Diffusion-weighted magnetic resonance imaging in diagnosing graft dysfunction : a non-invasive alternative to renal biopsy.

The thesis is divided into three parts. The first part focuses on background information including how the kidney functions, diseases, and available kidney disease treatment strategies. In addition, the thesis provides information on imaging instruments and how they can be used to diagnose renal graft dysfunction. The second part focuses on elucidating the parameters linked with highly accurate diagnosis of rejection. Four parameters categories were tested: clinical biomarkers alone, individual mean apparent diffusion coefficient (ADC) at 11-different b- values, mean ADCs of certain groups of b-value, and fusion of clinical biomarkers and all b-values. The most accurate model was found to be when the b-value of b=100 s/mm2 and b=700 s/mm2 were fused. The third part of this thesis focuses on a study that uses Diffusion-Weighted MRI to diagnose and differentiate two types of renal rejection. The system was found to correctly differentiate the two types of rejection with a 98% accuracy. The last part of this thesis concludes the work that has been done and states the possible trends and future avenues

A non-invasive diagnostic system for early assessment of acute renal transplant rejection.

Early diagnosis of acute renal transplant rejection (ARTR) is of immense importance for appropriate therapeutic treatment administration. Although the current diagnostic technique is based on renal biopsy, it is not preferred due to its invasiveness, recovery time (1-2 weeks), and potential for complications, e.g., bleeding and/or infection. In this thesis, a computer-aided diagnostic (CAD) system for early detection of ARTR from 4D (3D + b-value) diffusion-weighted (DW) MRI data is developed. The CAD process starts from a 3D B-spline-based data alignment (to handle local deviations due to breathing and heart beat) and kidney tissue segmentation with an evolving geometric (level-set-based) deformable model. The latter is guided by a voxel-wise stochastic speed function, which follows from a joint kidney-background Markov-Gibbs random field model accounting for an adaptive kidney shape prior and for on-going visual kidney-background appearances. A cumulative empirical distribution of apparent diffusion coefficient (ADC) at different b-values of the segmented DW-MRI is considered a discriminatory transplant status feature. Finally, a classifier based on deep learning of a non-negative constrained stacked auto-encoder is employed to distinguish between rejected and non-rejected renal transplants. In the “leave-one-subject-out” experiments on 53 subjects, 98% of the subjects were correctly classified (namely, 36 out of 37 rejected transplants and 16 out of 16 nonrejected ones). Additionally, a four-fold cross-validation experiment was performed, and an average accuracy of 96% was obtained. These experimental results hold promise of the proposed CAD system as a reliable non-invasive diagnostic tool

Noninvasive evaluation of renal tissue oxygenation with blood oxygen level-dependent magnetic resonance imaging early after transplantation has a limited predictive value for the delayed graft function

Purpose: The aim of this study was to evaluate the feasibility of renal oxygenation assessment using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in the early period after kidney transplantation and to estimate its prognostic value for delayed graft function. Material and methods: Examinations were performed in 50 subjects: 40 patients within a week after the kidney transplantation and 10 healthy controls, using T2*-weighted sequence. Measurements in transplant patients were correlated to basic laboratory parameters in the early period after transplantation and at follow-up. Results: Examinations of seven patients (18%) were rejected due to their poor technical quality. Mean R2* values in transplant recipients were lower than in controls (11.6 vs. 15.9 Hz; p = 0.0001). An R2* value of 0.28 Hz was calculated as the minimal detectable change. There was no relation between R2* values and laboratory parameters. However, patients eGFR ≥ 40 ml/min/1.73 m2 presented higher R2* values than recipients eGFR 0.7). Conclusions: Evaluation of renal graft oxygenation using BOLD MRI is technically challenging in the early period after transplantation. An R2* value of 0.28 Hz may in practice be considered as the minimal detectable change. The delayed graft function seems not to be dependent on early oxygenation values. Further, large-scale studies are necessary to confirm the latter observation

Role of machine learning in early diagnosis of kidney diseases.

