87 research outputs found
Probabilistic Models for Joint Segmentation, Detection and Tracking
Migrace buněk a buněčných částic hraje důležitou roli ve fungování živých organismů. Systematický výzkum buněčné migrace byl umožněn v posledních dvaceti letech rychlým rozvojem neinvazivních zobrazovacích technik a digitálních snímačů. Moderní zobrazovací systémy dovolují studovat chování buněčných populací složených z mnoha ticíců buněk. Manuální analýza takového množství dat by byla velice zdlouhavá, protože některé experimenty vyžadují analyzovat tvar, rychlost a další charakteristiky jednotlivých buněk. Z tohoto důvodu je ve vědecké komunitě velká poptávka po automatických metodách.Migration of cells and subcellular particles plays a crucial role in many processes in living organisms. Despite its importance a systematic research of cell motility has only been possible in last two decades due to rapid development of non-invasive imaging techniques and digital cameras. Modern imaging systems allow to study large populations with thousands of cells. Manual analysis of the acquired data is infeasible, because in order to gain insight into underlying biochemical processes it is sometimes necessary to determine shape, velocity and other characteristics of individual cells. Thus there is a high demand for automatic methods
Image Analysis for the Life Sciences - Computer-assisted Tumor Diagnostics and Digital Embryomics
Current research in the life sciences involves the analysis of such a huge amount of image data that automatization is required. This thesis presents several ways how pattern recognition techniques may contribute to improved tumor diagnostics and to the elucidation of vertebrate embryonic development. Chapter 1 studies an approach for exploiting spatial context for the improved estimation of metabolite concentrations from magnetic resonance spectroscopy imaging (MRSI) data with the aim of more robust tumor detection, and compares against a novel alternative. Chapter 2 describes a software library for training, testing and validating classification algorithms that estimate tumor probability based on MRSI. It allows flexible adaptation towards changed experimental conditions, classifier comparison and quality control without need for expertise in pattern recognition. Chapter 3 studies several models for learning tumor classifiers that allow for the common unreliability of human segmentations. For the first time, models are used for this task that additionally employ the objective image information. Chapter 4 encompasses two contributions to an image analysis pipeline for automatically reconstructing zebrafish embryonic development based on time-resolved microscopy: Two approaches for nucleus segmentation are experimentally compared, and a procedure for tracking nuclei over time is presented and evaluated
Single-cell analysis of cell competition using quantitative microscopy and machine learning
Cell competition is a widely conserved, fundamental biological quality control mechanism. The cell competition assay of MDCK wild-type versus mutant MDCK Scribble-knockdown (ScribKD) relies on a mechanical mechanism of competition, which posits that the emergence of compressing stresses within the tissue at high confluency drive the competitive outcome. According to this mechanism, proliferating wild-type cells out-compete mutant ScribKD cells, resulting in their apoptosis and apical extrusion. Previous studies show that there is an increased division rate of wild-type cells in neighbourhoods with high numbers of ScribKD cells, but what still remains a mystery is whether this is a cause or consequence of
increased apoptosis in the “loser” cell population. This project also interrogated the competitive assay of wild-type versus RasV12 , which is hypothesized to operate on a biochemical mechanism and results in the apical extrusion (but not apoptosis) of the loser RasV12 population. For both these mechanisms of competition it is still unknown which population of cells are driving the winner/loser outcome. Is the winner cell proliferation prompting the loser cell demise? Or is an autonomous loser elimination prompting a subsequent winner cell proliferation?
