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

Developing novel quantitative imaging analysis schemes based machine learning for cancer research

The computer-aided detection (CAD) scheme is a developing technology in the medical imaging field, and it attracted extensive research interest in recent years. In this dissertation, I investigated the feasibility of developing several new novel CAD schemes for different cancer research purposes. First, I investigated the feasibility of identifying a new quantitative imaging marker based on false-positives generated by a computer-aided detection (CAD) scheme to predict short-term breast cancer risk. For this study, an existing CAD scheme was applied “as is” to process each image. From CAD-generated results, some detection features were computed from each image. Two logistic regression models were then trained and tested using a leave-one-case-out cross-validation method to predict each testing case's likelihood of being positive in the next subsequent screening. This study demonstrated that CAD-generated false-positives contain valuable information to predict short-term breast cancer risk. Second, I identified and applied quantitative imaging features computed from ultrasound images of athymic nude mice to predict tumor response to treatment at an early stage. For this study, a CAD scheme was developed to perform tumor segmentation and image feature analysis. The study demonstrated the feasibility of extracting quantitative image features from the ultrasound images taken at an early treatment stage to predict tumor response to therapies. Last, I optimized a machine learning model for predicting peritoneal metastasis in gastric cancer. For this purpose, I have developed a CAD scheme to segment the tumor volume and extract quantitative image features automatically. Then, I reduced the dimensionality of features with a new method named random projection to optimize the model's performance. Finally, the gradient boosting machine model was applied along with a synthetic minority oversampling technique to predict peritoneal metastasis risk. Results suggested that the random projection method yielded promising results in improving the accuracy performance in peritoneal metastasis prediction. In summary, in my Ph.D. studies, I have investigated and tested several innovative approaches to develop different CAD schemes and identify quantitative imaging markers with high discriminatory power in various cancer research applications. Study results demonstrated the feasibility of applying CAD technology to several new application fields, which can help radiologists and gynecologists improve accuracy and consistency in disease diagnosis and prognosis assessment of using the medical image

Applying novel machine learning technology to optimize computer-aided detection and diagnosis of medical images

The purpose of developing Computer-Aided Detection (CAD) schemes is to assist physicians (i.e., radiologists) in interpreting medical imaging findings and reducing inter-reader variability more accurately. In developing CAD schemes, Machine Learning (ML) plays an essential role because it is widely used to identify effective image features from complex datasets and optimally integrate them with the classifiers, which aims to assist the clinicians to more accurately detect early disease, classify disease types and predict disease treatment outcome. In my dissertation, in different studies, I assess the feasibility of developing several novel CAD systems in the area of medical imaging for different purposes. The first study aims to develop and evaluate a new computer-aided diagnosis (CADx) scheme based on analysis of global mammographic image features to predict the likelihood of cases being malignant. CADx scheme is applied to pre-process mammograms, generate two image maps in the frequency domain using discrete cosine transform and fast Fourier transform, compute bilateral image feature differences from left and right breasts, and apply a support vector machine (SVM) method to predict the likelihood of the case being malignant. This study demonstrates the feasibility of developing a new global image feature analysis based CADx scheme of mammograms with high performance. This new CADx approach is more efficient in development and potentially more robust in future applications by avoiding difficulty and possible errors in breast lesion segmentation. In the second study, to automatically identify a set of effective mammographic image features and build an optimal breast cancer risk stratification model, I investigate advantages of applying a machine learning approach embedded with a locally preserving projection (LPP) based feature combination and regeneration algorithm to predict short-term breast cancer risk. To this purpose, a computer-aided image processing scheme is applied to segment fibro-glandular tissue depicted on mammograms and initially compute 44 features related to the bilateral asymmetry of mammographic tissue density distribution between left and right breasts. Next, an embedded LLP algorithm optimizes the feature space and regenerates a new operational vector with 4 features using a maximal variance approach. This study demonstrates that applying the LPP algorithm effectively reduces feature dimensionality, and yields higher and potentially more robust performance in predicting short-term breast cancer risk. In the third study, to more precisely classify malignant lesions, I investigate the feasibility of applying a random projection algorithm to build an optimal feature vector from the initially CAD-generated large feature pool and improve the performance of the machine learning model. In this process, a CAD scheme is first applied to segment mass regions and initially compute 181 features. An SVM model embedded with the feature dimensionality reduction method is then built to predict the likelihood of lesions being malignant. This study demonstrates that the random project algorithm is a promising method to generate optimal feature vectors to improve the performance of machine learning models of medical images. The last study aims to develop and test a new CAD scheme of chest X-ray images to detect coronavirus (COVID-19) infected pneumonia. To this purpose, the CAD scheme first applies two image preprocessing steps to remove the majority of diaphragm regions, process the original image using a histogram equalization algorithm, and a bilateral low-pass filter. Then, the original image and two filtered images are used to form a pseudo color image. This image is fed into three input channels of a transfer learning-based convolutional neural network (CNN) model to classify chest X-ray images into 3 classes of COVID-19 infected pneumonia, other community-acquired no-COVID-19 infected pneumonia, and normal (non-pneumonia) cases. This study demonstrates that adding two image preprocessing steps and generating a pseudo color image plays an essential role in developing a deep learning CAD scheme of chest X-ray images to improve accuracy in detecting COVID-19 infected pneumonia. In summary, I developed and presented several image pre-processing algorithms, feature extraction methods, and data optimization techniques to present innovative approaches for quantitative imaging markers based on machine learning systems in all these studies. The studies' simulation and results show the discriminative performance of the proposed CAD schemes on different application fields helpful to assist radiologists on their assessments in diagnosing disease and improve their overall performance

