Radiotherapy Treatment Assessment using DCE-MRI

Abstract

The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information.

This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.

I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising.

Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI.

II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response.

The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment.

In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.

[N]pT ensemble and finite-size-scaling study of the critical isostructural transition in the generalized exponential model of index 4.

First-order transitions of system where both lattice site occupancy and lattice spacing fluctuate, such as cluster crystals, cannot be efficiently studied by traditional simulation methods, which necessarily fix one of these two degrees of freedom. The difficulty, however, can be surmounted by the generalized [N]pT ensemble [J. Chem. Phys. 136, 214106 (2012)]. Here we show that histogram reweighting and the [N]pT ensemble can be used to study an isostructural transition between cluster crystals of different occupancy in the generalized exponential model of index 4 (GEM-4). Extending this scheme to finite-size scaling studies also allows us to accurately determine the critical point parameters and to verify that it belongs to the Ising universality class.

Oxygen isotope stratigraphy Ojplus03 for the last 838,000 years

Global warming is real and has been with us for at least two decades. Questions arise regarding the response of the ocean to greenhouse forcing, including expectations for changes in ocean circulation, in uptake of excess carbon dioxide, and in upwelling activity. The large climate variations of the ice ages, within the last million years, offer the opportunity to study responses of the ocean to climate change. A histogram of sealevel positions for the last 700,000 years (based on a new d/sup 18/O stratigraphy here compiled) shows that the present is near the margin of the range of fluctuations, with only 6 percent of positions indicating a warmer climate. Thus, the future will be largely outside of experience with regard to fluctuations of the recent geologic past. The same is true for greenhouse forcing. Our inability to explain sudden climate change in the past, including the rapid rise of carbon dioxide during deglaciation, and differences in ocean productivity between glacial and interglacial conditions, demonstrates a lack of understanding that makes predictions suspect. This is the lesson from ice age studies.

Reference list of 265 sources used for the discovery of relationships between data clusters and metadata properties

Visual cluster analysis provides valuable tools that help analysts to understand large data sets in terms of representative clusters and relationships thereof. Often, the found clusters are to be understood in context of belonging categorical, numerical or textual metadata which are given for the data elements. While often not part of the clustering process, such metadata play an important role and need to be considered during the interactive cluster exploration process. Traditionally, linked-views allow to relate (or loosely speaking: correlate) clusters with metadata or other properties of the underlying cluster data. Manually inspecting the distribution of metadata for each cluster in a linked-view approach is tedious, specially for large data sets, where a large search problem arises. Fully interactive search for potentially useful or interesting cluster to metadata relationships may constitute a cumbersome and long process. To remedy this problem, we propose a novel approach for guiding users in discovering interesting relationships between clusters and associated metadata. Its goal is to guide the analyst through the potentially huge search space. We focus in our work on metadata of categorical type, which can be summarized for a cluster in form of a histogram. We start from a given visual cluster representation, and compute certain measures of interestingness defined on the distribution of metadata categories for the clusters. These measures are used to automatically score and rank the clusters for potential interestingness regarding the distribution of categorical metadata. Identified interesting relationships are highlighted in the visual cluster representation for easy inspection by the user. We present a system implementing an encompassing, yet extensible, set of interestingness scores for categorical metadata, which can also be extended to numerical metadata. Appropriate visual representations are provided for showing the visual correlations, as well as the calculated ranking scores. Focusing on clusters of time series data, we test our approach on a large real-world data set of time-oriented scientific research data, demonstrating how specific interesting views are automatically identified, supporting the analyst discovering interesting and visually understandable relationships.

Video anomaly detection in real-time on a Power-Aware Heterogeneous Platform

FPGAs and GPUs are often used when real-time performance in video processing is required. An accelerated processor is chosen based on task-specific priorities (power consumption, processing time and detection accuracy), and this decision is normally made once at design time. All three characteristics are important, particularly in battery-powered systems. Here we propose a method for moving selection of processing platform from a single design-time choice to a continuous run time one.We implement Histogram of Oriented Gradients (HOG) detectors for cars and people and Mixture of Gaussians (MoG) motion detectors running across FPGA, GPU and CPU in a heterogeneous system. We use this to detect illegally parked vehicles in urban scenes. Power, time and accuracy information for each detector is characterised. An anomaly measure is assigned to each detected object based on its trajectory and location, when compared to learned contextual movement patterns. This drives processor and implementation selection, so that scenes with high behavioural anomalies are processed with faster but more power hungry implementations, but routine or static time periods are processed with power-optimised, less accurate, slower versions. Real-time performance is evaluated on video datasets including i-LIDS. Compared to power-optimised static selection, automatic dynamic implementation mapping is 10% more accurate but draws 12W extra power in our testbed desktop system.

