Determining The Detective Quantum Efficiency (DQE) Of X-Ray Detectors In Clinical Environments

According to Health Canada, dental and medical radiography accounts for more than 90% of total man-made radiation dose to the general population. Ensuring patients receive the health benefits of diagnostic x-ray imaging without use of higher radiation exposures requires knowledge and understanding of the detective quantum efficiency (DQE). Currently, the DQE is not measured in clinics because it requires specialized instrumentation and specific DQE-expertise to perform an accurate analysis. In this regard, the goals of this thesis were to: 1) address the limitations of measuring the DQE in clinical environments that affects the accuracy of the measurement; 2) develop and validate an automated method of measuring the DQE that is compliant with current regulatory standards to relieve experimental burden on the end-user. It is shown that the DQE can be measured with confidence using the automated method despite the limitations present in clinical environments. This work provides the opportunity for the clinical end-user who may not be familiar with the DQE-measurement process to accurately measure the DQE of clinical x-ray detectors, and provides the opportunity for the DQE to be a primary metric for quality assurance and control practices in the clinical environment

Assessment and optimisation of digital radiography systems for clinical use

Digital imaging has long been available in radiology in the form of computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Initially the transition to general radiography was slow and fragmented but in the last 10-15 years in particular, huge investment by the manufacturers, greater and cheaper computing power, inexpensive digital storage and high bandwidth data transfer networks have lead to an enormous increase in the number of digital radiography systems in the UK. There are a number of competing digital radiography (DR) technologies, the most common are computer radiography (CR) systems followed by indirect digital radiography (IDR) systems. To ensure and maintain diagnostic quality and effectiveness in the radiology department appropriate methods are required to evaluate and optimise the performance of DR systems. Current semi-quantitative test object based methods routinely used to examine DR performance suffer known short comings, mainly due to the subjective nature of the test results and difficulty in maintaining a constant decision threshold among observers with time. Objective image quality based measurements of noise power spectra (NPS) and modulation transfer function (MTF) are the ‘gold standard’ for assessing image quality. Advantages these metrics afford are due to their objective nature, the comprehensive noise analysis they permit and in the fact that they have been reported to be relatively more sensitive to changes in detector performance. The advent of DR systems and access to digital image data has opened up new opportunities in applying such measurements to routine quality control and this project initially focuses on obtaining NPS and MTF results for 12 IDR systems in routine clinical use. Appropriate automatic exposure control (AEC) device calibration and a reproducible measurement method are key to optimising X-ray equipment for digital radiography. The uses of various parameters to calibrate AEC devices specifically for DR were explored in the next part of the project and calibration methods recommended. Practical advice on dosemeter selection, measurement technique and phantoms were also given. A model was developed as part of the project to simulate CNR to optimise beam quality for chest radiography with an IDR system. The values were simulated for a chest phantom and adjusted to describe the performance of the system by inputting data on phosphor sensitivity, the signal transfer function (STF), the scatter removal method and the automatic exposure control (AEC) responses. The simulated values showed good agreement with empirical data measured from images of the phantom and so provide validation of the calculation methodology. It was then possible to apply the calculation technique to imaging of tissues to investigate optimisation of exposure parameters. The behaviour of a range of imaging phosphors in terms of energy response and variation in CNR with tube potential and various filtration options were investigated. Optimum exposure factors were presented in terms of kV-mAs regulation curves and the large dose savings achieved using additional metal filters were emphasised. Optimum tube potentials for imaging a simulated lesion in patient equivalent thicknesses of water ranging from 5-40 cm thick for example were: 90-110kVp for CsI (IDR); 80-100kVp for Gd2O2S (screen /film); and 65-85kVp for BaFBrI. Plots of CNR values allowed useful conclusions regarding the expected clinical operation of the various DR phosphors. For example 80-90 kVp was appropriate for maintaining image quality over an entire chest radiograph in CR whereas higher tube potentials of 100-110 kVp were indicated for the CsI IDR system. Better image quality is achievable for pelvic radiographs at lower tube potentials for the majority of detectors however, for gadolinium oxysulphide 70-80 kVp gives the best image quality. The relative phosphor sensitivity and energy response with tube potential were also calculated for a range of DR phosphors. Caesium iodide image receptors were significantly more sensitive than the other systems. The percentage relative sensitivities of the image receptors averaged over the diagnostic kV range were used to provide a method of indicating what the likely clinically operational dose levels would be, for example results suggested 1.8 µGy for CsI (IDR); 2.8 µGy for Gd2O2S (Screen/film); and 3.8 µGy for BaFBrI (CR). The efficiency of scatter reduction methods for DR using a range of grids and air gaps were also reviewed. The performance of various scatter reduction methods: 17/70; 15/80; 8/40 Pb grids and 15 cm and 20 cm air gaps were evaluated in terms of the improvement in CNR they afford, using two different models. The first, simpler model assumed quantum noise only and a photon counting detector. The second model incorporated quantum noise and system noise for a specific CsI detector and assumed the detector was energy integrating. Both models allowed the same general conclusions and suggest improved performance for air gaps over grids for medium to low scatter factors and both models suggest the best choice of grid for digital systems is the 15/80 grid, achieving comparable or better performance than air gaps for high scatter factors. The development, analysis and discussion of AEC calibration, CNR value, phosphor energy response, and scatter reduction methods are then brought together to form a practical step by step recipe that may be followed to optimise digital technology for clinical use. Finally, CNR results suggest the addition of 0.2 mm of copper filtration will have a negligible effect on image quality in DR. A comprehensive study examining the effect of copper filtration on image quality was performed using receiver operator characteristic (ROC) methodology to include observer performance in the analysis. A total of 3,600 observations from 80 radiographs and 3 observers were analysed to provide a confidence interval of 95% in detecting differences in image quality. There was no statistical difference found when 0.2 mm copper filtration was used and the benefit of the dose saving promote it as a valuable optimisation tool

