The Gamma characteristic of reconstructed PET images: Implications for ROI analysis

The basic emission process associated with PET imaging is Poisson in nature. Reconstructed images inherit some aspects of this—regional variability is typically proportional to the regional mean. Iterative reconstruction using expectation maximization (EM), widely used in clinical imaging now, impose positivity constraints that impact noise properties. The present work is motivated by analysis of data from a physical phantom study of a PET/CT scanner in routine clinical use. Both traditional filtered back-projection (FBP) and EM reconstructions of the images are considered. FBP images are quite Gaussian but the EM reconstructions exhibit Gamma-like skewness. The Gamma structure has implications for how reconstructed PET images might be processed statistically. Post-reconstruction inference— model fitting and diagnostics for regions of interest are of particular interest. Although the relevant Gamma parameterization is not within the framework of generalized linear models (GLM), iteratively re-weighted least squares (IRLS) techniques, which are often used to find the maximum likelihood estimates of a GLM, can be adapted for analysis in this setting. Our work highlights the use of a Gamma-based probability transform in producing normalized residuals as model diagnostics. The approach is demonstrated for quality assurance analyses associated with physical phantom studies—recovering estimates of local bias and variance characteristics in an operational scanner. Numerical simulations show that when the Gamma assumption is reasonable, gains in efficiency are obtained. The work shows that the adaptation of standard analysis methods to accommodate the Gamma structure is straightforward and beneficial

Positron emission tomography-based assessment of metabolic gradient and other prognostic features in sarcoma

Intratumoral heterogeneity biomarkers derived from positron emission tomography (PET) imaging with fluorodeoxyglucose (FDG) are of interest for a number of cancers, including sarcoma. A range of radiomic texture variables, adapted from general methodologies for image analysis, has shown promise in the setting. In the context of sarcoma, our group introduced an alternative model-based approach to the measurement of heterogeneity. In this approach, the heterogeneity of a tumor is characterized by the extent to which the 3-D FDG uptake pattern deviates from a simple elliptically contoured structure. By using a nonparametric analysis of the uptake profile obtained from this spatial model, a variable assessing the metabolic gradient of the tumor is developed. The work explores the prognostic potential of this new variable in the context of FDG-PET imaging of sarcoma. A mature clinical series involving 197 patients, 88 of whom have complete time-to-death information, is used. Texture variables based on the imaging data are also evaluated in this series and a range of appropriate machine learning methodologies are then used to explore the complementary prognostic roles for structure and texture variables. We conclude that both texture-based and model-based variables can be combined to achieve enhanced prognostic assessments of outcome for patients with sarcoma based on FDG-PET imaging information

Statistical assessment of treatment response in a cancer patient based on pre-therapy and post-therapy FDG-PET scans

This work arises from consideration of sarcoma patients in which fluorodeoxyglucose positron emission tomography (FDG-PET) imaging pre-therapy and post-chemotherapy is used to assess treatment response. Our focus is on methods for evaluation of the statistical uncertainty in the measured response for an individual patient. The gamma distribution is often used to describe data with constant coefficient of variation, but it can be adapted to describe the pseudo-Poisson character of PET measurements. We propose co-registering the pre-therapy and post- therapy images and modeling the approximately paired voxel-level data using the gamma statistics. Expressions for the estimation of the treatment effect and its variability are provided. Simulation studies explore the performance in the context of testing for a treatment effect. The impact of misregistration errors and how test power is affected by estimation of variability using simplified sampling assumptions, as might be produced by direct bootstrapping, is also clarified. The results illustrate a marked benefit in using a properly constructed paired approach. Remarkably, the power of the paired analysis is maintained even if the pre-image and post- image data are poorly registered. A theoretical explanation for this is indicated. The methodology is further illustrated in the context of a series of fluorodeoxyglucose-PET sarcoma patient studies. These data demonstrate the additional prognostic value of the proposed treatment effect test statistic

Computing environments, interactive graphics and nonparametric methods for data analysis

