Challenges and Opportunities of End-to-End Learning in Medical Image Classification

Das Paradigma des End-to-End Lernens hat in den letzten Jahren die Bilderkennung revolutioniert, aber die klinische Anwendung hinkt hinterher. Bildbasierte computergestützte Diagnosesysteme basieren immer noch weitgehend auf hochtechnischen und domänen-spezifischen Pipelines, die aus unabhängigen regelbasierten Modellen bestehen, welche die Teilaufgaben der Bildklassifikation wiederspiegeln: Lokalisation von auffälligen Regionen, Merkmalsextraktion und Entscheidungsfindung. Das Versprechen einer überlegenen Entscheidungsfindung beim End-to-End Lernen ergibt sich daraus, dass domänenspezifische Zwangsbedingungen von begrenzter Komplexität entfernt werden und stattdessen alle Systemkomponenten gleichzeitig, direkt anhand der Rohdaten, und im Hinblick auf die letztendliche Aufgabe optimiert werden. Die Gründe dafür, dass diese Vorteile noch nicht den Weg in die Klinik gefunden haben, d.h. die Herausforderungen, die sich bei der Entwicklung Deep Learning-basierter Diagnosesysteme stellen, sind vielfältig: Die Tatsache, dass die Generalisierungsfähigkeit von Lernalgorithmen davon abhängt, wie gut die verfügbaren Trainingsdaten die tatsächliche zugrundeliegende Datenverteilung abbilden, erweist sich in medizinische Anwendungen als tiefgreifendes Problem. Annotierte Datensätze in diesem Bereich sind notorisch klein, da für die Annotation eine kostspielige Beurteilung durch Experten erforderlich ist und die Zusammenlegung kleinerer Datensätze oft durch Datenschutzauflagen und Patientenrechte erschwert wird. Darüber hinaus weisen medizinische Datensätze drastisch unterschiedliche Eigenschaften im Bezug auf Bildmodalitäten, Bildgebungsprotokolle oder Anisotropien auf, und die oft mehrdeutige Evidenz in medizinischen Bildern kann sich auf inkonsistente oder fehlerhafte Trainingsannotationen übertragen. Während die Verschiebung von Datenverteilungen zwischen Forschungsumgebung und Realität zu einer verminderten Modellrobustheit führt und deshalb gegenwärtig als das Haupthindernis für die klinische Anwendung von Lernalgorithmen angesehen wird, wird dieser Graben oft noch durch Störfaktoren wie Hardwarelimitationen oder Granularität von gegebenen Annotation erweitert, die zu Diskrepanzen zwischen der modellierten Aufgabe und der zugrunde liegenden klinischen Fragestellung führen. Diese Arbeit untersucht das Potenzial des End-to-End-Lernens in klinischen Diagnosesystemen und präsentiert Beiträge zu einigen der wichtigsten Herausforderungen, die derzeit eine breite klinische Anwendung verhindern. Zunächst wird der letzten Teil der Klassifikations-Pipeline untersucht, die Kategorisierung in klinische Pathologien. Wir demonstrieren, wie das Ersetzen des gegenwärtigen klinischen Standards regelbasierter Entscheidungen durch eine groß angelegte Merkmalsextraktion gefolgt von lernbasierten Klassifikatoren die Brustkrebsklassifikation im MRT signifikant verbessert und eine Leistung auf menschlichem Level erzielt. Dieser Ansatz wird weiter anhand von kardiologischer Diagnose gezeigt. Zweitens ersetzen wir, dem Paradigma des End-to-End Lernens folgend, das biophysikalische Modell, das für die Bildnormalisierung in der MRT angewandt wird, sowie die Extraktion handgefertigter Merkmale, durch eine designierte CNN-Architektur und liefern eine eingehende Analyse, die das verborgene Potenzial der gelernten Bildnormalisierung und einen Komplementärwert der gelernten Merkmale gegenüber den handgefertigten Merkmalen aufdeckt. Während dieser Ansatz auf markierten Regionen arbeitet und daher auf manuelle Annotation angewiesen ist, beziehen wir im dritten Teil die Aufgabe der Lokalisierung dieser Regionen in den Lernprozess ein, um eine echte End-to-End-Diagnose baserend auf den Rohbildern zu ermöglichen. Dabei identifizieren wir eine weitgehend vernachlässigte Zwangslage zwischen dem Streben nach der Auswertung von Modellen auf klinisch relevanten Skalen auf der einen Seite, und der Optimierung für effizientes Training unter Datenknappheit auf der anderen Seite. Wir präsentieren ein Deep Learning Modell, das zur Auflösung dieses Kompromisses beiträgt, liefern umfangreiche Experimente auf drei medizinischen Datensätzen sowie eine Serie von Toy-Experimenten, die das Verhalten bei begrenzten Trainingsdaten im Detail untersuchen, und publiziren ein umfassendes Framework, das unter anderem die ersten 3D-Implementierungen gängiger Objekterkennungsmodelle umfasst. Wir identifizieren weitere Hebelpunkte in bestehenden End-to-End-Lernsystemen, bei denen Domänenwissen als Zwangsbedingung dienen kann, um die Robustheit von Modellen in der medizinischen Bildanalyse zu erhöhen, die letztendlich dazu beitragen sollen, den Weg für die Anwendung in der klinischen Praxis zu ebnen. Zu diesem Zweck gehen wir die Herausforderung fehlerhafter Trainingsannotationen an, indem wir die Klassifizierungskompnente in der End-to-End-Objekterkennung durch Regression ersetzen, was es ermöglicht, Modelle direkt auf der kontinuierlichen Skala der zugrunde liegenden pathologischen Prozesse zu trainieren und so die Robustheit der Modelle gegenüber fehlerhaften Trainingsannotationen zu erhöhen. Weiter adressieren wir die Herausforderung der Input-Heterogenitäten, mit denen trainierte Modelle konfrontiert sind, wenn sie an verschiedenen klinischen Orten eingesetzt werden, indem wir eine modellbasierte Domänenanpassung vorschlagen, die es ermöglicht, die ursprüngliche Trainingsdomäne aus veränderten Inputs wiederherzustellen und damit eine robuste Generalisierung zu gewährleisten. Schließlich befassen wir uns mit dem höchst unsystematischen, aufwendigen und subjektiven Trial-and-Error-Prozess zum Finden von robusten Hyperparametern für einen gegebene Aufgabe, indem wir Domänenwissen in ein Set systematischer Regeln überführen, die eine automatisierte und robuste Konfiguration von Deep Learning Modellen auf einer Vielzahl von medizinischen Datensetzen ermöglichen. Zusammenfassend zeigt die hier vorgestellte Arbeit das enorme Potenzial von End-to-End Lernalgorithmen im Vergleich zum klinischen Standard mehrteiliger und hochtechnisierter Diagnose-Pipelines auf, und präsentiert Lösungsansätze zu einigen der wichtigsten Herausforderungen für eine breite Anwendung unter realen Bedienungen wie Datenknappheit, Diskrepanz zwischen der vom Modell behandelten Aufgabe und der zugrunde liegenden klinischen Fragestellung, Mehrdeutigkeiten in Trainingsannotationen, oder Verschiebung von Datendomänen zwischen klinischen Standorten. Diese Beiträge können als Teil des übergreifende Zieles der Automatisierung von medizinischer Bildklassifikation gesehen werden - ein integraler Bestandteil des Wandels, der erforderlich ist, um die Zukunft des Gesundheitswesens zu gestalten

