Learning transition times in event sequences: the Event-Based Hidden Markov Model of disease progression

Progressive diseases worsen over time and are characterised by monotonic change in features that track disease progression. Here we connect ideas from two formerly separate methodologies -- event-based and hidden Markov modelling -- to derive a new generative model of disease progression. Our model can uniquely infer the most likely group-level sequence and timing of events (natural history) from limited datasets. Moreover, it can infer and predict individual-level trajectories (prognosis) even when data are missing, giving it high clinical utility. Here we derive the model and provide an inference scheme based on the expectation maximisation algorithm. We use clinical, imaging and biofluid data from the Alzheimer's Disease Neuroimaging Initiative to demonstrate the validity and utility of our model. First, we train our model to uncover a new group-level sequence of feature changes in Alzheimer's disease over a period of ${\sim}17.3$ years. Next, we demonstrate that our model provides improved utility over a continuous time hidden Markov model by area under the receiver operator characteristic curve ${\sim}0.23$. Finally, we demonstrate that our model maintains predictive accuracy with up to $50\%$ missing data. These results support the clinical validity of our model and its broader utility in resource-limited medical applications.

Learning To Pay Attention To Mistakes

In convolutional neural network based medical image segmentation, the periphery of foreground regions representing malignant tissues may be disproportionately assigned as belonging to the background class of healthy tissues \cite{attenUnet}\cite{AttenUnet2018}\cite{InterSeg}\cite{UnetFrontNeuro}\cite{LearnActiveContour}. This leads to high false negative detection rates. In this paper, we propose a novel attention mechanism to directly address such high false negative rates, called Paying Attention to Mistakes. Our attention mechanism steers the models towards false positive identification, which counters the existing bias towards false negatives. The proposed mechanism has two complementary implementations: (a) "explicit" steering of the model to attend to a larger Effective Receptive Field on the foreground areas; (b) "implicit" steering towards false positives, by attending to a smaller Effective Receptive Field on the background areas. We validated our methods on three tasks: 1) binary dense prediction between vehicles and the background using CityScapes; 2) Enhanced Tumour Core segmentation with multi-modal MRI scans in BRATS2018; 3) segmenting stroke lesions using ultrasound images in ISLES2018. We compared our methods with state-of-the-art attention mechanisms in medical imaging, including self-attention, spatial-attention and spatial-channel mixed attention. Across all of the three different tasks, our models consistently outperform the baseline models in Intersection over Union (IoU) and/or Hausdorff Distance (HD). For instance, in the second task, the "explicit" implementation of our mechanism reduces the HD of the best baseline by more than $26\%$, whilst improving the IoU by more than $3\%$. We believe our proposed attention mechanism can benefit a wide range of medical and computer vision tasks, which suffer from over-detection of background.

Disentangling Human Error from the Ground Truth in Segmentation of Medical Images

Recent years have seen increasing use of supervised learning methods for segmentation tasks. However, the predictive performance of these algorithms depends on the quality of labels. This problem is particularly pertinent in the medical image domain, where both the annotation cost and inter-observer variability are high. In a typical label acquisition process, different human experts provide their estimates of the 'true' segmentation labels under the influence of their own biases and competence levels. Treating these noisy labels blindly as the ground truth limits the performance that automatic segmentation algorithms can achieve. In this work, we present a method for jointly learning, from purely noisy observations alone, the reliability of individual annotators and the true segmentation label distributions, using two coupled CNNs. The separation of the two is achieved by encouraging the estimated annotators to be maximally unreliable while achieving high fidelity with the noisy training data. We first define a toy segmentation dataset based on MNIST and study the properties of the proposed algorithm. We then demonstrate the utility of the method on three public medical imaging segmentation datasets with simulated (when necessary) and real diverse annotations: 1) MSLSC (multiple-sclerosis lesions); 2) BraTS (brain tumours); 3) LIDC-IDRI (lung abnormalities). In all cases, our method outperforms competing methods and relevant baselines particularly in cases where the number of annotations is small and the amount of disagreement is large. The experiments also show strong ability to capture the complex spatial characteristics of annotators' mistakes.

Foveation for Segmentation of Ultra-High Resolution Images

Segmentation of ultra-high resolution images is challenging because of their enormous size, consisting of millions or even billions of pixels. Typical solutions include dividing input images into patches of fixed size and/or down-sampling to meet memory constraints. Such operations incur information loss in the field-of-view (FoV) i.e., spatial coverage and the image resolution. The impact on segmentation performance is, however, as yet understudied. In this work, we start with a motivational experiment which demonstrates that the trade-off between FoV and resolution affects the segmentation performance on ultra-high resolution images---and furthermore, its influence also varies spatially according to the local patterns in different areas. We then introduce foveation module, a learnable "dataloader" which, for a given ultra-high resolution image, adaptively chooses the appropriate configuration (FoV/resolution trade-off) of the input patch to feed to the downstream segmentation model at each spatial location of the image. The foveation module is jointly trained with the segmentation network to maximise the task performance. We demonstrate on three publicly available high-resolution image datasets that the foveation module consistently improves segmentation performance over the cases trained with patches of fixed FoV/resolution trade-off. Our approach achieves the SoTA performance on the DeepGlobe aerial image dataset. On the Gleason2019 histopathology dataset, our model achieves better segmentation accuracy for the two most clinically important and ambiguous classes (Gleason Grade 3 and 4) than the top performers in the challenge by 13.1% and 7.5%, and improves on the average performance of 6 human experts by 6.5% and 7.5%. Our code and trained models are available at $\text{https://github.com/lxasqjc/Foveation-Segmentation}$.

Image Quality Transfer Enhances Contrast and Resolution of Low-Field Brain MRI in African Paediatric Epilepsy Patients

1.5T or 3T scanners are the current standard for clinical MRI, but low-field (<1T) scanners are still common in many lower- and middle-income countries for reasons of cost and robustness to power failures. Compared to modern high-field scanners, low-field scanners provide images with lower signal-to-noise ratio at equivalent resolution, leaving practitioners to compensate by using large slice thickness and incomplete spatial coverage. Furthermore, the contrast between different types of brain tissue may be substantially reduced even at equal signal-to-noise ratio, which limits diagnostic value. Recently the paradigm of Image Quality Transfer has been applied to enhance 0.36T structural images aiming to approximate the resolution, spatial coverage, and contrast of typical 1.5T or 3T images. A variant of the neural network U-Net was trained using low-field images simulated from the publicly available 3T Human Connectome Project dataset. Here we present qualitative results from real and simulated clinical low-field brain images showing the potential value of IQT to enhance the clinical utility of readily accessible low-field MRIs in the management of epilepsy.