A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design.

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects >2years old at three time points over one year (baseline, 6 and 12months). Fifteen IIIA (9 male, 6 female; age 5.0±1.9years) and ten IIIB subjects (8 male, 2 female; age 8.6±3years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3year old developmental level, and showed a significant age-related decline over a 6month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8years of age, but showed significant mean declines over a 6month interval in those <7years old (p=0.0029) and in those with NVIQ score≥45 (p=0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6month intervals (p=0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p<0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials.

ULTRASOUND SPECTROSCOPY.

We introduce the concept of "Ultrasound Spectroscopy". The premise of ultrasound spectroscopy is that by acquiring ultrasound RF data at multiple power and frequency settings, a rich set of features can be extracted from that RF data and used to characterize the underlying tissues. This is beneficial for a variety of problems, such as accurate tissue classification, application-specific image generation, and numerous other quantitative tasks. These capabilities are particularly relevant to point-of-care ultrasound (POCUS) applications, where operator experience with ultrasound may be limited. Instead of displaying B-mode images, a POCUS application using ultrasound spectroscopy can, for example, automatically detect internal abdominal bleeding. In this paper, we present ex vivo tissue phantom studies to demonstrate the accuracy of ultrasound spectroscopy over previous approaches. Our studies suggest that ultrasound spectroscopy provides exceptional accuracy and informative features for classifying blood versus other tissues across image locations and body habitus.

Methods for displaying intracerebral vascular anatomy.

We are developing three-dimensional imaging methods to portray vascular anatomy better, including noise-free display of vessels extracted from 3-D data sets, tree-based display, and reconstruction of angiographic data (preliminary work has resulted in the successful reconstruction of aneurysms from angiographic data). Fast, interactive display permits real-time manipulation of viewing orientation.

The role of neural networks in improving the accuracy of MR spectroscopy for the diagnosis of head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: MR Spectroscopy (MRS) has the unique ability to analyze tissue at the molecular level noninvasively. The purpose of this study was to determine if peak heights revealed by proton MRS ((1)H-MRS) signals showed that neural networks (NN) provided better accuracy than linear discriminant analysis (LDA) in differentiating head and neck squamous cell carcinoma (SCCA) from muscle METHODS: In vitro 11-T (1)H-MR spectra were obtained on SCCA tissue samples (n = 16) and muscle (n = 12). The peak heights at seven metabolite resonances were measured: olefinic acids at 5.3 ppm, inositol at 3.5 ppm, taurine at 3.4 ppm, choline (Cho) at 3.2 ppm, creatine (Cr) at 3.0 ppm, sialic acid at 2.2 ppm, and methyl at 0.9 ppm. Using leave-one-out experimental design and receiver operating characteristic curve analysis, the ability of NN and LDA classifiers to distinguish SCCA from muscle were compared (given equal weighting of false-negative and false-positive errors). These classifiers were also compared with an existing method that forms a diagnosis by using LDA of the Cho/Cr peak area ratio. RESULTS: NN classifiers, which were identified using height data, achieved better sensitivity and specificity rates in distinguishing SCAA from muscle than did LDA using height or area data. Sensitivity/specificity for the NN analysis of the seven metabolite peak heights were 87.5 % and 83.3%, respectively, for a one-hidden-node network and 81.2% and 91.7%, respectively, for a two-hidden-node network. Additional nodes did not improve accuracy. The sensitivity and specificity were 81.2% and 50%, respectively, for LDA of the seven peak heights, and 68% and 83%, respectively, for LDA of the Cho/Cr peak area ratio. CONCLUSION: NN classifiers with peak height data were superior to LDA of the peak heights and LDA of the Cho/Cr peak area ratio for differentiating SCCA from normal muscle. These results show neural network analysis can improve the diagnostic accuracy of (1)H-MRS in differentiating muscle from malignant tissue. Further studies are necessary to confirm our initial findings.

Computer-assisted visualization of arteriovenous malformations on the home personal computer.

