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Accuracy and precision of the CellForm-Human automated sperm morphometry instrument.

OBJECTIVE: To evaluate the accuracy and precision of the CellForm-Human (CFH) automated sperm morphometry instrument (Motion Analysis Corp., Santa Rosa, CA). SETTING: Clinical and research andrology and in vitro fertilization laboratories. PATIENTS: Individuals undergoing semen evaluation and infertility work-up. RESULTS: Coefficients of variation for repeated measures of the same sperm were 1%. Coefficients of variation of normal sperm measurements were 7.4% to 12.8%, depending on the measure. Of the objects recognized as sperm by the instrument, 6.8% were debris; hence, the sperm recognition algorithms need improvement. Mean values for all CFH measures of normal sperm from specimens clinically classified as having predominantly normal, tapered, or amorphous sperm were not different; hence, the morphometry of normal sperm from normal specimens was similar to normal sperm from specimens with two different abnormalities. The instrument classified sperm as abnormal if their length or width fell outside a critical range of values recommended by the World Health Organization. Using this method, manual and CFH classification agreed unambiguously 60% of the time. When disagreement occurred, length or width marginally exceeded the range by no more than 0.1 microns. In these cases, the technician classified sperm as normal 25% of the time and classified them as abnormal 6% of the time. Because this disagreement between methods is well below the resolution of manual methods, the overall accuracy of CFH was 91% for cell type classification. CONCLUSION: At its present stage of development, the CFH instrument exceeds the accuracy and precision of most manual approaches. With improvements in sperm recognition and type classification algorithms, it could significantly improve the reliability of morphology assays in clinical and research laboratories.

Equipment Design

Peak flow records in asthma: evaluation of an algorithm for interpretation of patterns.

The clinical value of serial measurements of peak expiratory flow (PEF) in asthma is well established, but the analysis of the PEF records is not standardized. We developed an algorithm for interpretation of PEF, based upon the characteristic features of chronic airflow limitation, and retrospectively analysed the PEF of fifty outpatients affected by non-seasonal asthma. For each patient we correlated the developed indices of evolution of PEF with, respectively, the severity of asthma (evaluated in terms of consumption of drugs), forced expiratory volume in one second and with the trend of the indices over several months. The developed indices were well correlated with the severity score and to a lesser extent to other investigated parameters. These results seem to provide a useful approach to a computerized evaluation of the results of PEF monitoring.

Adolescent

Measurements of ultrasonic fields with optical diffraction tomography.

This article describes a light diffraction technique that allows a measurement of ultrasonic pressure and phase in the cross-section of an ultrasonic beam. The light diffraction measurements are based on the Raman-Nath model of ultrasonic continuous-wave light diffraction. The diffracted light intensity can be expressed as an integration of sound pressure along the light path. This integration is analogous to the integration of the absorption coefficient in x-ray tomography. Tomography algorithms can be employed on the light measurement data to calculate the pressure and phase in a measuring plane perpendicular to the ultrasound propagation vector. The reconstruction of the measurement plane is done with an implementation of an algebraic reconstruction technique (ART). Satisfactory results are obtained with 10 projections. The measurement method is applicable up to Raman-Nath parameter values of 2.3. The experimental results are compared to miniature PVDF hydrophone measurements.

Algorithms

Echocardiographic design of a multicenter investigation of free-living elderly subjects: the Cardiovascular Health Study.

The Framingham study has shown by M-mode echocardiography that left ventricular hypertrophy is a powerful, independent predictor for the development of coronary heart disease and that increased left atrial dimension has been associated with an increased risk of stroke. No previous population-based study has evaluated the risk factor correlates and predictive value for coronary heart disease and stroke of two-dimensional and Doppler, as well as M-mode, echocardiography. The Cardiovascular Health Study is a multi-year prospective epidemiologic study of 5201 men and women older than 65 recruited from four geographic sites in the United States. The main objectives of incorporating echocardiography were to determine whether echocardiographic indices, or changes in these indices, are (1) correlated with traditional risk factors for coronary heart disease and stroke; and (2) independent predictors of morbidity and mortality for coronary heart disease and stroke. Echocardiographic measurements of interest include those related to global and segmental left ventricular systolic and diastolic structure and function and left atrial size. For each subject, a baseline echocardiogram was recorded in super-VHS tape using a standard protocol and equipment. All studies were sent to a reading center where images were digitized and measurements were made using customized computer algorithms. Calculated data and images were stored on optical disks to facilitate retrieval and future comparisons in longitudinal studies. A second echocardiogram is scheduled in year 7, with a goal of determining whether changes in cardiac anatomy or function over a 5-year period are important predictors of morbidity or mortality from coronary heart disease and stroke. Quality control measures included standardized training of echocardiography technicians and readers, technician observation by a trained echocardiographer, periodic blind duplicate readings with reader review sessions, phantom studies, and quality control adults.