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

Development of novel imaging biomarkers using positron emission tomography for characterization of malignant phenotype and response evaluation

Positron emission tomography (PET) enables noninvasive tumour imaging, as changes in metabolic activity secondary to therapy can be measured before changes in tumour size are evident on standard anatomic imaging. Two imaging approaches representing proliferation dependent and independent technologies are evolving as potential methods for assessing growth signalling and, thus, treatment response: [18F]3’-deoxy-3’-fluorothymidine (FLT) and [11C]choline. The validity of the former in patients with pancreatic cancer is unproven and likewise, the role of the latter in response to androgen deprivation/radiotherapy in prostate cancer (PCa) remains unexplored. Using a variety of approaches, the aim of this thesis was to provide an understanding of the role of these tracers in lesion detection and response assessment in patients by PET/computed tomography (PET/CT). Given the high physiological hepatic localisation of FLT, a recently reported kinetic spatial filtering (KSF) algorithm was evaluated as a way to de-noise abdominal FLT-PET data from patients with advanced pancreatic cancer. Application of KSF led to improved lesion detection. FLT uptake (SUV60,max) significantly increased in mid-treatment (gemcitabine based) progressors (p=0.04). In this limited number of patients, reduction in FLT uptake did not predict overall survival. The role of [11C]choline PET/CT in lesion detection and response in prostate cancer (PCa) was also investigated using semi-quantitative and quantitative methods. As a prelude to the quantitative imaging studies, it was established that irreversible tracer uptake characterised tumour (breast cancer) [11C]choline kinetics. Similar irreversible uptake characterised PCa. An important finding was that tumour [11C]choline uptake (in 29 PCa patients) correlated with choline kinase (CHK) expression but not proliferation, as assessed by Ki67 labelling index. Immunohistochemistry of the above patients’ prostate cores with CHKα antibody demonstrated a spectrum of CHKα expression, ranging from expression in prostatic-intraepithelial-neoplasia to low to high expression in malignant cores. These findings were further corroborated in a larger cohort of 75 malignant cores derived from non-imaging studies. Having established [11C]choline as a proliferation independent marker of growth, its role in assessing treatment response was investigated. [11C]choline PET was sensitive to metabolic changes within prostate tumours following androgen deprivation and radical radiotherapy. While promising data were obtained with [11C]choline PET, the radiotracer is subject to metabolic degradation complicating data analysis. To this end, a novel metabolically stable analogue of choline ([18F]fluoromethyl-[1,2-2H4]-choline ([18F]D4FCH)) was transitioned into volunteers and patients to study its pharmacokinetics and preliminary diagnostic potential. This tracer embodies deuterium isotope substitution as a means to discourage systemic metabolism. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. Preliminary results in non-small cell lung cancer showed that the tracer is taken up in tumours. Further studies are warranted to characterise this new tracer in different tumour types. As a prelude to imaging cancer cell death in tumours, a caspase-3 specific radiotracer, [18F](S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4- difluorophenoxymethyl)-pyrrolidine-1-sulfonyl) isatin ([18F]ICMT-11) was also transitioned into volunteers. The radiotracer had favourable dosimetry (effective-dose: 0.025mSv/MBq) and safety. In summary, FLT-PET/CT combined with KSF and [11C]choline PET/CT were shown to be promising methods for imaging early treatment response in patients. Further work will be required to evaluate the clinical relevance of these data in terms of overall patient outcome. Furthermore, a new choline-based radiotracer and a caspase-3 specific radiotracer have been transitioned into humans.Open Acces

