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A method for analysis of encoding of stimulus separation in ensembles of afferents.

This paper describes a new method for the analysis of ensemble coding in populations of receptor afferents. The method is based on principal component analysis (PCA) combined with algorithms for calculation of stimulus separation (discrimination). It allows a quantification of the ability of ensembles of afferents to discriminate between stimuli of different intensity, and it can also be used to calculate to which extent each afferent in an ensemble contributes to the discrimination. Since the emphasis is put on discrimination of stimuli rather than on similarities between the representations of the stimulus in the ensemble response and the stimulus itself, it involves no implicit assumption about the unknown decoding mechanisms in the CNS. Examples of results obtained with analysis of and comparison of simultaneously recorded and pooled sequentially recorded populations of primary muscle spindle afferents are given. These results support some of the general arguments in favour of the ensemble coding theory, and indicate that the results of studies made on populations of simultaneously recorded receptor afferents may differ considerably from results obtained in studies on pooled sequentially recorded afferents. In contrast to when ensemble responses are based on parallel recordings, population responses constructed from sequential recordings will be distorted as a result of unavoidable temporal variations in physiological conditions.

Algorithms↗

Principal component analysis of neuronal ensemble activity reveals multidimensional somatosensory representations.

Principal components analysis (PCA) was used to define the linearly dependent factors underlying sensory information processing in the vibrissal sensory area of the ventral posterior medial (VPM) thalamus in eight awake rats. Ensembles of up to 23 single neurons were simultaneously recorded in this area, either during long periods of spontaneous behavior (including exploratory whisking) or controlled deflection of single whiskers. PCA rotated the matrices of correlation between these n neurons into a series of n uncorrelated principal components (PCs), each successive PC oriented to explain a maximum of the remaining variance. The fact that this transformation is mathematically equivalent to the general Hebb algorithm in linear neural networks provided a major rationale for performing it here on data from real neuronal ensembles. Typically, most information correlated across neurons in the ensemble was concentrated within the first 3-8 PCs. Each of these was found to encode distinct, and highly significant informational factors. These factor encodings were assessed in two ways, each making use of fact that each PC consisted of a matrix of weightings, one for each neuron. First, the neurons were rank ordered according to the locations of the central whiskers in their receptive fields, allowing their weightings within different PCs to be viewed as a function of their position within the whisker representation in the VPM. Each PC was found to define a distinctly different topographic mapping of the cutaneous surface. Next, the PCs were used to weight-sum the neurons' simultaneous activities to create population vectors (PVs). Each PV consisted of a single continuous time series which represented the expression of each PC's 'magnitude' in response to stimulation of different whiskers, or during behavioral events such as active tactile whisking. These showed that each PC functioned as a feature detector capable of selectively predicting significant sensory or behavioral events with far greater statistical reliability than could any single neuron. The encoding characteristics of the first few PCs were remarkably consistent across all animals and experimental conditions, including both spontaneous exploration and direct sensory stimulation: PC1 positively weighted all neurons, mainly according to their covariance. Thus it encoded global magnitude of ensemble activity, caused either by combined sensory inputs or intrinsic network activity, such as spontaneous oscillations. PC2 encoded spatial position contrast, generally in the rostrocaudal dimension, across the whole cutaneous surface represented by the ensemble. PC3 more selectively encoded contrast in an orthogonal (usually dorsoventral) dimension. A variable number of higher numbered PCs encoded local position contrast within one or more smaller regions of the cutaneous surface. The remaining PCs typically explained residual 'noise', i.e. the uncorrelated variance that constituted a major part of each neuron's activity. Differences in behavioral or sensory experience produced relatively little in the PC weighting patterns but often changed the variance they explained (eigenvalues) enough to alter their ordering. These results argue that PCA provides a powerful set of tools for selectively measuring neural ensemble activity within multiple functionally significant 'dimensions' of information processing. As such, it redefines the 'neuron' as an entity which contributes portions of its variance to processing not one, but several tasks.