Machine learning (ML) and deep learning (DL) approaches have been used as indispensable tools in modern artificial intelligence-based computer-aided diagnostic (AIbased CAD) systems that can provide non-invasive, early, and accurate diagnosis of a given medical condition. These AI-based CAD systems have proven themselves to be reproducible and have the generalization ability to diagnose new unseen cases with several diseases and medical conditions in different organs (e.g., kidneys, prostate, brain, liver, lung, breast, and bladder). In this dissertation, we will focus on the role of such AI-based CAD systems in early diagnosis of two kidney diseases, namely: acute rejection (AR) post kidney transplantation and renal cancer (RC). A new renal computer-assisted diagnostic (Renal-CAD) system was developed to precisely diagnose AR post kidney transplantation at an early stage. The developed Renal-CAD system perform the following main steps: (1) auto-segmentation of the renal allograft from surrounding tissues from diffusion weighted magnetic resonance imaging (DW-MRI) and blood oxygen level-dependent MRI (BOLD-MRI), (2) extraction of image markers, namely: voxel-wise apparent diffusion coefficients (ADCs) are calculated from DW-MRI scans at 11 different low and high b-values and then represented as cumulative distribution functions (CDFs) and extraction of the transverse relaxation rate (R2*) values from the segmented kidneys using BOLD-MRI scans at different echotimes, (3) integration of multimodal image markers with the associated clinical biomarkers, serum creatinine (SCr) and creatinine clearance (CrCl), and (4) diagnosing renal allograft status as nonrejection (NR) or AR by utilizing these integrated biomarkers and the developed deep learning classification model built on stacked auto-encoders (SAEs). Using a leaveone- subject-out cross-validation approach along with SAEs on a total of 30 patients with transplanted kidney (AR = 10 and NR = 20), the Renal-CAD system demonstrated 93.3% accuracy, 90.0% sensitivity, and 95.0% specificity in differentiating AR from NR. Robustness of the Renal-CAD system was also confirmed by the area under the curve value of 0.92. Using a stratified 10-fold cross-validation approach, the Renal-CAD system demonstrated its reproduciblity and robustness with a diagnostic accuracy of 86.7%, sensitivity of 80.0%, specificity of 90.0%, and AUC of 0.88. In addition, a new renal cancer CAD (RC-CAD) system for precise diagnosis of RC at an early stage was developed, which incorporates the following main steps: (1) estimating the morphological features by applying a new parametric spherical harmonic technique, (2) extracting appearance-based features, namely: first order textural features are calculated and second order textural features are extracted after constructing the graylevel co-occurrence matrix (GLCM), (3) estimating the functional features by constructing wash-in/wash-out slopes to quantify the enhancement variations across different contrast enhanced computed tomography (CE-CT) phases, (4) integrating all the aforementioned features and modeling a two-stage multilayer perceptron artificial neural network (MLPANN) classifier to classify the renal tumor as benign or malignant and identify the malignancy subtype. On a total of 140 RC patients (malignant = 70 patients (ccRCC = 40 and nccRCC = 30) and benign angiomyolipoma tumors = 70), the developed RC-CAD system was validated using a leave-one-subject-out cross-validation approach. The developed RC-CAD system achieved a sensitivity of 95.3% ± 2.0%, a specificity of 99.9% ± 0.4%, and Dice similarity coefficient of 0.98 ± 0.01 in differentiating malignant from benign renal tumors, as well as an overall accuracy of 89.6% ± 5.0% in the sub-typing of RCC. The diagnostic abilities of the developed RC-CAD system were further validated using a randomly stratified 10-fold cross-validation approach. The results obtained using the proposed MLP-ANN classification model outperformed other machine learning classifiers (e.g., support vector machine, random forests, and relational functional gradient boosting) as well as other different approaches from the literature. In summary, machine and deep learning approaches have shown potential abilities to be utilized to build AI-based CAD systems. This is evidenced by the promising diagnostic performance obtained by both Renal-CAD and RC-CAD systems. For the Renal- CAD, the integration of functional markers extracted from multimodal MRIs with clinical biomarkers using SAEs classification model, potentially improved the final diagnostic results evidenced by high accuracy, sensitivity, and specificity. The developed Renal-CAD demonstrated high feasibility and efficacy for early, accurate, and non-invasive identification of AR. For the RC-CAD, integrating morphological, textural, and functional features extracted from CE-CT images using a MLP-ANN classification model eventually enhanced the final results in terms of accuracy, sensitivity, and specificity, making the proposed RC-CAD a reliable noninvasive diagnostic tool for RC. The early and accurate diagnosis of AR or RC will help physicians to provide early intervention with the appropriate treatment plan to prolong the life span of the diseased kidney, increase the survival chance of the patient, and thus improve the healthcare outcome in the U.S. and worldwide

Role of deep learning techniques in non-invasive diagnosis of human diseases.