Novel Computer-Aided Diagnosis Schemes for Radiological Image Analysis

The computer-aided diagnosis (CAD) scheme is a powerful tool in assisting clinicians (e.g., radiologists) to interpret medical images more accurately and efficiently. In developing high-performing CAD schemes, classic machine learning (ML) and deep learning (DL) algorithms play an essential role because of their advantages in capturing meaningful patterns that are important for disease (e.g., cancer) diagnosis and prognosis from complex datasets. This dissertation, organized into four studies, investigates the feasibility of developing several novel ML-based and DL-based CAD schemes for different cancer research purposes. The first study aims to develop and test a unique radiomics-based CT image marker that can be used to detect lymph node (LN) metastasis for cervical cancer patients. A total of 1,763 radiomics features were first computed from the segmented primary cervical tumor depicted on one CT image with the maximal tumor region. Next, a principal component analysis algorithm was applied on the initial feature pool to determine an optimal feature cluster. Then, based on this optimal cluster, machine learning models (e.g., support vector machine (SVM)) were trained and optimized to generate an image marker to detect LN metastasis. The SVM based imaging marker achieved an AUC (area under the ROC curve) value of 0.841 ± 0.035. This study initially verifies the feasibility of combining CT images and the radiomics technology to develop a low-cost image marker for LN metastasis detection among cervical cancer patients. In the second study, the purpose is to develop and evaluate a unique global mammographic image feature analysis scheme to identify case malignancy for breast cancer. From the entire breast area depicted on the mammograms, 59 features were initially computed to characterize the breast tissue properties in both the spatial and frequency domain. Given that each case consists of two cranio-caudal and two medio-lateral oblique view images of left and right breasts, two feature pools were built, which contain the computed features from either two positive images of one breast or all the four images of two breasts. For each feature pool, a particle swarm optimization (PSO) method was applied to determine the optimal feature cluster followed by training an SVM classifier to generate a final score for predicting likelihood of the case being malignant. The classification performances measured by AUC were 0.79±0.07 and 0.75±0.08 when applying the SVM classifiers trained using image features computed from two-view and four-view images, respectively. This study demonstrates the potential of developing a global mammographic image feature analysis-based scheme to predict case malignancy without including an arduous segmentation of breast lesions. In the third study, given that the performance of DL-based models in the medical imaging field is generally bottlenecked by a lack of sufficient labeled images, we specifically investigate the effectiveness of applying the latest transferring generative adversarial networks (GAN) technology to augment limited data for performance boost in the task of breast mass classification. This transferring GAN model was first pre-trained on a dataset of 25,000 mammogram patches (without labels). Then its generator and the discriminator were fine-tuned on a much smaller dataset containing 1024 labeled breast mass images. A supervised loss was integrated with the discriminator, such that it can be used to directly classify the benign/malignant masses. Our proposed approach improved the classification accuracy by 6.002%, when compared with the classifiers trained without traditional data augmentation. This investigation may provide a new perspective for researchers to effectively train the GAN models on a medical imaging task with only limited datasets. Like the third study, our last study also aims to alleviate DL models’ reliance on large amounts of annotations but uses a totally different approach. We propose employing a semi-supervised method, i.e., virtual adversarial training (VAT), to learn and leverage useful information underlying in unlabeled data for better classification of breast masses. Accordingly, our VAT-based models have two types of losses, namely supervised and virtual adversarial losses. The former loss acts as in supervised classification, while the latter loss works towards enhancing the model’s robustness against virtual adversarial perturbation, thus improving model generalizability. A large CNN and a small CNN were used in this investigation, and both were trained with and without the adversarial loss. When the labeled ratios were 40% and 80%, VAT-based CNNs delivered the highest classification accuracy of 0.740±0.015 and 0.760±0.015, respectively. The experimental results suggest that the VAT-based CAD scheme can effectively utilize meaningful knowledge from unlabeled data to better classify mammographic breast mass images. In summary, several innovative approaches have been investigated and evaluated in this dissertation to develop ML-based and DL-based CAD schemes for the diagnosis of cervical cancer and breast cancer. The promising results demonstrate the potential of these CAD schemes in assisting radiologists to achieve a more accurate interpretation of radiological images