FPGA-based soft-core processors for image processing applications

With security and surveillance, there is an increasing need to process image data efficiently and effectively either at source or in a large data network. Whilst a Field-Programmable Gate Array (FPGA) has been seen as a key technology for enabling this, the design process has been viewed as problematic in terms of the time and effort needed for implementation and verification. The work here proposes a different approach of using optimized FPGA-based soft-core processors which allows the user to exploit the task and data level parallelism to achieve the quality of dedicated FPGA implementations whilst reducing design time. The paper also reports some preliminary
progress on the design flow to program the structure. An implementation for a Histogram of Gradients algorithm is also reported which shows that a performance of 328 fps can be achieved with this design approach, whilst avoiding the long design time, verification and debugging steps associated with conventional FPGA implementations.

Navegação de robô móvel em ambiente com humanos

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Mecânica

Detection of mesoscale thermal fronts from 4km data using smoothing techniques: Gradient-based fronts classification and basin scale application

In order to optimize frontal detection in sea surface temperature fields at 4 km resolution, a combined statistical and expert-based approach is applied to test different spatial smoothing of the data prior to the detection process. Fronts are usually detected at 1 km resolution using the histogram-based, single image edge detection (SIED) algorithm developed by Cayula and Cornillon in 1992, with a standard preliminary smoothing using a median filter and a 3 × 3 pixel kernel. Here, detections are performed in three study regions (off Morocco, the Mozambique Channel, and north-western Australia) and across the Indian Ocean basin using the combination of multiple windows (CMW) method developed by Nieto, Demarcq and McClatchie in 2012 which improves on the original Cayula and Cornillon algorithm. Detections at 4 km and 1 km of resolution are compared. Fronts are divided in two intensity classes (“weak” and “strong”) according to their thermal gradient. A preliminary smoothing is applied prior to the detection using different convolutions: three type of filters (median, average and Gaussian) combined with four kernel sizes (3 × 3, 5 × 5, 7 × 7, and 9 × 9 pixels) and three detection window sizes (16 × 16, 24 × 24 and 32 × 32 pixels) to test the effect of these smoothing combinations on reducing the background noise of the data and therefore on improving the frontal detection. The performance of the combinations on 4 km data are evaluated using two criteria: detection efficiency and front length. We find that the optimal combination of preliminary smoothing parameters in enhancing detection efficiency and preserving front length includes a median filter, a 16 × 16 pixel window size, and a 5 × 5 pixel kernel for strong fronts and a 7 × 7 pixel kernel for weak fronts. Results show an improvement in detection performance (from largest to smallest window size) of 71% for strong fronts and 120% for weak fronts. Despite the small window used (16 × 16 pixels), the length of the fronts has been preserved relative to that found with 1 km data. This optimal preliminary smoothing and the CMW detection algorithm on 4 km sea surface temperature data are then used to describe the spatial distribution of the monthly frequencies of occurrence for both strong and weak fronts across the Indian Ocean basin. In general strong fronts are observed in coastal areas whereas weak fronts, with some seasonal exceptions, are mainly located in the open ocean. This study shows that adequate noise reduction done by a preliminary smoothing of the data considerably improves the frontal detection efficiency as well as the global quality of the results. Consequently, the use of 4 km data enables frontal detections similar to 1 km data (using a standard median 3 × 3 convolution) in terms of detectability, length and location. This method, using 4 km data is easily applicable to large regions or at the global scale with far less constraints of data manipulation and processing time relative to 1 km data.

Run-time profiling of Algol 68-R programs using DIDYMUS and SCAMP

Information concerning the run-time behaviour of programs ("program profiling") can be of the greatest assistance in improving program efficiency. Two software devices have been developed for use on ICL 1900 Series machines to provide such information. DIDYMUS is probabilistic in approach and uses multi- tasking facilities to sample the instruction addresses used by a program at run time. It will work regardless of the source language of the program and matches the detected addresses against a loader map to produce a histogram. SCAMP is restricted to profiling Algol 68-R programs, but provides deterministic information concerning those language constructs that are monitored. Procedure calls to appropriate counting routines are inserted into the source text in a pre-pass prior to compilation. The profile information is printed out at the end of the program run. It has been found that these two approaches complement each other very effectively.

