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Conditional entropy as an indicator of pleomorphism in astrocytic tumors.

The entropies of nuclear arrangements as an indicator of pleomorphism are assessed using a morphometric method. Sixty astrocytic tumors (grades I, II, III and IV; 15 cases each) were reviewed and analyzed. All slides were stained with HE and MIB-1 antibody. The MIB-1 labeling index (LI) was assessed by counting nuclei under a microscope. Images of HE-stained slides were digitized and segmented using the watershed algorithm. Then, six nuclear parameters were measured automatically: (i) the number of total nuclei in the image, (ii) percentage of total nuclear area in the image, (iii) the mean area of the nucleus, (iv) the standard deviation of the area of the nucleus, (v) the entropy of nuclear arrangement (Entropysimple), and (vi) conditional entropy of nuclear arrangement (Entropyconditional). Entropysimple was defined according to the area of the nucleus and Entropyconditional was defined according to both the area of the nucleus and the area of its neighboring nuclei. Image processing and image analysis were performed with public domain software developed in the laboratory. Segmentation of the images resulted in inappropriate segmentation in a few percent of the images. The measurements obtained for each parameter were classified using discriminant analysis. The percentage of correct classification with Entropyconditional was 62%, which was the highest value among all the measurements. Classification based on the combination of all measurements resulted in a rate of correct classification of 88%. Thus, conditional entropy of nuclear arrangement is useful for grading of astrocytic tumors and it is proposed as an indicator of pleomorphism.

Astrocytoma↗

The prevention of mechanical birth trauma by means of computer aided simulation of delivery by means of nuclear magnetic resonance imaging and finite element analysis.

Anatomic disproportion gains an increasing interest in obstetrics. Imaging procedures (radiologic pelvimetry, computed or magnetic resonance imaging (MRI) fail to reflect the dynamics of delivery including deformations of the birth channel as well as of fetal structures. To validate findings of imaging procedures in this respect a method has been developed to perform a dynamic, biomechanical postprocessing of the static informations obtained from MRI. Using an especially developed software MRI pixel matrices of maternal pelvis and fetal head were color-codef1p4d--according to the principle of same density--line data were created. After sectional attribution of the resulting polygones a three-dimensional mesh of so called Finite elements (FE) was created, which then can be used for deformation analysis. Fetal head was then moved through the birth channel by means of computed simulation. This allows not only ongoing deformations to be visualized but also resulting forces to be calculated for at any time of the delivery process for any point of the anatomical model. Performing these simulations assuming various anatomic and physiologic conditions an obstetrical-biomechanical data basis could be obtained, that was implemented in a PC-based expert system. This allows interpretation of pelvimetric data with regard to birth dynamics.

Biomechanical Phenomena↗

A new device combining laser Doppler perfusion imaging and digital photography.

We describe a new method for acquisition and analysis of skin perfusion images acquired by laser Doppler scanning and digital photographs of the area scanned. Photographs are obtained with a commercial digital still video camera. A commercial software package is used to handle the perfusion image file and the digital photo. We describe software developed to assess blood flow distribution in detail in relation to the visual appearance of the skin, palpatory findings and other clinical signs. Possible clinical applications of the method described by case reports are post-operative evaluation of vascularized grafts and monitoring of treatment of chronic skin ulcers.

Blood Flow Velocity↗

Value of automatic processing and reliability of stored data in an implanted pacemaker: initial results in 59 patients.

Stored data in implantable pacemakers have rarely been used as a diagnostic tool because of the complexity. Our group has developed software called AIDA, providing an automatic interpretation of data stored in memories of the Chorus (ELA medical) pacemaker. We compared the results of AIDA analysis to surface ECG Holter interpretation in 59 patients (age 75 +/- 9 years). In 33 cases, neither AIDA nor the Holter found any anomaly. Eleven patients demonstrated episodes of supraventricular tachycardia (SVT), confirmed by AIDA in ten patients; AIDA failure was due to nonsustained episodes of SVT not inducing mode switch. Loss of atrial sensing, pacemaker-mediated tachycardia, and ventricular extrasystoles were detected by AIDA in ten patients. Traditional Holter missed three cases. This initial study confirms that stored pacemaker data, automatically interpreted can provide reliable information over a 24-hour period.

Aged↗

Use of potentiodynamic polarization technique for corrosion testing of dental alloys.

