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PubMed2005

On the slow convergence of EM and VBEM in low-noise linear models.

We analyze convergence of the expectation maximization (EM) and variational Bayes EM (VBEM) schemes for parameter estimation in noisy linear models. The analysis shows that both schemes are inefficient in the low-noise limit. The linear model with additive noise includes as special cases independent component analysis, probabilistic principal component analysis, factor analysis, and Kalman filtering. Hence, the results are relevant for many practical applications.

Algorithms↗

PubMed2005

The three-phase model of cardiac arrest as applied to ventricular fibrillation in a large, urban emergency medical services system.

BACKGROUND: Cardiac arrest is responsible for significant morbidity and mortality, with consistently poor outcomes despite the rapid availability of prehospital personnel for defibrillation attempts in patients with ventricular fibrillation (VF). Recent evidence suggests a period of cardiopulmonary resuscitation (CPR) prior to defibrillation attempts may improve outcomes in patients with moderate time since collapse (4-10 min). OBJECTIVES: To determine cardiac arrest outcomes in our community and explore the relationship between time since collapse, performance of bystander CPR, and survival. METHODS: Non-traumatic cardiac arrest data were collected prospectively over an 18-month period. Patients were excluded for: age <18 years, a "Do Not Attempt Resuscitation" (DNAR) directive, determination of a non-cardiac etiology for arrest, and an initially recorded rhythm other than VF. Patients were stratified by time since collapse (<4, 4-10, > 10 min, and unknown) and compared with regard to survival and neurological outcome. In addition, patients with and without bystander CPR were compared with regard to survival. RESULTS: : A total of 1141 adult non-traumatic cardiac arrest victims were identified over the 18-month study period. This included 272 patients with VF as the initially recorded rhythm. Of these, 185 had a suspected cardiac etiology for the arrest; survival to hospital discharge was 15% in this group, with 82% of these having a good outcome or only moderate disability. Survival was highest among patients with time since collapse of less than 4 min and decreased with increasing time since collapse. There were no survivors among patients with time since collapse greater than 10 min. Among patients with time since collapse of 4 min or longer, survival was significantly higher with the performance of bystander CPR; there was no survival advantage to bystander CPR among patients with time since collapse less than 4 min. CONCLUSIONS: The performance of bystander CPR prior to defibrillation by EMS personnel is associated with improved survival among patients with time since collapse longer than 4 min but not less than 4 min. These data are consistent with the three-phase model of cardiac arrest.

Aged↗

PubMed2003

Dressed symbolic dynamics.

A strange attractor (SA) with symmetry group G can be mapped down to an image strange attractor SA without symmetry by a smooth mapping with singularities. The image SA can be lifted to many distinct structurally stable strange attractors, each equivariant under G, all with the same image SA. If the symbolic dynamics of the image SA requires s symbols sigma(1),sigma(2), em leader,sigma(s), then |G|s symbols are required for symbolic dynamics in the covers, and there are |G|(s) distinct equivariant covers. The covers are distinguished by an index. The index is an assignment of a group operator to each symbol sigma(i):sigma(i)-->g(alpha(i)). The subgroup H subset G generated by the group operators g(alpha(i)) in the index determines how many disconnected components (|G|/|H|) each equivariant cover has. The components are labeled by coset representatives from G/H. The structure of each connected component is determined by H. A simple algorithm is presented for determining the number and the period of orbits in an equivariant attractor that cover an orbit of period p in the image attractor. Modifications of these results for structurally unstable covers are summarized by an adjacency diagram.

Journal Article↗

PubMed2004

A hydration study of (1-->4) and (1-->6) linked alpha-glucans by comparative 10 ns molecular dynamics simulations and 500-MHz NMR.

The hydration behavior of two model disaccharides, methyl-alpha-D-maltoside (1) and methyl-alpha-D-isomaltoside (2), has been investigated by a comparative 10 ns molecular dynamics study. The detailed hydration of the two disaccharides was described using three force fields especially developed for modeling of carbohydrates in explicit solvent. To validate the theoretical results the two compounds were synthesized and subjected to 500 MHz NMR spectroscopy, including pulsed field gradient diffusion measurements (1: 4.0. 10(-6) cm(2). s(-1); 2: 4.2. 10(-6) cm(2). s(-1)). In short, the older CHARMM-based force field exhibited a more structured carbohydrate-water interaction leading to better agreement with the diffusional properties of the two compounds, whereas especially the alpha-(1-->6) linkage and the primary hydroxyl groups were inaccurately modeled. In contrast, the new generation of the CHARMM-based force field (CSFF) and the most recent version of the AMBER-based force field (GLYCAM-2000a) exhibited less structured carbohydrate-water interactions with the result that the diffusional properties of the two disaccharides were underestimated, whereas the simulations of the alpha-(1-->6) linkage and the primary hydroxyl groups were significantly improved and in excellent agreement with homo- and heteronuclear coupling constants. The difference between the two classes of force field (more structured and less structured carbohydrate-water interaction) was underlined by calculation of the isotropic hydration as calculated by radial pair distributions. At one extreme, the radial O em leader O pair distribution function yielded a peak density of 2.3 times the bulk density in the first hydration shell when using the older CHARMM force field, whereas the maximum density observed in the GLYCAM force field was calculated to be 1.0, at the other extreme.

