation and ecosystem-based fisheries management. We build a low-dimensional latent representation of trajectories using convolutional neural networks as non-linear mapping. This is done by training a conditional variational auto-encoder taking into account covariates. The posterior distributions of the latent representations can be linked to the characteristics of the actual trajectories. The latent distributions of the trajectories are compared with the Bhattacharyya coefficient, which is well-suited for comparing distributions. Using this coefficient, we analyse the variation of the individual behaviour of each vessel during time. For collective behaviour analysis, we build proximity graphs and use an extension of the stochastic block model for multiple networks. This model results in a clustering of the individuals based on their set of trajectories. The application to French fishing vessels enables us to obtain groups of vessels whose individual and collective behaviours exhibit spatio-temporal patterns over the period 2014-2018.
Spatio-temporal pathogen spread is often partially observed at the metapopulation scale. Available data correspond to proxies and are incomplete, censored and heterogeneous. Moreover, representing such biological systems often leads to complex stochastic models. Such complexity together with data characteristics make the analysis of these systems a challenge. Our objective was to develop a new inference procedure to estimate key parameters of stochastic metapopulation models of animal disease spread from longitudinal and spatial datasets, while accurately accounting for characteristics of census data. We applied our procedure to provide new knowledge on the regional spread of \emph{Mycobacterium avium} subsp. \emph{paratuberculosis} (\emph{Map}), which causes bovine paratuberculosis, a worldwide endemic disease. \emph{Map} spread between herds through trade movements was modeled with a stochastic mechanistic model. Comprehensive data from 2005 to 2013 on cattle movements in 12,857 dairy herds in Brittany (western France) and partial data on animal infection status in 2,278 herds sampled from 2007 to 2013 were used. Inference was performed using a new criterion based on a Monte-Carlo approximation of a composite likelihood, coupled to a numerical optimization algorithm (Nelder-Mead Simplex-like). Our criterion showed a clear superiority to alternative ones in identifying the right parameter values, as assessed by an empirical identifiability on simulated data. Point estimates and profile likelihoods allowed us to establish the initial state of the system, identify the risk of pathogen introduction from outside the metapopulation, and confirm the assumption of the low sensitivity of the diagnostic test. Our inference procedure could easily be applied to other spatio-temporal infection dynamics, especially when ABC-like methods face challenges in defining relevant summary statistics.
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