Allied Health Personnel

3D PET using a conventional multislice tomograph without septa.

A conventional multislice positron emission tomography scanner was modified to operate without interplane septa to evaluate its performance in collecting and reconstructing data in a three-dimensional (3D) format, thereby significantly increasing system sensitivity. A 3D filtered backprojection algorithm was implemented and tested, using both computer simulations and phantom measurements. No artifacts were apparent in the test images, although the algorithm was shown to lead to a 11% degradation in transaxial resolution in the outer planes. Following septa removal, sensitivity was found to increase by a factor of 7 with an increase in scatter fraction from 16 to 41%. Axial resolution degraded from 6.9 to 7.7 mm full width at half maximum at the center of the field of view. The maximum count rate without septa was 2.4 x 10(5) cps, at a concentration of 0.4 microCi/ml, compared with 1.3 x 10(5) cps at 1.5 microCi/ml with septa. Brain studies were performed with volunteers using 18F-fluorodeoxyglucose, 18F-fluorodopa, and H2 15O to compare noise-equivalent count rates and qualitatively assess image quality over a wide range of imaging conditions.

Algorithms

A geometric algorithm for medical image correlations.

An automatic image correlation algorithm is discussed for the cranial region which is based on the geometric properties of the second moment tensor associated with a volume. The second moment tensor of two identical volumes represented in two different coordinate frames is evaluated to obtain the set of translations, rotations, and anisotropic scaling operators which relate the two coordinate frames. The theory is presented along with a discussion of quantitative error analysis to measure the usefulness of such an algorithm in the clinical setting.

Algorithms

Image analysis techniques for automatic evaluation of two-dimensional electrophoresis.

Techniques for automatic analysis of two-dimensional electrophoresis gels by computer-aided image analysis are described. Original gels or photographic films are scanned using a laser scanner and the files are transferred to a microcomputer. The program package first performs a compression and preevaluation of the files. Spot identification and quantification is performed by the chain code algorithm after appropriate zooming and cutting. Labeling facilitates spot identification and quantification in numerical and graphical (pseudocolor) representation on peripheral devices for camera ready output. Interpolation between measured basepoints is performed by cubic spline algorithms which are automatically switched on and off, depending on the need by the program. High speed analysis and graphic representation is achieved using fast Assembler language routines rather than high level languages. One-dimensional gels can be analyzed using the same software. Spot matching between parallel two-dimensional gels has not yet been implemented.

Electrophoresis, Gel, Two-Dimensional

Principles of morphometric grading.

Grading of the severity of lesions has increased in importance in histopathology. The simplest grading system has 2 grades. If there is variation in the measuring system, the grading will not be perfect, and there are also misgraded samples. We estimated the fraction of falsely graded cases by applying th NAG (Numerical Algorithm Group) Fortran Library. If all possible measurement values are equally probable the grades based on measurements within +/- 1 SD around the division line are false in 31.6% of cases. The corresponding figures for regions +/- 2 SD, +/- 3 SD, 1 to 2 SD, 1 to 3 SD, and 2 to 3 SD are 19.6, 13.3, 7.5, 4.2, and 0.8%, respectively. Detailed calculations were made which allowed accurate determination of the probability of a grade being false in different positions of the measurement scale. The results suggest that for diagnostic grading a borderline region should be defined (e.g. +/- 2 SD or +/- 3 SD around the division line).

Diagnostic Errors

Jitter correction: a computer algorithm for reduction of the velocity recovery function artifact.

The measurement of neuromuscular jitter in single fiber electromyography may be artifactually raised by a component of interdischarge interval (IDI)-dependent jitter caused by the velocity recovery function (VRF) in muscle fibers. We have developed a computer algorithm for on-line mathematical correction for this artifact, thus improving the reliability of neuromuscular jitter estimates. The method, based on a modeling technique, was validated using intramuscular stimulation in order to either exclude an IDI-dependent component (using regular stimulation) or to include an IDI-dependent component (using pseudorandom stimulation). In 10 normal subjects the distribution of 106 corrected jitter values obtained using voluntary activity showed no difference from the measured values. This finding implies that previously published values for normal jitter are not likely to have been influenced by the VRF effect.

Action Potentials

A new algorithm for the identification of multiple input Wiener systems.