Algorithms↗

PubMed2000

Docking structures of domains into maps from cryo-electron microscopy using local correlation.

Accurate maps of large macromolecular complexes can be calculated from cryo-electron micrographs of non-crystalline specimens to resolutions of about 10 A. A method to dock the atomic structures of domains solved by X-ray crystallography or nuclear magnetic resonance into cryo-EM maps is presented. Domains can be docked independently into large complexes without prior definition of the boundaries. No special symmetry is assumed and the procedure is suitable for general application to almost any system where a cryo-EM map (at 15 A resolution or better) of a complex has been obtained and the atomic structures of the components are available. This is achieved through use of a real-space density-matching procedure based on local correlation. A complete asymmetric unit search correlating a density object derived from the atomic coordinates and the density of the EM map is performed. The correlation coefficient is calculated locally in real space using only values of the search object and corresponding samples extracted from the EM map which are under the 'footprint' of the positioned search object. The procedure has been demonstrated by docking the domains of GroEL from the crystal structure into a cryo-EM map Fourier filtered to 12 or 15 A resolution. The correct positions were found without applying any additional constraints. A model of the oligomer built from the docked domains compared favourably with the known crystal structure, confirming the validity of the approach. The procedure is designed to facilitate the incorporation of additional constraints on the docking solutions, which could help to dock using lower resolution maps.

Algorithms↗

PubMed2003

Extending the resolution of light microscopy and electron microscopy digitized images with reference to cellular changes after in vivo low oxygen exposure.

When processing frame-grabbed images from light microscopy (LM) and electron microscopy (EM), even a state-of-the-art digital camera is the weakest link between the microscope and the image processor. Details, which can be seen directly in the ocular at LM and in a negative recorded at EM, will not necessarily be represented in the frame-grabbed images. Because of this, there is a tendency to prefer a higher magnification at the expense of overview, i.e. only smaller areas are described. We find that the inadequacy of the camera can be overcome by taking multiple images of the same object, and align, expand, and add them into a more highly resolved image. At the LM level, the method has proved useful for describing the relation of the zinc pattern versus local in vivo oxygen measurements. At the EM level, we show that it is possible to achieve information about the spatial conditions in a given area, and the method may have applications on, e.g., visualization of ultra-small antibody-bound gold particles. The method can be performed on color and black and white images at any magnification and it has been tested in Adobe Photoshop (4.0 and higher) in WINDOWS 95, 98, and 2000.

Algorithms↗

PubMed2004

Handling missing values in population data: consequences for maximum likelihood estimation of haplotype frequencies.

Haplotype frequency estimation in population data is an important problem in genetics and different methods including expectation maximisation (EM) methods have been proposed. The statistical properties of EM methods have been extensively assessed for data sets with no missing values. When numerous markers and/or individuals are tested, however, it is likely that some genotypes will be missing. Thus, it is of interest to investigate the behaviour of the method in the presence of incomplete genotype observations. We propose an extension of the EM method to handle missing genotypes, and we compare it with commonly used methods (such as ignoring individuals with incomplete genotype information or treating a missing allele as any other allele). Simulations were performed, starting from data sets of haematopoietic stem cell donors genotyped at three HLA loci. We deleted some data to create incomplete genotype observations in various proportions. We then compared the haplotype frequencies obtained on these incomplete data sets using the different methods to those obtained on the complete data. We found that the method proposed here provides better estimations, both qualitatively and quantitatively, but increases the computation time required. We discuss the influence of missing values on the algorithm's efficiency and the advantages and disadvantages of deleting incomplete genotypes. We propose guidelines for missing data handling in routine analysis.

Computational Biology↗

PubMed2006

HaploRec: efficient and accurate large-scale reconstruction of haplotypes.

