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PubMed2000

On the genealogy of a sample of neutral rare alleles.

This paper concerns the genealogical structure of a sample of chromosomes sharing a neutral rare allele. We suppose that the mutation giving rise to the allele has only happened once in the history of the entire population, and that the allele is of known frequency q in the population. Within a coalescent framework C. Wiuf and P. Donnelly (1999, Theor. Popul. Biol. 56, 183-201) derived an exact analysis of the conditional genealogy but it is inconvenient for applications. Here, we develop an approximation to the exact distribution of the conditional genealogy, including an approximation to the distribution of the time at which the mutation arose. The approximations are accurate for frequencies q<5-10%. In addition, a simple and fast simulation scheme is constructed. We consider a demography parameterized by a d-dimensional vector alpha=(alpha(1), em leader, alpha(d)). It is shown that the conditional genealogy and the age of the mutation have distributions that depend on a=qalpha and q only, and that the effect of q is a linear scaling of times in the genealogy; if q is doubled, the lengths of all branches in the genealogy are doubled. The theory is exemplified in two different demographies of some interest in the study of human evolution: (1) a population of constant size and (2) a population of exponentially decreasing size (going backward in time).

Algorithms↗

PubMedDate not supplied

OP or not OP: the medical challenge at the chemical terrorism scene.

Since the 1995 Tokyo subway sarin attack, terrorist attacks involving weapons of mass destruction or other industrial chemicals present worldwide security and health concerns. On-scene medical triage and treatment in such events is crucial to save as many lives as possible and minimize the deleterious effects of the toxic agent involved. Since there are many chemicals that can be used as potential terrorist weapons, the medical challenge for the emergency medical services (EMS) is a combination of: (1) recognizing that a chemical terrorist attack (non-conventional) has occurred; and (2) identifying the toxic agent followed by proper antidotal treatment. The latter must be done as quickly as possible, preferably on-scene. The most valuable decision at this stage should be whether the agent is organophosphate (OP) or not OP, based on clinical findings observed by pre-trained, first responders. This decision is crucial, since only OP intoxication has readily available, rapidly acting, onscene, specific agents such as atropine and one of the oximes, preferably administered using autoinjectors. Due to the lack of a specific antidote, exposure to other agents (such as industrial chemicals, e.g., chlorine, bromide, or ammonia) should be treated on-scene symptomatically with non-specific measures, such as decontamination and supportive treatment. This paper proposes an algorithm as a cognitive framework for the medical teams on-scene. This algorithm should be part of the medical team's training for preparedness for chemical terrorist attacks, and the team should be trained to use it in drills. Implementing this path of thinking should improve the medical outcome of such an event.

Chemical Warfare↗

PubMed2002

Joint linkage and linkage disequilibrium mapping of quantitative trait loci in natural populations.

Linkage analysis and allelic association (also referred to as linkage disequilibrium) studies are two major approaches for mapping genes that control simple or complex traits in plants, animals, and humans. But these two approaches have limited utility when used alone, because they use only part of the information that is available for a mapping population. More recently, a new mapping strategy has been designed to integrate the advantages of linkage analysis and linkage disequilibrium analysis for genome mapping in outcrossing populations. The new strategy makes use of a random sample from a panmictic population and the open-pollinated progeny of the sample. In this article, we extend the new strategy to map quantitative trait loci (QTL), using molecular markers within the EM-implemented maximum-likelihood framework. The most significant advantage of this extension is that both linkage and linkage disequilibrium between a marker and QTL can be estimated simultaneously, thus increasing the efficiency and effectiveness of genome mapping for recalcitrant outcrossing species. Simulation studies are performed to test the statistical properties of the MLEs of genetic and genomic parameters including QTL allele frequency, QTL effects, QTL position, and the linkage disequilibrium of the QTL and a marker. The potential utility of our mapping strategy is discussed.

Algorithms↗

PubMed2002

Ca(2+)-induced movement of tropomyosin in skeletal muscle thin filaments observed by multi-site FRET.