Multiple-input Wiener systems consist of two or more linear dynamic elements, whose outputs are transformed by a multiple-input static non-linearity. Korenberg (1985) demonstrated that the linear elements of these systems can be estimated using either a first order input-output cross-covariance or a slice of the second, or higher, order input-output cross-covariance function. Korenberg's work used a multiple input LNL structure, in which the output of the static nonlinearity was then filtered by a linear dynamic system. In this paper we show that by restricting our study to the slightly simpler Wiener structure, it is possible to improve the linear subsystem estimates obtained from the measured cross-covariance functions. Three algorithms, which taken together can identify any multiple-input Wiener system, have been developed. We present the theory underlying these algorithms and detail their implementation. Simulation results are then presented which demonstrate that the algorithms are robust in the presence of output noise, and provide good estimates of the system dynamics under a wide set of conditions.

Algorithms

Real-time tracking of parameters of lung mechanics: emphasis on algorithm tuning.

We consider the problem of tracking rapid changes in the viscous and elastic properties of the respiratory system by using mouth flow and transpulmonary pressure data measured during mechanical ventilation. A recursive least-squares algorithm with adjustable compensator is used for online estimation of an R-C model of the breathing mechanics. Specific simulation experiments are presented to provide guidelines to select suitable values for the key variable, which controls the compromise between tracking ability and noise sensitivity. The results obtained confirm the critical role of the optimum tuning in relation to the noise level. Experimental results obtained from data measured on mechanically-ventilated dogs, in which respiratory distress syndrome was intravenously induced by oleic acid, demonstrate that the tuned algorithm is able to track appropriately both the viscous and elastic properties of lung mechanics. Parameter estimates are consistent with those obtained by standard and robust offline algorithms and their time course is in qualitative agreement with known physiopathological behaviour.

Airway Resistance

Variceal hemorrhage.

Figure 2 is the algorithm followed in our institution for management of acute variceal hemorrhage. A small percentage of patients who present with active variceal hemorrhage will stop bleeding after gastric lavage alone. However, most patients require an intravenous vasopressin infusion at a dose of 0.4 units per minute, preferably combined with intravenous administration of nitroglycerin. Although glypressin and somatostatin may be associated with fewer side effects than vasopressin, the superiority of these drugs remains to be determined. Whether pharmacologic therapy succeeds or fails, most patients then proceed to endoscopic sclerotherapy. Sclerotherapy may be used as a temporizing measure in preparation for elective surgery or as a long-term, definitive treatment for prevention of recurrent hemorrhage. Balloon tamponade is reserved for patients who are bleeding too rapidly for effective sclerotherapy and for sclerotherapy failures in preparation for emergency surgery. Because recurrent hemorrhage frequently occurs after balloon deflation, a more definitive treatment (surgery or endoscopic sclerotherapy) should be planned for all patients who undergo balloon tamponade. Because operative risk is unacceptably high for patients with hepatic functional decompensation secondary to variceal hemorrhage, we believe that a policy of routine emergency surgery is unwise. Rather, emergency surgical intervention is reserved for the relatively small number of patients (15 to 25 per cent) who continue to bleed after nonoperative options have failed. Shunt surgery should be considered early in the course of patients with bleeding secondary to gastric varices and portal hypertensive gastropathy, both of which respond poorly to nonoperative measures.

Algorithms

In vivo dosimetry during pelvic treatment.

High precision in vivo entrance and exit dose measurements have been performed with p-type diodes on patients during 8 MV X-ray irradiation of the pelvis, to investigate the accuracy of dose calculations in this region. Based on phantom measurements the accuracy of the p-type diode measuring system itself, i.e. the agreement with ionisation chamber dose measurements, was shown to be better than 0.7% while the reproducibility in the dose determination was 1.1%, 1.5% and 1.6% (1 S.D.) at the entrance point, isocentre and exit point, respectively, for the wedged lateral fields. Patient movement and the uncertainty in the diode position increased these values to 1.7%, 1.5% and 3.1% (1 S.D.) for dose determinations on patients. From the entrance and exit in vivo dose values the dose actually delivered to the isocentre was determined. For the anterior-posterior beams a good correspondence for most patients was observed at the entrance and exit point and at the isocentre between the in vivo and calculated dose values. For the wedged lateral beams a systematic deviation of about 3% was observed. In addition to the in vivo dose measurements phantom dose measurements have been performed to quantify the accuracy of the dose calculation algorithms including the computation of the number of monitor units. These measurements also served to quantify the effects of the actual patient on the dose delivery. The measurements showed that accurate calculation of the dose requires a separation of the head and phantom scatter contribution of the output of the treatment machine. The dependence of the wedge factor on field size, depth and source-skin-distance has also to be considered for accurate dose calculations. The effect of the patient on the dose calculation is mainly related to the actual electron densities of fat and bone structures compared to water: neglecting these densities in the dose computation could yield deviations up to 8.5% for the exit point in wedged beams. Based on these results, improvements in the dose calculation algorithms and monitor unit calculation including the use of the actual electron densities will be implemented in the treatment planning procedure.