Digital chest radiography: an update on modern technology, dose containment and control of image quality

The introduction of digital radiography not only has revolutionized communication between radiologists and clinicians, but also has improved image quality and allowed for further reduction of patient exposure. However, digital radiography also poses risks, such as unnoticed increases in patient dose and suboptimum image processing that may lead to suppression of diagnostic information. Advanced processing techniques, such as temporal subtraction, dual-energy subtraction and computer-aided detection (CAD) will play an increasing role in the future and are all targeted to decrease the influence of distracting anatomic background structures and to ease the detection of focal and subtle lesions. This review summarizes the most recent technical developments with regard to new detector techniques, options for dose reduction and optimized image processing. It explains the meaning of the exposure indicator or the dose reference level as tools for the radiologist to control the dose. It also provides an overview over the multitude of studies conducted in recent years to evaluate the options of these new developments to realize the principle of ALARA. The focus of the review is hereby on adult applications, the relationship between dose and image quality and the differences between the various detector systems

Establishment of Clonal MIN-O Transplant Lines for Molecular Imaging via Lentiviral Transduction & In Vitro Culture

As the field of molecular imaging evolves and increasingly is asked to fill the discovery and validation space between basic science and clinical applications, careful consideration should be given to the models in which studies are conducted. The MIN-O mouse model series is an established in vivo model of human mammary precancer ductal carcinoma in situ with progression to invasive carcinoma. This series of transplant lines is propagated in vivo and experiments utilizing this model can be completed in non-engineered immune intact FVB/n wild type mice thereby modeling the tumor microenvironment with biological relevance superior to traditional tumor cell xenografts. Unfortunately, the same qualities that make this and many other transplant lines more biologically relevant than standard cell lines for molecular imaging studies present a significant obstacle as somatic genetic re-engineering modifications common to many imaging applications can be technically challenging. Here, we describe a protocol for the efficient lentiviral transduction of cell slurries derived from precancerous MIN-O lesions, in vitro culture of “MIN-O-spheres” derived from single cell clones, and the subsequent transplantation of these spheres to produce transduced sublines suitable for optical imaging applications. These lines retain the physiologic and pathologic properties, including multilineage differentiation, and complex microanatomic interaction with the host stroma characteristic of the MIN-O model. We also present the in vivo imaging and immunohistochemical analysis of serial transplantation of one such subline and detail the progressive multifocal loss of the transgene in successive generations

