Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ cancer and is costly and tissue destructive, requires specialized platforms and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA-sequencing techniques to predict the expression of 138 genes (incorporated from six commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E) stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n=335). We demonstrate successful gene prediction on a held-out test set (n=160, corr=0.82 across patients, corr=0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n=498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index=0.56, hazard ratio=2.16 (95% CI 1.12-3.06), p<5x10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index=0.65, hazard ratio=1.85 (95% CI 1.30-2.68), p<5x10-3).
Objective: To develop and validate a deep learning model for the identification of out-of-body images in endoscopic videos. Background: Surgical video analysis facilitates education and research. However, video recordings of endoscopic surgeries can contain privacy-sensitive information, especially if out-of-body scenes are recorded. Therefore, identification of out-of-body scenes in endoscopic videos is of major importance to preserve the privacy of patients and operating room staff. Methods: A deep learning model was trained and evaluated on an internal dataset of 12 different types of laparoscopic and robotic surgeries. External validation was performed on two independent multicentric test datasets of laparoscopic gastric bypass and cholecystectomy surgeries. All images extracted from the video datasets were annotated as inside or out-of-body. Model performance was evaluated compared to human ground truth annotations measuring the receiver operating characteristic area under the curve (ROC AUC). Results: The internal dataset consisting of 356,267 images from 48 videos and the two multicentric test datasets consisting of 54,385 and 58,349 images from 10 and 20 videos, respectively, were annotated. Compared to ground truth annotations, the model identified out-of-body images with 99.97% ROC AUC on the internal test dataset. Mean $\pm$ standard deviation ROC AUC on the multicentric gastric bypass dataset was 99.94$\pm$0.07% and 99.71$\pm$0.40% on the multicentric cholecystectomy dataset, respectively. Conclusion: The proposed deep learning model can reliably identify out-of-body images in endoscopic videos. The trained model is publicly shared. This facilitates privacy preservation in surgical video analysis.
Key Point Analysis (KPA) has been recently proposed for deriving fine-grained insights from collections of textual comments. KPA extracts the main points in the data as a list of concise sentences or phrases, termed key points, and quantifies their prevalence. While key points are more expressive than word clouds and key phrases, making sense of a long, flat list of key points, which often express related ideas in varying levels of granularity, may still be challenging. To address this limitation of KPA, we introduce the task of organizing a given set of key points into a hierarchy, according to their specificity. Such hierarchies may be viewed as a novel type of Textual Entailment Graph. We develop ThinkP, a high quality benchmark dataset of key point hierarchies for business and product reviews, obtained by consolidating multiple annotations. We compare different methods for predicting pairwise relations between key points, and for inferring a hierarchy from these pairwise predictions. In particular, for the task of computing pairwise key point relations, we achieve significant gains over existing strong baselines by applying directional distributional similarity methods to a novel distributional representation of key points, and further boost performance via weak supervision.
We introduce the mean inverse integrator (MII), a novel approach to increase the accuracy when training neural networks to approximate vector fields of dynamical systems from noisy data. This method can be used to average multiple trajectories obtained by numerical integrators such as Runge-Kutta methods. We show that the class of mono-implicit Runge-Kutta methods (MIRK) has particular advantages when used in connection with MII. When training vector field approximations, explicit expressions for the loss functions are obtained when inserting the training data in the MIRK formulae, unlocking symmetric and high-order integrators that would otherwise be implicit for initial value problems. The combined approach of applying MIRK within MII yields a significantly lower error compared to the plain use of the numerical integrator without averaging the trajectories. This is demonstrated with experiments using data from several (chaotic) Hamiltonian systems. Additionally, we perform a sensitivity analysis of the loss functions under normally distributed perturbations, supporting the favorable performance of MII.
