Martin Stanton

Tomographic mammography using a limited number of low-dose cone- beam projection images

A method is described for using a limited number (typically 10-50) of low-dose radiographs to reconstruct the three-dimensional (3D) distribution of x-ray attenuation in the breast. The method uses x-ray cone-beam imaging, an electronic digital detector, and constrained nonlinear iterative computational techniques. Images are reconstructed with high resolution in two dimensions and lower resolution in the third dimension. The 3D distribution of attenuation that is projected into one image in conventional mammography can be separated into many layers (typically 30-80 1-mm-thick layers, depending on breast thickness), increasing the conspicuity of features that are often obscured by overlapping structure in a single-projection view. Schemes that record breast images at nonuniform angular increments, nonuniform image exposure, and nonuniform detector resolution are investigated in order to reduce the total x-ray exposure necessary to obtain diagnostically useful 3D reconstructions, and to improve the quality of the reconstructed images for a given exposure. The total patient radiation dose can be comparable to that used for a standard two-view mammogram. The method is illustrated with images from mastectomy specimens, a phantom, and human volunteers. The results show how image quality is affected by various data-collection protocols.

Aptamer-based biosensor arrays for detection and quantification of biological macromolecules

We have developed a chip-based biosensor for multiplex analysis of protein analytes. The biosensor utilizes immobilized DNA and RNA aptamers, selected against several different protein targets, to simultaneously detect and quantify levels of individual proteins in complex biological mixtures. Aptamers were each fluorescently labeled and immobilized on a glass substrate. Fluorescence polarization anisotropy was used for solid- and solution-phase measurements of target protein binding. We show that solid-phase aptamer-protein interactions recapitulate binding interactions seen in solution. Furthermore, we demonstrate specific detection and quantitation of cancer-associated proteins (inosine monophosphate dehydrogenase II, vascular endothelial factor, basic fibroblast growth factor) in the context of human serum and in cellular extracts. It is expected that this technology could speed diagnosis of cancer by enabling direct detection of the expression and modification of proteins closely correlated with disease.

Analysis of the detective quantum efficiency of a developmental detector for digital mammography.

We are developing a modular detector for applications in full field digital mammography and for diagnostic breast imaging. The detector is based on a design that has been refined over the past decade for applications in x-ray crystallography [Kalata et al., Proc. SPIE 1345, 270-279 (1990); Phillips et al. ibid. 2009, 133-138 (1993), Phillips et al., Nucl. Instrum. Methods Phys. Rev. A 334, 621-630 (1993)]. The full field mammographic detector, currently undergoing clinical evaluation, is formed from a 19 cm x 28 cm phosphor screen, read out by a 2 x 3 array of butted charge-coupled device (CCD) modules. Each 2k x 2k CCD is optically coupled to the phosphor via a fiber optic taper with dimensions of 9.4 cm x 9.4cm at the phosphor. This paper describes the imaging performance of a two-module prototype, built using a similar design. In this paper we use cascaded linear systems analysis to develop a model for calculating the spatial frequency dependent noise power spectrum (NPS) and detective quantum efficiency (DQE) of the detector using the measured modulation transfer function (MTF). We compare results of the calculation with the measured NPS and DQE of the prototype. Calculated and measured DQEs are compared over a range of clinically relevant x-ray exposures and kVps. We find that for x-ray photon energies between 10 and 28 keV, the detector gain ranges between 2.5 and 3.7 CCD electrons per incident x-ray, or approximately 5-8 electrons per absorbed x ray. Using a Mo/Mo beam and acrylic phantom, over a detector entrance exposure range of approximately 10 to 80 mR, the volume under the measured 2-d NPS of the prototype detector is proportional to the x-ray exposure, indicating quantum limited performance. Substantial agreement between the calculated and measured values was obtained for the frequency and exposure dependent NPS and DQE over a range of tube voltage from 25 to 30 kVp.

High-sensitivity CCD-based X-ray detector

The detector is designed for imaging measurements requiring relatively high sensitivity and high spatial resolution. The detector can discriminate single X-ray photons, yet has the wide dynamic range ( approximately 10000:1) associated with integrating detectors. A GdO2S2 phosphor screen converts the incoming X-ray image into an optical image. The optical image is coupled (without demagnification) to the CCD image sensor using a fiber optic faceplate. The CCD (Philips Semiconductors) has an area of 4.9 x 8.6 cm with 4000 x 7000 12 microm pixels. A single 12 keV X-ray photon produces a signal of 100 e-. With 2 x 2 pixel binning, the total noise per 24 microm pixel in a 100 s image is approximately 30 e- the detective quantum efficiency is >0.6 at 1 X-ray photon per pixel, and the full image can be read out in <4 s. The spatial resolution is 50 microm. The CCD readout system is fully computer-controlled, allowing flexible operation in time-resolved experiments. The detector has been characterized using visible-light images, X-ray images and time-resolved muscle diffraction measurements.