OBJECTIVE: Arteriovenous malformations (AVMs) are difficult lesions to treat, partly because it is difficult to formulate a three-dimensional mental image of the nidus and its supplying arteries, draining veins, and arteries of passage. Our purpose is to develop personal computer software that allows better visualization of complex, three-dimensional, connected vascular anatomy for surgical planning. METHODS: Vessels are defined from magnetic resonance angiograms and are symbolically linked to form vascular trees. The nidus of the AVM is also defined by magnetic resonance angiography. These representations of the nidus and vasculature can be viewed together in a software program that allows the user to color-code groups of vessels or to selectively turn connected groups of vessels "off" to avoid obscuring the part of the image that the user wants to observe. Structures can be viewed from any angle. The vessels can also be shown intersecting any magnetic resonance angiogram slice or superimposed upon digital subtraction angiograms obtained from the same patient. RESULTS: We report results from two patients with AVMs in which our representations were compared with the findings during surgery. Our three-dimensional vascular trees correctly depicted the relationship of the nidus to feeding vessels in three dimensions. We show findings in an additional, unoperated patient for whom vessel trees were created from three-dimensional digital subtraction angiography data and compared with a volume rendering of the original data set. CONCLUSION: Computer-assisted, three-dimensional visualizations of complex vascular anatomy can be helpful in planning the surgical excision of AVMs. Software programs that produce these images can provide important information that is difficult to obtain by traditional techniques. This imaging method is also applicable to guidance of endovascular procedures and removal of complex tumors.

Registration of 3D cerebral vessels with 2D digital angiograms: clinical evaluation.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the accuracy and speed of a new, semiautomatic method of three-dimensional (3D)-two-dimensional (2D) vascular registration. This method should help guide endovascular procedures by allowing interpretation of each digital subtraction angiographic (DSA) image in terms of precreated, 3D vessel trees that contain "parent-child" connectivity information. MATERIALS AND METHODS: Connected, 3D vessel trees were created from segmented magnetic resonance (MR) angiograms. Eleven total DSA images were registered with such trees by using both our method and the current standard (manual registration). The accuracy of each method was compared by using repeated-measures analysis of variance with correction for heterogeneity of variance to evaluate separation of curve pairs on the view plane. Subjective clinical comparisons of the two registration methods were evaluated with the sign test. Registration times were evaluated for both methods and also as a function of the error in the initial estimate of MR angiographic position. RESULTS: The new registration method produced results that were numerically superior to those of manual registration (P < .001) and was subjectively judged to be as good as or better by clinical reviewers. Registration time with the new method was faster (P < .001). If the rotational error in the initial estimate of MR angiographic position is less than 10 degrees around each axis, the registration itself took only 1-2 minutes. CONCLUSION: This method is quicker than and produces results as good as or better than those of manual registration. This method should be able to calculate an initial registration matrix during endovascular embolization and adjust that matrix intermittently with registration updates provided by automatic tracking systems.

Symbolic description of intracerebral vessels segmented from magnetic resonance angiograms and evaluation by comparison with X-ray angiograms.

We describe and evaluate methods that create detailed vessel trees by linking vessels that have been segmented from magnetic resonance angiograms (MRA). The tree-definition process can automatically exclude erroneous vessel segmentations. The parent-child connectivity information provided by our vessel trees is important to both surgical planning and to guidance of endovascular procedures. We evaluated the branch connection accuracy of our 3D vessel trees by asking two neuroradiologists to evaluate 140 parent-child connections comprising seven vascular trees against 17 digital subtraction angiography (DSA) views. Each reviewer rated each connection as (1) Correct, (2) Incorrect, (3) Partially correct (a minor error without clinical significance), or (4) Indeterminate. Analysis was summarized for each evaluator by calculating 95% confidence intervals for both the proportion completely correct and the proportion clinically acceptable (completely or partially correct). In order to protect the overall Type I error rate, alpha-splitting was done using a top down strategy. We additionally evaluated segmentation completeness by examining each slice in 11 MRA datasets in order to determine unlabeled vessels identifiable in cross-section following segmentation. Results indicate that only one vascular parent-child connection was judged incorrect by both reviewers. MRA segmentations appeared complete within MRA resolution limits. We conclude that our methods permit creation of detailed vascular trees from segmented 3D image data. We review the literature and compare other approaches to our own. We provide examples of clinically useful visualizations enabled by our methodology and taken from a visualization program now in clinical use.