The number and in particular the diversity in types and composition of alloys used in dentistry are increasing, thus enhancing the need for predictive corrosion testing. No corrosion test is generally accepted as being both applicable to and relevant for all dental alloys. However, some methods have gained a certain recognition, and among these are the potentiodynamic polarization techniques. The purpose of the present work was to study the application, the reproducibility and the influence of some methodological variables on the results of potentiodynamic polarization corrosion testing. Embedded specimens of 18 different dental alloys, representing all major types, were subjected to anodic polarization scan within the potential range of -700 mV to 1000 mV (SCE). Artificial saliva, with and without organic compounds, and sodium sulfide solution were used as electrolytes. The results were processed on a microcomputer using locally developed software. The curves of current density versus potential showed fair reproducibility, with great differences between some of the alloys, showing a clear relationship to nobility or passivity of the alloy. There were marked differences between the results obtained in artificial saliva and in sodium sulfide solution, while addition of organic components to the artificial saliva only had a minor effect. The potentiodynamic polarization corrosion test supplies detailed information such as anodic charge, and open circuit, rupture, and passivation potential. Furthermore, it indicates the passive range and sensitivity to pitting corrosion. These are all useful when evaluating the corrosion properties of a dental alloy. An analysis of variance of the results in this study showed that possible differences between the alloys were clearly detectable with this method. However, for alloys releasing non-ionic products during corrosion/degradation, the method may be inappropriate. It is thus concluded that the method appears applicable as an in vitro corrosion test for most dental alloys, with the possible exception of amalgams.

Analysis of Variance↗

Neural network computer simulation of medical aerosols.

Preliminary investigations have been conducted to assess the potential for using artificial neural networks to simulate aerosol behaviour, with a view to employing this type of methodology in the evaluation and design of pulmonary drug-delivery systems. Details are presented of the general purpose software developed for these tasks; it implements a feed-forward back-propagation algorithm with weight decay and connection pruning, the user having complete run-time control of the network architecture and mode of training. A series of exploratory investigations is then reported in which different network structures and training strategies are assessed in terms of their ability to simulate known patterns of fluid flow in simple model systems. The first of these involves simulations of cellular automata-generated data for fluid flow through a partially obstructed two-dimensional pipe. The artificial neural networks are shown to be highly successful in simulating the behaviour of this simple linear system, but with important provisos relating to the information content of the training data and the criteria used to judge when the network is properly trained. A second set of investigations is then reported in which similar networks are used to simulate patterns of fluid flow through aerosol generation devices, using training data furnished through rigorous computational fluid dynamics modelling. These more complex three-dimensional systems are modelled with equal success. It is concluded that carefully tailored, well trained networks could provide valuable tools not just for predicting but also for analysing the spatial dynamics of pharmaceutical aerosols.

Aerosols↗

Performance of a commercial optical CT scanner and polymer gel dosimeters for 3-D dose verification.

Performance analysis of a commercial three-dimensional (3-D) dose mapping system based on optical CT scanning of polymer gels is presented. The system consists of BANG 3 polymer gels (MGS Research, Inc., Madison, CT), OCTOPUS laser CT scanner (MGS Research, Inc., Madison, CT), and an in-house developed software for optical CT image reconstruction and 3-D dose distribution comparison between the gel, film measurements and the radiation therapy treatment plans. Various sources of image noise (digitization, electronic, optical, and mechanical) generated by the scanner as well as optical uniformity of the polymer gel are analyzed. The performance of the scanner is further evaluated in terms of the reproducibility of the data acquisition process, the uncertainties at different levels of reconstructed optical density per unit length and the effects of scanning parameters. It is demonstrated that for BANG 3 gel phantoms held in cylindrical plastic containers, the relative dose distribution can be reproduced by the scanner with an overall uncertainty of about 3% within approximately 75% of the radius of the container. In regions located closer to the container wall, however, the scanner generates erroneous optical density values that arise from the reflection and refraction of the laser rays at the interface between the gel and the container. The analysis of the accuracy of the polymer gel dosimeter is exemplified by the comparison of the gel/OCT-derived dose distributions with those from film measurements and a commercial treatment planning system (Cadplan, Varian Corporation, Palo Alto, CA) for a 6 cm x 6 cm single field of 6 MV x rays and a 3-D conformal radiotherapy (3DCRT) plan. The gel measurements agree with the treatment plans and the film measurements within the "3%-or-2 mm" criterion throughout the usable, artifact-free central region of the gel volume. Discrepancies among the three data sets are analyzed.