In my research, I have employed multi-modal, time-lapse microscopy to image competition assays continuously for several days. These data were then segmented into wild-type or mutant instances using a Convolutional Neural Network (CNN) that can differentiate between the cell types, after which they were tracked across cellular generations using a Bayesian multi-object tracker. A conjugate analysis of fluorescent cell-cycle indicator probes was then utilised to automatically identify key time points of cellular fate commitment using deep-learning image classification. A spatio-temporal analysis was then conducted in order to quantify any correlation between wild-type proliferation and mutant cell demise. For the case of wild-type versus ScribKD , there was no clear evidence for the wild-type cells mitoses directly impacting upon the ScribKD cell apoptotic elimination. Instead, a subsequent analysis found that a more subtle mechanism of pre-emptive, local density increases around the apoptosis site appeared to be determining the eventual ScribKD fate. On the other hand, there was clear evidence of a direct impact of wild-type mitoses on the subsequent apical extrusion and competitive elimination of RasV12 cells. Both of these conclusions agree with the prevailing classification of cell competition types: mechanical interactions are more diffuse and occur over a larger spatio-temporal domain, whereas biochemical interactions are constrained to nearest neighbour cells. The hypothesized density-dependency of ScribKD elimination was further quantified on a single-cell scale by these analyses, as well as a potential new understanding of RasV12 extrusion. Most interestingly, it appears that there is a clear biophysical mechanism to the elimination in the biochemical RasV12 cell competition. This suggests that perhaps a new semantic approach is needed in the field of cell competition in order to accurately classify different mechanisms of elimination
Learning based biological image analysis
The fate of contemporary scientific research in biology and medicine is bound to the advancements in computational methods. The unprecedented data explosion in microscopy and the crescent interest of life scientists in studying more complex and more subtle interactions stimulate the research for innovative computational solutions on challenging real world applications. Extensions and novel formulations
of generic and flexible methods based on learning/inference are necessary to cope with the large variety of the produced data and to avoid continuous reimplementation
and heavy parameter tuning. This thesis exploits cutting edge machine learning methods based on structured probabilistic models and weakly supervised learning
to provide four novel solutions in the areas of large-scale microscopic imaging and multiple objects tracking.
Chapter 2 introduces a weakly supervised learning framework to tackle the problem of detecting defect images while mining massive microscopic imagery databases. This thesis demonstrates accurate prediction with low user annotation
effort. Chapter 3 presents a learning approach for counting overlapping objects in images based on local structured predictors. This problem has numerous applications
in high throughput microscopy screening such as cells counting for drug toxicity assays. Chapter 4 develops a deterministic graphical model to impose temporal consistency in objects counts when dealing with a video sequence. This Chapter shows that global (temporal and spatial) structural inference consistently
improves over local (only spatial) predictions. The method developed in Chapter 4 is used in a novel downstream tracking algorithm which is introduced in Chapter 5.
This Chapter tackles, for the first time, the difficult problem of tracking heavily overlapping, translucent and indistinguishable objects. The mutual occlusion event
handling of such objects is formulated as a novel structured inference problem based on the minimization of a convex multi-commodity flow energy. The optimal
weights of the energy terms are learned with partial user supervision using structured learning with latent variables.To support behavioral biologists, we apply this method to the problem of tracking a community of interacting Drosophila larvae
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When the machine does not know measuring uncertainty in deep learning models of medical images
This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonRecently, Deep learning (DL), which involves powerful black box predictors, has outperformed
human experts in several medical diagnostic problems. However, these methods focus
exclusively on improving the accuracy of point predictions without assessing their outputs’
quality and ignore the asymmetric cost involved in different types of misclassification errors.
Neural networks also do not deliver confidence in predictions and suffer from over and
under confidence, i.e. are not well calibrated. Knowing how much confidence there is in a
prediction is essential for gaining clinicians’ trust in the technology.
Calibrated uncertainty quantification is a challenging problem as no ground truth is
available. To address this, we make two observations: (i) cost-sensitive deep neural networks
with Dropweights models better quantify calibrated predictive uncertainty, and (ii) estimated
uncertainty with point predictions in Deep Ensembles Bayesian Neural Networks with
DropWeights can lead to a more informed decision and improve prediction quality.
This dissertation focuses on quantifying uncertainty using concepts from cost-sensitive
neural networks, calibration of confidence, and Dropweights ensemble method. First, we
show how to improve predictive uncertainty by deep ensembles of neural networks with Dropweights
learning an approximate distribution over its weights in medical image segmentation
and its application in active learning. Second, we use the Jackknife resampling technique
to correct bias in quantified uncertainty in image classification and propose metrics to measure
uncertainty performance. The third part of the thesis is motivated by the discrepancy
between the model predictive error and the objective in quantified uncertainty when costs for
misclassification errors or unbalanced datasets are asymmetric. We develop cost-sensitive
modifications of the neural networks in disease detection and propose metrics to measure the
quality of quantified uncertainty. Finally, we leverage an adaptive binning strategy to measure
uncertainty calibration error that directly corresponds to estimated uncertainty performance
and address problematic evaluation methods.
We evaluate the effectiveness of the tools on nuclei images segmentation, multi-class
Brain MRI image classification, multi-level cell type-specific protein expression prediction in
ImmunoHistoChemistry (IHC) images and cost-sensitive classification for Covid-19 detection
from X-Rays and CT image dataset. Our approach is thoroughly validated by measuring the
quality of uncertainty. It produces an equally good or better result and paves the way for the
future that addresses the practical problems at the intersection of deep learning and Bayesian
decision theory.