To obtain information on Ca(2+)-induced tropomyosin (Tm) movement in Ca(2+)-regulated muscle thin filaments, frequency-domain fluorescence energy transfer data were collected between 5-(2-iodoacetyl-amino-ethyl-amino)naphthalene-1-sulfonic acid at Cys-190 of Tm and phalloidin-tetramethylrhodamine B isothiocyanate bound to F-actin. Two models were used to fit the experimental data: an atomic coordinate (AC) model coupled with a search algorithm that varies the position and orientation of Tm on F-actin, and a double Gaussian distance distribution (DD) model. The AC model showed that little or no change in transfer efficiency is to be expected between different sites on F-actin and Tm if Ca(2+) causes azimuthal movement of Tm of the magnitude suggested by structural data (C. Xu, R. Craig, L. Tobacman, R. Horowitz, and W. Lehman. 1999. Biophys. J. 77:985-992). However, Ca(2+) produced a small but significant change in our phase/modulation versus frequency data, showing that changes in lifetime decay can be detected even when a change of the steady-state transfer efficiency is very small. A change in Tm azimuthal position of 17 on the actin filament obtained with the AC model indicates that solution data are in reasonable agreement with EM image reconstruction data. In addition, the data indicate that Tm also appears to rotate about its axis, resulting in a rolling motion over the F-actin surface. The DD model showed that the distance from one of the two chains of Tm to F-actin was mainly affected, further verifying that Ca(2+) causes Tm to roll over the F-actin surface. The width of the distance distributions indicated that the position of Tm in absence and in presence of Ca(2+) is well defined with appreciable local flexibility.

Adenosine Triphosphatases↗

PubMed1992

A personal computer based implementation of the maximum-likelihood method of analysis of electron microscope autoradiographs.

The maximum-likelihood (ML) method for the quantitative analysis of electron-microscopic autoradiographs has been shown to be substantially superior to the conventional crossfire (CF) method. It can generate reliable and accurate tracer concentration estimates with far fewer micrographs and produce valid estimates even at counts low enough to preclude the use of the crossfire method while eliminating the need for special ad hoc treatment of narrow membranous structures as well as the secondary verification of the tracer concentration estimates. Despite these significant advantages, the large computational requirements of the ML method has to date hampered its widespread use. In this paper, we present a new line-integration method that allows us to reduce the computational requirements of the ML method to a point where it becomes feasible to implement it on a small computer system of the type typically available to a laboratory user of EM autoradiography. We present the complete line-integration method for the particular case of EM autoradiography with tritium, and show how it can be adapted to other isotopes. We have constructed a software package that implements the complete maximum-likelihood method on the IBM PC class of machines using our line-integration method. Features of this software package which are of particular importance to the research community are device independence, which makes it usable with a large variety of currently available laboratory equipment, and easy portability of the software and data between different computer systems.

Algorithms↗

PubMedDate not supplied

RF hyperthermia array modelling; validation by means of measured EM-field distributions.

The accuracy of a hyperthermia treatment simulation determines its role in prospective treatment planning and dosimetry for the individual patient. Of importance are (1) the accuracy of the numerical simulation method, and (2) the numerical description of the hyperthermia treatment system. The accuracy of the numerical method is generally determined by analysis of a problem that is analytically solvable. The validity of the description of the hyperthermia system is to be investigated by comparison of the simulated and measured EM-field amplitude and phase of the clinical operational hyperthermia system. In this paper, the numerical description of the AMC-4 waveguide phased array for which treatment planning is performed by the Weak Form of the Conjugate Gradient FFT method is investigated. The accuracy of the description is analysed for four set-ups, varying the bolus size and the number of waveguides attached to a phantom. The comparison of experimental and numerical data has demonstrated the ability of the Weak Formulation of the Conjugate Gradient FFT method to predict the EM-field of the AMC-4 waveguide array hyperthermia system, including effects due to bolus size variations. However, based on the comparison of the measured EM-field distributions and those obtained from simulations, the accuracy of the planning system is found to be insufficient for quantitative SAR dosimetry for individual patients. Qualitative SAR dosimetry can be applied in cases where the accuracy is of minor importance, e.g. for the retrospective analysis of problematic hyperthermia treatments. Prospective applications of the treatment planning system include the (qualitative) determination/simulation of a set of starting points giving a 'close to optimal' amplitude and phase setting, the prediction of possible problem areas and the analysis of the performance of new/improved hyperthermia devices.

