Browsing by Subject "diagnostic"

Virtual imaging trials (VITs) are a growing part of medical imaging research. VITs are a powerful alternative to the current gold-standard for determining or verifying the efficacy of new technology in healthcare: the clinical trial. Prohibitively high expenses, multi-site standardization of protocols, and risks to the health of the trial’s patient population are all challenges associated with the clinical trial; conversely, these challenges highlight the strengths of virtualization, particularly with regard to evaluating medical imaging technologies.Virtual imaging requires a combination of virtual subjects, physics-based imaging simulation platforms, and virtual pathologies. Currently, most computational phantom organs and pathologies are segmented or generated from clinical CT images. With this approach, most computational organs and pathologies are necessarily static, comprising only a single instantaneous representation. Further, this static-anatomy–static-pathology approach does not address the underlying physiological constraints acting on the organs or their pathologies—making some imaging exams (e.g., perfusion, coronary angiography) difficult to simulate robustly. It also does not provide a clear path toward including anatomical and physiological (functional) detail at sub-CT resolution. This project aims to integrate high-resolution, dynamic features into computational human models. The focus is primarily an advanced model known as XCAT. These additions include healthy and progressive-disease anatomy and physiology, micron-level–resolution coronary artery lesions, and an array of pathologies. In particular, we focus on the physiology needed for CT perfusion studies, dynamic lesions, or coronary artery disease (CAD), and means to integrate each of these features into XCAT via custom software. The outcome is further to demonstrate the utility of each of these advances with representative simulated imaging. Chapter 1 presents a method using clinical information and physiological theory to develop a mathematical model that produces the liver vasculature within a given XCAT. The model can be used to simulate contrast perfusion by taking into account contrast position and concentration at an initial time t and the spatial extent of the contrast in the liver vasculature at subsequent times. The mathematical method enables the simulation of hepatic contrast perfusion in the presence or absence of abnormalities (e.g., focal or diffuse disease) for arbitrary imaging protocols, contrast concentrations, and virtual patient body habitus. The vessel growing method further generalizes to vascular models of other organs as it is based on a parameterized approach, allowing for flexible repurposing of the developed tool. Chapter 2 presents a method for using cardiac plaque histology and morphology data acquired at micron-level resolution to generate new, novel plaques informed by a large, original patient cohort. A methodology for curating and validating the anatomical and physiological realism was further applied to the synthesized plaques to ensure realism. This method was integrated with the XCAT heart and coronary artery models to allow simulated imaging of a wide variety of coronary artery plaques in varied orientations and with unique material distribution and composition. Generation of 200 unique plaques has been optimized to take as little as 5 seconds with GPU acceleration. This work enables future studies to optimize current and emerging CT imaging methods used to detect, diagnose, and treat coronary artery disease. Chapter 3 focuses on small-scale modeling of the internal structure of the bones of the chest. The internal structure of the bones appears as a diffuse but recognizable texture under medical imaging and corresponds to a complex physical structure tuned to meet the physical purpose of the bone (e.g., weight-bearing, protective structure, etc.). The project aimed to address the limitations of prior texture-based modelling by creating mathematically based fine bone structures. The method was used to generate realistic bone structures, defined as polygon meshes, with accurate morphological and topological detail for 45 chest bones for each XCAT phantom. This new method defines the spatial extent of the complementary bone–marrow structures that are the root cause of the characteristic image texture 1-4 and provides a transition from using image-informed characteristic power law textures to a ground-truth model with exact morphology—which we additionally paired with the DukeSim CT simulator5 and XCAT phantoms6 to produce radiography and CT images with physics-based bone textures. This work enables CT acquisition parameter optimization studies that can inform clinical image assessment of osteoporosis and bone fractures. Chapter 4 proposes a new model of lesion morphology and insertion and was created with the intent to be informed and validated by—rather than constrained by—imaging data. It additionally includes the new incorporation of biological data, intended to provide dynamic computational lung lesion models for use in CT simulation applications. Each chapter includes a section presenting an example application of the respective tools in virtual medical imaging. Chapter 5 concludes this work with a brief summary of the content and is followed by Appendices A–D. The appendices are organized by topic and contain a visual demonstration of the work in a series of high-resolution, full-page images.

Background: Maternal and congenital syphilis are pressing concerns in Latin America, with consequences ranging from newborn mental retardation to perinatal death. Widespread, accurate screening and timely penicillin treatment can help. Simple, affordable, point of care rapid syphilis tests (RSTs) promise to improve screening coverage among pregnant women.

Methods: From September 2009 to November 2010, Project CISNE implemented the SD Bioline Syphilis 3.0 RST into two health networks, offering the test to pregnant women aged 16 55 who attended antenatal care, delivery/postpartum, and abortion services. The performance analysis compared Bioline RST results with reference standards TPPA and RPR+TPPA, adjusting estimates according to sampling realities.

Results: 17,147 rapid syphilis tests were performed in the field and 11,169 were screened in the central laboratory. Syphilis prevalence was 1.05% (0.73% adjusted) according to the gold standard vs. 0.90% according to the field RST. The Bioline RST displayed an unadjusted sensitivity of 91.0% (95% CI 86.4 95.0) and specificity of 99.1% (98.1 99.6) compared to TPPA, and an unadjusted sensitivity of 91.5% (84.8 95.8) and specificity of 99.6% (99.4 99.7) compared to RPR+TPPA. When adjusted, overall sensitivity and specificity compared to RPR+TPPA were 86.5% (78.8 92.0) and 99.7% (99.6 99.8), respectively. The Bioline RST yielded more false positive than false negative results due to the observed low prevalence.

