Heterogeneidad tumoral en imágenes PET-CT

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, Departamento de Estructura de la Materia, Física Térmica y Electrónica, leída el 28/01/2021Cancer is a leading cause of morbidity and mortality [1]. The most frequent cancers worldwide are non–small cell lung carcinoma (NSCLC) and breast cancer [2], being their management a challenging task [3]. Tumor diagnosis is usually made through biopsy [4]. However, medical imaging also plays an important role in diagnosis, staging, response to treatment, and recurrence assessment [5]. Tumor heterogeneity is recognized to be involved in cancer treatment failure, with worse clinical outcomes for highly heterogeneous tumors [6,7]. This leads to the existence of tumor sub-regions with different biological behavior (some more aggressive and treatment-resistant than others) [8-10]. Which are characterized by a different pattern of vascularization, vessel permeability, metabolism, cell proliferation, cell death, and other features, that can be measured by modern medical imaging techniques, including positron emission tomography/computed tomography (PET/CT) [10-12]. Thus, the assessment of tumor heterogeneity through medical images could allow the prediction of therapy response and long-term outcomes of patients with cancer [13]. PET/CT has become essential in oncology [14,15] and is usually evaluated through semiquantitative metabolic parameters, such as maximum/mean standard uptake value (SUVmax, SUVmean) or metabolic tumor volume (MTV), which are valuables as prognostic image-based biomarkers in several tumors [16-17], but these do not assess tumor heterogeneity. Likewise, fluorodeoxyglucose (18F-FDG) PET/CT is important to differentiate malignant from benign solitary pulmonary nodules (SPN), reducing so the number of patients who undergo unnecessary surgical biopsies. Several publications have shown that some quantitative image features, extracted from medical images, are suitable for diagnosis, tumor staging, the prognosis of treatment response, and long-term evolution of cancer patients [18-20]. The process of extracting and relating image features with clinical or biological variables is called “Radiomics” [9,20-24]. Radiomic parameters, such as textural features have been related directly to tumor heterogeneity [25]. This thesis investigated the relationships of the tumor heterogeneity, assessed by 18F-FDG-PET/CT texture analysis, with metabolic parameters and pathologic staging in patients with NSCLC, and explored the diagnostic performance of different metabolic, morphologic, and clinical criteria for classifying (malignant or not) of solitary pulmonary nodules (SPN). Furthermore, 18F-FDG-PET/CT radiomic features of patients with recurrent/metastatic breast cancer were used for constructing predictive models of response to the chemotherapy, based on an optimal combination of several feature selection and machine learning (ML) methods...El cáncer es una de las principales causas de morbilidad y mortalidad. Los más frecuentes son el carcinoma de pulmón de células no pequeñas (NSCLC) y el cáncer de mama, siendo su tratamiento un reto. El diagnóstico se suele realizar mediante biopsia. La heterogeneidad tumoral (HT) está implicada en el fracaso del tratamiento del cáncer, con peores resultados clínicos para tumores muy heterogéneos. Esta conduce a la existencia de subregiones tumorales con diferente comportamiento biológico (algunas más agresivas y resistentes al tratamiento); las cuales se caracterizan por diferentes patrones de vascularización, permeabilidad de los vasos sanguíneos, metabolismo, proliferación y muerte celular, que se pueden medir mediante imágenes médicas, incluida la tomografía por emisión de positrones/tomografía computarizada con fluorodesoxiglucosa (18F-FDG-PET/CT). La evaluación de la HT a través de imágenes médicas, podría mejorar la predicción de la respuesta al tratamiento y de los resultados a largo plazo, en pacientes con cáncer. La 18F-FDG-PET/CT es esencial en oncología, generalmente se evalúa con parámetros metabólicos semicuantitativos, como el valor de captación estándar máximo/medio (SUVmáx, SUVmedio) o el volumen tumoral metabólico (MTV), que tienen un gran valor pronóstico en varios tumores, pero no evalúan la HT. Asimismo, es importante para diferenciar los nódulos pulmonares solitarios (NPS) malignos de los benignos, reduciendo el número de pacientes que van a biopsias quirúrgicas innecesarias. Publicaciones recientes muestran que algunas características cuantitativas, extraídas de las imágenes médicas, son robustas para diagnóstico, estadificación, pronóstico de la respuesta al tratamiento y la evolución, de pacientes con cáncer. El proceso de extraer y relacionar estas características con variables clínicas o biológicas se denomina “Radiomica”. Algunos parámetros radiómicos, como la textura, se han relacionado directamente con la HT. Esta tesis investigó las relaciones entre HT, evaluada mediante análisis de textura (AT) de imágenes 18F-FDG-PET/CT, con parámetros metabólicos y estadificación patológica en pacientes con NSCLC, y exploró el rendimiento diagnóstico de diferentes criterios metabólicos, morfológicos y clínicos para la clasificación de NPS. Además, se usaron características radiómicas de imágenes 18F-FDG-PET/CT de pacientes con cáncer de mama recurrente/metastásico, para construir modelos predictivos de la respuesta a la quimioterapia, combinándose varios métodos de selección de características y aprendizaje automático (ML)...Fac. de Ciencias FísicasTRUEunpu