Machine learning, a sub-discipline in the domain of artificial intelligence, concentrates on algorithms able to learn and/or adapt their structure (e.g., parameters) based on a set of observed data. The adaptation is performed by optimizing over a cost function. Machine learning obtained a great attention in the biomedical community because it offers a promise for improving sensitivity and/or specificity of detection and diagnosis of diseases. It also can increase objectivity of the decision making, decrease the time and effort on health care professionals during the process of disease detection and diagnosis. The potential impact of machine learning is greater than ever due to the increase in medical data being acquired, the presence of novel modalities being developed and the complexity of medical data. In all of these scenarios, machine learning can come up with new tools for interpreting the complex datasets that confront clinicians. Much of the excitement for the application of machine learning to biomedical research comes from the development of deep learning which is modeled after computation in the brain. Deep learning can help in attaining insights that would be impossible to obtain through manual analysis. Deep learning algorithms and in particular convolutional neural networks are different from traditional machine learning approaches. Deep learning algorithms are known by their ability to learn complex representations to enhance pattern recognition from raw data. On the other hand, traditional machine learning requires human engineering and domain expertise to design feature extractors and structure data. With increasing demands upon current radiologists, there are growing needs for automating the diagnosis. This is a concern that deep learning is able to address. In this dissertation, we present four different successful applications of deep learning for diseases diagnosis. All the work presented in the dissertation utilizes medical images. In the first application, we introduce a deep-learning based computer-aided diagnostic system for the early detection of acute renal transplant rejection. The system is based on the fusion of both imaging markers (apparent diffusion coefficients derived from diffusion-weighted magnetic resonance imaging) and clinical biomarkers (creatinine clearance and serum plasma creatinine). The fused data is then used as an input to train and test a convolutional neural network based classifier. The proposed system is tested on scans collected from 56 subjects from geographically diverse populations and different scanner types/image collection protocols. The overall accuracy of the proposed system is 92.9% with 93.3% sensitivity and 92.3% specificity in distinguishing non-rejected kidney transplants from rejected ones. In the second application, we propose a novel deep learning approach for the automated segmentation and quantification of the LV from cardiac cine MR images. We aimed at achieving lower errors for the estimated heart parameters compared to the previous studies by proposing a novel deep learning segmentation method. Using fully convolutional neural networks, we proposed novel methods for the extraction of a region of interest that contains the left ventricle, and the segmentation of the left ventricle. Following myocardial segmentation, functional and mass parameters of the left ventricle are estimated. Automated Cardiac Diagnosis Challenge dataset was used to validate our framework, which gave better segmentation, accurate estimation of cardiac parameters, and produced less error compared to other methods applied on the same dataset. Furthermore, we showed that our segmentation approach generalizes well across different datasets by testing its performance on a locally acquired dataset. In the third application, we propose a novel deep learning approach for automated quantification of strain from cardiac cine MR images of mice. For strain analysis, we developed a Laplace-based approach to track the LV wall points by solving the Laplace equation between the LV contours of each two successive image frames over the cardiac cycle. Following tracking, the strain estimation is performed using the Lagrangian-based approach. This new automated system for strain analysis was validated by comparing the outcome of these analysis with the tagged MR images from the same mice. There were no significant differences between the strain data obtained from our algorithm using cine compared to tagged MR imaging. In the fourth application, we demonstrate how a deep learning approach can be utilized for the automated classification of kidney histopathological images. Our approach can classify four classes: the fat, the parenchyma, the clear cell renal cell carcinoma, and the unusual cancer which has been discovered recently, called clear cell papillary renal cell carcinoma. Our framework consists of three convolutional neural networks and the whole-slide kidney images were divided into patches with three different sizes to be inputted to the networks. Our approach can provide patch-wise and pixel-wise classification. Our approach classified the four classes accurately and surpassed other state-of-the-art methods such as ResNet (pixel accuracy: 0.89 Resnet18, 0.93 proposed). In conclusion, the results of our proposed systems demonstrate the potential of deep learning for the efficient, reproducible, fast, and affordable disease diagnosis