Algorithms↗

PubMed2004

Reuse of imputed data in microarray analysis increases imputation efficiency.

BACKGROUND: The imputation of missing values is necessary for the efficient use of DNA microarray data, because many clustering algorithms and some statistical analysis require a complete data set. A few imputation methods for DNA microarray data have been introduced, but the efficiency of the methods was low and the validity of imputed values in these methods had not been fully checked. RESULTS: We developed a new cluster-based imputation method called sequential K-nearest neighbor (SKNN) method. This imputes the missing values sequentially from the gene having least missing values, and uses the imputed values for the later imputation. Although it uses the imputed values, the efficiency of this new method is greatly improved in its accuracy and computational complexity over the conventional KNN-based method and other methods based on maximum likelihood estimation. The performance of SKNN was in particular higher than other imputation methods for the data with high missing rates and large number of experiments. Application of Expectation Maximization (EM) to the SKNN method improved the accuracy, but increased computational time proportional to the number of iterations. The Multiple Imputation (MI) method, which is well known but not applied previously to microarray data, showed a similarly high accuracy as the SKNN method, with slightly higher dependency on the types of data sets. CONCLUSIONS: Sequential reuse of imputed data in KNN-based imputation greatly increases the efficiency of imputation. The SKNN method should be practically useful to save the data of some microarray experiments which have high amounts of missing entries. The SKNN method generates reliable imputed values which can be used for further cluster-based analysis of microarray data.

Efficiency, Organizational↗

PubMedDate not supplied

Robust filtering and particle picking in micrograph images towards 3D reconstruction of purified proteins with cryo-electron microscopy.

In order to make a high resolution model of macromolecular structures from cryo-electron microscope (cryo-EM) raw images one has to be precise at every processing step from particle picking to 3D image reconstruction. In this paper we propose a collection of novel methods for filtering cryo-EM images and for automatic picking of particles. These methods have been developed for two cases: (1) when particles can be identified and (2) when particle are not distinguishable. The advantages of these methods are demonstrated in standard purified protein samples and to generalize them we do not use any ad hoc presumption of the geometry of the particle projections. We have also suggested a filtering method to increase the signal-to-noise (S/N) ratio which has proved to be useful for other levels of reconstruction, i.e., finding orientations and 3D model reconstruction.

Algorithms↗

PubMed2006

Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro.

Polymerization of the amyloid beta-peptide (Abeta) has been identified as one of the major characteristics of Alzheimer's disease (AD). Thus, finding molecules to prevent the aggregation of Abeta could be of therapeutic value in AD. We describe an original routine in vitro assay to search for inhibitors of Abeta(25-35) fibril formation which uses UV-visible measurements and electron microscopy (EM). In particular, this routine assay was used to examine the effects of stilbenes, a well-known polyphenol class, as inhibitors of Abeta fibril formation. The inhibitory properties of resveratrol (RES), piceid (PIC), resveratrol diglucoside (DIG), piceatannol (PIA), astringine (AST), and viniferin (VIN) were characterized and compared. RES and PIC effectively and dose-dependently inhibited Abeta polymerization while other polyphenols exerted less inhibition. Although the mechanism of anti-amyloidogenic activity is still unknown, these results support the hypothesis that stilbenes could be of therapeutic value in AD.

Algorithms↗

PubMed1988

Factors contributing to paramedic onscene time during evaluation and management of blunt trauma.