Modulation of thyroxine uptake and efflux in vitro by temelastine and phenobarbital in cultured hepatocytes from different species, in relation to toxicological effects on the thyroid gland.

Toxicological studies in the rat with phenobarbital and temelastine (SK&F 93944) are associated with thyroid lesions, characterized by thyroid stimulated hormone-mediated thyroid follicular cell hypertrophy and hyperplasia. It has previously been demonstrated that these compounds enhance the hepatocellular accumulation and clearance of thyroxine (T(4)), in rat but not dog or mouse. In this study these events were further characterized in vitro using cultured hepatocytes from different species. Exposure of rat hepatocytes in vitro to phenobarbital and temelastine produced significant increases (P < 0.05) in hepatocellular [(125)I]l-thyroxine accumulation, following 3 hr of exposure to either drug (at a concentration of 10 mum), in the presence of [(125)I]T(4) (0.107 nm final concentration). At this concentration the accumulation of [(125)I]T(4) after xenobiotic exposure was 132.6 +/- 1.5% (phenobarbital) and 135 +/- 2.0% (temelastine) of control values. There was no apparent xenobiotic-induced cytotoxicity (as determined by the mitochondrial MTT index) up to 20 mum temelastine and 50 mum phenobarbital in rat hepatocytes. Experiments performed at 4 degrees C [or under conditions of cellular ATP depletion, induced by 1 mum carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) treatment] failed to show any such increase in hepatocellular thyroxine accumulation. Pretreatment of hepatocytes with either phenobarbital or temelastine for 3 hr before the addition of radiolabelled thyroxine produced increases in hepatocellular hormone accumulation similar to those observed when [(125)I]T(4) and drug were added to the cultures simultaneously. The earliest time at which any increase in [(125)I]T(4) accumulation was observed after drug exposure was approximately 90 min. Exposure of hepatocytes from guinea pig or beagle dog to phenobarbital or temelastine in vitro failed to produce similar increases in hepatocellular [(125)I]T(4) accumulation, demonstrating species specificity of the xenobiotic effect in vitro.

Using Taguchi's method of experimental design to control errors in layered perceptrons.

A significant problem in the design and construction of an artificial neural network for function approximation is limiting the magnitude and the variance of errors when the network is used in the field. Network errors can occur when the training data does not faithfully represent the required function due to noise or low sampling rates, when the network's flexibility does not match the variability of the data, or when the input data to the resultant network is noisy. This paper reports on several experiments whose purpose was to rank the relative significance of these error sources and thereby find neural network design principles for limiting the magnitude and variance of network errors.

Localizing target structures in ultrasound video - a phantom study.

The problem of localizing specific anatomic structures using ultrasound (US) video is considered. This involves automatically determining when an US probe is acquiring images of a previously defined object of interest, during the course of an US examination. Localization using US is motivated by the increased availability of portable, low-cost US probes, which inspire applications where inexperienced personnel and even first-time users acquire US data that is then sent to experts for further assessment. This process is of particular interest for routine examinations in underserved populations as well as for patient triage after natural disasters and large-scale accidents, where experts may be in short supply. The proposed localization approach is motivated by research in the area of dynamic texture analysis and leverages several recent advances in the field of activity recognition. For evaluation, we introduce an annotated and publicly available database of US video, acquired on three phantoms. Several experiments reveal the challenges of applying video analysis approaches to US images and demonstrate that good localization performance is possible with the proposed solution.

Computer-assisted measurement of vessel shape from 3T magnetic resonance angiography of mouse brain.

Blood vessel morphology (vessel radius, branching pattern, and tortuosity) is altered by a multitude of diseases. Although murine models of human pathology are important to the investigation of many diseases, there are few publications that address quantitative measurements of murine vascular morphology. This report outlines methods of imaging mice in vivo using magnetic resonance angiograms obtained on a clinical 3T unit, of defining mouse vasculature from these images, and of quantifying measures of vessel shape. We provide examples of both healthy and diseased vasculature and illustrate how the approach can be used to assess pathology both visually and quantitatively. The method is amenable to the assessment of many diseases in both human beings and mice.

Modalities for the assessment of burn wound depth.