Discussion: Despite limitations, this study displays the field RST to be reliable, reproducible, as valid as previous studies, and diagnostically apt for implementation in maternal care services in Peru.

The translational potential of diagnostic and prognostic platforms developed using expression microarray technology is evident. However, the majority of array-based diagnostics have yet to make their way into the clinical laboratory. Current approaches tend to focus on development of multi-gene classifiers of disease subtypes, but very few studies evaluate the translational potential of these assays. Likewise, only a handful of studies focus on development of approaches to optimize array-based tests for the ultimate goal of clinical utility. Prior to translation into the clinical setting, molecular diagnostic platforms should demonstrate a number of characteristics to ensure optimal and efficient testing and patient care. Assays should be accurate and precise, technically and biologically robust, and should take into account normal sources of biological variance that could ultimately affect test results. The overarching goal of the research presented in this dissertation is to develop methods for evaluating and optimizing the translational potential of molecular diagnostics developed using expression microarray technology.

The first research section of this dissertation is focused on our evaluation of the impact of intratumor heterogeneity on precision in microarray-based assays in breast cancer. We conducted genome-wide expression profiling on 50 needle core biopsies from 18 breast cancer patients. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen (ER) and progesterone receptor (PR) status were compared to immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics were evaluated by interclass correlation. Results demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single gene predictors of ER (intraclass correlation coefficient (ICC)=0.94) and PR expression (ICC=0.90), and in a multi-gene predictor of ER pathway activation (ICC=0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multi-gene signatures of cancer recurrence (ICC=0.71), and chemotherapeutic sensitivity (ICC=0.72 and 0.64). Together, these results demonstrated that intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise micro-array based predictions of tumor behavior or clinical outcome in breast cancer patients.

Leading into the second research section, we observed that in some cancer types, certain genes behave as molecular switches and have either an "on" or "off" expression state. Specifically, we observed these molecular switch genes exist in breast cancer as robust diagnostic and prognostic markers, including ER, PR, and HER2, and define tumor subtypes associated with different treatment and patient survival. We hypothesized that clinically relevant molecular switch (bimodal) genes exist in epithelial ovarian cancer, a type of cancer with no established molecular subgroups. To test this hypothesis, we applied a bimodal discovery algorithm to a publically available ovarian cancer expression microarray dataset (GSE9891:285 tumors; 246 malignant serous (MS), 20 endometrioid (EM), 18 low malignant potential (LMP) ovarian carcinomas). Genes with robust bimodal expression were identified across all ovarian tumor types and within selected subtypes. Of these bimodal genes, 73 demonstrated differential expression between LMP vs. MS and EM, and 22 genes distinguished MS from EM. Fourteen bimodal genes had significant association with survival among MS tumors. When these genes were combined into a single survival score, the median survival for patients with a favorable versus unfavorable score was 65 versus 29 months (p<0.0001, HR=0.4221). Two independent datasets (n=53 high grade, advanced stage serous and n=119 advanced stage ovarian tumors) validated the survival score performance. Taken together, the results of this study revealed that genes with bimodal expression patterns not only define clinically relevant molecular subtypes of ovarian carcinoma, but also provide ideal targets for translation into the clinical laboratory.

Finally, the third research section of this dissertation focuses on development of robust blood-based molecular markers of decompression stress (DS). DS is defined as the pathophysiological response to inert gas coming out of solution in the blood and tissues when a body experiences a reduction in ambient pressure. To date, there are no established molecular markers of DS. We hypothesized that comparing gene expression before and after human decompression exposures by genome-wide expression profiling would identify candidate molecular markers of DS. Peripheral blood was collected 1hr before and 2hr after 93 hyperoxic, heliox experimental dives (n=54). Control arms included samples collected 1 hour before and 2 hours after high pressure oxygen breathing (n= 9) and surface exercise (n=9), and samples collected at 7am and 5pm for time of day (n=11). Pre and post-dive expression data collected from normoxic nitrox experimental dives were utilized for independent validation. Blood samples were collected into PaxGene RNA tubes. RNA was extracted and processed for globin reduction prior to cDNA synthesis and Affymetrix U133A GeneChip hybridization. 746 genes were differentially expressed following hyperoxic, heliox decompression exposures (permutation adjusted p-value cutoff 1.0E-4). After filtering control significant genes, 726 genes remained. Pathway analysis demonstrated a significant portion of genes were associated with innate immune response (p<0.0001). A 362 multi-gene signature of significant, covariant genes was then applied to the independent dataset and demonstrated differentiation between pre and post-dive samples (p=0.0058). There was no significant correlation between signature and venous bubble grade or bottom time in the validation study. Our results showed that expression profiling of peripheral blood following decompression exposures, while controlling for experimental and normal sources of biological variance, identifies a reproducible multi-gene signature of differentially expressed genes, primarily comprising genes associated with innate immune response and independent of venous bubble grade or dive profile.

Taken together, the research and results presented in this dissertation represent considerable advances in the development of approaches to guide microarray-based diagnostics towards the ultimate goal of clinical translation.