Prehospital patient management decisions are complex because the traumatized patient population is heterogeneous with respect to demographics, mechanism of injury, physiological response to injury, and time from injury to medical care. One hundred and nine blunt trauma patient evaluations by paramedics in a county-wide semirural emergency medical services (EMS) system were analyzed to determine paramedic time on the scene and the factors that might influence onscene time. Onscene time linearly correlated with a prolonged transport time. Hemodynamic and respiratory dysfunction were also associated with increased onscene time. Mean onscene time was not significantly different between high (greater than 13) and low (less than or equal to 13) trauma score (TS) groups, although patients with low TS did receive more interventions (more intravenous lines, more frequent intubation, and more frequent pneumatic antishock garment use). Similar results were found when high (greater than 10) and low (less than or equal to 10) Glasgow Coma Scale (GCS) groups were compared. The correlation of emergency department TS with initial prehospital TS and onscene time demonstrated a small improvement in TS with increasing onscene time for the patient with an initial TS greater than or equal to 13. However, patient groups with either a low TS or a low GCS score showed no significant improvement in TS with increasing onscene time. Without a strict management algorithm, paramedics use a variety of cues to guide their actions during the onscene management of blunt trauma. Future studies should address the impact of strict management algorithms on onscene time and ultimate patient outcome.

Adolescent↗

PubMed2005

An incremental EM-based learning approach for on-line prediction of hospital resource utilization.

OBJECTIVE: Inpatient length of stay (LOS) is an important measure of hospital activity, health care resource consumption, and patient acuity. This research work aims at developing an incremental expectation maximization (EM) based learning approach on mixture of experts (ME) system for on-line prediction of LOS. The use of a batch-mode learning process in most existing artificial neural networks to predict LOS is unrealistic, as the data become available over time and their pattern change dynamically. In contrast, an on-line process is capable of providing an output whenever a new datum becomes available. This on-the-spot information is therefore more useful and practical for making decisions, especially when one deals with a tremendous amount of data. METHODS AND MATERIAL: The proposed approach is illustrated using a real example of gastroenteritis LOS data. The data set was extracted from a retrospective cohort study on all infants born in 1995-1997 and their subsequent admissions for gastroenteritis. The total number of admissions in this data set was n = 692. Linked hospitalization records of the cohort were retrieved retrospectively to derive the outcome measure, patient demographics, and associated co-morbidities information. A comparative study of the incremental learning and the batch-mode learning algorithms is considered. The performances of the learning algorithms are compared based on the mean absolute difference (MAD) between the predictions and the actual LOS, and the proportion of predictions with MAD < or = 1 day (Prop(MAD < or = 1)). The significance of the comparison is assessed through a regression analysis. RESULTS: The incremental learning algorithm provides better on-line prediction of LOS when the system has gained sufficient training from more examples (MAD = 1.77 days and Prop(MAD < or = 1) = 54.3%), compared to that using the batch-mode learning. The regression analysis indicates a significant decrease of MAD (p-value = 0.063) and a significant (p-value = 0.044) increase of Prop(MAD < or = 1) with the incremental learning algorithm. CONCLUSIONS: The incremental learning feature and the self-adaptive model-selection ability of the ME network enhance its effective adaptation to non-stationary LOS data. It is demonstrated that the incremental learning algorithm outperforms the batch-mode algorithm in the on-line prediction of LOS.

Algorithms↗

PubMed2004

pO2 and regional blood flow in a rabbit model of limb ischemia.

Oxygen tension (pO2) in muscles and regional blood flow were measured in a rabbit model of limb ischemia. pO2 was measured repetitively by EPR oximetry with EMS char in four different muscle groups in the same animals. Blood flow in the same muscles at several time points was measured using microspheres. A linear mixed effects model was developed to analyze the data on pO2 and blood flow. The results suggest that while under normal conditions pO2 in muscles does not depend significantly on blood flow, immediately after arterial occlusion pO2 correlates linearly with blood flow. Within two weeks of occlusion the pO2 is recovered to 45% of baseline. This study demonstrates, for the first time, the applicability of EPR oximetry in animals larger than rodents.

