Randomization inference is a powerful tool in early phase vaccine trials to estimate the causal effect of a regimen against a placebo or another regimen. Traditionally, randomization-based inference often focuses on testing either Fisher's sharp null hypothesis of no treatment effect for any unit or Neyman's weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results by incorporating auxiliary information often available in a vaccine trial. These methods are suitable for four scenarios: (i) a randomized controlled trial (RCT) where the potential outcomes under one regimen are constant; (ii) an RCT with no restriction on any potential outcomes; (iii) an RCT with some user-specified bounds on potential outcomes; and (iv) a matched study comparing two non-randomized, possibly confounded treatment arms. We then conduct two extensive simulation studies, one comparing the performance of each method in many practical clinical settings and the other evaluating the usefulness of the methods in ranking and advancing experimental therapies. We apply these methods to an early-phase clinical trail, HIV Vaccine Trials Network Study 086 (HVTN 086), to showcase the usefulness of the methods.
Brain atrophy and white matter hyperintensity (WMH) are critical neuroimaging features for ascertaining brain injury in cerebrovascular disease and multiple sclerosis. Automated segmentation and quantification is desirable but existing methods require high-resolution MRI with good signal-to-noise ratio (SNR). This precludes application to clinical and low-field portable MRI (pMRI) scans, thus hampering large-scale tracking of atrophy and WMH progression, especially in underserved areas where pMRI has huge potential. Here we present a method that segments white matter hyperintensity and 36 brain regions from scans of any resolution and contrast (including pMRI) without retraining. We show results on six public datasets and on a private dataset with paired high- and low-field scans (3T and 64mT), where we attain strong correlation between the WMH ($\rho$=.85) and hippocampal volumes (r=.89) estimated at both fields. Our method is publicly available as part of FreeSurfer, at: //surfer.nmr.mgh.harvard.edu/fswiki/WMH-SynthSeg.
We investigate long-term cognitive effects of an intervention, where systolic blood pressure (sBP) is monitored at more optimal levels, in a large representative sample. A limitation with previous research on the potential risk reduction of such interventions is that they do not properly account for the reduction of mortality rates. Hence, one can only speculate whether the effect is a result from changes in cognition or changes in mortality. As such, we extend previous research by providing both an etiological and a prognostic effect estimate. To do this we propose a Bayesian semi-parametric estimation approach for an incremental intervention, using the extended G-formula. We also introduce a novel sparsity-inducing Dirichlet hyperprior for longitudinal data, demonstrate the usefulness of our approach in simulations, and compare the performance relative to other Bayesian decision tree ensemble approaches. In our study, there were no significant prognostic- or etiological effects across all ages, indicating that sBP interventions likely do not have a strong effect on memory neither at the population level nor at the individual level.
Developing robust and effective artificial intelligence (AI) models in medicine requires access to large amounts of patient data. The use of AI models solely trained on large multi-institutional datasets can help with this, yet the imperative to ensure data privacy remains, particularly as membership inference risks breaching patient confidentiality. As a proposed remedy, we advocate for the integration of differential privacy (DP). We specifically investigate the performance of models trained with DP as compared to models trained without DP on data from institutions that the model had not seen during its training (i.e., external validation) - the situation that is reflective of the clinical use of AI models. By leveraging more than 590,000 chest radiographs from five institutions, we evaluated the efficacy of DP-enhanced domain transfer (DP-DT) in diagnosing cardiomegaly, pleural effusion, pneumonia, atelectasis, and in identifying healthy subjects. We juxtaposed DP-DT with non-DP-DT and examined diagnostic accuracy and demographic fairness using the area under the receiver operating characteristic curve (AUC) as the main metric, as well as accuracy, sensitivity, and specificity. Our results show that DP-DT, even with exceptionally high privacy levels (epsilon around 1), performs comparably to non-DP-DT (P>0.119 across all domains). Furthermore, DP-DT led to marginal AUC differences - less than 1% - for nearly all subgroups, relative to non-DP-DT. Despite consistent evidence suggesting that DP models induce significant performance degradation for on-domain applications, we show that off-domain performance is almost not affected. Therefore, we ardently advocate for the adoption of DP in training diagnostic medical AI models, given its minimal impact on performance.
Neufeld and Wu (arXiv:2310.12545) developed a multilevel Picard (MLP) algorithm which can approximately solve general semilinear parabolic PDEs with gradient-dependent nonlinearities, allowing also for coefficient functions of the corresponding PDE to be non-constant. By introducing a particular stochastic fixed-point equation (SFPE) motivated by the Feynman-Kac representation and the Bismut-Elworthy-Li formula and identifying the first and second component of the unique fixed-point of the SFPE with the unique viscosity solution of the PDE and its gradient, they proved convergence of their algorithm. However, it remained an open question whether the proposed MLP schema in arXiv:2310.12545 does not suffer from the curse of dimensionality. In this paper, we prove that the MLP algorithm in arXiv:2310.12545 indeed can overcome the curse of dimensionality, i.e. that its computational complexity only grows polynomially in the dimension $d\in \mathbb{N}$ and the reciprocal of the accuracy $\varepsilon$, under some suitable assumptions on the nonlinear part of the corresponding PDE.