Towards Interpretable Machine Learning in Medical Image Analysis

Over the past few years, ML has demonstrated human expert level performance in many medical image analysis tasks. However, due to the black-box nature of classic deep ML models, translating these models from the bench to the bedside to support the corresponding stakeholders in the desired tasks brings substantial challenges. One solution is interpretable ML, which attempts to reveal the working mechanisms of complex models. From a human-centered design perspective, interpretability is not a property of the ML model but an affordance, i.e., a relationship between algorithm and user. Thus, prototyping and user evaluations are critical to attaining solutions that afford interpretability. Following human-centered design principles in highly specialized and high stakes domains, such as medical image analysis, is challenging due to the limited access to end users. This dilemma is further exacerbated by the high knowledge imbalance between ML designers and end users. To overcome the predicament, we first define 4 levels of clinical evidence that can be used to justify the interpretability to design ML models. We state that designing ML models with 2 levels of clinical evidence: 1) commonly used clinical evidence, such as clinical guidelines, and 2) iteratively developed clinical evidence with end users are more likely to design models that are indeed interpretable to end users. In this dissertation, we first address how to design interpretable ML in medical image analysis that affords interpretability with these two different levels of clinical evidence. We further highly recommend formative user research as the first step of the interpretable model design to understand user needs and domain requirements. We also indicate the importance of empirical user evaluation to support transparent ML design choices to facilitate the adoption of human-centered design principles. All these aspects in this dissertation increase the likelihood that the algorithms afford interpretability and enable stakeholders to capitalize on the benefits of interpretable ML. In detail, we first propose neural symbolic reasoning to implement public clinical evidence into the designed models for various routinely performed clinical tasks. We utilize the routinely applied clinical taxonomy for abnormality classification in chest x-rays. We also establish a spleen injury grading system by strictly following the clinical guidelines for symbolic reasoning with the detected and segmented salient clinical features. Then, we propose the entire interpretable pipeline for UM prognostication with cytopathology images. We first perform formative user research and found that pathologists believe cell composition is informative for UM prognostication. Thus, we build a model to analyze cell composition directly. Finally, we conduct a comprehensive user study to assess the human factors of human-machine teaming with the designed model, e.g., whether the proposed model indeed affords interpretability to pathologists. The human-centered design process is proven to be truly interpretable to pathologists for UM prognostication. All in all, this dissertation introduces a comprehensive human-centered design for interpretable ML solutions in medical image analysis that affords interpretability to end users