O comprimento descritivo mínimo na amostragem por transectos lineares

Apresenta·se um breve resumo histórico da evolução da amostragem por transectos lineares e desenvolve·se a sua teoria. Descrevemos a teoria de amostragem por transectos lineares, proposta por Buckland (1992), sendo apresentados os pontos mais relevantes, no que diz respeito à modelação da função de detecção. Apresentamos uma descrição do princípio CDM (Rissanen, 1978) e a sua aplicação à estimação de uma função densidade por um histograma (Kontkanen e Myllymãki, 2006), procedendo à aplicação de um exemplo prático, recorrendo a uma mistura de densidades. Procedemos à sua aplicação ao cálculo do estimador da probabilidade de detecção, no caso dos transectos lineares e desta forma estimar a densidade populacional de animais. Analisamos dois casos práticos, clássicos na amostragem por distâncias, comparando os resultados obtidos. De forma a avaliar a metodologia, simulámos vários conjuntos de observações, tendo como base o exemplo das estacas, recorrendo às funções de detecção semi-normal, taxa de risco, exponencial e uniforme com um cosseno. Os resultados foram obtidos com o programa DISTANCE (Thomas et al., in press) e um algoritmo escrito em linguagem C, cedido pelo Professor Doutor Petri Kontkanen (Departamento de Ciências da Computação, Universidade de Helsínquia). Foram desenvolvidos programas de forma a calcular intervalos de confiança recorrendo à técnica bootstrap (Efron, 1978). São discutidos os resultados finais e apresentadas sugestões de desenvolvimentos futuros. ABSTRACT; We present a brief historical note on the evolution of line transect sampling and its theoretical developments. We describe line transect sampling theory as proposed by Buckland (1992), and present the most relevant issues about modeling the detection function. We present a description of the CDM principle (Rissanen, 1978) and its application to histogram density estimation (Kontkanen and Myllymãki, 2006), with a practical example, using a mixture of densities. We proceed with the application and estimate probability of detection and animal population density in the context of line transect sampling. Two classical examples from the literature are analyzed and compared. ln order to evaluate the proposed methodology, we carry out a simulation study based on a wooden stakes example, and using as detection functions half normal, hazard rate, exponential and uniform with a cosine term. The results were obtained using program DISTANCE (Thomas et al., in press), and an algorithm written in C language, kindly offered by Professor Petri Kontkanen (Department of Computer Science, University of Helsinki). We develop some programs in order to estimate confidence intervals using the bootstrap technique (Efron, 1978). Finally, the results are presented and discussed with suggestions for future developments.

Ensemble Stream Model for Data-Cleaning in Sensor Networks

Ensemble Stream Modeling and Data-cleaning are sensor information processing systems have different training and testing methods by which their goals are cross-validated. This research examines a mechanism, which seeks to extract novel patterns by generating ensembles from data. The main goal of label-less stream processing is to process the sensed events to eliminate the noises that are uncorrelated, and choose the most likely model without over fitting thus obtaining higher model confidence. Higher quality streams can be realized by combining many short streams into an ensemble which has the desired quality. The framework for the investigation is an existing data mining tool. First, to accommodate feature extraction such as a bush or natural forest-fire event we make an assumption of the burnt area (BA*), sensed ground truth as our target variable obtained from logs. Even though this is an obvious model choice the results are disappointing. The reasons for this are two: One, the histogram of fire activity is highly skewed. Two, the measured sensor parameters are highly correlated. Since using non descriptive features does not yield good results, we resort to temporal features. By doing so we carefully eliminate the averaging effects; the resulting histogram is more satisfactory and conceptual knowledge is learned from sensor streams. Second is the process of feature induction by cross-validating attributes with single or multi-target variables to minimize training error. We use F-measure score, which combines precision and accuracy to determine the false alarm rate of fire events. The multi-target data-cleaning trees use information purity of the target leaf-nodes to learn higher order features. A sensitive variance measure such as f-test is performed during each node’s split to select the best attribute. Ensemble stream model approach proved to improve when using complicated features with a simpler tree classifier. The ensemble framework for data-cleaning and the enhancements to quantify quality of fitness (30% spatial, 10% temporal, and 90% mobility reduction) of sensor led to the formation of streams for sensor-enabled applications. Which further motivates the novelty of stream quality labeling and its importance in solving vast amounts of real-time mobile streams generated today.

Quantitative susceptibility mapping as biomarker of neurodegeneration: methodological models and clinical applications

Quantitative Susceptibility Mapping (QSM) is an advanced magnetic resonance technique that can quantify in vivo biomarkers of pathology, such as alteration in iron and myelin concentration. It allows for the comparison of magnetic susceptibility properties within and between different subject groups. In this thesis, QSM acquisition and processing pipeline are discussed, together with clinical and methodological applications of QSM to neurodegeneration. In designing the studies, significant emphasis was placed on results reproducibility and interpretability. The first project focuses on the investigation of cortical regions in amyotrophic lateral sclerosis. By examining various histogram susceptibility properties, a pattern of increased iron content was revealed in patients with amyotrophic lateral sclerosis compared to controls and other neurodegenerative disorders. Moreover, there was a correlation between susceptibility and upper motor neuron impairment, particularly in patients experiencing rapid disease progression. Similarly, in the second application, QSM was used to examine cortical and sub-cortical areas in individuals with myotonic dystrophy type 1. The thalamus and brainstem were identified as structures of interest, with relevant correlations with clinical and laboratory data such as neurological evaluation and sleep records. In the third project, a robust pipeline for assessing radiomic susceptibility-based features reliability was implemented within a cohort of patients with multiple sclerosis and healthy controls. Lastly, a deep learning super-resolution model was applied to QSM images of healthy controls. The employed model demonstrated excellent generalization abilities and outperformed traditional up-sampling methods, without requiring a customized re-training. Across the three disorders investigated, it was evident that QSM is capable of distinguishing between patient groups and healthy controls while establishing correlations between imaging measurements and clinical data. These studies lay the foundation for future research, with the ultimate goal of achieving earlier and less invasive diagnoses of neurodegenerative disorders within the context of personalized medicine.