This report summarizes the research in areas of computing environments, interactive graphics and visualization, and nonparametric methods

Demodex-Associated Bacillus Proteins Induce an Aberrant Wound Healing Response in a Corneal Epithelial Cell Line: Possible Implications for Corneal Ulcer Formation in Ocular Rosacea

PURPOSE. The aim of the work presented here was to establish the response of a corneal epithelial cell line (hTCEpi) to protein extracted from a bacterium (Bacillus oleronius) previously isolated from a Demodex mite from a rosacea patient. METHODS. The response of the corneal epithelial cell line to Bacillus proteins was measured in terms of alterations in cell migration and invasiveness. Changes in the expression of metalloproteinase genes and proteins were also assessed. RESULTS. The results indicated increased cell migration (14.5- fold, P ¼ 0.001) as measured using 8-lm PET inserts (BD Falcon) in a transwell assay and invasiveness (1.7-fold, P ¼ 0.003) as measured using 8-lm Matrigel (BD Biocoat) invasion inserts in a 24-well plate assay format, following exposure to the Bacillus proteins. Cells exposed to the Bacillus protein showed a dose-dependent increase in expression of genes coding for matrix metalloprotease (MMP)-3 (61-fold) and MPP-9 (301-fold). This dose-dependent increase in gene expression was also reflected in elevated levels of MMP-9 protein (1.34- fold, P ¼ 0.033) and increased matrix metalloprotease activity (1.96-fold, P¼0.043) being present in the culture supernatant. Cells also displayed reduced levels of b-integrin (1.25-fold, P ¼ 0.01), indicative of increased motility and elevated levels of vinculin (2.7-fold, P ¼ 0.0009), suggesting altered motility. CONCLUSIONS. The results indicate that exposure of corneal epithelial cells to Bacillus proteins results in an aberrant wound healing response as visualized using a scratch wound assay. These results suggest a possible link between the high density of Demodex mites on the eyelashes of ocular rosacea patients and the development of corneal ulcers. (Invest Ophthalmol Vis Sci. 2012;53:3250–3259) DOI:10.1167/ iovs.11-929

Demodex-Associated Bacillus Proteins Induce an Aberrant Wound Healing Response in a Corneal Epithelial Cell Line: Possible Implications for Corneal Ulcer Formation in Ocular Rosacea

PURPOSE. The aim of the work presented here was to establish the response of a corneal epithelial cell line (hTCEpi) to protein extracted from a bacterium (Bacillus oleronius) previously isolated from a Demodex mite from a rosacea patient. METHODS. The response of the corneal epithelial cell line to Bacillus proteins was measured in terms of alterations in cell migration and invasiveness. Changes in the expression of metalloproteinase genes and proteins were also assessed. RESULTS. The results indicated increased cell migration (14.5- fold, P ¼ 0.001) as measured using 8-lm PET inserts (BD Falcon) in a transwell assay and invasiveness (1.7-fold, P ¼ 0.003) as measured using 8-lm Matrigel (BD Biocoat) invasion inserts in a 24-well plate assay format, following exposure to the Bacillus proteins. Cells exposed to the Bacillus protein showed a dose-dependent increase in expression of genes coding for matrix metalloprotease (MMP)-3 (61-fold) and MPP-9 (301-fold). This dose-dependent increase in gene expression was also reflected in elevated levels of MMP-9 protein (1.34- fold, P ¼ 0.033) and increased matrix metalloprotease activity (1.96-fold, P¼0.043) being present in the culture supernatant. Cells also displayed reduced levels of b-integrin (1.25-fold, P ¼ 0.01), indicative of increased motility and elevated levels of vinculin (2.7-fold, P ¼ 0.0009), suggesting altered motility. CONCLUSIONS. The results indicate that exposure of corneal epithelial cells to Bacillus proteins results in an aberrant wound healing response as visualized using a scratch wound assay. These results suggest a possible link between the high density of Demodex mites on the eyelashes of ocular rosacea patients and the development of corneal ulcers. (Invest Ophthalmol Vis Sci. 2012;53:3250–3259) DOI:10.1167/ iovs.11-929