Algorithms↗

PubMed2001

Production of griseofulvin nanoparticles using supercritical CO(2) antisolvent with enhanced mass transfer.

Griseofulvin (GF) is a poor water soluble, antifungal agent. The bioavailability of the drug and its absorption from the gastrointestinal tract can be greatly improved by particle size reduction. In this work, supercritical antisolvent precipitation with enhanced mass transfer (SAS-EM) has been proposed for the production of GF nanoparticles. SAS-EM is a modification of the currently existing supercritical antisolvent (SAS) precipitation technique and also utilizes supercritical CO(2) as the antisolvent. In SAS-EM however, the solution jet is deflected by a surface vibrating at an ultrasonic frequency that atomizes the jet into small micro droplets. Further, the ultrasound field generated by the vibrating surface inside the supercritical media enhances mass transfer and prevents agglomeration due to increased mixing. GF nanoparticles of different sizes and morphologies have been obtained by varying the vibration intensity of the deflecting surface, which in turn is adjusted by changing the power supply to the attached ultrasound transducer. GF nanoparticles as low as 130 nm in size have been obtained corresponding to a power supply of 180 W. The effect of using different solvents on the size and morphology of the particles has also been studied.

Algorithms↗

PubMed1999

Estimation of the depth-dependent component of the point spread function of SPECT.

The point spread function (PSF) of a gamma camera describes the photon count density distribution at the detector surface when a point source is imaged. Knowledge of the PSF is important for computer simulation and accurate image reconstruction of single photon emission computed tomography (SPECT) images. To reduce the number of measurements required for PSF characterization and the amount of computer memory to store PSF tables, and to enable generalization of the PSF to different collimator-to-source distances, the PSF may be modeled as the two-dimensional (2D) convolution of the depth-dependent component which is free of detector blurring (PSF(ideal)) and the distance-dependent detector response. Owing to limitations imposed by the radioactive strength of point sources, extended sources have to be used for measurements. Therefore, if PSF(ideal) is estimated from measured responses, corrections have to be made for both the detector blurring and for the extent of the source. In this paper, an approach based on maximum likelihood expectation-maximization (ML-EM) is used to estimate PSF(ideal). In addition, a practical measurement procedure which avoids problems associated with commonly used line-source measurements is proposed. To decrease noise and to prevent nonphysical solutions, shape constraints are applied during the estimation of PSF(ideal). The estimates are generalized to depths other than those which have been measured and are incorporated in a SPECT simulator. The method is validated for Tc-99m and T1-201 by means of measurements on physical phantoms. The corrected responses have the desired shapes and simulated responses closely resemble measured responses. The proposed methodology may, consequently, serve as a basis for accurate three-dimensional (3D) SPECT reconstruction.

Algorithms↗

PubMedDate not supplied

A binary segmentation approach for boxing ribosome particles in cryo EM micrographs.

Three-dimensional reconstruction of ribosome particles from electron micrographs requires selection of many single-particle images. Roughly 100,000 particles are required to achieve approximately 10 A resolution. Manual selection of particles, by visual observation of the micrographs on a computer screen, is recognized as a bottleneck in automated single-particle reconstruction. This paper describes an efficient approach for automated boxing of ribosome particles in micrographs. Use of a fast, anisotropic non-linear reaction-diffusion method to pre-process micrographs and rank-leveling to enhance the contrast between particles and the background, followed by binary and morphological segmentation constitute the core of this technique. Modifying the shape of the particles to facilitate segmentation of individual particles within clusters and boxing the isolated particles is successfully attempted. Tests on a limited number of micrographs have shown that over 80% success is achieved in automatic particle picking.

Algorithms↗

PubMed2004

Transfer function restoration in 3D electron microscopy via iterative data refinement.