Performance evaluation of detectors for digital radiography

To date the hospital radiological workflow is completing a transition from analog to digital technology. Since the X-rays digital detection technologies have become mature, hospitals are trading on the natural devices turnover to replace the conventional screen film devices with digital ones. The transition process is complex and involves not just the equipment replacement but also new arrangements for image transmission, display (and reporting) and storage. This work is focused on 2D digital detector’s characterization with a concern to specific clinical application; the systems features linked to the image quality are analyzed to assess the clinical performances, the conversion efficiency, and the minimum dose necessary to get an acceptable image. The first section overviews the digital detector technologies focusing on the recent and promising technological developments. The second section contains a description of the characterization methods considered in this thesis categorized in physical, psychophysical and clinical; theory, models and procedures are described as well. The third section contains a set of characterizations performed on new equipments that appears to be some of the most advanced technologies available to date. The fourth section deals with some procedures and schemes employed for quality assurance programs

Relative Merits of 3D Visualization for the Detection of Subtle Lung Nodules

A new imaging modality called bi-plane correlation imaging (BCI) was examined to determine the merits of using BCI with stereoscopic visualization to detect subtle lung nodules. In the first aim of this project, the optimal geometry for conventional projection imaging applications was assessed using a theoretical model to develop generic results for MTF, NNPS, eDQE. The theoretical model was tested with a clinical system using two magnifications and two anthropomorphic chest phantoms to assess the modalities of single view CXR and stereo/BCI. Results indicated that magnification can potentially improve the signal and noise performance of digital images. Results also demonstrated that a cross over point occurs in the spatial frequency above and below which the effects of magnification differ indicating that there are task dependent tradeoffs associated with magnification. Results indicated that magnification can potentially improve the detection performance primarily due to the air gap which reduced scatter by 30-40%. For both anthropomorphic phantoms, at iso-dose, eDQE(0) for stereo/BCI was ~100 times higher than that for CXR. Magnification at iso-dose improved eDQE(0) by ~10 times for BCI. Increasing the dose did not improve results. The findings indicated that stereo/BCI with magnification may improve detection of subtle lung nodules compared to single view CXR. With quantitative results in place, a pilot clinical trial was constructed. Human subject data was acquired with a BCI acquisition system. Subjects were imaged in the PA position as well as two oblique angles. Realistic simulated lesions were added to a subset of subjects determined to be nodule free. A BCI CAD algorithm was also applied. In randomized readings, radiologists read the cases according to viewing protocol. For the radiologist trainees, the AUC of lesion detection was seen to improve by 2.8% (p < 0.05) for stereoscopic viewing after monoscopic viewing compared to monoscopic viewing only. A 13% decrease in false positives was observed. Stereo/BCI as an adjunct modality was beneficial. However, the full potential of stereo/BCI as a replacement modality for single view chest x-ray may be realized with improved observer training, clinically relevant stereoscopic displays, and more challenging detection tasks.Doctor of Philosoph

Digital radiography: image acquisition and scattering reduction in x-ray imaging.

Since the discovery of the X-rays in 1895, their use in both medical and industrial imaging applications has gained increasing importance. As a consequence, X-ray imaging devices have evolved and adapted to the needs of individual applications, leading to the appearance of digital image capture devices. Digital technologies introduced the possibility of separating the image acquisition and image processing steps, allowing their individual optimization. This thesis explores both areas, by seeking the improvement in the design of the new family of Varex Imaging CMOS X-ray detectors and by developing a method to reduce the scatter contribution in mammography examinations using image post-processing techniques. During the CMOS X-ray detector product design phase, it is crucial to detect any short- comings that the detector might present. Image characterization techniques are a very efficient method for finding these possible detector features. This first part of the thesis focused in taking these well-known test methods and adapt and optimize them, so they could act as a red flag indicating when something needed to be investigated. The methods chosen in this study have proven to be very effective in finding detector short- comings and the designs have been optimised in accordance with the results obtained. With the aid of the developed imaging characterization tests, new sensor designs have been successfully integrated into a detector, resulting in the recent release into the market of a new family of Varex Imaging CMOS X-ray detectors. The second part of the thesis focuses in X-ray mammography applications, the gold standard technique in breast cancer screening programmes. Scattered radiation degrades the quality of the image and complicates the diagnosis process. Anti-scatter grids, the main scattering reduction technique, are not a perfect solution. This study is concerned with the use of image post-processing to reduce the scatter contribution in the image, by convolving the output image with kernels obtained from simplified Monte Carlo simulations. The proposed semi-empirical approach uses three thickness-dependant symmetric kernels to accurately estimate the environment contribution to the breast, which has been found to be of key importance in the correction of the breast-edge area. When using a single breast thickness-dependant kernel to convolve the image, the post-processing technique can over-estimate the scattering up to 60%. The method presented in this study reduces the uncertainty to a 4-10% range for a 35 to 70 mm breast thickness range, making it a very efficient scatter modelling technique. The method has been successfully proven against full Monte Carlo simulations and mammography phantoms, where it shows clear improvements in terms of the contrast to noise ratio and variance ratio when the performance is compared against images acquired with anti-scatter grids