Algorithms

A reliable potentiometric measurement of ionized calcium and pH on the ICA2 Radiometer in clinical practice.

A second generation analyser for potentiometric measurement of ionized calcium and pH (ICA2 Radiometer, Copenhagen) was tested with respect to analytical performance in two different laboratories. Newly-developed aqueous buffered solutions were used at different Ca2+ concentrations as well as biological specimens prepared from human subjects. The overall precision of ICA2 was very good: CV = 0.0-0.4% for within-run and 0.4-1.7% for day-to-day precision with protein-free solutions and CV = 0.3-0.9% for within-run precision on biological specimens. The adjusted value of Ca2+ to pH 7.40 is an analytical advantage for which the calculation is correct but the assumption made for this algorithm may limit its clinical relevance. Measurements were comparable on ICA2 when performed on either whole blood, serum or plasma. Pre-analytical conditions should be observed such as the choice of anticoagulant and anaerobic conditions. Such a reliable and accurate instrument may promote the use of ionized calcium measurement in daily clinical practice.

Calcium

Diffraction tomography using arbitrary transmitter and receiver surfaces.

The theory of diffraction tomography for two-dimensional objects within the Born approximation is presented for cases where the scattered field is measured over arbitrarily shaped boundaries surrounding the object. Reconstruction algorithms are presented for both plane wave (parallel beam) and cylindrical wave (fan beam) insonification. Special attention is devoted to cases where the measurement and source boundaries are either lines or circles. The theory and algorithms presented are shown to be readily extended to the case of three-dimensional objects.

Filtration

DESIGN: computerized optimization of experimental design for estimating Kd and Bmax in ligand binding experiments. I. Homologous and heterologous binding to one or two classes of sites.

We have developed a versatile computer program for optimization of ligand binding experiments (e.g., radioreceptor assay system for hormones, drugs, etc.). This optimization algorithm is based on an overall measure of precision of the parameter estimates (D-optimality). The program DESIGN uses an exact mathematical model of the equilibrium ligand binding system with up to two ligands binding to any number of classes of binding sites. The program produces a minimal list of the optimal ligand concentrations for use in the binding experiment. This potentially reduces the time and cost necessary to perform a binding experiment. The program allows comparison of any proposed experimental design with the D-optimal design or with assay protocols in current use. The level of nonspecific binding is regarded as an unknown parameter of the system, along with the affinity constant (Kd) and binding capacity (Bmax). Selected parameters can be fixed at constant values and thereby excluded from the optimization algorithm. Emphasis may be placed on improving the precision of a single parameter or on improving the precision of all the parameters simultaneously. We present optimal designs for several of the more commonly used assay protocols (saturation binding with a single labeled ligand, competition or displacement curve, one or two classes of binding sites), and evaluate the robustness of these designs to changes in parameter values of the underlying models. We also derive the theoretical D-optimal design for the saturation binding experiment with a homogeneous receptor class.

Binding Sites

Automated radioautographic grain counting. Correction for grain overlap.

An algorithm is described for the calculation of radioautographic cell grain count from measurements of total cell nuclear area and total grain area. This algorithm provides a statistical correction for grain overlap that is based on the solution to the occupancy problem in probability theory. This method permits the use of automated grain counting over a wide range of grain counts per cell, and extends the useful dynamic range of radioautographic grain counting to well over 200 grains/cell.

Autoradiography

Tracking time-varying properties of the systemic vascular bed.

The problem of tracking changes in viscoelastic properties of the systemic arterial bed is considered and a recursive estimation procedure, belonging to the class of output-error algorithms with adjustable compensator, is developed and discussed. By means of computer simulations, suitable values are determined for the key design variable which controls the tradeoff between tracking ability and noise sensitivity of the algorithm. In this way, the algorithm allows on-line estimation of arterial compliance, peripheral resistance, and characteristic impedance on the basis of aortic pressure and flow signals. Furthermore, the results obtained from data numerically simulated, as well as measured on a mock circulatory system, demonstrate that the dominant arterial time-constant can be tracked by the algorithm using only measurements of the aortic pressure during diastole.

Algorithms