OBJECTIVE: Burn wound depth is a significant determinant of patient treatment and morbidity. While superficial partial-thickness burns generally heal by re-epithelialization with minimal scarring, deeper wounds can form hypertrophic or contracted scars, often requiring surgical excision and grafting to prevent a suboptimal result. In addition, without timely intervention, more superficial burn wounds can convert to deeper wounds. As such, the rapid and accurate assessment of burn wound depth is a priority in treating burn-injured patients. The object of this article is to review current research on modalities useful in the assessment of burn wound depth with emphasis on the relative costs and benefits of each technique. METHODS: PubMed and Cochrane computerized databases were used for data retrieval, using the search terms "burns," "burn wounds," "burn depth," "burn depth measurement," and "burn depth progression." In addition, bibliographic references from prior reviews of burn depth were reviewed. All peer-reviewed, English-language articles relevant to the topic of burn depth measurement were reviewed, including those focusing on animal and human populations. Where appropriate, conclusions drawn from review articles and expert analyses were included. RESULTS: Although bedside evaluation remains the most common modality of diagnosing the depth of burn wounds, recent technological advances have broadened the scope of depth assessment modalities available to clinicians. Other depth assessment techniques include biopsy and histology, and perfusion measurements techniques such as thermography, vital dyes, indocyanine green video angiography, and laser Doppler techniques. CONCLUSION: Of the depth assessment modalities currently used in clinical practice, LDI and ICG video angiography offer the best data-supported estimates of accuracy. Until the future of new modalities unfolds, a combination of clinical evaluation and another modality--thermography, biopsy, or, ideally, ICG video angiography or LDI--is advised to best assess the depth of acute burn wounds.

Radiologists' preferences for digital mammographic display. The International Digital Mammography Development Group.

PURPOSE: To determine the preferences of radiologists among eight different image processing algorithms applied to digital mammograms obtained for screening and diagnostic imaging tasks. MATERIALS AND METHODS: Twenty-eight images representing histologically proved masses or calcifications were obtained by using three clinically available digital mammographic units. Images were processed and printed on film by using manual intensity windowing, histogram-based intensity windowing, mixture model intensity windowing, peripheral equalization, multiscale image contrast amplification (MUSICA), contrast-limited adaptive histogram equalization, Trex processing, and unsharp masking. Twelve radiologists compared the processed digital images with screen-film mammograms obtained in the same patient for breast cancer screening and breast lesion diagnosis. RESULTS: For the screening task, screen-film mammograms were preferred to all digital presentations, but the acceptability of images processed with Trex and MUSICA algorithms were not significantly different. All printed digital images were preferred to screen-film radiographs in the diagnosis of masses; mammograms processed with unsharp masking were significantly preferred. For the diagnosis of calcifications, no processed digital mammogram was preferred to screen-film mammograms. CONCLUSION: When digital mammograms were preferred to screen-film mammograms, radiologists selected different digital processing algorithms for each of three mammographic reading tasks and for different lesion types. Soft-copy display will eventually allow radiologists to select among these options more easily.

Image processing algorithms for digital mammography: a pictorial essay.

Digital mammography systems allow manipulation of fine differences in image contrast by means of image processing algorithms. Different display algorithms have advantages and disadvantages for the specific tasks required in breast imaging-diagnosis and screening. Manual intensity windowing can produce digital mammograms very similar to standard screen-film mammograms but is limited by its operator dependence. Histogram-based intensity windowing improves the conspicuity of the lesion edge, but there is loss of detail outside the dense parts of the image. Mixture-model intensity windowing enhances the visibility of lesion borders against the fatty background, but the mixed parenchymal densities abutting the lesion may be lost. Contrast-limited adaptive histogram equalization can also provide subtle edge information but might degrade performance in the screening setting by enhancing the visibility of nuisance information. Unsharp masking enhances the sharpness of the borders of mass lesions, but this algorithm may make even an indistinct mass appear more circumscribed. Peripheral equalization displays lesion details well and preserves the peripheral information in the surrounding breast, but there may be flattening of image contrast in the nonperipheral portions of the image. Trex processing allows visualization of both lesion detail and breast edge information but reduces image contrast.