Ultrasensitive Molecular Monitoring of Breast Cancer and Acute Myeloid Leukemia

Cancer is the common name to a group of biologically diverse malignant neoplastic diseases. Approximately 18 million people are diagnosed with cancer annually and 8.8 million patients die from it. Tumorigenesis and progression of cancer are driven by alterations in the cancer cell genome. These alterations lead to gain of oncogenic functions, loss of tumor suppressor functions, or may be chromosomal rearrangements without obvious function, and these alterations themselves can serve as tumor-specific biomarkers that may have diagnostic and clinical utility.In this thesis, we investigated oncogenic and tumor suppressive genes in breast cancers and leukemias, with a focus on the PTEN/PIK3CA pathway as well as minimally-invasive monitoring of cancer patients using “liquid biopsies.” We studied the underlying mechanism of PTEN protein loss in breast cancer, and showed how various types of tumor-specific mutations, including those in PIK3CA, can be used as biomarkers to monitor the dynamics of occult tumor burden, evaluate the degree of tumor content dissemination into the bloodstream with mammographic compression, and detect minimal residual disease in breast cancer and acute myeloid leukemia.In Paper I, we found that the frequent loss of PTEN protein in human breast cancer is not attributable to the overexpression of the E3 ubiquitin ligase NEDD4, and thus NEDD4 is unlikely to be a regulator of the oncogenic PI3K/PTEN signaling pathway. In Paper II, we showed that serial monitoring of tumor specific chromosomal rearrangements, identified with low coverage whole genome sequencing and then measured in blood samples by digital PCR (dPCR), is a highly sensitive and specific approach to detect occult breast cancer disease prior to the onset of symptoms and clinical detection. Detected plasma ctDNA level was a quantitative predictor of poor relapse-free and overall survival. In Paper III, we confirmed the general safety of mammography, using FDA approved CellSearch® and our ultrasensitive mutation detection dPCR technology IBSAFE, that mammographic compression of the breast with a breast tumor does not appear to lead to significant additional dissemination of CTCs and ctDNA into the bloodstream. In Paper IV, we showed that acute myeloid leukemia specific mutations can be serially monitored in follow-up bone marrow samples by IBSAFE, providing an insight in subclonal evolution of the leukemia and the status of minimal residual disease.These results and our mutation detection technology suggest they have high potential to be utilized in assessing treatment response, monitoring the disease course, detecting remnant tumor deposits with targetable mutations, and helping to speed the development of new drugs in in the future

Zebrafish : a resourceful vertebrate model to investigate skeletal disorders

Animal models are essential tools for addressing fundamental scientific questions about skeletal diseases and for the development of new therapeutic approaches. Traditionally, mice have been the most common model organism in biomedical research, but their use is hampered by several limitations including complex generation, demanding investigation of early developmental stages, regulatory restrictions on breeding, and high maintenance cost. The zebrafish has been used as an efficient alternative vertebrate model for the study of human skeletal diseases, thanks to its easy genetic manipulation, high fecundity, external fertilization, transparency of rapidly developing embryos, and low maintenance cost. Furthermore, zebrafish share similar skeletal cells and ossification types with mammals. In the last decades, the use of both forward and new reverse genetics techniques has resulted in the generation of many mutant lines carrying skeletal phenotypes associated with human diseases. In addition, transgenic lines expressing fluorescent proteins under bone cell- or pathway- specific promoters enable in vivo imaging of differentiation and signaling at the cellular level. Despite the small size of the zebrafish, many traditional techniques for skeletal phenotyping, such as x-ray and microCT imaging and histological approaches, can be applied using the appropriate equipment and custom protocols. The ability of adult zebrafish to remodel skeletal tissues can be exploited as a unique tool to investigate bone formation and repair. Finally, the permeability of embryos to chemicals dissolved in water, together with the availability of large numbers of small-sized animals makes zebrafish a perfect model for high-throughput bone anabolic drug screening. This review aims to discuss the techniques that make zebrafish a powerful model to investigate the molecular and physiological basis of skeletal disorders