Animals↗

Explaining the output of ensembles in medical decision support on a case by case basis.

The use of ensembles in machine learning (ML) has had a considerable impact in increasing the accuracy and stability of predictors. This increase in accuracy has come at the cost of comprehensibility as, by definition, an ensemble model is considerably more complex than its component models. This is of significance for decision support systems in medicine because of the reluctance to use models that are essentially black boxes. Work on making ensembles comprehensible has so far focused on global models that mirror the behaviour of the ensemble as closely as possible. With such global models there is a clear tradeoff between comprehensibility and fidelity. In this paper, we pursue another tack, looking at local comprehensibility where the output of the ensemble is explained on a case-by-case basis. We argue that this meets the requirements of medical decision support systems. The approach presented here identifies the ensemble members that best fit the case in question and presents the behaviour of these in explanation.

Anticoagulants↗

Prediction of postoperative morbidity after lung resection using an artificial neural network ensemble.

OBJECTIVE: To propose an ensemble model of artificial neural networks (ANNs) to predict cardio-respiratory morbidity after pulmonary resection for non-small cell lung cancer (NSCLC). METHODS: Prospective clinical study was based on 489 NSCLC operated cases. An artificial neural network ensemble was developed using a training set of 348 patients undergoing lung resection between 1994 and 1999. Predictive variables used were: sex of the patient, age, body mass index, ischemic heart disease, cardiac arrhythmia, diabetes mellitus, induction chemotherapy, extent of resection, chest wall resection, perioperative blood transfusion, tumour staging, forced expiratory volume in 1s percent (FEV(1)%), and predicted postoperative FEV(1)% (ppoFEV(1)%). The analysed outcome was the occurrence of postoperative cardio-respiratory complications prospectively recorded and codified. The artificial neural network ensemble consists of 100 backpropagation networks combined via a simple averaging method. The probabilities of complication calculated by ensemble model were obtained to the actual occurrence of complications in 141 cases operated on between January 2000 and December 2001 and a receiver operating characteristic (ROC) curve for this method was constructed. RESULTS: The prevalence of cardio-respiratory morbidity was 0.25 in the training and 0.30 in the validation series. The accuracy for morbidity prediction (area under the ROC curve) was 0.98 by the ensemble model. CONCLUSION: In this series an artificial neural network ensemble offered a high performance to predict postoperative cardio-respiratory morbidity.

Aged↗

High-speed GC and GC/MS with a series-coupled column ensemble using stop-flow operation.

A pneumatically actuated valve is used to connect the junction point of a series-coupled column ensemble to a ballast chamber containing carrier gas at the ensemble inlet pressure in order to periodically stop the carrier gas flow in the first column. When the valve is opened, mixture components, which have migrated across the column junction, are accelerated toward a time-of-flight mass spectrometer that is used as an ensemble detector. Mixture components, which are still in the first column, are frozen in position. This allows for the insertion of time windows into the ensemble chromatogram that can aid in the separation of some overlapping component peaks. The capillary column ensemble (0.18-mm i.d. x 0.18-microm film thickness) consists of a 7.0-m length of polar, (trifluoropropyl)methyl polysiloxane column followed by a 7.0-m length of nonpolar dimethyl polysiloxane column. A flame ionization detector located at the column junction point is used to monitor a portion of the effluent from the first column in order to determine the valve timing sequence needed to enhance the separation of component pairs that are separated by the first column but coelute from the column ensemble. When one of the components of a targeted pair has crossed the junction but the other component is still in the first column, the valve is opened, typically for 1-5 s. The stop-flow system is used to enhance the separation of a mixture containing some common essential oil components and a mixture containing some common pesticides.

Journal Article↗

Conformational propensities of protein folding intermediates: distribution of species in the 1S, 2S, and 3S ensembles of the [C40A,C95A] mutant of bovine pancreatic ribonuclease A.

