Performance of a novel wafer scale CMOS active pixel sensor for bio-medical imaging

Recently CMOS Active Pixels Sensors (APSs) have become a valuable alternative to amorphous Silicon and Selenium Flat Panel Imagers (FPIs) in bio-medical imaging applications. CMOS APSs can now be scaled up to the standard 20 cm diameter wafer size by means of a reticle stitching block process. However despite wafer scale CMOS APS being monolithic, sources of non-uniformity of response and regional variations can persist representing a significant challenge for wafer scale sensor response. Non-uniformity of stitched sensors can arise from a number of factors related to the manufacturing process, including variation of amplification, variation between readout components, wafer defects and process variations across the wafer due to manufacturing processes. This paper reports on an investigation into the spatial non-uniformity and regional variations of a wafer scale stitched CMOS APS. For the first time a per-pixel analysis of the electro-optical performance of a wafer CMOS APS is presented, to address inhomogeneity issues arising from the stitching techniques used to manufacture wafer scale sensors. A complete model of the signal generation in the pixel array has been provided and proved capable of accounting for noise and gain variations across the pixel array. This novel analysis leads to readout noise and conversion gain being evaluated at pixel level, stitching block level and in regions of interest, resulting in a coefficient of variation ≤ 1.9%. The uniformity of the image quality performance has been further investigated in a typical X-ray application, i.e. mammography, showing a uniformity in terms of CNR among the highest when compared with mammography detectors commonly used in clinical practise. Finally, in order to compare the detection capability of this novel APS with the currently used technology (i.e. FPIs), theoretical evaluation of the Detection Quantum Efficiency (DQE) at zero-frequency has been performed, resulting in a higher DQE for this detector compared to FPIs. Optical characterization, X-ray contrast measurements and theoretical DQE evaluation suggest that a trade off can be found between the need of a large imaging area and the requirement of a uniform imaging performance, making the DynAMITe large area CMOS APS suitable for a range of bio-medical applications

Single-breath-hold photoacoustic computed tomography of the breast

We have developed a single-breath-hold photoacoustic computed tomography (SBH-PACT) system to reveal detailed angiographic structures in human breasts. SBH-PACT features a deep penetration depth (4 cm in vivo) with high spatial and temporal resolutions (255 µm in-plane resolution and a 10 Hz 2D frame rate). By scanning the entire breast within a single breath hold (~15 s), a volumetric image can be acquired and subsequently reconstructed utilizing 3D back-projection with negligible breathing-induced motion artifacts. SBH-PACT clearly reveals tumors by observing higher blood vessel densities associated with tumors at high spatial resolution, showing early promise for high sensitivity in radiographically dense breasts. In addition to blood vessel imaging, the high imaging speed enables dynamic studies, such as photoacoustic elastography, which identifies tumors by showing less compliance. We imaged breast cancer patients with breast sizes ranging from B cup to DD cup, and skin pigmentations ranging from light to dark. SBH-PACT identified all the tumors without resorting to ionizing radiation or exogenous contrast, posing no health risks

Enhanced Digital Breast Tomosynthesis diagnosis using 3D visualization and automatic classification of lesions

Breast cancer represents the main cause of cancer-related deaths in women. Nonetheless, the mortality rate of this disease has been decreasing over the last three decades, largely due to the screening programs for early detection. For many years, both screening and clinical diagnosis were mostly done through Digital Mammography (DM). Approved in 2011, Digital Breast Tomosynthesis (DBT) is similar to DM but it allows a 3D reconstruction of the breast tissue, which helps the diagnosis by reducing the tissue overlap. Currently, DBT is firmly established and is approved as a stand-alone modality to replace DM. The main objective of this thesis is to develop computational tools to improve the visualization and interpretation of DBT data. Several methods for an enhanced visualization of DBT data through volume rendering were studied and developed. Firstly, important rendering parameters were considered. A new approach for automatic generation of transfer functions was implemented and two other parameters that highly affect the quality of volume rendered images were explored: voxel size in Z direction and sampling distance. Next, new image processing methods that improve the rendering quality by considering the noise regularization and the reduction of out-of-plane artifacts were developed. The interpretation of DBT data with automatic detection of lesions was approached through artificial intelligence methods. Several deep learning Convolutional Neural Networks (CNNs) were implemented and trained to classify a complete DBT image for the presence or absence of microcalcification clusters (MCs). Then, a faster R-CNN (region-based CNN) was trained to detect and accurately locate the MCs in the DBT images. The detected MCs were rendered with the developed 3D rendering software, which provided an enhanced visualization of the volume of interest. The combination of volume visualization with lesion detection may, in the future, improve both diagnostic accuracy and also reduce analysis time. This thesis promotes the development of new computational imaging methods to increase the diagnostic value of DBT, with the aim of assisting radiologists in their task of analyzing DBT volumes and diagnosing breast cancer

