Study design in the evaluation of breast cancer imaging technologies.

RATIONALE AND OBJECTIVES: Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. MATERIALS AND METHODS: The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. CONCLUSION: Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

Molybdenum, rhodium, and tungsten anode spectral models using interpolating polynomials with application to mammography.

Computer simulation is a convenient and frequently used tool in the study of x-ray mammography, for the design of novel detector systems, the evaluation of dose deposition, x-ray technique optimization, and other applications. An important component in the simulation process is the accurate computer-generation of x-ray spectra. A computer model for the generation of x-ray spectra in the mammographic energy range from 18 kV to 40 kV has been developed. The proposed model requires no assumptions concerning the physics of x-ray production in an x-ray tube, but rather makes use of x-ray spectra recently measured experimentally in the laboratories of the Center for Devices and Radiological Health. Using x-ray spectra measured for molybdenum, rhodium, and tungsten anode x-ray tubes at 13 different kV's (18, 20, 22, ..., 42 kV), a spectral model using interpolating polynomials was developed. At each energy in the spectrum, the x-ray photon fluence was fit using 2, 3, or 4 term (depending on the energy) polynomials as a function of the applied tube voltage (kV). Using the polynomial fit coefficients determined at each 0.5 keV interval in the x-ray spectrum, accurate x-ray spectra can be generated for any arbitrary kV between 18 and 40 kV. Each anode material (Mo, Rh, W) uses a different set of polynomial coefficients. The molybdenum anode spectral model using interpolating polynomials is given the acronym MASMIP, and the rhodium and tungsten spectral models are called RASMIP and TASMIP, respectively. It is shown that the mean differences in photon fluence calculated over the energy channels and over the kV range from 20 to 40 kV were -0.073% (sigma = 1.58%) for MASMIP, -0.145% (sigma = 1.263%) for RASMIP, and 0.611% (sigma = 2.07%) for TASMIP. The polynomial coefficients for all three models are given in an Appendix. A short C subroutine which uses the polynomial coefficients and generates x-ray spectra based on the proposed model is available on the World Wide Web at http:/(/)www.aip.org/epaps/epaps.html.

Absence of enhanced sympathoadrenal activity and behaviorally evoked cardiovascular reactivity among offspring of hypertensives.

To determine whether offspring of hypertensives show enhanced sympathetic nervous system activity, we evaluated several indices of sympathoadrenal activation and cardiovascular responsiveness to behavioral stimuli among 90 normotensive, young adult men having either one or two hypertensive parents (PH+(-), PH++) or normotensive parents only (PH--) (n = 30/group). Measurements included heart rate (HR) and blood pressure (BP) reactions to three mental stressors (the Stroop test, mental arithmetic, mirror tracing), a cold pressor test, postural adjustment (60 degrees upright tilt), isometric exercise and bicycle ergometry, as well as the 24-h excretion of catecholamines (epinephrine [E], norepinephrine [NE]) and venous plasma catecholamine concentrations, both at rest (seated and supine) and in response to the Stroop test and upright tilt. The three groups did not differ in age, education, body mass index (BMI), estimated aerobic fitness, resting HR, cardiac preejection period (PEP) and PEP:LVET (left ventricular ejection time) ratio, 24-h Na or K excretion, or fasting lipids, insulin or plasma renin activity. Resting systolic and diastolic BP varied as a function of parental hypertension, and were significantly higher in PH++ than among PH-- subjects (P < .05). No significant group difference was observed on any measure of plasma or urinary catecholamines, nor did offspring of hypertensives (PH++ or PH+-) showed greater HR or BP reactions than PH-- subjects to any of the several laboratory challenges. In sum, we find no evidence of enhanced sympathetic activity or heightened cardiovascular responsiveness among normotensive young adults who are familially predisposed to essential hypertension.

Comparison of beam-hardening and K-edge filters for imaging barium and iodine during fluoroscopy.