Non-Invasive Imaging of Acute Renal Allograft Rejection in Rats Using Small Animal 18F-FDG-PET

BACKGROUND: At present, renal grafts are the most common solid organ transplants world-wide. Given the importance of renal transplantation and the limitation of available donor kidneys, detailed analysis of factors that affect transplant survival are important. Despite the introduction of new and effective immunosuppressive drugs, acute cellular graft rejection (AR) is still a major risk for graft survival. Nowadays, AR can only be definitively by renal biopsy. However, biopsies carry a risk of renal transplant injury and loss. Most important, they can not be performed in patients taking anticoagulant drugs. METHODOLOGY/PRINCIPAL FINDINGS: We present a non-invasive, entirely image-based method to assess AR in an allogeneic rat renal transplantation model using small animal positron emission tomography (PET) and (18)F-fluorodeoxyglucose (FDG). 3 h after i.v. injection of 30 MBq FDG into adult uni-nephrectomized, allogeneically transplanted rats, tissue radioactivity of renal parenchyma was assessed in vivo by a small animal PET-scanner (post operative day (POD) 1,2,4, and 7) and post mortem dissection. The mean radioactivity (cps/mm(3) tissue) as well as the percent injected dose (%ID) was compared between graft and native reference kidney. Results were confirmed by histological and autoradiographic analysis. Healthy rats, rats with acute CSA nephrotoxicity, with acute tubular necrosis, and syngeneically transplanted rats served as controls. FDG-uptake was significantly elevated only in allogeneic grafts from POD 1 on when compared to the native kidney (%ID graft POD 1: 0.54+/-0.06; POD 2: 0.58+/-0.12; POD 4: 0.81+/-0.06; POD 7: 0.77+/-0.1; CTR: 0.22+/-0.01, n = 3-28). Renal FDG-uptake in vivo correlated with the results obtained by micro-autoradiography and the degree of inflammatory infiltrates observed in histology. CONCLUSIONS/SIGNIFICANCE: We propose that graft FDG-PET imaging is a new option to non-invasively, specifically, early detect, and follow-up acute renal rejection. This method is potentially useful to improve post-transplant rejection monitoring

Analysis of contrast-enhanced medical images.