Deep multiple-instance learning for detecting multiple myeloma in CT scans of large bones

S nástupem moderních algoritmů strojového učení vzrostla popularita tématu automatické interpretace výstupů zobrazovacích metod v medicíně pomocí počítačů. Konvoluční neuronové sítě v současné době excelují v mnoha oblastech strojového vidění včetně rozpoznávání obrazu. V této diplomové práci zkoumáme možnosti využití konvolučních sítí jako diagnostického nástroje pro detekci abnormalit v CT snímcích stehenních kostí. Zaměřujeme se na diagnózu mnohočetného myelomu pro nějž jsou charakteristické viditelné léze v kostní dřeni, které lze pozorovat při vyšetření pomocí počítačové tomografie. Bylo otestováno několik různých přístupů včetně učení z více instancí. Náš klasifikátor podává spolehlivý výkon v experimentech s plně supervizovaným učením, vykazuje ovšem zásadní neschopnost konvergence při učení z více instancí. Předpokládáme, že náš navrhovaný neuronový model potřebuje ke konvergenci silnější chybovou odezvu a na toto téma navrhujeme budoucí možná vylepšení.The employment of computer aided diagnosis (CAD) systems for interpretation of medical images has become an increasingly popular topic with the arrival of modern machine learning algorithms. Convolutional neural networks perform exceptionally well nowadays in various pattern recognition tasks including image classification. In this thesis we examine the capabilities of a convolutional neural network binary classifier as a CAD system for detection of abnormalities in CT images of femurs. We focus on the diagnosis of multiple myeloma characterized by symptomatic bone marrow lesions commonly observable through computer tomography screening. Different approaches to the problem including multiple instance learning (MIL) were tested. The classifier showed a solid performance in our fully supervised experimental setting, it however exhibits a serious inability to learn from multiple instances. We conclude that the proposed neural model needs a stronger error signal in order to converge in the standard MIL setting and suggest potential improvements for further work in this area

Image Quality Assessment for Population Cardiac MRI: From Detection to Synthesis

Cardiac magnetic resonance (CMR) images play a growing role in diagnostic imaging of cardiovascular diseases. Left Ventricular (LV) cardiac anatomy and function are widely used for diagnosis and monitoring disease progression in cardiology and to assess the patient's response to cardiac surgery and interventional procedures. For population imaging studies, CMR is arguably the most comprehensive imaging modality for non-invasive and non-ionising imaging of the heart and great vessels and, hence, most suited for population imaging cohorts. Due to insufficient radiographer's experience in planning a scan, natural cardiac muscle contraction, breathing motion, and imperfect triggering, CMR can display incomplete LV coverage, which hampers quantitative LV characterization and diagnostic accuracy. To tackle this limitation and enhance the accuracy and robustness of the automated cardiac volume and functional assessment, this thesis focuses on the development and application of state-of-the-art deep learning (DL) techniques in cardiac imaging. Specifically, we propose new image feature representation types that are learnt with DL models and aimed at highlighting the CMR image quality cross-dataset. These representations are also intended to estimate the CMR image quality for better interpretation and analysis. Moreover, we investigate how quantitative analysis can benefit when these learnt image representations are used in image synthesis. Specifically, a 3D fisher discriminative representation is introduced to identify CMR image quality in the UK Biobank cardiac data. Additionally, a novel adversarial learning (AL) framework is introduced for the cross-dataset CMR image quality assessment and we show that the common representations learnt by AL can be useful and informative for cross-dataset CMR image analysis. Moreover, we utilize the dataset invariance (DI) representations for CMR volumes interpolation by introducing a novel generative adversarial nets (GANs) based image synthesis framework, which enhance the CMR image quality cross-dataset