Artificial intelligence in cancer imaging: Clinical challenges and applications

Judgement, as one of the core tenets of medicine, relies upon the integration of multilayered data with nuanced decision making. Cancer offers a unique context for medical decisions given not only its variegated forms with evolution of disease but also the need to take into account the individual condition of patients, their ability to receive treatment, and their responses to treatment. Challenges remain in the accurate detection, characterization, and monitoring of cancers despite improved technologies. Radiographic assessment of disease most commonly relies upon visual evaluations, the interpretations of which may be augmented by advanced computational analyses. In particular, artificial intelligence (AI) promises to make great strides in the qualitative interpretation of cancer imaging by expert clinicians, including volumetric delineation of tumors over time, extrapolation of the tumor genotype and biological course from its radiographic phenotype, prediction of clinical outcome, and assessment of the impact of disease and treatment on adjacent organs. AI may automate processes in the initial interpretation of images and shift the clinical workflow of radiographic detection, management decisions on whether or not to administer an intervention, and subsequent observation to a yet to be envisioned paradigm. Here, the authors review the current state of AI as applied to medical imaging of cancer and describe advances in 4 tumor types (lung, brain, breast, and prostate) to illustrate how common clinical problems are being addressed. Although most studies evaluating AI applications in oncology to date have not been vigorously validated for reproducibility and generalizability, the results do highlight increasingly concerted efforts in pushing AI technology to clinical use and to impact future directions in cancer care

Preoperative Systems for Computer Aided Diagnosis based on Image Registration: Applications to Breast Cancer and Atherosclerosis