Equipment Design↗

ROC study of the effect of stereoscopic imaging on assessment of breast lesions.

An observer performance study was conducted to evaluate the usefulness of assessing breast lesion characteristics with stereomammography. Stereoscopic image pairs of 158 breast biopsy tissue specimens were acquired with a GE Senographe 2000D full field digital mammography system using a 1.8x magnification geometry. A phantom-shift method equivalent to a stereo shift angle of +/- 3 degrees relative to a central axis perpendicular to the detector was used. For each specimen, two pairs of stereo images were taken at approximately orthogonal orientations. The specimens contained either a mass, microcalcifications, both, or normal tissue. Based on pathological analysis, 39.9% of the specimens were found to contain malignancy. The digital specimen radiographs were displayed on a high resolution MegaScan CRT monitor driven by a DOME stereo display board using in-house developed software. Five MQSA radiologists participated as observers. Each observer read the 316 specimen stereo image pairs in a randomized order. For each case, the observer first read the monoscopic image and entered his/her confidence ratings on the presence of microcalcifications and/or masses, margin status, BI-RADS assessment, and the likelihood of malignancy. The corresponding stereoscopic images were then displayed on the same monitor and were viewed through stereoscopic LCD glasses. The observer was free to change the ratings in every category after stereoscopic reading. The ratings of the observers were analyzed by ROC methodology. For the 5 MQSA radiologists, the average Az value for estimation of the likelihood of malignancy of the lesions improved from 0.70 for monoscopic reading to 0.72 (p=0.04) after stereoscopic reading, and the average Az value for the presence of microcalcifications improved from 0.95 to 0.96 (p=0.02). The Az value for the presence of masses improved from 0.80 to 0.82 after stereoscopic reading, but the difference fell short of statistical significance (p=0.08). The visual assessment of margin clearance was found to have very low correlation with microscopic analysis with or without stereoscopic reading. This study demonstrates the potential of using stereomammography to improve the detection and characterization of mammographic lesions.

Biopsy↗

Development and application of a real-time monitoring and feedback system for deep inspiration breath hold based on external marker tracking.

Respiration can cause tumor movements in thoracic regions of up to 3 cm. To minimize motion effects several approaches, such as gating and deep inspiration breath hold (DIBH), are still under development. The goal of our study was to develop and evaluate a noninvasive system for gated DIBH (GDIBH) based on external markers. DIBH monitoring was based on an infrared tracking system and an in-house-developed software. The in-house software provided the breathing curve in real time and was used as on-line information for a prototype of a feedback device. Reproducibility and stability of the breath holds were evaluated without and with feedback. Thirty-five patients undergoing stereotactic body radiotherapy (SBRT) performed DIBH maneuvers after each treatment. For 16 patients dynamic imaging sequences on a multislice CT were used to determine the correlation between tumor and external markers. The relative reproducibility of DIBH maneuvers was improved with the feedback device (74.5% +/- 17.1% without versus 93.0% +/- 4.4% with feedback). The correlation between tumor and marker was good (Pearson correlation coefficient 0.83 +/- 0.17). The regression slopes showed great intersubject variability but on average the internal margin in a DIBH treatment situation could be theoretically reduced by 3 mm with the feedback device. DIBH monitoring could be realized in a noninvasive manner through external marker tracking. We conclude that reduction of internal margins can be achieved with a feedback system but should be performed with great care due to the individual behavior of target motion.

Artifacts↗

CT-based simulation with laser patient marking.

A CT-based simulator has been assembled based on a commercial CT scanner, virtual simulation software developed at the University of North Carolina and a laser drawing device to transfer the radiation portals from the virtual simulator to the patient. The simulation process can be completed in approximately 1 h; under most cases, the treatment portals can be designed and the patient marked in one session. The device has an inherent accuracy of +/- 1 mm. The portal projection accuracy in clinical cases is observed to be better than 2 mm.

Computer Simulation↗

Trainable rule-based algorithm for the measurement of joint space width in digital radiographic images of the knee.