Current approaches to generic segmentation start by creating a hierarchy of nested image partitions and then specifying a segmentation from it. Our first contribution is to describe several ways, most of them new, for specifying segmentations using the hierarchy elements. Then, we consider the best hierarchy-induced segmentation specified by a limited number of hierarchy elements. We focus on a common quality measure for binary segmentations, the Jaccard index (also known as IoU). Optimizing the Jaccard index is highly non-trivial, and yet we propose an efficient approach for doing exactly that. This way we get algorithm-independent upper bounds on the quality of any segmentation created from the hierarchy. We found that the obtainable segmentation quality varies significantly depending on the way that the segments are specified by the hierarchy elements, and that representing a segmentation with only a few hierarchy elements is often possible. (Code is available).
We present a rigorous and precise analysis of the maximum degree and the average degree in a dynamic duplication-divergence graph model introduced by Sol\'e, Pastor-Satorras et al. in which the graph grows according to a duplication-divergence mechanism, i.e. by iteratively creating a copy of some node and then randomly alternating the neighborhood of a new node with probability $p$. This model captures the growth of some real-world processes e.g. biological or social networks. In this paper, we prove that for some $0 < p < 1$ the maximum degree and the average degree of a duplication-divergence graph on $t$ vertices are asymptotically concentrated with high probability around $t^p$ and $\max\{t^{2 p - 1}, 1\}$, respectively, i.e. they are within at most a polylogarithmic factor from these values with probability at least $1 - t^{-A}$ for any constant $A > 0$.
This research investigates the numerical approximation of the two-dimensional convection-dominated singularly perturbed problem on square, circular, and elliptic domains. Singularly perturbed boundary value problems present a significant challenge due to the presence of sharp boundary layers in their solutions. Additionally, the considered domain exhibits characteristic points, giving rise to a degenerate boundary layer problem. The stiffness of the problem is attributed to the sharp singular layers, which can result in substantial computational errors if not appropriately addressed. Traditional numerical methods typically require extensive mesh refinements near the boundary to achieve accurate solutions, which can be computationally expensive. To address the challenges posed by singularly perturbed problems, we employ physics-informed neural networks (PINNs). However, PINNs may struggle with rapidly varying singularly perturbed solutions over a small domain region, leading to inadequate resolution and potentially inaccurate or unstable results. To overcome this limitation, we introduce a semi-analytic method that augments PINNs with singular layers or corrector functions. Through our numerical experiments, we demonstrate significant improvements in both accuracy and stability, thus demonstrating the effectiveness of our proposed approach.
Hesitant fuzzy sets are widely used in the instances of uncertainty and hesitation. The inclusion relationship is an important and foundational definition for sets. Hesitant fuzzy set, as a kind of set, needs explicit definition of inclusion relationship. Base on the hesitant fuzzy membership degree of discrete form, several kinds of inclusion relationships for hesitant fuzzy sets are proposed. And then some foundational propositions of hesitant fuzzy sets and the families of hesitant fuzzy sets are presented. Finally, some foundational propositions of hesitant fuzzy information systems with respect to parameter reductions are put forward, and an example and an algorithm are given to illustrate the processes of parameter reductions.
The prediction accuracy of machine learning methods is steadily increasing, but the calibration of their uncertainty predictions poses a significant challenge. Numerous works focus on obtaining well-calibrated predictive models, but less is known about reliably assessing model calibration. This limits our ability to know when algorithms for improving calibration have a real effect, and when their improvements are merely artifacts due to random noise in finite datasets. In this work, we consider detecting mis-calibration of predictive models using a finite validation dataset as a hypothesis testing problem. The null hypothesis is that the predictive model is calibrated, while the alternative hypothesis is that the deviation from calibration is sufficiently large. We find that detecting mis-calibration is only possible when the conditional probabilities of the classes are sufficiently smooth functions of the predictions. When the conditional class probabilities are H\"older continuous, we propose T-Cal, a minimax optimal test for calibration based on a debiased plug-in estimator of the $\ell_2$-Expected Calibration Error (ECE). We further propose Adaptive T-Cal, a version that is adaptive to unknown smoothness. We verify our theoretical findings with a broad range of experiments, including with several popular deep neural net architectures and several standard post-hoc calibration methods. T-Cal is a practical general-purpose tool, which -- combined with classical tests for discrete-valued predictors -- can be used to test the calibration of virtually any probabilistic classification method.
Recent advances in 3D fully convolutional networks (FCN) have made it feasible to produce dense voxel-wise predictions of volumetric images. In this work, we show that a multi-class 3D FCN trained on manually labeled CT scans of several anatomical structures (ranging from the large organs to thin vessels) can achieve competitive segmentation results, while avoiding the need for handcrafting features or training class-specific models. To this end, we propose a two-stage, coarse-to-fine approach that will first use a 3D FCN to roughly define a candidate region, which will then be used as input to a second 3D FCN. This reduces the number of voxels the second FCN has to classify to ~10% and allows it to focus on more detailed segmentation of the organs and vessels. We utilize training and validation sets consisting of 331 clinical CT images and test our models on a completely unseen data collection acquired at a different hospital that includes 150 CT scans, targeting three anatomical organs (liver, spleen, and pancreas). In challenging organs such as the pancreas, our cascaded approach improves the mean Dice score from 68.5 to 82.2%, achieving the highest reported average score on this dataset. We compare with a 2D FCN method on a separate dataset of 240 CT scans with 18 classes and achieve a significantly higher performance in small organs and vessels. Furthermore, we explore fine-tuning our models to different datasets. Our experiments illustrate the promise and robustness of current 3D FCN based semantic segmentation of medical images, achieving state-of-the-art results. Our code and trained models are available for download: //github.com/holgerroth/3Dunet_abdomen_cascade.