Pre and Post-hoc Diagnosis and Interpretation of Malignancy from Breast DCE-MRI

We propose a new method for breast cancer screening from DCE-MRI based on a post-hoc approach that is trained using weakly annotated data (i.e., labels are available only at the image level without any lesion delineation). Our proposed post-hoc method automatically diagnosis the whole volume and, for positive cases, it localizes the malignant lesions that led to such diagnosis. Conversely, traditional approaches follow a pre-hoc approach that initially localises suspicious areas that are subsequently classified to establish the breast malignancy -- this approach is trained using strongly annotated data (i.e., it needs a delineation and classification of all lesions in an image). Another goal of this paper is to establish the advantages and disadvantages of both approaches when applied to breast screening from DCE-MRI. Relying on experiments on a breast DCE-MRI dataset that contains scans of 117 patients, our results show that the post-hoc method is more accurate for diagnosing the whole volume per patient, achieving an AUC of 0.91, while the pre-hoc method achieves an AUC of 0.81. However, the performance for localising the malignant lesions remains challenging for the post-hoc method due to the weakly labelled dataset employed during training.Comment: Submitted to Medical Image Analysi

Prevalence of incidental breast cancer and precursor lesions in autopsy studies: A systematic review and meta-analysis

Abstract Background Autopsy studies demonstrate the prevalence pool of incidental breast cancer in the population, but estimates are uncertain due to small numbers in any primary study. We aimed to conduct a systematic review of autopsy studies to estimate the prevalence of incidental breast cancer and precursors. Methods Relevant articles were identified through searching PubMed and Embase from inception up to April 2016, and backward and forward citations. We included autopsy studies of women with no history of breast pathology, which included systematic histological examination of at least one breast, and which allowed calculation of the prevalence of incidental breast cancer or precursor lesions. Data were pooled using logistic regression models with random intercepts (non-linear mixed models). Results We included 13 studies from 1948 to 2010, contributing 2363 autopsies with 99 cases of incidental cancer or precursor lesions. More thorough histological examination (≥20 histological sections) was a strong predictor of incidental in-situ cancer and atypical hyperplasia (OR = 126·8 and 21·3 respectively, p < 0·001), but not invasive cancer (OR = 1·1, p = 0·75). The estimated mean prevalence of incidental cancer or precursor lesion was 19·5% (0·85% invasive cancer + 8·9% in-situ cancer + 9·8% atypical hyperplasia). Conclusion Our systematic review in ten countries over six decades found that incidental detection of cancer in situ and breast cancer precursors is common in women not known to have breast disease during life. The large prevalence pool of undetected cancer in-situ and atypical hyperplasia in these autopsy studies suggests screening programs should be cautious about introducing more sensitive tests that may increase detection of these lesions

Computer aided diagnosis system for breast cancer using deep learning.