This study investigated the dose reduction performance of several beam-hardening and K-edge filter materials for the imaging of barium or iodine during fluoroscopy. A computer model was developed to simulate the effect of added filtration on entrance exposure rate (Xp), integral dose rate (Di), contrast (C), signal to noise ratio (SNR), imaging performance per dose (SNR2/Di), and tube load. The model incorporated the response characteristics, in both manual and automatic control modes of operation, of fluoroscopic systems to increasing or decreasing x-ray intensity at the input of the image intensifier. Input parameters to the computer model included choice of filter material and thickness, a barium or iodine test object, tube potential, phantom thickness, a CsI input phosphor, and a set of algorithms for controlling the fluoroscopic system. In all cases, the performance of systems with added filtration was judged with respect to a reference system operating under comparable conditions. In general, either beam-hardening or K-edge filters provided a significant reduction in entrance exposure and integral dose rates, but with an attendant increase in tube load. For a fluoroscopic system constrained to follow a representative automatic brightness control algorithm, added filtration provided a reduction in entrance exposure and integral dose rates for all phantom or uniformly distributed barium thickness. However, the imaging performance per dose, in some cases, decreased rapidly and was less than that of the reference system at large thicknesses. Only as change in the algorithm controlling the kVcp and mA operating points on the fluoroscopic system provided an imaging performance per dose greater than the reference system's at large thicknesses. The practical implementation of adding filtration to fluoroscopic systems is most simply accomplished with beam-hardening filters rather than K-edge filters. However, the systems with K-edge added filtration can provide slightly better performance when used over a limited range of phantom thicknesses such as the range normally associated with pediatric patients.

A patient-equivalent attenuation phantom for estimating patient exposures from automatic exposure controlled x-ray examinations of the abdomen and lumbo-sacral spine.

The Joint Commission on Accreditation of Healthcare Organizations requires diagnostic radiology facilities to known the approximate amount of radiation received by an average patient during radiographic examinations at the facility. Automatic exposure controlled (AEC) techniques are used for many of these exams, and a standard patient-equivalent phantom is necessary when estimating patient exposure on such systems. This is of particular importance if exposures are to be compared among AEC systems with different entrance x-ray spectra. We have developed a phantom, LucA1 Abdomen, to facilitate determining the average patient exposure from AEC anteroposterior (AP) abdomen and lumbo-sacral (LS) spine radiography. The phantom is relatively lightweight, transportable, sturdy, and made of readily available inexpensive materials (Lucite and aluminum). It accurately simulates the primary and scatter transmission through the soft tissue and L-4 spinal regions of a patient-equivalent anthropomorphic phantom for x-ray spectra typically used in abdomen/LS spine radiography. A clinical evaluation to verify the patient-equivalence of three commercial anthropomorphic phantoms (Humanoid, Rando, 3-M) and two acrylic/aluminum phantoms (ANSI and LucA1 Abdomen) has been conducted. The design and development of the LucA1 Abdomen phantom and the evaluation of all phantoms is described.

A method for comparing beam-hardening filter materials for diagnostic radiology.

The necessity for using adequate beam filtration in diagnostic radiology is well known. Although aluminum is the most widely used filter material for diagnostic x-ray applications, the possibility that other materials might have superior properties has prompted a number of studies that have attempted to determine both the type and the amount of filtration most appropriate for a given situation. This paper describes a method based on precise matching of spectral shape that permits the absolute ranking of beam-hardening materials. Matching of spectral shape ensures equality of such parameters as image contrast and patient dose. Spectrally equivalent filters can then be ranked on the basis of the transmission of one relative to another. Following the development of the theory behind the method and an algorithm for implementing it, the method is applied to the evaluation of a variety of materials for use as filters in diagnostic radiology. Experimental verification of a few of the calculated results is also described. Both calculated and experimental results show that normal aluminum filters are about 10% less efficient than filters of materials such as copper, brass, or iron. Since the approach followed here was the basis for several early investigations of filtration for orthovoltage therapy, a brief comparison of results from these early reports with results calculated using the method developed here is also presented.