An exploration of the prognostic utility of shortened dynamic imaging protocols for PET-FDG scans

Standard whole-body clinical fluoro-deoxyglucose (FDG)-PET scans typically involve imaging for around 15 minutes about 60 minutes after tracer injection. The scan duration is often the critical constraint limiting patient through-put. Scans taken long after tracer injection restrict the ability to assess vascular and perfusion information that might be revealed by the early pattern of tracer uptake. On the other hand, early scanning may compromise the recovery of the late time uptake (SUV) which in many contexts has well established prognostic value. In this study, we explore the potential for short-duration dynamic scans, acquired immediately after tracer injection, to recover information that can predict late-stage uptake of FDG. The work involves re-analysis of existing series of dynamic brain and breast tumour imaging data to simulate the type of information that would arise from early and late scanning. Using a collection of machine learning techniques (including random forests, neural networks, gradient boosting), we find that short-duration clinical protocols, soon after the tracer injection, show significant potential to recover the late stage FDG flux information

Spatial auto-regressive analysis of correlation in 3-D PET with application to model-based simulation of data

When a scanner is installed and begins to be used operationally, its actual performance may deviate somewhat from the predictions made at the design stage. Thus it is recommended that routine quality assurance (QA) measurements be used to provide an operational understanding of scanning properties. While QA data are primarily used to evaluate sensitivity and bias patterns, there is a possibility to also make use of such data sets for a more refined understanding of the 3-D scanning properties. Building on some recent work on analysis of the distributional characteristics of iteratively reconstructed PET data, we construct an auto-regression model for analysis of the 3-D spatial auto-covariance structure of iteratively reconstructed data, after normalization. Appropriate likelihood-based statistical techniques for estimation of the auto-regression model coefficients are described. The fitted model leads to a simple process for approximate simulation of scanner performance-one that is readily implemented in an R script. The analysis provides a practical mechanism for evaluating the operational error characteristics of iteratively reconstructed PET images. Simulation studies are used for validation. The approach is illustrated on QA data from an operational clinical scanner and numerical phantom data. We also demonstrate the potential for use of these techniques, as a form of model-based bootstrapping, to provide assessments of measurement uncertainties in variables derived from clinical FDG-PET scans. This is illustrated using data from a clinical scan in a lung cancer patient, after a 3-minute acquisition has been re-binned into three consecutive 1-minute time-frames. An uncertainty measure for the tumor SUVmax value is obtained. The methodology is seen to be practical and could be a useful support for quantitative decision making based on PET data

Quantitation of multiple injection dynamic PET scans: an investigation of the benefits of pooling data from separate scans when mapping kinetics

Multiple injection dynamic positron emission tomography (PET) scanning is used in the clinical management of certain groups of patients and in medical research. The analysis of these studies can be approached in two ways: (i) separate analysis of data from individual tracer injections, or (ii), concatenate/pool data from separate injections and carry out a combined analysis. The simplicity of separate analysis has some practical appeal but may not be statistically efficient. We use a linear model framework associated with a kinetic mapping scheme to develop a simplified theoretical understanding of separate and combined analysis. The theoretical framework is explored numerically using both 1D and 2D simulation models. These studies are motivated by the breast cancer flow-metabolism mismatch studies involving 15O-water (H2O) and 18F-Fluorodeoxyglucose (FDG) and repeat 15O-H2O injections used in brain activation investigations. Numerical results are found to be substantially in line with the simple theoretical analysis: mean square error characteristics of alternative methods are well described by factors involving the local voxel-level resolution of the imaging data, the relative activities of the individual scans and the number of separate injections involved. While voxel-level resolution has dependence on scan dose, after adjustment for this effect, the impact of a combined analysis is understood in simple terms associated with the linear model used for kinetic mapping. This is true for both data reconstructed by direct filtered backprojection or iterative maximum likelihood. The proposed analysis has potential to be applied to the emerging long axial field-of-view PET scanners