The recent rise of big data technology surrounding the electronic systems and developed toolkits gave birth to new promises for Artificial Intelligence (AI). With the continuous use of data-centric systems and machines in our lives, such as social media, surveys, emails, reports, etc., there is no doubt that data has gained the center of attention by scientists and motivated them to provide more decision-making and operational support systems across multiple domains. With the recent breakthroughs in artificial intelligence, the use of machine learning and deep learning models have achieved remarkable advances in computer vision, ecommerce, cybersecurity, and healthcare. Particularly, numerous applications provided efficient solutions to assist radiologists and doctors for medical imaging analysis, which has remained the essence of the visual representation that is used to construct the final observation and diagnosis. Medical research in cancerology and oncology has been recently blended with the knowledge gained from computer engineering and data science experts. In this context, an automatic assistance or commonly known as Computer-aided Diagnosis (CAD) system has become a popular area of research and development in the last decades. As a result, the CAD systems have been developed using multidisciplinary knowledge and expertise and they have been used to analyze the patient information to assist clinicians and practitioners in their decision-making process. Treating and preventing cancer remains a crucial task that radiologists and oncologists face every day to detect and investigate abnormal tumors. Therefore, a CAD system could be developed to provide decision support for many applications in the cancer patient care processes, such as lesion detection, characterization, cancer staging, tumors assessment, recurrence, and prognosis prediction. Breast cancer has been considered one of the common types of cancers in females across the world. It was also considered the leading cause of mortality among women, and it has been increased drastically every year. Early detection and diagnosis of abnormalities in screened breasts has been acknowledged as the optimal solution to examine the risk of developing breast cancer and thus reduce the increasing mortality rate. Accordingly, this dissertation proposes a new state-of-the-art CAD system for breast cancer diagnosis that is based on deep learning technology and cutting-edge computer vision techniques. Mammography screening has been recognized as the most effective tool to early detect breast lesions for reducing the mortality rate. It helps reveal abnormalities in the breast such as Mass lesion, Architectural Distortion, Microcalcification. With the number of daily patients that were screened is continuously increasing, having a second reading tool or assistance system could leverage the process of breast cancer diagnosis. Mammograms could be obtained using different modalities such as X-ray scanner and Full-Field Digital mammography (FFDM) system. The quality of the mammograms, the characteristics of the breast (i.e., density, size) or/and the tumors (i.e., location, size, shape) could affect the final diagnosis. Therefore, radiologists could miss the lesions and consequently they could generate false detection and diagnosis. Therefore, this work was motivated to improve the reading of mammograms in order to increase the accuracy of the challenging tasks. The efforts presented in this work consists of new design and implementation of neural network models for a fully integrated CAD system dedicated to breast cancer diagnosis. The approach is designed to automatically detect and identify breast lesions from the entire mammograms at a first step using fusion models’ methodology. Then, the second step only focuses on the Mass lesions and thus the proposed system should segment the detected bounding boxes of the Mass lesions to mask their background. A new neural network architecture for mass segmentation was suggested that was integrated with a new data enhancement and augmentation technique. Finally, a third stage was conducted using a stacked ensemble of neural networks for classifying and diagnosing the pathology (i.e., malignant, or benign), the Breast Imaging Reporting and Data System (BI-RADS) assessment score (i.e., from 2 to 6), or/and the shape (i.e., round, oval, lobulated, irregular) of the segmented breast lesions. Another contribution was achieved by applying the first stage of the CAD system for a retrospective analysis and comparison of the model on Prior mammograms of a private dataset. The work was conducted by joining the learning of the detection and classification model with the image-to-image mapping between Prior and Current screening views. Each step presented in the CAD system was evaluated and tested on public and private datasets and consequently the results have been fairly compared with benchmark mammography datasets. The integrated framework for the CAD system was also tested for deployment and showcase. The performance of the CAD system for the detection and identification of breast masses reached an overall accuracy of 97%. The segmentation of breast masses was evaluated together with the previous stage and the approach achieved an overall performance of 92%. Finally, the classification and diagnosis step that defines the outcome of the CAD system reached an overall pathology classification accuracy of 96%, a BIRADS categorization accuracy of 93%, and a shape classification accuracy of 90%. Results given in this dissertation indicate that our suggested integrated framework might surpass the current deep learning approaches by using all the proposed automated steps. Limitations of the proposed work could occur on the long training time of the different methods which is due to the high computation of the developed neural networks that have a huge number of the trainable parameters. Future works can include new orientations of the methodologies by combining different mammography datasets and improving the long training of deep learning models. Moreover, motivations could upgrade the CAD system by using annotated datasets to integrate more breast cancer lesions such as Calcification and Architectural distortion. The proposed framework was first developed to help detect and identify suspicious breast lesions in X-ray mammograms. Next, the work focused only on Mass lesions and segment the detected ROIs to remove the tumor’s background and highlight the contours, the texture, and the shape of the lesions. Finally, the diagnostic decision was predicted to classify the pathology of the lesions and investigate other characteristics such as the tumors’ grading assessment and type of the shape. The dissertation presented a CAD system to assist doctors and experts to identify the risk of breast cancer presence. Overall, the proposed CAD method incorporates the advances of image processing, deep learning, and image-to-image translation for a biomedical application