Focal cortical dysplasia (FCD) is a leading cause of drug-resistant focal epilepsy, which can be cured by surgery. These lesions are extremely subtle and often missed even by expert neuroradiologists. "Ground truth" manual lesion masks are therefore expensive, limited and have large inter-rater variability. Existing FCD detection methods are limited by high numbers of false positive predictions, primarily due to vertex- or patch-based approaches that lack whole-brain context. Here, we propose to approach the problem as semantic segmentation using graph convolutional networks (GCN), which allows our model to learn spatial relationships between brain regions. To address the specific challenges of FCD identification, our proposed model includes an auxiliary loss to predict distance from the lesion to reduce false positives and a weak supervision classification loss to facilitate learning from uncertain lesion masks. On a multi-centre dataset of 1015 participants with surface-based features and manual lesion masks from structural MRI data, the proposed GCN achieved an AUC of 0.74, a significant improvement against a previously used vertex-wise multi-layer perceptron (MLP) classifier (AUC 0.64). With sensitivity thresholded at 67%, the GCN had a specificity of 71% in comparison to 49% when using the MLP. This improvement in specificity is vital for clinical integration of lesion-detection tools into the radiological workflow, through increasing clinical confidence in the use of AI radiological adjuncts and reducing the number of areas requiring expert review.
The sparse Mixture-of-Experts (Sparse-MoE) framework efficiently scales up model capacity in various domains, such as natural language processing and vision. Sparse-MoEs select a subset of the "experts" (thus, only a portion of the overall network) for each input sample using a sparse, trainable gate. Existing sparse gates are prone to convergence and performance issues when training with first-order optimization methods. In this paper, we introduce two improvements to current MoE approaches. First, we propose a new sparse gate: COMET, which relies on a novel tree-based mechanism. COMET is differentiable, can exploit sparsity to speed up computation, and outperforms state-of-the-art gates. Second, due to the challenging combinatorial nature of sparse expert selection, first-order methods are typically prone to low-quality solutions. To deal with this challenge, we propose a novel, permutation-based local search method that can complement first-order methods in training any sparse gate, e.g., Hash routing, Top-k, DSelect-k, and COMET. We show that local search can help networks escape bad initializations or solutions. We performed large-scale experiments on various domains, including recommender systems, vision, and natural language processing. On standard vision and recommender systems benchmarks, COMET+ (COMET with local search) achieves up to 13% improvement in ROC AUC over popular gates, e.g., Hash routing and Top-k, and up to 9% over prior differentiable gates e.g., DSelect-k. When Top-k and Hash gates are combined with local search, we see up to $100\times$ reduction in the budget needed for hyperparameter tuning. Moreover, for language modeling, our approach improves over the state-of-the-art MoEBERT model for distilling BERT on 5/7 GLUE benchmarks as well as SQuAD dataset.
This paper presents an extended version of Deeper, a search-based simulation-integrated test solution that generates failure-revealing test scenarios for testing a deep neural network-based lane-keeping system. In the newly proposed version, we utilize a new set of bio-inspired search algorithms, genetic algorithm (GA), $({\mu}+{\lambda})$ and $({\mu},{\lambda})$ evolution strategies (ES), and particle swarm optimization (PSO), that leverage a quality population seed and domain-specific cross-over and mutation operations tailored for the presentation model used for modeling the test scenarios. In order to demonstrate the capabilities of the new test generators within Deeper, we carry out an empirical evaluation and comparison with regard to the results of five participating tools in the cyber-physical systems testing competition at SBST 2021. Our evaluation shows the newly proposed test generators in Deeper not only represent a considerable improvement on the previous version but also prove to be effective and efficient in provoking a considerable number of diverse failure-revealing test scenarios for testing an ML-driven lane-keeping system. They can trigger several failures while promoting test scenario diversity, under a limited test time budget, high target failure severity, and strict speed limit constraints.
Despite the widespread application of latent factor analysis, existing methods suffer from the following weaknesses: requiring the number of factors to be known, lack of theoretical guarantees for learning the model structure, and nonidentifiability of the parameters due to rotation invariance properties of the likelihood. We address these concerns by proposing a fast correlation thresholding (CT) algorithm that simultaneously learns the number of latent factors and a rotationally identifiable model structure. Our novel approach translates this structure learning problem into the search for so-called independent maximal cliques in a thresholded correlation graph that can be easily constructed from the observed data. Our clique analysis technique scales well up to thousands of variables, while competing methods are not applicable in a reasonable amount of running time. We establish a finite-sample error bound and high-dimensional consistency for the structure learning of our method. Through a series of simulation studies and a real data example, we show that the CT algorithm is an accurate method for learning the structure of factor analysis models and is robust to violations of its assumptions.