Generating semantically enriched diagnostics for radiological images using machine learning

Development of Computer Aided Diagnostic (CAD) tools to aid radiologists in pathology detection and decision making relies considerably on manually annotated images. With the advancement of deep learning techniques for CAD development, these expert annotations no longer need to be hand-crafted, however, deep learning algorithms require large amounts of data in order to generalise well. One way in which to access large volumes of expert-annotated data is through radiological exams consisting of images and reports. Using past radiological exams obtained from hospital archiving systems has many advantages: they are expert annotations available in large quantities, covering a population-representative variety of pathologies, and they provide additional context to pathology diagnoses, such as anatomical location and severity. Learning to auto-generate such reports from images presents many challenges such as the difficulty in representing and generating long, unstructured textual information, accounting for spelling errors and repetition or redundancy, and the inconsistency across different annotators. In this thesis, the problem of learning to automate disease detection from radiological exams is approached from three directions. Firstly, a report generation model is developed such that it is conditioned on radiological image features. Secondly, a number of approaches are explored aimed at extracting diagnostic information from free-text reports. Finally, an alternative approach to image latent space learning from current state-of-the-art is developed that can be applied to accelerated image acquisition.Open Acces

Optimization of neural networks for deep learning and applications to CT image segmentation

[eng] During the last few years, AI development in deep learning has been going so fast that even important researchers, politicians, and entrepreneurs are signing petitions to try to slow it down. The newest methods for natural language processing and image generation are achieving results so unbelievable that people are seriously starting to think they can be dangerous for society. In reality, they are not dangerous (at the moment) even if we have to admit we reached a point where we have no more control over the flux of data inside the deep networks. It is impossible to open a modern deep neural network and interpret how it processes the information and, in many cases, explain how or why it gives back that particular result. One of the goals of this doctoral work has been to study the behavior of weights in convolutional neural networks and in transformers. We hereby present a work that demonstrates how to invert 3x3 convolutions after training a neural network able to learn how to classify images, with the future aim of having precisely invertible convolutional neural networks. We demonstrate that a simple network can learn to classify images on an open-source dataset without loss in accuracy, with respect to a non-invertible one. All that with the ability to reconstruct the original image without detectable error (on 8-bit images) in up to 20 convolutions stacked in a row. We present a thorough comparison between our method and the standard. We tested the performances of the five most used transformers for image classification on an open- source dataset. Studying the embedded matrices, we have been able to provide two criteria that can help transformers learn with a training time reduction of up to 30% and with no impact on classification accuracy. The evolution of deep learning techniques is also touching the field of digital health. With tens of thousands of new start-ups and more than 1B $ of investments only in the last year, this field is growing rapidly and promising to revolutionize healthcare. In this thesis, we present several neural networks for the segmentation of lungs, lung nodules, and areas affected by pneumonia induced by COVID-19, in chest CT scans. The architecturesm we used are all residual convolutional neural networks inspired by UNet and Inception. We customized them with novel loss functions and layers studied to achieve high performances on these particular applications. The errors on the surface of nodule segmentation masks are not over 1mm in more than 99% of the cases. Our algorithm for COVID-19 lesion detection has a specificity of 100% and overall accuracy of 97.1%. In general, it surpasses the state-of-the-art in all the considered statistics, using UNet as a benchmark. Combining these with other algorithms able to detect and predict lung cancer, the whole work was presented in a European innovation program and judged of high interest by worldwide experts. With this work, we set the basis for the future development of better AI tools in healthcare and scientific investigation into the fundamentals of deep learning.