Kingshuk Roy Choudhury

Predicting Cognitive Decline in Subjects at Risk for Alzheimer Disease by Using Combined Cerebrospinal Fluid, MR Imaging, and PET Biomarkers

PURPOSE To assess the extent to which multiple Alzheimer disease (AD) biomarkers improve the ability to predict future decline in subjects with mild cognitive impairment (MCI) compared with predictions based on clinical parameters alone. MATERIALS AND METHODS All protocols were approved by the institutional review board at each site, and written informed consent was obtained from all subjects. The study was HIPAA compliant. Alzheimers Disease Neuroimaging Initiative (ADNI) baseline magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies for 97 subjects with MCI were used. MR imaging-derived gray matter probability maps and FDG PET images were analyzed by using independent component analysis, an unbiased data-driven method to extract independent sources of information from whole-brain data. The loading parameters for all MR imaging and FDG components, along with cerebrospinal fluid (CSF) proteins, were entered into logistic regression models (dependent variable: conversion to AD within 4 years). Eight models were considered, including all combinations of MR imaging, PET, and CSF markers with the covariates (age, education, apolipoprotein E genotype, Alzheimers Disease Assessment Scale-Cognitive subscale score). RESULTS Combining MR imaging, FDG PET, and CSF data with routine clinical tests significantly increased the accuracy of predicting conversion to AD compared with clinical testing alone. The misclassification rate decreased from 41.3% to 28.4% (P < .00001). FDG PET contributed more information to routine tests (P < .00001) than CSF (P = .32) or MR imaging (P = .08). CONCLUSION Imaging and CSF biomarkers can improve prediction of conversion from MCI to AD compared with baseline clinical testing. FDG PET appears to add the greatest prognostic information.

Observation of dually decoded regions of the human genome using ribosome profiling data

The recently developed ribosome profiling technique (Ribo-Seq) allows mapping of the locations of translating ribosomes on mRNAs with subcodon precision. When ribosome protected fragments (RPFs) are aligned to mRNA, a characteristic triplet periodicity pattern is revealed. We utilized the triplet periodicity of RPFs to develop a computational method for detecting transitions between reading frames that occur during programmed ribosomal frameshifting or in dual coding regions where the same nucleotide sequence codes for multiple proteins in different reading frames. Application of this method to ribosome profiling data obtained for human cells allowed us to detect several human genes where the same genomic segment is translated in more than one reading frame (from different transcripts as well as from the same mRNA) and revealed the translation of hitherto unpredicted coding open reading frames.

Fitting an ellipse to an arbitrary shape: implications for strain analysis

An ellipse can be fit to an arbitrary shape using a linear least squares approach applied to boundary data. Alternatively, this problem can also be solved by calculating the second moments of the entire region, a technique popular in image analysis applications. If the irregular shape can be approximated by a polygon then Greens theorem allows efficient calculation of the second moments. If the shape is pixelated then the second moments can be calculated by a simple summation process. By considering the behaviour of these fitting methods with increasing deformation it is shown that as an arbitrary shape passively deforms, the best-fit ellipse also behaves as if it were deforming passively. This implies that all techniques of strain analysis that were previously restricted to populations of elliptical objects may now be applied to populations of arbitrary shapes, provided the best-fit ellipse is calculated by one of the methods described here. Furthermore it implies that selective sampling based on shape or methods of weighting based upon shape are invalid and tend to bias the raw data.

The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions

The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies.

A robust automated measure of average antibody staining in immunohistochemistry images

Identifying and scoring cancer markers plays a key role in oncology, helping to characterize the tumor and predict the clinical course of the disease. The current method for scoring immunohistochemistry (IHC) slides is labor intensive and has inherent issues of quantitation. Although multiple attempts have been made to automate IHC scoring in the past decade, a major limitation in these efforts has been the setting of the threshold for positive staining. In this report, we propose the use of an averaged threshold measure (ATM) score that allows for automatic threshold setting. The ATM is a single multiplicative measure that includes both the proportion and intensity scores. It can be readily automated to allow for large-scale processing, and it is applicable in situations in which individual cells are hard to distinguish. The ATM scoring method was validated by applying it to simulated images, to a sequence of images from the same tumor, and to tumors from different patient biopsies that showed a broad range of staining patterns. Comparison between the ATM score and manual scoring by an expert pathologist showed that both methods resulted in essentially identical scores when applied to these patient biopsies. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Marked gender differences in progression of mild cognitive impairment over 8 years

This study examined whether, among subjects with mild cognitive impairment (MCI), women progressed at faster rates than men.

Impact of Dual-Energy Multi–Detector Row CT with Virtual Monochromatic Imaging on Renal Cyst Pseudoenhancement: In Vitro and in Vivo Study