BACKGROUND: Haplotypes extracted from human DNA can be used for gene mapping and other analysis of genetic patterns within and across populations. A fundamental problem is, however, that current practical laboratory methods do not give haplotype information. Estimation of phased haplotypes of unrelated individuals given their unphased genotypes is known as the haplotype reconstruction or phasing problem. RESULTS: We define three novel statistical models and give an efficient algorithm for haplotype reconstruction, jointly called HaploRec. HaploRec is based on exploiting local regularities conserved in haplotypes: it reconstructs haplotypes so that they have maximal local coherence. This approach--not assuming statistical dependence for remotely located markers--has two useful properties: it is well-suited for sparse marker maps, such as those used in gene mapping, and it can actually take advantage of long maps. CONCLUSION: Our experimental results with simulated and real data show that HaploRec is a powerful method for the large scale haplotyping needed in association studies. With sample sizes large enough for gene mapping it appeared to be the best compared to all other tested methods (Phase, fastPhase, PL-EM, Snphap, Gerbil; simulated data), with small samples it was competitive with the best available methods (real data). HaploRec is several orders of magnitude faster than Phase and comparable to the other methods; the running times are roughly linear in the number of subjects and the number of markers. HaploRec is publicly available at http://www.cs.helsinki.fi/group/genetics/haplotyping.html.

Chromosome Mapping↗

PubMed2001

Evaluation of flow properties of dry powder inhalation of salbutamol sulfate with lactose carrier.

The effects of the flow and packing properties of a drug/carrier powder mixture on emission of drug adhering to the carrier from capsules and inhalation devices were investigated. Model powder mixtures were designed consisting of lactose carriers with different particle shapes were prepared by surface treatment and micronized salbutamol sulfate. These powder mixtures were aerosolized by a Spinhaler, and in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The flow properties of the mixed powders were evaluated by the Carr's flowability index (FI) and Hausner's ratio (HR). The packing properties of the mixed powders were determined employing the tapping method. Compared with the powder mixed with the untreated lactose carrier, the FI, HR, and the constant K in Kawakita's equation of the powder mixture prepared using the surface-treated lactose carrier were significantly different, showing that the flow and packing properties of the drug/carrier powder mixture were improved. Using this surface-treated system, the handling of the powder mixture when packing into capsules is improved, which is desirable for handling dry powder inhalants. The fraction (%) of drug emitted from capsules and devices (EM) and the FI of the powder mixture were correlated. As the flow properties improved, the outflow of the powder mixture from capsules and devices became easier, and emission of drug adhering on the carrier from capsules and devices improved. Improvement of the inhalation process, such as the drug particles emitted from the inhalation system, is valuable for increasing inhalation properties of dry powder inhalation.

Aerosols↗

PubMed2006

Multi-resolution anchor-point registration of biomolecular assemblies and their components.

An atomic scale interpretation facilitates the assignment of functional properties to 3D reconstructions of macromolecular assemblies in electron microscopy (EM). Such a high-resolution interpretation is typically achieved by docking the known atomic structures of components into the volumetric EM maps. Docking locations are often determined by maximizing the cross-correlation coefficient of the two objects in a slow, exhaustive search. If time is of essence, such as in related visualization and image processing fields, the matching of data is accelerated by incorporating feature points that form a compact description of 3D objects. The complexity reduction afforded by the feature point representation enables a near-instantaneous matching. We show that such reduced matching can also deliver robust and accurate results in the presence of noise or artifacts. We therefore propose a novel multi-resolution registration technique employing feature-based shape descriptions of the volumetric and structural data. The pattern-matching algorithm carries out a hierarchical alignment of the point sets generated by vector quantization. The search-space complexity is reduced by an integrated tree-pruning technique, which permits the detection of subunits in large macromolecular assemblies in real-time. The efficiency and accuracy of the novel algorithm are validated on a standard test system of homo-oligomeric assemblies.

Algorithms↗

PubMedDate not supplied

The geriatric obstacle course: a training session designed to help prehospital personnel recognize geriatric stereotypes and misconceptions.

A significant proportion of ambulance transports to the Emergency Department involve elderly patients, and this use of EMS services by the elderly is expected to increase. Emergency medical technicians (EMTs) may have preconceived notions about the behavior they observe in this group of patients, who tend to be difficult to assess. To provide EMTs with the perspective from which their elderly patients view the situations in which they find themselves, we developed and implemented training scenarios in which the EMTs were required to play the role of the geriatric patient. The EMTs' evaluations of the sessions were enthusiastically positive and indicated that the course did enable them to reevaluate their attitudes toward elderly patients. It is our conviction that this type of sensitivity training is an easily implemented and highly valuable method of augmenting the facts and algorithms taught to these prehospital care providers.