Three-dimensional electron microscopy (3D-EM) is a powerful tool for visualizing complex biological systems. As with any other imaging device, the electron microscope introduces a transfer function (called in this field the contrast transfer function, CTF) into the image acquisition process that modulates the various frequencies of the signal. Thus, the 3D reconstructions performed with these CTF-affected projections are also affected by an implicit 3D transfer function. For high-resolution electron microscopy, the effect of the CTF is quite dramatic and limits severely the achievable resolution. In this work we make use of the iterative data refinement (IDR) technique to ameliorate the effect of the CTF. It is demonstrated that the approach can be successfully applied to noisy data.

Algorithms↗

PubMedDate not supplied

Using geographic information systems to evaluate cardiac arrest survival.

OBJECTIVE: To evaluate cardiac arrest survival using geographical information systems (GIS) methodology. METHODS: Patient data were obtained from a fire district Utstein-style adult cardiac arrest registry that also included address data. All incident locations were geocoded and fire station first-due areas were mapped by using the new computer-aided dispatch geographic data. Retrospective assignment of first-due versus second-due fire response unit was done by using a GIS "point-in-polygon" algorithm Survival to hospital admission was the primary outcome measure for incidents responded to by first-due versus second-due apparatus controlling for other potential predictors of survival using logistic regression. Cluster analysis was also performed to evaluate potential areas of high or low rates of survival. RESULTS: There were 461 eligible patients with an average age of 67+/-17 years, 63% were male, 53% had a witnessed arrest, bystander cardiopulmonary resuscitation was performed in 38%, bystander automatic external defibrillator (AED) Page: 1 was used in 0.01%, ventricular fibrillation or ventricular tachycardia were the presenting rhythms in 44%, the average response time was 5.5+/-2.1 minutes, and survival to hospital admission was 17%. There was no significant difference in response time between survivors (4.97 minutes) and non-survivors (5.52 minutes), (difference 0.55 minutes, 95%CI -0.08 to 1.18 min). The number of cardiac arrest calls varied from 1 to 49 for each station and the rate of second-due response varied from 0 to 19%. There was a nonsignificant association of survival to hospital admission for the first-due area cohort: odds ratio 0.70, 95% CI 0.38-1.29. CONCLUSION: GIS is a new methodology for analyzing EMS incident data. It adds a spatial component of analysis to traditional statistical techniques. No spatial difference was found on patient survival in this analysis.

Aged↗

PubMed2005

Interaction of mobile phones with superficial passive metallic implants.

The dosimetry of exposure to radiofrequency (RF) electromagnetic (EM) fields of mobile phones is generally based on the specific absorption rate (SAR, W kg(-1)), which is the electromagnetic energy absorbed in the tissues per unit mass and time. In this study, numerical methods and modelling were used to estimate the effect of a passive, metallic (conducting) superficial implant on a mobile phone EM field and especially its absorption in tissues in the near field. Two basic implant models were studied: metallic pins and rings in the surface layers of the human body near the mobile phone. The aim was to find out 'the worst case scenario' with respect to energy absorption by varying different parameters such as implant location, orientation, size and adjacent tissues. Modelling and electromagnetic field calculations were carried out using commercial SEMCAD software based on the FDTD (finite difference time domain) method. The mobile phone was a 900 MHz or 1800 MHz generic phone with a quarter wave monopole antenna. A cylindrical tissue phantom models different curved sections of the human body such as limbs or a head. All the parameters studied (implant size, orientation, location, adjacent tissues and signal frequency) had a major effect on the SAR distribution and in certain cases high local EM fields arose near the implant. The SAR values increased most when the implant was on the skin and had a resonance length or diameter, i.e. about a third of the wavelength in tissues. The local peak SAR values increased even by a factor of 400-700 due to a pin or a ring. These highest values were reached in a limited volume close to the implant surface in almost all the studied cases. In contrast, without the implant the highest SAR values were generally reached on the skin surface. Mass averaged SAR(1 g) and SAR(10 g) values increased due to the implant even by a factor of 3 and 2, respectively. However, at typical power levels of mobile phones the enhancement is unlikely to be problematic.

Adipose Tissue↗