[spa] Durante los últimos años, el desarrollo de la IA en el aprendizaje profundo ha ido tan rápido que Incluso importantes investigadores, políticos y empresarios están firmando peticiones para intentar para ralentizarlo. Los métodos más nuevos para el procesamiento y la generación de imágenes y lenguaje natural, están logrando resultados tan increíbles que la gente está empezando a preocuparse seriamente. Pienso que pueden ser peligrosos para la sociedad. En realidad, no son peligrosos (al menos de momento) incluso si tenemos que admitir que llegamos a un punto en el que ya no tenemos control sobre el flujo de datos dentro de las redes profundas. Es imposible abrir una moderna red neuronal profunda e interpretar cómo procesa la información y, en muchos casos, explique cómo o por qué devuelve ese resultado en particular, uno de los objetivos de este doctorado. El trabajo ha consistido en estudiar el comportamiento de los pesos en redes neuronales convolucionales y en transformadores. Por la presente presentamos un trabajo que demuestra cómo invertir 3x3 convoluciones después de entrenar una red neuronal capaz de aprender a clasificar imágenes, con el objetivo futuro de tener redes neuronales convolucionales precisamente invertibles. Nosotros queremos demostrar que una red simple puede aprender a clasificar imágenes en un código abierto conjunto de datos sin pérdida de precisión, con respecto a uno no invertible. Todo eso con la capacidad de reconstruir la imagen original sin errores detectables (en imágenes de 8 bits) en hasta 20 convoluciones apiladas en fila. Presentamos una exhaustiva comparación entre nuestro método y el estándar. Probamos las prestaciones de los cinco transformadores más utilizados para la clasificación de imágenes en abierto. conjunto de datos de origen. Al estudiar las matrices incrustadas, hemos sido capaz de proporcionar dos criterios que pueden ayudar a los transformadores a aprender con un tiempo de capacitación reducción de hasta el 30% y sin impacto en la precisión de la clasificación. La evolución de las técnicas de aprendizaje profundo también está afectando al campo de la salud digital. Con decenas de miles de nuevas empresas y más de mil millones de dólares en inversiones sólo en el año pasado, este campo está creciendo rápidamente y promete revolucionar la atención médica. En esta tesis, presentamos varias redes neuronales para la segmentación de pulmones, nódulos pulmonares, y zonas afectadas por neumonía inducida por COVID-19, en tomografías computarizadas de tórax. La arquitectura que utilizamos son todas redes neuronales convolucionales residuales inspiradas en UNet. Las personalizamos con nuevas funciones y capas de pérdida, estudiado para lograr altos rendimientos en estas aplicaciones particulares. Los errores en la superficie de las máscaras de segmentación de los nódulos no supera 1 mm en más del 99% de los casos. Nuestro algoritmo para la detección de lesiones de COVID-19 tiene una especificidad del 100% y en general precisión del 97,1%. En general supera el estado del arte en todos los aspectos considerados, estadísticas, utilizando UNet como punto de referencia. Combinando estos con otros algoritmos capaces de detectar y predecir el cáncer de pulmón, todo el trabajo se presentó en una innovación europea programa y considerado de gran interés por expertos de todo el mundo. Con este trabajo, sentamos las bases para el futuro desarrollo de mejores herramientas de IA en Investigación sanitaria y científica sobre los fundamentos del aprendizaje profundo

Multi-modal Chest X-Ray analysis: classification and report generation using self-supervised learning

Automated medical systems for classification, localization and diagnosis are increasingly being researched and developed. Accurate and automated disease detection is beneficial both to medical personnel, who do not have to perform tedious examinations and to patients, for whom accurate prediction could save their lives. In this work, the models involved in classification and report generation from chest X-rays are studied. Due to the widespread use of the latter, we were able to collect several datasets, which allowed us to employ the self-supervised learning paradigm. This paradigm allows the methods to learn more representative and inherent internal representations for the domain in question. Two different models are used in this project, one for classification and the other for language modelling. The former is pretrained with the BarlowTwins framework, which is fed two modified copies of the same example, and a custom loss function allows learning of internal weights invariant to the applied transformations. The possible improvements that this approach brings are verified by performing a classification task on a reference dataset and compared with the same model which has not been pretrained with the proposed method. Regarding the language model, a pretraining step was performed at the character level on a large text corpus that includes a collection of medical reports. The fine-tuning process is the culmination of this project and involves the merging of the two models, with the former providing meaningful embeddings and the latter transforming these inputs into natural language. We were able to verify that pre-training with BarlowTwins, brings improvements in classification performance, and by pretraining the language model, one is able to generate text with appropriate grammatical and semantic correctness. However, fine-tuning did not bring satisfactory results, making this a starting point for future studies