Early detection of human organ diseases is of great importance for the accurate diagnosis and institution of appropriate therapies. This can potentially prevent progression to end-stage disease by detecting precursors that evaluate organ functionality. In addition, it also assists the clinicians for therapy evaluation, tracking diseases progression, and surgery operations. Advances in functional and contrast-enhanced (CE) medical images enabled accurate noninvasive evaluation of organ functionality due to their ability to provide superior anatomical and functional information about the tissue-of-interest. The main objective of this dissertation is to develop a computer-aided diagnostic (CAD) system for analyzing complex data from CE magnetic resonance imaging (MRI). The developed CAD system has been tested in three case studies: (i) early detection of acute renal transplant rejection, (ii) evaluation of myocardial perfusion in patients with ischemic heart disease after heart attack; and (iii), early detection of prostate cancer. However, developing a noninvasive CAD system for the analysis of CE medical images is subject to multiple challenges, including, but are not limited to, image noise and inhomogeneity, nonlinear signal intensity changes of the images over the time course of data acquisition, appearances and shape changes (deformations) of the organ-of-interest during data acquisition, determination of the best features (indexes) that describe the perfusion of a contrast agent (CA) into the tissue. To address these challenges, this dissertation focuses on building new mathematical models and learning techniques that facilitate accurate analysis of CAs perfusion in living organs and include: (i) accurate mathematical models for the segmentation of the object-of-interest, which integrate object shape and appearance features in terms of pixel/voxel-wise image intensities and their spatial interactions; (ii) motion correction techniques that combine both global and local models, which exploit geometric features, rather than image intensities to avoid problems associated with nonlinear intensity variations of the CE images; (iii) fusion of multiple features using the genetic algorithm. The proposed techniques have been integrated into CAD systems that have been tested in, but not limited to, three clinical studies. First, a noninvasive CAD system is proposed for the early and accurate diagnosis of acute renal transplant rejection using dynamic contrast-enhanced MRI (DCE-MRI). Acute rejection–the immunological response of the human immune system to a foreign kidney–is the most sever cause of renal dysfunction among other diagnostic possibilities, including acute tubular necrosis and immune drug toxicity. In the U.S., approximately 17,736 renal transplants are performed annually, and given the limited number of donors, transplanted kidney salvage is an important medical concern. Thus far, biopsy remains the gold standard for the assessment of renal transplant dysfunction, but only as the last resort because of its invasive nature, high cost, and potential morbidity rates. The diagnostic results of the proposed CAD system, based on the analysis of 50 independent in-vivo cases were 96% with a 95% confidence interval. These results clearly demonstrate the promise of the proposed image-based diagnostic CAD system as a supplement to the current technologies, such as nuclear imaging and ultrasonography, to determine the type of kidney dysfunction. Second, a comprehensive CAD system is developed for the characterization of myocardial perfusion and clinical status in heart failure and novel myoregeneration therapy using cardiac first-pass MRI (FP-MRI). Heart failure is considered the most important cause of morbidity and mortality in cardiovascular disease, which affects approximately 6 million U.S. patients annually. Ischemic heart disease is considered the most common underlying cause of heart failure. Therefore, the detection of the heart failure in its earliest forms is essential to prevent its relentless progression to premature death. While current medical studies focus on detecting pathological tissue and assessing contractile function of the diseased heart, this dissertation address the key issue of the effects of the myoregeneration therapy on the associated blood nutrient supply. Quantitative and qualitative assessment in a cohort of 24 perfusion data sets demonstrated the ability of the proposed framework to reveal regional perfusion improvements with therapy, and transmural perfusion differences across the myocardial wall; thus, it can aid in follow-up on treatment for patients undergoing the myoregeneration therapy. Finally, an image-based CAD system for early detection of prostate cancer using DCE-MRI is introduced. Prostate cancer is the most frequently diagnosed malignancy among men and remains the second leading cause of cancer-related death in the USA with more than 238,000 new cases and a mortality rate of about 30,000 in 2013. Therefore, early diagnosis of prostate cancer can improve the effectiveness of treatment and increase the patient’s chance of survival. Currently, needle biopsy is the gold standard for the diagnosis of prostate cancer. However, it is an invasive procedure with high costs and potential morbidity rates. Additionally, it has a higher possibility of producing false positive diagnosis due to relatively small needle biopsy samples. Application of the proposed CAD yield promising results in a cohort of 30 patients that would, in the near future, represent a supplement of the current technologies to determine prostate cancer type. The developed techniques have been compared to the state-of-the-art methods and demonstrated higher accuracy as shown in this dissertation. The proposed models (higher-order spatial interaction models, shape models, motion correction models, and perfusion analysis models) can be used in many of today’s CAD applications for early detection of a variety of diseases and medical conditions, and are expected to notably amplify the accuracy of CAD decisions based on the automated analysis of CE images

A novel MRA-based framework for the detection of changes in cerebrovascular blood pressure.

Background: High blood pressure (HBP) affects 75 million adults and is the primary or contributing cause of mortality in 410,000 adults each year in the United States. Chronic HBP leads to cerebrovascular changes and is a significant contributor for strokes, dementia, and cognitive impairment. Non-invasive measurement of changes in cerebral vasculature and blood pressure (BP) may enable physicians to optimally treat HBP patients. This manuscript describes a method to non-invasively quantify changes in cerebral vasculature and BP using Magnetic Resonance Angiography (MRA) imaging. Methods: MRA images and BP measurements were obtained from patients (n=15, M=8, F=7, Age= 49.2 ± 7.3 years) over a span of 700 days. A novel segmentation algorithm was developed to identify brain vasculature from surrounding tissue. The data was processed to calculate the vascular probability distribution function (PDF); a measure of the vascular diameters in the brain. The initial (day 0) PDF and final (day 700) PDF were used to correlate the changes in cerebral vasculature and BP. Correlation was determined by a mixed effects linear model analysis. Results: The segmentation algorithm had a 99.9% specificity and 99.7% sensitivity in identifying and delineating cerebral vasculature. The PDFs had a statistically significant correlation to BP changes below the circle of Willis (p-value = 0.0007), but not significant (p-value = 0.53) above the circle of Willis, due to smaller blood vessels. Conclusion: Changes in cerebral vasculature and pressure can be non-invasively obtained through MRA image analysis, which may be a useful tool for clinicians to optimize medical management of HBP