Developing and Applying CAD-generated Image Markers to Assist Disease Diagnosis and Prognosis Prediction

Developing computer-aided detection and/or diagnosis (CAD) schemes has been an active research topic in medical imaging informatics (MII) with promising results in assisting clinicians in making better diagnostic and/or clinical decisions in the last two decades. To build robust CAD schemes, we need to develop state-of-the-art image processing and machine learning (ML) algorithms to optimize each step in the CAD pipeline, including detection and segmentation of the region of interest, optimal feature generation, followed by integration to ML classifiers. In my dissertation, I conducted multiple studies investigating the feasibility of developing several novel CAD schemes in the field of medicine concerning different purposes. The first study aims to investigate how to optimally develop a CAD scheme of contrast-enhanced digital mammography (CEDM) images to classify breast masses. CEDM includes both low energy (LE) and dual-energy subtracted (DES) images. A CAD scheme was applied to segment mass regions depicting LE and DES images separately. Optimal segmentation results generated from DES images were also mapped to LE images or vice versa. After computing image features, multilayer perceptron-based ML classifiers integrated with a correlation-based feature subset evaluator and leave-one-case-out cross-validation method were built to classify mass regions. The study demonstrated that DES images eliminated the overlapping effect of dense breast tissue, which helps improve mass segmentation accuracy. By mapping mass regions segmented from DES images to LE images, CAD yields significantly improved performance. The second study aims to develop a new quantitative image marker computed from the pre-intervention computed tomography perfusion (CTP) images and evaluate its feasibility to predict clinical outcome among acute ischemic stroke (AIS) patients undergoing endovascular mechanical thrombectomy after diagnosis of large vessel occlusion. A CAD scheme is first developed to pre-process CTP images of different scanning series for each study case, perform image segmentation, quantify contrast-enhanced blood volumes in bilateral cerebral hemispheres, and compute image features related to asymmetrical cerebral blood flow patterns based on the cumulative cerebral blood flow curves of two hemispheres. Next, image markers based on a single optimal feature and ML models fused with multi-features are developed and tested to classify AIS cases into two classes of good and poor prognosis based on the Modified Rankin Scale. The study results show that ML model trained using multiple features yields significantly higher classification performance than the image marker using the best single feature (p<0.01). This study demonstrates the feasibility of developing a new CAD scheme to predict the prognosis of AIS patients in the hyperacute stage, which has the potential to assist clinicians in optimally treating and managing AIS patients. The third study aims to develop and test a new CAD scheme to predict prognosis in aneurysmal subarachnoid hemorrhage (aSAH) patients using brain CT images. Each patient had two sets of CT images acquired at admission and prior to discharge. CAD scheme was applied to segment intracranial brain regions into four subregions, namely, cerebrospinal fluid (CSF), white matter (WM), gray matter (GM), and extraparenchymal blood (EPB), respectively. CAD then computed nine image features related to 5 volumes of the segmented sulci, EPB, CSF, WM, GM, and four volumetrical ratios to sulci. Subsequently, 16 ML models were built using multiple features computed either from CT images acquired at admission or prior to discharge to predict eight prognosis related parameters. The results show that ML models trained using CT images acquired at admission yielded higher accuracy to predict short-term clinical outcomes, while ML models trained using CT images acquired prior to discharge had higher accuracy in predicting long-term clinical outcomes. Thus, this study demonstrated the feasibility of predicting the prognosis of aSAH patients using new ML model-generated quantitative image markers. The fourth study aims to develop and test a new interactive computer-aided detection (ICAD) tool to quantitatively assess hemorrhage volumes. After loading each case, the ICAD tool first segments intracranial brain volume, performs CT labeling of each voxel. Next, contour-guided image-thresholding techniques based on CT Hounsfield Unit are used to estimate and segment hemorrhage-associated voxels (ICH). Next, two experienced neurology residents examine and correct the markings of ICH categorized into either intraparenchymal hemorrhage (IPH) or intraventricular hemorrhage (IVH) to obtain the true markings. Additionally, volumes and maximum two-dimensional diameter of each sub-type of hemorrhage are also computed for understanding ICH prognosis. The performance to segment hemorrhage regions between semi-automated ICAD and the verified neurology residents’ true markings is evaluated using dice similarity coefficient (DSC). The data analysis results in the study demonstrate that the new ICAD tool enables to segment and quantify ICH and other hemorrhage volumes with higher DSC. Finally, the fifth study aims to bridge the gap between traditional radiomics and deep learning systems by comparing and assessing these two technologies in classifying breast lesions. First, one CAD scheme is applied to segment lesions and compute radiomics features. In contrast, another scheme applies a pre-trained residual net architecture (ResNet50) as a transfer learning model to extract automated features. Next, the principal component algorithm processes both initially computed radiomics and automated features to create optimal feature vectors. Then, several support vector machine (SVM) classifiers are built using the optimized radiomics or automated features. This study indicates that (1) CAD built using only deep transfer learning yields higher classification performance than the traditional radiomic-based model, (2) SVM trained using the fused radiomics and automated features does not yield significantly higher AUC, and (3) radiomics and automated features contain highly correlated information in lesion classification. In summary, in all these studies, I developed and investigated several key concepts of CAD pipeline, including (i) pre-processing algorithms, (ii) automatic detection and segmentation schemes, (iii) feature extraction and optimization methods, and (iv) ML and data analysis models. All developed CAD models are embedded with interactive and visually aided graphical user interfaces (GUIs) to provide user functionality. These techniques present innovative approaches for building quantitative image markers to build optimal ML models. The study results indicate the underlying CAD scheme's potential application to assist radiologists in clinical settings for their assessments in diagnosing disease and improving their overall performance