CCD-based detector for protein crystallography with synchrotron X-rays☆

A detector with a 114 mm aperture, based on a charge-coupled device (CCD), has been designed for X-ray diffraction studies in protein crystallography. The detector was tested at the National Synchrotron Light Source with a beam intensity, through a 0.3 mm collimator, of greater than 10(9) X-ray photons/s. A fiberoptic taper, an image intensifier, and a lens demagnify, intensify, and focus the image onto a CCD having 512 x 512 pixels. The statistical uncertainty in the detector output was evaluated as a function of conversion gain. From this, a detective quantum efficiency (DQE) of 0.36 was derived. The dynamic range of a 4 x 4 pixel resolution element, comparable in size to a diffraction peak, was 10(4). The point-spread function shows FWHM resolution of approximately 1 pixel, where a pixel is 160-mu-m on the detector face. A data set collected from a chicken egg-white lysozyme crystal, consisting of 495 0.1-degrees frames, was processed by the MADNES data reduction program. The symmetry R-factors for the data were 3.2-3.5%. In a separate experiment a complete lysozyme data set consisting of 45 1-degrees frames was obtained in just 36 s of X-ray exposure. Diffraction images from crystals of the myosin S1 head (a = 275 angstrom) were also recorded; the Bragg spots, only 5 pixels apart, were separated but not fully resolved. Changes in the detector design that will improve the DQE and spatial resolution are outlined. The overall performance showed that this type of detector is well suited for X-ray scattering investigations with synchrotron sources.

Multiple CCD detector for macromolecular X-ray crystallography

A charge-coupled device (CCD)-based detector designed for macromolecular crystallography is described. The detector has an area of 200 × 200 mm, a readout time of 1.6 s, and total noise equivalent to approximately three 12 keV X-ray photons per pixel. The detector is constructed from a 2 × 2 array of four identical units, each unit consisting of a 4.1:1 demagnifying fiber-optic taper bonded to a 1 k × 1 k, 24 µm pixel, CCD sensor. Each CCD is read out in parallel though four channels and digitized to 16 bits. A Gd2O2S phosphor X-ray-to-light converter bonded to an aluminized-plastic film is held in contact with the input surfaces of the fiber-optic tapers with an air pillow. The full width at half-maximum (FWHM) of the point response function is 120 µm, the response is linear to better than 1% over the entire range of intensity from background to nearly full well, the gain is 3.4 e per 8 keV incident X-ray photon, the noise is 12.6 e per pixel for a 10 s integration time, the modulation transfer function (MTF) is 0.35 at 5 line pairs (lp) mm−1 (the Nyquest frequency), and the measured detective quantum efficiency (DQE) is 0.74 for relatively strong Bragg peaks. Data collected from crystallographic studies with synchrotron radiation are presented. In an anomalous difference Patterson map for a data set collected in 40 min on a monoclinic myoglobin crystal, the magnitude of the Fe–Fe peaks is 18 times the standard uncertainty of the map.

Automation of the SomaLogic Proteomics Assay: A Platform for Biomarker Discovery

At SomaLogic, we have embarked on an ambitious program of clinical studies using a novel aptamerbased proteomics technology to discover biomarkers and develop new tools to diagnose, understand, and treat human disease. As part of this program, we designed and implemented an automated assay for its highly multiplexed proteomics discovery platform. The performance of the automated assay was validated in a study that compared the automated assay to the specifications of an established manual method. Results showed that the automated method performed to the required specifications, and that the automation system improved the efficiency, productivity, and economics of our biomarker discovery program.

Integrated CT-SPECT system for small animal imaging

We are developing a scanner for simultaneous acquisition of x-ray computed tomography (CT) and single photon emission tomography (SPECT) images of small animals such as mice and rats. The scanner uses a cone beam geometry for both the x- ray transmission and gamma emission projections by using an area x-ray detector and pinhole collimator, respectively. The CT and SPECT data set are overlaid to form a coregistered structural-functional 3D image. The CT system includes a single CCD-based x-ray detector and a microfocus x-ray source. The SPECT scanner utilizes tungsten pinhole collimators and arrays of CsI(Tl) scintillation detectors. We describe considerations and the early performance of a prototype scanner.

Characterization and data collection on a direct-coupled CCD X-ray detector

Abstract A large-area, multi-module, CCD-based detector without intensification stages is being developed by our group for X-ray diffraction applications. Each module consists of a fiberoptic taper with a phosphor deposited on the large end and a large-format, scientific CCD bonded to the small end. A single module has been constructed to evaluate the performance of this type of detector. This module has an active area of 43 × 43 mm2, a point response function FWHM = 80 μm, a dynamic range of > 20 000:1, and a high DQE. Using four parallel readout circuits, the CCD can be read out in 1.8 s. Crystallographic data collected using a rotating-anode source demonstrate the capability of this type of detector.

Area detector design Part II. Application to a modular CCD-based detector for X-ray crystallography

Abstract The performance of laboratory and synchrotron CCD-based detectors for X-ray crystallography is modeled using expressions which describe both the detector and the experiment. The detectors are constructed from an array of identical modules, each module consisting of a phosphor X-ray-to-light convertor, a fiberoptic taper and a CCD. The performance is characterized by the detective quantum efficiency (DQE) and dynamic range (DR), and by four additional expressions; the detective collective efficiency (DCE), experimental detective quantum efficiency (XDQE), experimental detective collection efficiency (XDCE) and experimental dynamic range (XDR). These additional expressions provide a means for including experimental constraints in the design of the detector. For a crystallography detector, these constraints include the requirements that the detector a) integrate Bragg peaks to maximum precision, and b) efficiently collect data to high resolution (large Bragg angle). Results obtained using these expressions demonstrate the need for a detector with a relatively large area. In order to build a such a detector from a reasonable number of modules using currently available fiberoptic tapers and CCDs, tapers with a demagnification ratio of > 3:1 are required. A different conclusion would be arrived at if the DQE alone were considered, demonstrating the importance of this method.