The progression of osteoarthritis (OA) can be monitored by measuring the minimum joint space width (mJSW) between the edges of the femoral condyle and the tibial plateau on radiographs of the knee. This is generally performed by a trained physician using a graduated magnifying lens and is prone to the subjectivity and variation associated with observer measurement. We have developed software that performs this measurement automatically on digitized radiographs. The test data consisted of 180 digitized radiographs of the knee (90 duplicate acquisitions) from 18 normal (nonarthritic) subjects and 38 images from 10 subjects with OA. These were digitized and manually cropped so that the images were free of nonanatomical structures and the knee was approximately centered. The software first determined the edge of the femoral condyle on 400 microm pixel subsampled images. Contours marking the location of the tibial plateau in the medial compartment were found on 100 microm images using the femoral edge as a reference. The algorithm was trained using an independent but similar data set and using a jackknife approach with the test data. The results were compared to contours drawn by a trained reader and the duplicate acquisitions were used to measure the reproducibility of the mJSW measurement. The reproducibility was 0.16 mm and 0.18 mm for normal and osteoarthritic knees, respectively, representing an improvement of approximately a factor of 2 over manual measurement. The algorithm also showed excellent agreement with the hand-drawn contours and with mJSW determined by the manual method.

Algorithms↗

Dugong (Dugong dugon) vocalization patterns recorded by automatic underwater sound monitoring systems.

To quantitatively examine the diurnal, or tidal, effects on dugong behavior, we employed passive acoustic observation techniques to monitor the animals. Automatic underwater sound monitoring systems for dugongs (AUSOMS-D) were deployed on the sea floor at depths of about 5 m south of Talibong Island, Thailand. The AUSOMS-D recorded underwater sound in stereo at a sampling frequency of 44.1 kHz for more than 116 consecutive hours. Dugong calls were automatically detected by newly developed software with a detection rate of 36.1% and a false alarm rate of 2.9%. In total, 3453 calls were detected during the 164 h of recording. The autocorrelation of the call rate indicated an attendance cycle of about 24 or 25 h, and the most frequent vocalizations were observed from 0300 to 0500 h. The calculated bearings of the sound sources, i.e., dugongs, were used as an indicator to track the relative numbers of dugongs during the monitoring periods.

Animals↗

Diffusion coefficient through the blood-aqueous barrier using a standard protocol.

AIMS/BACKGROUND: Comparison of the diffusion coefficient through the blood-aqueous barrier of healthy volunteers measured in different cities with identical fluorophotometers using a standardised protocol. METHODS: Healthy volunteers aged between 20 and 70 years were studied in seven European cities. The fluorescein concentration in the anterior segment of each eye was measured with a commercial scanning fluorophotometer 30 and 40 minutes after intravenous fluorescein. The decay of non-protein bound fluorescein concentration in blood plasma was determined with the use of three blood samples taken at 7, 15, and 55 minutes after injection. The diffusion coefficient through the blood-aqueous barrier was calculated from the ratio between the fluorescein concentration in the anterior chamber and the time integral of non-protein bound fluorescein concentration in plasma using specially developed software. RESULTS: The mean values of the diffusion coefficient (SD) (X10(-4) min-1) were 4.76 (1.51) (n = 20, Brussels), 5.48 (2.33) (n = 17, Coimbra), 3.47 (2.09) (n = 12, Cologne), 6.09 (2.77) (n = 21, Frankfurt), 3.85 (1.59) (n = 11, Ghent), 4.99 (1.69) (n = 23, Leiden), and 4.87 (1.05) (n = 20, Madrid). The values between centres were similar (Kruskal-Wallis test p > 0.05) except for Cologne and Frankfurt (p = 0.013). No differences were found when repeating measurements (four centres, interval time 1-8 months, Wilcoxon paired test p > 0.39). CONCLUSION: The diffusion coefficients had similar values and standard deviations. The concerted action demonstrated the usefulness of a standardised protocol.

Adult↗

Automated, real time extraction of fundus images from slit lamp fundus biomicroscope video image sequences.

AIMS: Slit lamp fundus biomicroscopy allows for high magnification, stereoscopic diagnosis, and treatment of macular diseases. Variable contrast, narrow field of view, and specular reflections arising from the cornea, sclera, and examining lens reduce image quality; these images are of limited clinical utility for diagnosis, treatment planning, and photodocumentation when compared with fundus camera images. Algorithms are being developed to segment fundus imagery from slit lamp biomicroscopic video image sequences in order to improve clinical utility. METHODS: Video fundus image sequences of human volunteers were acquired with a video equipped, Nikon NS-1V slit lamp biomicroscope. Custom developed software identified specular reflections based on brightness and colour content, and extracted the illuminated fundus image based on colour image analysis and size constraints. RESULTS: In five subjects with variable image quality, the approach allowed for automatic, robust, accurate extraction of that portion of the video image corresponding to the illuminated portion of the fundus. Non-real time analysis allowed for fundus image segmentation for each frame of the image sequence. In real time, segmentation occurs at 2 Hz, and improvements are being implemented for video rate performance. CONCLUSIONS: Computer vision algorithms allow for real time extraction of fundus imagery from marginal quality, slit lamp fundus biomicroscope image sequences.