Activities of Daily Living↗

PubMed2003

Feasibility of neuroprotective agent administration by prehospital personnel in an urban setting.

BACKGROUND AND PURPOSE: Studies have demonstrated the importance of early stroke treatment. If a neuroprotective agent (NA) clinical trial is successful, the greatest benefit might be attained with early prehospital administration. This study determined the potential reduction in time to treatment of stroke patients when NAs were administered in the prehospital setting. METHODS: Twenty-three urban emergency medical services (EMS) agencies participated in this study. Prehospital personnel completed a stroke assessment checklist on any potential stroke victim. The checklist collected clinical inclusion/exclusion criteria for NA administration and event/decision times. Patients meeting the hypothetical clinical inclusion criteria were enrolled into this study. Time data included scene arrival/departure, emergency department (ED) arrival, and estimated time of theoretical NA administration. The reduction in time to stroke treatment was calculated as the difference between the time of ED arrival and the reported time of NA administration. The t test and simple linear regression were used to probe for differences in treatment time reduction between selected subgroups. EMS personnel's ability to obtain informed consent for theoretical NA administration was calculated. RESULTS: Two hundred twenty-two patients were enrolled in this study; of these, 75 were deemed eligible for hypothetical NA administration and had complete time data. On average, EMS personnel documented the theoretical time of NA administration at 12.04+/-2.07 minutes before arrival at the ED (17.06+/-1.74 minutes when the NA was given on scene [n=43]; 6.65+/-1.14 minutes when the NA was given en route [n=32]). CONCLUSIONS: Prehospital NA administration can potentially significantly reduce the time to first intervention in stroke patients.

Aged↗

PubMed2000

Active constrained truncated Newton method for simple-bound optical tomography

In the past, nonlinear unconstrained optimization of the optical imaging problem has focused on Newton-Raphson techniques. Besides requiring expensive computation of the Jacobian, the unconstrained minimization with Tikhonov regularization can pose significant storage problems for large-scale reconstructions, involving a large number of unknowns necessary for realization of optical imaging. We formulate the inverse optical imaging problem as both simple-bound constrained and unconstrained minimization problems in order to illustrate the reduction in computational time and storage associated with constrained image reconstructions. The forward simulator of excitation and generated fluorescence, consisting of the Galerkin finite-element formulation, is used in an inverse algorithm to find the spatial distribution of absorption and lifetime that minimizes the difference between predicted and synthetic frequency-domain measurements. The inverse approach employs the truncated Newton method with trust region and a modification of automatic reverse differentiation to speed the computation of the optimization problem. The reconstruction results confirm that the physically based, constrained minimization with efficient optimization schemes may offer a more logical approach to the large-scale optical imaging problem than unconstrained minimization with regularization.

Journal Article↗

PubMed2006

A fully automatic 3D reconstruction method using simulated annealing enables accurate posterioric angular assignment of protein projections.

Single-particle analysis is a structure determining method using electron microscopic (EM) images, which does not require protein crystal. In this method, projections are picked up and used to reconstruct a three-dimensional (3D) structure. When the conical tilting method is not available, the particle images are usually classified and averaged to improve the signal-to-noise ratio. The Euler angles of these average images must be posteriorically assigned to create a primary 3D model. We developed a new, fully automatic unsupervised Euler angle assignment method, which does not require an initial 3D reference and which is applicable to asymmetric molecules. In this method, the Euler angle of each average image is initially set randomly and then automatically corrected in relation to those of the other averages by iterated optimizations using the Simulated Annealing (SA) algorithm. At each iteration, the 3D structure is reconstructed based on the current Euler angles and reprojected back in the average-input directions. A modified cross-correlation between each reprojection and its corresponding original average is then calculated. The correlations are summed as a total 3D echo-correlation score to evaluate the Euler angles at this iteration. Then, one of the projections is selected, its Euler angle is changed randomly, and the score is also calculated. Based on the score change, judgment of whether to accept or reject the new angle is made using the SA algorithm, which is introduced to overcome the local minimums. After a certain number of iterations of this process, the angles of all averages converge so as to create a reliable primary 3D model. This echo-correlated 3D reconstruction with simulated annealing also has potential for wide application to general 3D reconstruction from various types of 2D images.

Algorithms↗

PubMed1998

Effect of faecal consistency on virological diagnosis.