Computer Aided Diagnosis (CAD) systems assist clinicians including radiologists and cardiologists to detect abnormalities and highlight conspicuous possible disease. Implementing a pre-operative CAD system contains a framework that accepts related technical as well as clinical parameters as input by analyzing the predefined method and demonstrates the prospective output. In this work we developed the Computer Aided Diagnostic System for biomedical imaging analysis of two applications on Breast Cancer and Atherosclerosis. The aim of the first CAD application is to optimize the registration strategy specifically for Breast Dynamic Infrared Imaging and to make it user-independent. Base on the fact that automated motion reduction in dynamic infrared imaging is on demand in clinical applications, since movement disarranges time-temperature series of each pixel, thus originating thermal artifacts that might bias the clinical decision. All previously proposed registration methods are feature based algorithms requiring manual intervention. We implemented and evaluated 3 different 3D time-series registration methods: 1. Linear affine, 2. Non-linear Bspline, 3. Demons applied to 12 datasets of healthy breast thermal images. The results are evaluated through normalized mutual information with average values of 0.70±0.03, 0.74±0.03 and 0.81±0.09 (out of 1) for Affine, BSpline and Demons registration, respectively, as well as breast boundary overlap and Jacobian determinant of the deformation field. The statistical analysis of the results showed that symmetric diffeomorphic Demons registration method outperforms also with the best breast alignment and non-negative Jacobian values which guarantee image similarity and anatomical consistency of the transformation, due to homologous forces enforcing the pixel geometric disparities to be shortened on all the frames. We propose Demons registration as an effective technique for time-series dynamic infrared registration, to stabilize the local temperature oscillation. The aim of the second implemented CAD application is to assess contribution of calcification in plaque vulnerability and wall rupture and to find its maximum resistance before break in image-based models of carotid artery stenting. The role of calcification inside fibroatheroma during carotid artery stenting operation is controversial in which cardiologists face two major problems during the placement: (i) “plaque protrusion” (i.e. elastic fibrous caps containing early calcifications that penetrate inside the stent); (ii) “plaque vulnerability” (i.e. stiff plaques with advanced calcifications that break the arterial wall or stent). Finite Element Analysis was used to simulate the balloon and stent expansion as a preoperative patient-specific virtual framework. A nonlinear static structural analysis was performed on 20 patients acquired using in vivo MDCT angiography. The Agatston Calcium score was obtained for each patient and subject-specific local Elastic Modulus (EM) was calculated. The in silico results showed that by imposing average ultimate external load of 1.1MPa and 2.3MPa on balloon and stent respectively, average ultimate stress of 55.7±41.2kPa and 171±41.2kPa are obtained on calcifications. The study reveals that a significant positive correlation (R=0.85, p<0.0001) exists on stent expansion between EM of calcification and ultimate stress as well as Plaque Wall Stress (PWS) (R=0.92, p<0.0001), comparing to Ca score that showed insignificant associations with ultimate stress (R=0.44, p=0.057) and PWS (R=0.38, p=0.103), suggesting minor impact of Ca score in plaque rupture. These average data are in good agreement with results obtained by other research groups and we believe this approach enriches the arsenal of tools available for pre-operative prediction of carotid artery stenting procedure in the presence of calcified plaques

Determinants and influence of mammographic features on breast cancer risk

Mammographic density and mammographic microcalcifications are the key imaging features in mammography examination. Mammographic density is known as a strong risk factor for breast cancer and is the radiographic appearance of epithelial and fibrous tissue which appears white on a mammogram. While, the dark part of a mammogram represents the fatty tissue. Mammographic microcalcifications appear as small deposits of calcium and they are one of the earliest sign of breast cancer. Malignant microcalcifications are seen in both in situ and invasive lesions. In this thesis we used the data from the prospective KARMA cohort to study the association between established breast cancer risk factors with mammographic density change over time (Study I), to examine the association between annual mammographic density change and risk of breast cancer (Study II), to investigate the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry (Study III), and finally to elucidate the association between microcalcification clusters, their asymmetry, and risk of overall and subtype specific breast cancer (Study IV). The lifestyle and reproductive factors were assessed using web-based questionnaires. Average mammographic density and total microcalcification clusters were measured using a Computer Aided Detection system (CAD) and the STRATUS method, respectively. In Study I, the average yearly dense area change was -1.0 cm . Body mass index (BMI) and physical activity were statistically associated with density change. Beside age, lean and physically active women had the largest decrease in mammographic density per year. In Study II, overall, 563 women were diagnosed with breast cancer and annual mammographic density change did not seem to influence the risk of breast cancer. Furthermore, density change does not seem to modify the association between baseline density and risk of breast cancer. In Study III, age, mammographic density, genetic factors related to breast cancer, having more children, longer duration of breast-feeding were significantly associated with increased risk of presence of microcalcification clusters. In Study IV, 676 women were diagnosed with breast cancer. Further, women with 33 microcalcification clusters had 2 times higher risk of breast cancer compared to women with no clusters. Microcalcification clusters were associated with both in situ and invasive breast cancer. Finally, during postmenopausal period, microcalcification clusters influence risk of breast cancer to the similar extend as baseline mammographic density. In conclusion, we have identified novel determinants of mammographic density changes and potential predictors of suspicious mammographic microcalcification clusters. Further, our results suggested that annual mammographic density change does not influence breast cancer risk, while presence of suspicious microcalcification clusters was strongly associated with breast cancer risk