Algorithms↗

A fast and sensitive algorithm for aligning ESTs to the human genome.

There is a pressing need to align the growing set of expressed sequence tags (ESTs) with the newly sequenced human genome. However, the problem is complicated by the exon/intron structure of eukaryotic genes misread nucleotides in ESTs, and the millions of repetitive sequences in genomic sequences. To solve this problem, algorithms that use dynamic programming have been proposed. In reality, however, these algorithms require an enormous amount of processing time. In an effort to improve the computational efficiency of these classical DP algorithms, we developed software that fully utilizes lookup-tables to detect the start- and endpoints of an EST within a given DNA sequence efficiently, and subsequently promptly identify exons and introns. In addition, the locations of all splice sites must be calculated correctly with high sensitivity and accuracy, while retaining high computational efficiency. This goal is hard to accomplish in practice, due to misread nucleotides in ESTs and repetitive sequences in the genome. Nevertheless, we present two heuristics that effectively settle this issue. Experimental results confirm that our technique improves the overall computation time by orders of magnitude compared with common tools, such as SIM4 and BLAT, and simultaneously attains high sensitivity and accuracy against a clean dataset of documented genes.

Algorithms↗

Automated identification of single nucleotide polymorphisms from sequencing data.

The single nucleotide polymorphism (SNP) is the difference of the DNA sequence between individuals and provides abundant information about genetic variation. Large scale discovery of high frequency SNPs is being undertaken using various methods. However, the publicly available SNP data sometimes need to be verified. If only a particular gene locus is concerned, locus-specific polymerase chain reaction amplification may be useful. Problem of this method is that the secondary peak has to be measured. We have analyzed trace data from conventional sequencing equipment and found an applicable rule to discern SNPs from noise. The rule is applied to multiply aligned sequences with a trace and the peak height of the traces are compared between samples. We have developed software that integrates this function to automatically identify SNPs. The software works accurately for high quality sequences and also can detect SNPs in low quality sequences. Further, it can determine allele frequency, display this information as a bar graph and assign corresponding nucleotide combinations. It is also designed for a person to verify and edit sequences easily on the screen. It is very useful for identifying de novo SNPs in a DNA fragment of interest.

Algorithms↗

Statistical measures of the structure of genomic sequences: entropy, complexity, and position information.

Identifying regions of DNA with extreme statistical characteristics is an important aspect of the structural analysis of complete genomes. Linguistic methods, mainly based on estimating word frequency, can be used for this as they allow for the delineation of regions of low complexity. Low complexity may be due to biased nucleotide composition, by tandem- or dispersed repeats, by palindrome-hairpin structures, as well as by a combination of all these features. We developed software tools in which various numerical measures of text complexity are implemented, including combinatorial and linguistic ones. We also added Hurst exponent estimate to the software to measure dependencies in DNA sequences. By applying these tools to various functional genomic regions, we demonstrate that the complexity of introns and regulatory regions is lower than that of coding regions, whilst Hurst exponent is larger. Further analysis of promoter sequences revealed that the lower complexity of these regions is associated with long-range correlations caused by transcription factor binding sites.

Algorithms↗

Methods for improving regression analysis for skewed continuous or counted responses.

Standard inference procedures for regression analysis make assumptions that are rarely satisfied in practice. Adjustments must be made to insure the validity of statistical inference. These adjustments, known for many years, are used routinely by some health researchers but not by others. We review some of these methods and give an example of their use in a health services study for a continuous and a count outcome. For the continuous outcome, we describe re-transformation using the smear factor, accounting for missing cases via multiple imputation and attrition weights and improving results with bootstrap methods. For the count outcome, we describe zero inflated Poisson and negative binomial models and the two-part model to account for overabundance of zero values. Recent advances in computing and software development have produced user-friendly computer programs that enable the data analyst to improve prediction and inference based on regression analysis.

Data Interpretation, Statistical↗