Noise analysis of scintillation camera images: stochastic and non-stochastic effects.

An analysis of noise was performed on scintillation camera images. The analysis was performed on sets of field floods, uniform exposures over the field of view, in such a way that stochastic and non-stochastic effects were separable. Stochastic noise for the digitally acquired images was found to approach the limit of Poisson count statistics. The non-stochastic component of the calculations dominated the results at the lower spatial frequencies. These results hold true even after standard methods of uniformity correction are applied, primarily due to the effects of Compton scatter events. The noise power spectrum calculations carry information about the patterns of the noise in flood images. Examples of digitisation, photomultiplier tube mottle and edge-packing artefacts are presented.

Beam quality independent attenuation phantom for estimating patient exposure from x-ray automatic exposure controlled chest examinations.

The periodic assessment of exposures in diagnostic radiology is an important part of a comprehensive quality assurance program. The most frequent radiologic examination conducted in the United States is chest radiography. Automatic exposure controlled (AEC) techniques are often used for this exam, and a standard patient-equivalent chest phantom is useful when estimating patient exposures on such systems. This is of particular importance if exposures are to be compared among AEC systems with different entrance x-ray spectra. Such a phantom has been developed to facilitate surveys of the average patient exposure from AEC posteroanterior chest radiography. The phantom is relatively lightweight and easily transportable, sturdy and made of readily available and relatively inexpensive materials (Lucite and aluminum). It accurately simulates the primary and scatter transmission through the lung-field regions of a patient-equivalent anthropomorphic phantom for x-ray spectra typically used in chest radiography. A clinical evaluation has been conducted to verify the patient equivalence of the phantom. Measurements of patient entrance skin exposure were obtained for a large number of patients on a variety of x-ray systems operated in the AEC mode using one or both lung-field detectors. Comparison of these data with exposure estimates derived from the phantom indicate that the phantom attenuates the x-ray beam in such a way that it can be employed to accurately and consistently estimate the mean exposure of the average patient under a variety of radiographic conditions. The design, development, and evaluation of the patient-equivalent attenuation phantom is described.

Effects of chronic modification of dietary fat and carbohydrate in rats.

1. Rats were fed on diets enriched with starch, sucrose, corn oil or beef tallow for 3 weeks and the activities of various enzymes in the liver were measured. 2. The mitochondrial glycerol phosphate acyltransferase activity was lower in rats fed on the starch diet than on the two high-fat diets. 3. The non-microsomal (presumably peroxisomal) dihydroxyacetone phosphate acyltransferase activity was higher in rats fed on the starch diet and corn-oil diets than in those fed on the sucrose and beef-tallow diets. Urate oxidase activity was higher in rats fed on the starch diet than in the three other groups. There were no significant differences in the activity of acyl-CoA oxidase among the groups. 4. The activity of soluble phosphatidate phosphohydrolase was not significantly different among the dietary groups. There were increases of 3.3--4.3-fold in this activity in the dietary groups 6h after injection of corticotropin. The equivalent increases for the mitochondrial glycerol phosphate acyltransferase were 1.4--1.6 fold. 5. The corticosterone responses to the corticotropin injection were not significantly different between dietary groups. However, the corticosterone response of the rats fed on the two high-fat diets was prolonged when the rats were given an acute load of fructose [Brindley, Cooling, Glenny, Burditt & McKechnie (1981) Biochem. J. 200. 275--283]. 6. Rats fed on the high-fat diets had higher concentrations of circulating cholesterol than those fed on the starch and sucrose diets. Serum triacylglycerol concentrations were lower in the rats fed on the starch diet than in the three other groups. 7. The results are discussed in terms of the relationship between diet, hormonal balance and hepatic glycerolipid metabolism.