PURPOSE To investigate whether dual-energy multi-detector row computed tomography (CT) with virtual monochromatic imaging can overcome renal cyst pseudoenhancement in a phantom experiment and a clinical study. MATERIALS AND METHODS This retrospective single-center HIPAA-compliant study was approved by the institutional review board, with waiver of informed consent. Four renal compartments inserted into torso phantoms were filled with saline to simulate the unenhanced state and with iodinated solutions to simulate the three levels of renal parenchyma enhancement (140, 180, and 240 HU). Saline-filled spheres simulating renal cysts (15 and 18 mm in diameter) were serially suspended in the renal compartments and imaged with dual-energy and single-energy multi-detector row CT at four different energy levels (80, 100, 120, and 140 kVp). In addition, 28 patients (mean age, 66 years ± 10; mean body mass index, 31.3 kg/m(2) ± 6.2) with 34 intrarenal cysts were included. Virtual monochromatic images were reconstructed in 10-keV increments at energy levels ranging from 40 to 140 keV. Phantom and clinical data were analyzed by using multivariate regression analysis. RESULTS In the phantom experiment, all polychromatic image data sets showed pseudoenhancement (postcontrast attenuation increase >10 HU) in all investigated conditions, with a significant effect on cyst size (P <.001), location (P <.001), and renal background attenuation level (P <.001). Virtual monochromatic images at energy levels ranging from 80 to 140 keV did not show pseudoenhancement, with the minimum attenuation increase (mean, 6.1 HU ± 1.6; range, 1.6-7.7 HU) on 80-keV images. In patients, pseudoenhancement never occurred on virtual monochromatic images at energy levels ranging from 90 to 140 keV. Patient body size had a significant effect (P = .007) on selection of the optimal monochromatic energy level. CONCLUSION Dual-energy multi-detector row CT with reconstruction of virtual monochromatic images at an optimal energy level can overcome renal cyst pseudoenhancement.

Dual-Energy Multidetector CT for the Characterization of Incidental Adrenal Nodules: Diagnostic Performance of Contrast-enhanced Material Density Analysis

PURPOSE To determine whether contrast material-enhanced dual-energy multidetector computed tomography (CT) with material decomposition analysis allows differentiation of adrenal adenomas from nonadenomatous lesions and to compare findings with those of nonenhanced multidetector CT. MATERIALS AND METHODS This retrospective HIPAA-compliant study was approved by the institutional review board of Duke University, with waiver of informed consent. Thirty-eight nonconsecutive patients (22 men and 16 women; mean age, 65 years) with 47 adrenal nodules underwent nonenhanced and contrast-enhanced dual-energy multidetector CT of the abdomen. For each adrenal nodule, nonenhanced attenuation values were recorded; dual-energy density measurements were obtained by using fat-iodine and fat-water material density basis pairs. Mean and median values of nonenhanced attenuation and material densities were compared between adenomas and nonadenomas by using the two-sample t test and Wilcoxon rank sum test, respectively. The diagnostic performance of nonenhanced multidetector CT and dual-energy material densities was assessed by setting the specificity for diagnosis of adenomas at 100%. RESULTS Adenomas (lipid rich and lipid poor) displayed significantly different mean density values (in milligrams per cubic centimeter) than those of nonadenomas on fat-iodine (970.4 ± 17.2 vs 1012.3 ± 9.3), iodine-fat (2.5 ± 0.3 vs 4.5 ± 1.5), fat-water (-666.7 ± 154.8 vs -2141.8 ± 953.2), and water-fat (1628.4 ± 177.3 vs 3225 ± 986.1) images, respectively (P < .0001). For diagnosis of adenomas, dual-energy material density analysis showed a sensitivity of 96% (23 of 24 lesions) at a specificity of 100% (23 of 23 lesions), yielding significantly improved diagnostic performance compared with nonenhanced multidetector CT attenuation (sensitivity of 67% [16 of 24 lesions] at a specificity of 100% [23 of 23 lesions]) (P = .035). CONCLUSION Contrast-enhanced dual-energy multidetector CT with material density analysis allows differentiation between adrenal adenomas and nonadenomas, reflecting an improved ability over nonenhanced multidetector CT for diagnosis of lipid-poor adenoma.

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

PURPOSE To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively. METHODS AND MATERIALS Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined. RESULTS MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors. CONCLUSIONS MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drugs ability to radioprotect normal tissue while radiosensitizing tumor.

Dual-Energy MDCT in Hypervascular Liver Tumors: Effect of Body Size on Selection of the Optimal Monochromatic Energy Level

OBJECTIVE The purpose of this article is to investigate the effect of body size on the selection of optimal monochromatic energy level for maximizing the conspicuity of hypervascular liver tumors during late hepatic arterial phase using dual-energy MDCT. MATERIALS AND METHODS An anthropomorphic liver phantom in three body sizes and iodine-containing inserts simulating low- and high-contrast hypervascular lesions was imaged with dual- and single-energy MDCT at various energy levels (80, 100, 120, and 140 kVp). Dual-energy MDCT was also performed in 48 patients with 114 hypervascular liver tumors; virtual monochromatic images were reconstructed at energy levels from 40 to 140 keV. The effect of body size and lesion iodine concentration on noise and tumor-to-liver contrast-to-noise ratio was compared among different datasets for phantoms and patients. RESULTS The highest tumor-to-liver contrast-to-noise ratio was noted at 80 kVp for all phantom sizes. On virtual monochromatic images, the minimum noise was noted at 70 keV for small and medium phantoms and at 80 keV for the large phantom. Tumor-to-liver contrast-to-noise ratio was highest at 50 keV for small and medium phantoms and at 60 keV for the large phantom (p<0.0001). Compared with 80-kVp images, an optimal monochromatic energy level yielded a significantly higher (p<0.0001) tumor-to-liver contrast-to-noise ratio for high-contrast lesions in the large body size and for low-contrast lesions in all phantom sizes. In patients, the optimal monochromatic energy level for tumor-to-liver contrast-to-noise ratio increased proportionally along with body size (p<0.0001). CONCLUSION Selection of the optimal monochromatic energy level for maximizing the conspicuity of hypervascular liver tumors is significantly affected by patients body size.