Quantile regression (QR) is a powerful tool for estimating one or more conditional quantiles of a target variable $\mathrm{Y}$ given explanatory features $\boldsymbol{\mathrm{X}}$. A limitation of QR is that it is only defined for scalar target variables, due to the formulation of its objective function, and since the notion of quantiles has no standard definition for multivariate distributions. Recently, vector quantile regression (VQR) was proposed as an extension of QR for vector-valued target variables, thanks to a meaningful generalization of the notion of quantiles to multivariate distributions via optimal transport. Despite its elegance, VQR is arguably not applicable in practice due to several limitations: (i) it assumes a linear model for the quantiles of the target $\boldsymbol{\mathrm{Y}}$ given the features $\boldsymbol{\mathrm{X}}$; (ii) its exact formulation is intractable even for modestly-sized problems in terms of target dimensions, number of regressed quantile levels, or number of features, and its relaxed dual formulation may violate the monotonicity of the estimated quantiles; (iii) no fast or scalable solvers for VQR currently exist. In this work we fully address these limitations, namely: (i) We extend VQR to the non-linear case, showing substantial improvement over linear VQR; (ii) We propose {vector monotone rearrangement}, a method which ensures the quantile functions estimated by VQR are monotone functions; (iii) We provide fast, GPU-accelerated solvers for linear and nonlinear VQR which maintain a fixed memory footprint, and demonstrate that they scale to millions of samples and thousands of quantile levels; (iv) We release an optimized python package of our solvers as to widespread the use of VQR in real-world applications.
In the study of cancer evolution and therapeutic strategies, scientific evidence shows that a key dynamics lies in the tumor-environment interaction. In particular, oxygen concentration plays a central role in the determination of the phenotypic heterogeneity of cancer cell populations, whose qualitative and geometric characteristics are predominant factors in the occurrence of relapses and failure of eradication. We propose a mathematical model able to describe the eco-evolutionary spatial dynamics of tumour cells in their adaptation to hypoxic microenvironments. As a main novelty with respect to the existing literature, we combine a phenotypic indicator reflecting the experimentally-observed metabolic trade-off between the hypoxia-resistance ability and the proliferative potential with a 2d geometric domain, without the constraint of radial symmetry. The model is settled in the mathematical framework of phenotype-structured population dynamics and it is formulated in terms of systems of coupled non-linear integro-differential equations. The computational outcomes demonstrate that hypoxia-induced selection results in a geometric characterization of phenotypic-defined tumour niches that impact on tumour aggressiveness and invasive ability. Furthermore, results show how the knowledge of environmental characteristics provides a predictive advantage on tumour mass development in terms of size, shape, and composition.
Breast cancer remains a global challenge, causing over 1 million deaths globally in 2018. To achieve earlier breast cancer detection, screening x-ray mammography is recommended by health organizations worldwide and has been estimated to decrease breast cancer mortality by 20-40%. Nevertheless, significant false positive and false negative rates, as well as high interpretation costs, leave opportunities for improving quality and access. To address these limitations, there has been much recent interest in applying deep learning to mammography; however, obtaining large amounts of annotated data poses a challenge for training deep learning models for this purpose, as does ensuring generalization beyond the populations represented in the training dataset. Here, we present an annotation-efficient deep learning approach that 1) achieves state-of-the-art performance in mammogram classification, 2) successfully extends to digital breast tomosynthesis (DBT; "3D mammography"), 3) detects cancers in clinically-negative prior mammograms of cancer patients, 4) generalizes well to a population with low screening rates, and 5) outperforms five-out-of-five full-time breast imaging specialists by improving absolute sensitivity by an average of 14%. Our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide.