Computer-aided detection and diagnosis of breast cancer in 2D and 3D medical imaging through multifractal analysis

This Thesis describes the research work performed in the scope of a doctoral research program and presents its conclusions and contributions. The research activities were carried on in the industry with Siemens S.A. Healthcare Sector, in integration with a research team. Siemens S.A. Healthcare Sector is one of the world biggest suppliers of products, services and complete solutions in the medical sector. The company offers a wide selection of diagnostic and therapeutic equipment and information systems. Siemens products for medical imaging and in vivo diagnostics include: ultrasound, computer tomography, mammography, digital breast tomosynthesis, magnetic resonance, equipment to angiography and coronary angiography, nuclear imaging, and many others. Siemens has a vast experience in Healthcare and at the beginning of this project it was strategically interested in solutions to improve the detection of Breast Cancer, to increase its competitiveness in the sector. The company owns several patents related with self-similarity analysis, which formed the background of this Thesis. Furthermore, Siemens intended to explore commercially the computer- aided automatic detection and diagnosis eld for portfolio integration. Therefore, with the high knowledge acquired by University of Beira Interior in this area together with this Thesis, will allow Siemens to apply the most recent scienti c progress in the detection of the breast cancer, and it is foreseeable that together we can develop a new technology with high potential. The project resulted in the submission of two invention disclosures for evaluation in Siemens A.G., two articles published in peer-reviewed journals indexed in ISI Science Citation Index, two other articles submitted in peer-reviewed journals, and several international conference papers. This work on computer-aided-diagnosis in breast led to innovative software and novel processes of research and development, for which the project received the Siemens Innovation Award in 2012. It was very rewarding to carry on such technological and innovative project in a socially sensitive area as Breast Cancer.No cancro da mama a deteção precoce e o diagnóstico correto são de extrema importância na prescrição terapêutica e caz e e ciente, que potencie o aumento da taxa de sobrevivência à doença. A teoria multifractal foi inicialmente introduzida no contexto da análise de sinal e a sua utilidade foi demonstrada na descrição de comportamentos siológicos de bio-sinais e até na deteção e predição de patologias. Nesta Tese, três métodos multifractais foram estendidos para imagens bi-dimensionais (2D) e comparados na deteção de microcalci cações em mamogramas. Um destes métodos foi também adaptado para a classi cação de massas da mama, em cortes transversais 2D obtidos por ressonância magnética (RM) de mama, em grupos de massas provavelmente benignas e com suspeição de malignidade. Um novo método de análise multifractal usando a lacunaridade tri-dimensional (3D) foi proposto para classi cação de massas da mama em imagens volumétricas 3D de RM de mama. A análise multifractal revelou diferenças na complexidade subjacente às localizações das microcalci cações em relação aos tecidos normais, permitindo uma boa exatidão da sua deteção em mamogramas. Adicionalmente, foram extraídas por análise multifractal características dos tecidos que permitiram identi car os casos tipicamente recomendados para biópsia em imagens 2D de RM de mama. A análise multifractal 3D foi e caz na classi cação de lesões mamárias benignas e malignas em imagens 3D de RM de mama. Este método foi mais exato para esta classi cação do que o método 2D ou o método padrão de análise de contraste cinético tumoral. Em conclusão, a análise multifractal fornece informação útil para deteção auxiliada por computador em mamogra a e diagnóstico auxiliado por computador em imagens 2D e 3D de RM de mama, tendo o potencial de complementar a interpretação dos radiologistas

DEVELOPING NOVEL COMPUTER-AIDED DETECTION AND DIAGNOSIS SYSTEMS OF MEDICAL IMAGES

Reading medical images to detect and diagnose diseases is often difficult and has large inter-reader variability. To address this issue, developing computer-aided detection and diagnosis (CAD) schemes or systems of medical images has attracted broad research interest in the last several decades. Despite great effort and significant progress in previous studies, only limited CAD schemes have been used in clinical practice. Thus, developing new CAD schemes is still a hot research topic in medical imaging informatics field. In this dissertation, I investigate the feasibility of developing several new innovative CAD schemes for different application purposes. First, to predict breast tumor response to neoadjuvant chemotherapy and reduce unnecessary aggressive surgery, I developed two CAD schemes of breast magnetic resonance imaging (MRI) to generate quantitative image markers based on quantitative analysis of global kinetic features. Using the image marker computed from breast MRI acquired pre-chemotherapy, CAD scheme enables to predict radiographic complete response (CR) of breast tumors to neoadjuvant chemotherapy, while using the imaging marker based on the fusion of kinetic and texture features extracted from breast MRI performed after neoadjuvant chemotherapy, CAD scheme can better predict the pathologic complete response (pCR) of the patients. Second, to more accurately predict prognosis of stroke patients, quantifying brain hemorrhage and ventricular cerebrospinal fluid depicting on brain CT images can play an important role. For this purpose, I developed a new interactive CAD tool to segment hemorrhage regions and extract radiological imaging marker to quantitatively determine the severity of aneurysmal subarachnoid hemorrhage at presentation and correlate the estimation with various homeostatic/metabolic derangements and predict clinical outcome. Third, to improve the efficiency of primary antibody screening processes in new cancer drug development, I developed a CAD scheme to automatically identify the non-negative tissue slides, which indicate reactive antibodies in digital pathology images. Last, to improve operation efficiency and reliability of storing digital pathology image data, I developed a CAD scheme using optical character recognition algorithm to automatically extract metadata from tissue slide label images and reduce manual entry for slide tracking and archiving in the tissue pathology laboratories. In summary, in these studies, we developed and tested several innovative approaches to identify quantitative imaging markers with high discriminatory power. In all CAD schemes, the graphic user interface-based visual aid tools were also developed and implemented. Study results demonstrated feasibility of applying CAD technology to several new application fields, which has potential to assist radiologists, oncologists and pathologists improving accuracy and consistency in disease diagnosis and prognosis assessment of using medical image

A Survey on Deep Learning in Medical Image Analysis

Deep learning algorithms, in particular convolutional networks, have rapidly become a methodology of choice for analyzing medical images. This paper reviews the major deep learning concepts pertinent to medical image analysis and summarizes over 300 contributions to the field, most of which appeared in the last year. We survey the use of deep learning for image classification, object detection, segmentation, registration, and other tasks and provide concise overviews of studies per application area. Open challenges and directions for future research are discussed.Comment: Revised survey includes expanded discussion section and reworked introductory section on common deep architectures. Added missed papers from before Feb 1st 201

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

Analyzing the breast tissue in mammograms using deep learning

La densitat mamogràfica de la mama (MBD) reflecteix la quantitat d'àrea fibroglandular del teixit mamari que apareix blanca i brillant a les mamografies, comunament coneguda com a densitat percentual de la mama (PD%). El MBD és un factor de risc per al càncer de mama i un factor de risc per emmascarar tumors. Tot i això, l'estimació precisa de la DMO amb avaluació visual continua sent un repte a causa del contrast feble i de les variacions significatives en els teixits grassos de fons en les mamografies. A més, la interpretació correcta de les imatges de mamografia requereix experts mèdics altament capacitats: És difícil, laboriós, car i propens a errors. No obstant això, el teixit mamari dens pot dificultar la identificació del càncer de mama i associar-se amb un risc més gran de càncer de mama. Per exemple, s'ha informat que les dones amb una alta densitat mamària en comparació amb les dones amb una densitat mamària baixa tenen un risc de quatre a sis vegades més gran de desenvolupar la malaltia. La clau principal de la computació de densitat de mama i la classificació de densitat de mama és detectar correctament els teixits densos a les imatges mamogràfiques. S'han proposat molts mètodes per estimar la densitat mamària; no obstant això, la majoria no estan automatitzats. A més, s'han vist greument afectats per la baixa relació senyal-soroll i la variabilitat de la densitat en aparença i textura. Seria més útil tenir un sistema de diagnòstic assistit per ordinador (CAD) per ajudar el metge a analitzar-lo i diagnosticar-lo automàticament. El desenvolupament actual de mètodes daprenentatge profund ens motiva a millorar els sistemes actuals danàlisi de densitat mamària. L'enfocament principal de la present tesi és desenvolupar un sistema per automatitzar l'anàlisi de densitat de la mama ( tal com; Segmentació de densitat de mama (BDS), percentatge de densitat de mama (BDP) i classificació de densitat de mama (BDC) ), utilitzant tècniques d'aprenentatge profund i aplicant-la a les mamografies temporals després del tractament per analitzar els canvis de densitat de mama per trobar un pacient perillós i sospitós.La densidad mamográfica de la mama (MBD) refleja la cantidad de área fibroglandular del tejido mamario que aparece blanca y brillante en las mamografías, comúnmente conocida como densidad porcentual de la mama (PD%). El MBD es un factor de riesgo para el cáncer de mama y un factor de riesgo para enmascarar tumores. Sin embargo, la estimación precisa de la DMO con evaluación visual sigue siendo un reto debido al contraste débil y a las variaciones significativas en los tejidos grasos de fondo en las mamografías. Además, la interpretación correcta de las imágenes de mamografía requiere de expertos médicos altamente capacitados: Es difícil, laborioso, caro y propenso a errores. Sin embargo, el tejido mamario denso puede dificultar la identificación del cáncer de mama y asociarse con un mayor riesgo de cáncer de mama. Por ejemplo, se ha informado que las mujeres con una alta densidad mamaria en comparación con las mujeres con una densidad mamaria baja tienen un riesgo de cuatro a seis veces mayor de desarrollar la enfermedad. La clave principal de la computación de densidad de mama y la clasificación de densidad de mama es detectar correctamente los tejidos densos en las imágenes mamográficas. Se han propuesto muchos métodos para la estimación de la densidad mamaria; sin embargo, la mayoría de ellos no están automatizados. Además, se han visto gravemente afectados por la baja relación señal-ruido y la variabilidad de la densidad en apariencia y textura. Sería más útil disponer de un sistema de diagnóstico asistido por ordenador (CAD) para ayudar al médico a analizarlo y diagnosticarlo automáticamente. El desarrollo actual de métodos de aprendizaje profundo nos motiva a mejorar los sistemas actuales de análisis de densidad mamaria. El enfoque principal de la presente tesis es desarrollar un sistema para automatizar el análisis de densidad de la mama ( tal como; Segmentación de densidad de mama (BDS), porcentaje de densidad de mama (BDP) y clasificación de densidad de mama (BDC)), utilizando técnicas de aprendizaje profundo y aplicándola en las mamografías temporales después del tratamiento para analizar los cambios de densidad de mama para encontrar un paciente peligroso y sospechoso.Mammographic breast density (MBD) reflects the amount of fibroglandular breast tissue area that appears white and bright on mammograms, commonly referred to as breast percent density (PD%). MBD is a risk factor for breast cancer and a risk factor for masking tumors. However, accurate MBD estimation with visual assessment is still a challenge due to faint contrast and significant variations in background fatty tissues in mammograms. In addition, correctly interpreting mammogram images requires highly trained medical experts: it is difficult, time-consuming, expensive, and error-prone. Nevertheless, dense breast tissue can make it harder to identify breast cancer and be associated with an increased risk of breast cancer. For example, it has been reported that women with a high breast density compared to women with a low breast density have a four- to six-fold increased risk of developing the disease. The primary key of breast density computing and breast density classification is to detect the dense tissues in the mammographic images correctly. Many methods have been proposed for breast density estimation; however, most are not automated. Besides, they have been badly affected by low signal-to-noise ratio and variability of density in appearance and texture. It would be more helpful to have a computer-aided diagnosis (CAD) system to assist the doctor analyze and diagnosing it automatically. Current development in deep learning methods motivates us to improve current breast density analysis systems. The main focus of the present thesis is to develop a system for automating the breast density analysis ( such as; breast density segmentation(BDS), breast density percentage (BDP), and breast density classification ( BDC)), using deep learning techniques and applying it on the temporal mammograms after treatment for analyzing the breast density changes to find a risky and suspicious patient