Stochastic Decision Modeling to Improve Breast Cancer Preventive Care

Breast cancer is a leading cause of premature mortality among women in the United States. Breast cancer screening tests can help with detecting breast cancer in early stages and thereby reducing the breast cancer mortality risk. However, due to the imperfect nature of screening tests, there is always some associated overdiagnosis, false positives, and false negatives risks. Therefore, to improve breast cancer preventive care, we defined the focus of this dissertation on modeling breast cancer screening decisions.Breast cancer overdiagnosis is the first issue that is addressed in this dissertation. Although overdiagnosis is known to be the major risk inherent in mammography screening; currently there is no way to distinguish between overdiagnosed cancers and the ones that would cause problems over a patient’s lifetime. Overdiagnosis risk significantly depends on a patient’s compliance with screening recommendations. In Chapter 2, we use a stochastic framework to perform a harm-benefit analysis to compare the overdiagnosis risk with the benefits that breast cancer screening provides. In addition, we estimate the lifetime mortality risk of breast cancer while considering the overdiagnosis risk and the uncertainty in a patient’s adherence behavior. Our results show that, although overdiagnosis rate is relatively high in breast cancer screening, the benefits of breast cancer mammography screening outweigh the overdiagnosis risk.The second issue that is addressed in this dissertation is false negative results caused by density of breast tissue. Breast density is known to increase breast cancer risk and decrease mammography screening sensitivity. Breast density notification laws, require physicians to inform women with high breast density of these potential risks. The laws usually require healthcare providers to notify patients of the possibility of using more sensitive supplemental screening tests (e.g., ultrasound). Since the enactment of the laws, there have been controversial debates over i) their implementations due to the potential radiologists bias in breast density classification of mammogram images and ii) the necessity of supplemental screenings for all patients with high breast density. Breast density is a dynamic risk factor. Therefore, in the third chapter, we apply a hidden Markov model (HMM) on a sparse unbalanced longitudinal data to quantify the yearly progression of breast density based on Breast Imaging Reporting and Data System (BI-RADs) classifications.In Chapter 4, we use the results from previous chapter to investigate the effectiveness of supplemental screening and the impact of radiologists’ bias on patients’ outcomes under the breast density notification law. We consider the conditional probability of eventually detecting breast cancer in early states given that the patient develops breast cancer in her lifetime and the expected number of supplemental tests as patient’s outcome. Our results indicate that referring patients to a supplemental test solely based on their breast density may not necessarily improve their health outcomes and other risk factors need to be considered when making such referrals. Additionally, average-skilled radiologists’ performances are shown to be comparable with the performance of a perfect radiologist

Non-invasive optical estimate of tissue composition to differentiate malignant from benign breast lesions: A pilot study

Several techniques are being investigated as a complement to screening mammography, to reduce its false-positive rate, but results are still insufficient to draw conclusions. This initial study explores time domain diffuse optical imaging as an adjunct method to classify non-invasively malignant vs benign breast lesions. We estimated differences in tissue composition (oxy-and deoxyhemoglobin, lipid, water, collagen) and absorption properties between lesion and average healthy tissue in the same breast applying a perturbative approach to optical images collected at 7 red-near infrared wavelengths (635-1060 nm) from subjects bearing breast lesions. The Discrete AdaBoost procedure, a machine-learning algorithm, was then exploited to classify lesions based on optically derived information (either tissue composition or absorption) and risk factors obtained from patient's anamnesis (age, body mass index, familiarity, parity, use of oral contraceptives, and use of Tamoxifen). Collagen content, in particular, turned out to be the most important parameter for discrimination. Based on the initial results of this study the proposed method deserves further investigation