The activities of lipoprotein lipase and of enzymes involved in triacylglycerol synthesis in rat adipose tissue. Effects of starvation, dietary modification and of corticotropin injection.

1. The effects of dietary modification, including starvation, and of corticotropin injection on the activities of acyl-CoA synthetase, glycerol phosphate acyltransferase, dihydroxyacetone phosphate acyltransferase, phosphatidate phosphohydrolase, diacylglycerol acyltransferase and lipoprotein lipase were measured in adipose tissue. 2. Lipoprotein lipase activities in heart were increased and those in adipose tissue were decreased when rats were fed on diets enriched with corn oil or beef tallow rather than with sucrose or starch. The lipoprotein lipase activity was lower in the adipose tissue of rats fed on the sucrose rather than on the starch diet. 3. Rats fed on the beef tallow diet had slightly higher activities of the total glycerol phosphate acyltransferase in adipose tissue than did rats fed on the sucrose or starch diet. The diacylglycerol acyltransferase and the mitochondrial glycerol phosphate acyltransferase activities were higher for the rats fed on the tallow diet than for those fed on the corn-oil diet. 4. Starvation significantly decreased the activities of lipoprotein lipase (after 24 and 48 h), acyl-CoA synthetase (after 24 h) and of the mitochondrial glycerol phosphate acyltransferase and the N-ethylmaleimide-insensitive dihydroxyacetone phosphate acyltransferase (after 48 h) in adipose tissue. The activities of the microsomal glycerol phosphate acyltransferase, diacylglycerol acyltransferase and the soluble phosphatidate phosphohydrolase were not significantly changed after 24 or 48 h of starvation. 5. The activities of lipoprotein lipase and phosphatidate phosphohydrolase in adipose tissue were decreased 15 min after corticotropin was injected into rats during November to December. No statistically significant differences were found when these experiments were performed during March to September. These differences may be related to the seasonal variation in acute lipolytic responses. 6. These results are discussed in relation to the control of triacylglycerol synthesis and lipoprotein metabolism.

Efficiency of human visual signal discrimination.

We have measured the overall statistical efficiency of human subjects discriminating the amplitude of visual pattern signals added to noisy backgrounds. By changing the noise amplitude, the amount of intrinsic noise can be estimated and allowed for. For a target containing a few cycles of a spatial sinusoid of about 5 cycles per degree, the overall statistical efficiency is as high as 0.7 +/- 0.07, and after correction for intrinsic noise, efficiency reaches 0.83 +/- 0.15. Such a high figure leaves little room for residual inefficiencies in the neural mechanisms that handle these patterns.

Optimal x-ray spectra for screen-film mammography.

Theoretical and experimental techniques have been used to study optimal x-ray for screen-film mammography. A simple model of mammographic imaging predicts optimum x-ray energies which are significantly higher than the K-characteristic energies of Mo. A subjective comparison of x-ray spectra from Mo-anode and W-anode tubes indicates that spectra produced by a W-anode tube filtered with materials of atomic number just above that of Mo are more suitable for screen-film mammography than spectra produced by the Mo-anode/Mo-filter system. The imaging performance of K-edge filtered, W-anode tube spectra was compared to the performance of Mo-anode spectra using phantom measurements and mastectomy specimen radiography. It was shown that optimal W-anode spectra can produce equal contrast with an exposure reduction of a factor of two to three, a dose reduction of a factor of two, and equal or reducing tube loading, compared to Mo-anode spectra. A computer simulation was carried out to extend the initial, monoenergetic theory to the case of real, polychromatic sources. The effects of varying filter material and thickness, tube operating potential, and breast thickness were all studied. Since W-anode x-ray tubes are considered to be better for Xerox mammography than Mo-anode tubes, this study has shown that both Xerox and screen-film techniques can be performed optimally with a single, properly designed, W-anode x-ray tube.