Multi-fractal dimension features by enhancing and segmenting mammogram images of breast cancer

The common malignancy which causes deaths in women is breast cancer. Early detection of breast cancer using mammographic image can help in reducing the mortality rate and the probability of recurrence. Through mammographic examination, breast lesions can be detected and classified. Breast lesions can be detected using many popular tools such as Magnetic Resonance Imaging (MRI), ultrasonography, and mammography. Although mammography is very useful in the diagnosis of breast cancer, the pattern similarities between normal and pathologic cases makes the process of diagnosis difficult. Therefore, in this thesis Computer Aided Diagnosing (CAD) systems have been developed to help doctors and technicians in detecting lesions. The thesis aims to increase the accuracy of diagnosing breast cancer for optimal classification of cancer. It is achieved using Machine Learning (ML) and image processing techniques on mammogram images. This thesis also proposes an improvement of an automated extraction of powerful texture sign for classification by enhancing and segmenting the breast cancer mammogram images. The proposed CAD system consists of five stages namely pre-processing, segmentation, feature extraction, feature selection, and classification. First stage is pre-processing that is used for noise reduction due to noises in mammogram image. Therefore, based on the frequency domain this thesis employed wavelet transform to enhance mammogram images in pre-processing stage for two purposes which is to highlight the border of mammogram images for segmentation stage, and to enhance the region of interest (ROI) using adaptive threshold in the mammogram images for feature extraction purpose. Second stage is segmentation process to identify ROI in mammogram images. It is a difficult task because of several landmarks such as breast boundary and artifacts as well as pectoral muscle in Medio-Lateral Oblique (MLO). Thus, this thesis presents an automatic segmentation algorithm based on new thresholding combined with image processing techniques. Experimental results demonstrate that the proposed model increases segmentation accuracy of the ROI from breast background, landmarks, and pectoral muscle. Third stage is feature extraction where enhancement model based on fractal dimension is proposed to derive significant mammogram image texture features. Based on the proposed, model a powerful texture sign for classification are extracted. Fourth stage is feature selection where Genetic Algorithm (GA) technique has been used as a feature selection technique to select the important features. In last classification stage, Artificial Neural Network (ANN) technique has been used to differentiate between Benign and Malignant classes of cancer using the most relevant texture feature. As a conclusion, classification accuracy, sensitivity, and specificity obtained by the proposed CAD system are improved in comparison to previous studies. This thesis has practical contribution in identification of breast cancer using mammogram images and better classification accuracy of benign and malign lesions using ML and image processing techniques