In conclusion, our study highlights the opportunities and challenges of the application of
estimated uncertainty in deep learning models of medical images, representing the confidence of the model’s prediction, and the uncertainty quality metrics show a significant improvement
when using Deep Ensembles Bayesian Neural Networks with DropWeights
Hidden Markov Models
Hidden Markov Models (HMMs), although known for decades, have made a big career nowadays and are still in state of development. This book presents theoretical issues and a variety of HMMs applications in speech recognition and synthesis, medicine, neurosciences, computational biology, bioinformatics, seismology, environment protection and engineering. I hope that the reader will find this book useful and helpful for their own research
Cancer Outcome Prediction with Multiform Medical Data using Deep Learning
This thesis illustrated the work done for my PhD project, which aims to develop personalised cancer outcome prediction models using various types of medical data. A predictive modelling workflow that can analyse data with different forms and generate comprehensive outcome prediction was designed and implemented on a variety of datasets. The model development was accompanied by applying deep learning techniques for multivariate survival analysis, medical image analysis and sequential data processing.
The modelling workflow was applied to three different tasks:
1. Deep learning models were developed for estimating the progression probability of patients with colorectal cancer after resection and after different lines of chemotherapy, which got significantly better predictive performance than the Cox regression models. Besides, CT-based models were developed for predicting the tumour local response after chemotherapy of patients with lung metastasis, which got an AUC of 0. 769 on disease progression detection and 0.794 on treatment response classification.
2. Deep learning models were developed for predicting the survival state of patients with non-small cell lung cancer after radiotherapy using CT scans, dose distribution and disease and treatment variables. The eventual model obtained by ensemble voting got an AUC of 0.678, which is significantly higher than the score achieved by the radiomics model (0.633).
3. Deep-learning-aided approaches were used for estimating the progression risk for patients with solitary fibrous tumours using digital pathology slides. The deep learning architecture was able to optimise the WHO risk assessment model using automatically identified levels of mitotic activity. Compared to manual counting given by pathologists, deep-learning-aided mitosis counting can re-grade the patients whose risks were underestimated.
The applications proved that the predictive models based on hybrid neural networks were able to analyse multiform medical data for generating data-based cancer outcome prediction. The results can be used for realising personalised treatment planning, evaluating treatment quality, and aiding clinical decision-making
Automatic Segmentation of Cells of Different Types in Fluorescence Microscopy Images
Recognition of different cell compartments, types of cells, and their interactions is a critical aspect of quantitative cell biology. This provides a valuable insight for understanding cellular and subcellular interactions and mechanisms of biological processes, such as cancer cell dissemination, organ development and wound healing. Quantitative analysis of cell images is also the mainstay of numerous clinical diagnostic and grading procedures, for example in cancer, immunological, infectious, heart and lung disease. Computer automation of cellular biological samples quantification requires segmenting different cellular and sub-cellular structures in microscopy images. However, automating this problem has proven to be non-trivial, and requires solving multi-class image segmentation tasks that are challenging owing to the high similarity of objects from different classes and irregularly shaped structures.
This thesis focuses on the development and application of probabilistic graphical models to multi-class cell segmentation. Graphical models can improve the segmentation accuracy by their ability to exploit prior knowledge and model inter-class dependencies. Directed acyclic graphs, such as trees have been widely used to model top-down statistical dependencies as a prior for improved image segmentation. However, using trees, a few inter-class constraints can be captured. To overcome this limitation, polytree graphical models are proposed in this thesis that capture label proximity relations more naturally compared to tree-based approaches. Polytrees can effectively impose the prior knowledge on the inclusion of different classes by capturing both same-level and across-level dependencies. A novel recursive mechanism based on two-pass message passing is developed to efficiently calculate closed form posteriors of graph nodes on polytrees. Furthermore, since an accurate and sufficiently large ground truth is not always available for training segmentation algorithms, a weakly supervised framework is developed to employ polytrees for multi-class segmentation that reduces the need for training with the aid of modeling the prior knowledge during segmentation. Generating a hierarchical graph for the superpixels in the image, labels of nodes are inferred through a novel efficient message-passing algorithm and the model parameters are optimized with Expectation Maximization (EM).
Results of evaluation on the segmentation of simulated data and multiple publicly available fluorescence microscopy datasets indicate the outperformance of the proposed method compared to state-of-the-art. The proposed method has also been assessed in predicting the possible segmentation error and has been shown to outperform trees. This can pave the way to calculate uncertainty measures on the resulting segmentation and guide subsequent segmentation refinement, which can be useful in the development of an interactive segmentation framework
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