A study was set up to investigate the effect of consistency of routine faecal specimens on the diagnostic yield by electron microscopy (EM) and virus isolation. A total of 3078 specimens were characterized as solid, semisolid, or liquid. Of 2568 specimens processed by EM a virus was demonstrated in 8.6% of liquid, 19.9% of semisolid and 25.2% of solid specimens (Chi-squared for linear trend, P value <0.0001). This observation was valid for both adenovirus (2.4%, 5.0% and 6.6%) and rotavirus (5.2%, 13.6% and 16.6%). Virus isolation was positive in 3.6% of liquid, 17.4% of semisolid and 18.1% of solid specimens. (Chi-squared for linear trend, P value <0.0001). We suggest that solid faecal specimens at the end of an episode of diarrhoea will have a higher diagnostic yield than liquid specimens at the peak of symptoms. Our findings repudiate the commonly held dogma that viruses of gastroenteritis are more likely to be found in liquid than in solid faecal specimens. This finding has important implications for those establishing diagnostic algorithms for the investigation of viral gastroenteritis.

Adenoviridae↗

PubMed1999

Quantitative pulmonary single photon emission computed tomography for radiotherapy applications.

Pulmonary imaging using single photon emission computed tomography (SPECT) is the focus of current radiotherapy research, including dose-response analysis and three-dimensional (3D) radiation treatment planning. Improvement in the quantitative capability of SPECT may help establish its potential role in this application as well as others requiring accurate knowledge of pulmonary blood flow. The purposes of this study were to quantitatively evaluate SPECT filtered backprojection (FBP) and ordered subset-expectation maximization (OS-EM) reconstruction implementations for measuring absolute activity concentration in lung phantom experiments, and to incorporate quantitative SPECT techniques in 3D-RTP for lung cancer. Quantitative FBP (nonuniform iterative Chang attenuation compensation, scatter correction, and 3D postreconstruction Metz filtering) and OS-EM implementations were compared with a "clinical" implementation of FBP (uniform multiplicative Chang attenuation compensation and post-reconstruction von Hann filtering), for their ability to improve quantification of inactive and active spherical defects in the lungs of an anthropomorphic torso phantom. Activity concentration estimates were found to depend on many factors, such as region of interest size, scatter subtraction constant (k), postreconstruction deconvolution filtering and, in the case of OS-EM, total number of iterations. In general, reconstruction implementations incorporating compensation for nonuniform attenuation and scatter provided reduced bias relative to the clinical implementation. Potential applications to lung radiotherapy, including dose-functional histograms and treatment planning are also discussed. SPECT has the potential to provide accurate estimates of lung activity distributions that, together with improved image quality, may be useful for the study and prediction of therapeutic response.

Algorithms↗

PubMed1995

Semi-automatic external defibrillation and implanted cardiac pacemakers: understanding the interactions during resuscitation.

Many emergency medical service (EMS) systems are currently implementing semi-automatic external defibrillation (AED) by emergency medical technicians. Surprisingly little information is available on the possible interactions between AEDs and implanted cardiac pacemakers. Therefore, at present there are no clear guidelines for the use of AEDs on patients having a cardiac pacemaker. During resuscitation, multiple interactions between pacemakers and AEDs are possible. External defibrillation can cause damage to several functions of the pacemaker. On the other hand, the presence of pacemaker spikes during cardiac arrest might prohibit recognition of the ventricular fibrillation by the AED. We report on two resuscitation attempts in which the interaction between the ventricular fibrillation, an implanted dual chamber pacemaker and the AED was decisive for the defibrillation success. A clear understanding of these possible interactions is necessary for the further refining of diagnostic algorithms and clinical strategies of prehospital defibrillation.

Adult↗

PubMed2006

Insights into latent class analysis of diagnostic test performance.

Latent class analysis is used to assess diagnostic test accuracy when a gold standard assessment of disease is not available but results of multiple imperfect tests are. We consider the simplest setting, where 3 tests are observed and conditional independence (CI) is assumed. Closed-form expressions for maximum likelihood parameter estimates are derived. They show explicitly how observed 2- and 3-way associations between test results are used to infer disease prevalence and test true- and false-positive rates. Although interesting and reasonable under CI, the estimators clearly have no basis when it fails. Intuition for bias induced by conditional dependence follows from the analytic expressions. Further intuition derives from an Expectation Maximization (EM) approach to calculating the estimates. We discuss implications of our results and related work for settings where more than 3 tests are available. We conclude that careful justification of assumptions about the dependence between tests in diseased and nondiseased subjects is necessary in order to ensure unbiased estimates of prevalence and test operating characteristics and to provide these estimates clinical interpretations. Such justification must be based in part on a clear clinical definition of disease and biological knowledge about mechanisms giving rise to test results.

Algorithms↗