Deep Learning in Medical Image Analysis

The accelerating power of deep learning in diagnosing diseases will empower physicians and speed up decision making in clinical environments. Applications of modern medical instruments and digitalization of medical care have generated enormous amounts of medical images in recent years. In this big data arena, new deep learning methods and computational models for efficient data processing, analysis, and modeling of the generated data are crucially important for clinical applications and understanding the underlying biological process. This book presents and highlights novel algorithms, architectures, techniques, and applications of deep learning for medical image analysis

Eye Tracking Methods for Analysis of Visuo-Cognitive Behavior in Medical Imaging

Predictive modeling of human visual search behavior and the underlying metacognitive processes is now possible thanks to significant advances in bio-sensing device technology and machine intelligence. Eye tracking bio-sensors, for example, can measure psycho-physiological response through change events in configuration of the human eye. These events include positional changes such as visual fixation, saccadic movements, and scanpath, and non-positional changes such as blinks and pupil dilation and constriction. Using data from eye-tracking sensors, we can model human perception, cognitive processes, and responses to external stimuli. In this study, we investigated the visuo-cognitive behavior of clinicians during the diagnostic decision process for breast cancer screening under clinically equivalent experimental conditions involving multiple monitors and breast projection views. Using a head-mounted eye tracking device and a customized user interface, we recorded eye change events and diagnostic decisions from 10 clinicians (three breast-imaging radiologists and seven Radiology residents) for a corpus of 100 screening mammograms (comprising cases of varied pathology and breast parenchyma density). We proposed novel features and gaze analysis techniques, which help to encode discriminative pattern changes in positional and non-positional measures of eye events. These changes were shown to correlate with individual image readers' identity and experience level, mammographic case pathology and breast parenchyma density, and diagnostic decision. Furthermore, our results suggest that a combination of machine intelligence and bio-sensing modalities can provide adequate predictive capability for the characterization of a mammographic case and image readers diagnostic performance. Lastly, features characterizing eye movements can be utilized for biometric identification purposes. These findings are impactful in real-time performance monitoring and personalized intelligent training and evaluation systems in screening mammography. Further, the developed algorithms are applicable in other application domains involving high-risk visual tasks

AI in Medical Imaging Informatics: Current Challenges and Future Directions

This paper reviews state-of-the-art research solutions across the spectrum of medical imaging informatics, discusses clinical translation, and provides future directions for advancing clinical practice. More specifically, it summarizes advances in medical imaging acquisition technologies for different modalities, highlighting the necessity for efficient medical data management strategies in the context of AI in big healthcare data analytics. It then provides a synopsis of contemporary and emerging algorithmic methods for disease classification and organ/ tissue segmentation, focusing on AI and deep learning architectures that have already become the de facto approach. The clinical benefits of in-silico modelling advances linked with evolving 3D reconstruction and visualization applications are further documented. Concluding, integrative analytics approaches driven by associate research branches highlighted in this study promise to revolutionize imaging informatics as known today across the healthcare continuum for both radiology and digital pathology applications. The latter, is projected to enable informed, more accurate diagnosis, timely prognosis, and effective treatment planning, underpinning precision medicine