A key problem in experimental protein folding is that of characterizing the conformational ensemble of denatured proteins under folding conditions. We address this problem by studying the conformational propensities of reductively unfolded RNase A under folding conditions, since earlier work has indicated that the equilibrium conformational ensemble of fully reduced RNase A resembles the transient conformational ensemble of a burst-phase folding intermediate of disulfide-intact RNase A. To assess these propensities, the relative disulfide-bond populations of the 1S, 2S, and 3S ensembles of the [C40A,C95A] mutant of RNase A were measured. Thirteen of the fifteen possible disulfide bonds are observed, consistent with earlier results and with the rapid reshuffling and lack of stable tertiary structure in these ensembles. This broad distribution contradicts recent observations by another group, but rigorous cross-checks show unambiguously that our data are self-consistent whereas their data are not. The distributions of disulfide bonds in the wild-type and mutant proteins show a power-law dependence on loop length, with an exponent that is significantly smaller than the exponents of either ideal or excluded-volume polymers. The 65-72 disulfide bond is much more strongly favored than would be predicted by this power law, consistent with earlier peptide studies and the disulfide-bond distributions of the 1S and 2S ensembles in wild-type RNase A. Experimental evidence suggests that this preference results from conformational biases in the backbone, rather than from differing accessibilities or reactivities of the two cysteine residues. In general, the other disulfide species do not deviate significantly from the power-law dependence, indicating that the conformational biases are relatively weak.

Alanine↗

Monitoring the sizes of denatured ensembles of staphylococcal nuclease proteins: implications regarding m values, intermediates, and thermodynamics.

Fluorescence and size-exclusion chromatography (SEC) are used to monitor urea denaturation of wild-type staphylococcal nuclease (SN) as well as the m+ and m- mutants A69T and V66W, respectively. It is found that the SEC partition coefficient, 1/Kd, is directly proportional to the Stokes radii of proteins. From the Stokes radii, the denatured ensembles of the three proteins are found to be highly compact in the limit of low urea concentration and expand significantly with increasing urea concentration. The m values from fluorescence-detected denaturation of the SN proteins are generally considered to reflect the relative sizes of denatured ensembles. However, the rank order of m values of the SN proteins studied do not correspond to the rank order of denatured ensemble sizes detected by 1/Kd, suggesting that m values reflect more than just surface area increases on denaturation. SEC provides two complementary ways to demonstrate the existence of intermediates in urea denaturation and illustrates that V66W undergoes a three-state transition. Fluorescence-detected urea denaturations of A69T and wt SN do not correspond with 1/Kd-detected denaturation profiles, a result that would ordinarily mean that the transitions are non-two-state. However, this interpretation fails to recognize the rapidly changing size and thermodynamic character of the denatured ensembles of these proteins both within and outside of the transition zone. The implications of the changing sizes and thermodynamic character of the denatured ensembles for SN proteins are manifold, requiring a reconsideration of the thermodynamics of proteins whose denatured ensembles behave as those of SN proteins.

Alanine↗

WBGT clothing adjustments for four clothing ensembles under three relative humidity levels.

Threshold limit values for heat stress and strain are based on an upper limit wet bulb globe temperature (WBGT) for ordinary work clothes, with clothing adjustment factors (CAF) for other clothing ensembles. The purpose of this study was to determine the CAF for four clothing ensembles (Cotton Coveralls, Tyvek 1424 Coveralls, NexGen Coveralls, and Tychem QC Coveralls) against a baseline of cotton work clothes and to determine what effect relative humidity may have. A climatic chamber was used to slowly increase the level of heat stress by increasing air temperature at three levels of relative humidity (20%, 50%, and 70%). Study participants wore one of the five ensembles while walking on a treadmill at a moderate metabolic rate of 155 W m-2 (about 300 W). Physiological data and environmental data were collected. When the participant's core temperature reached a steady state, the dry bulb temperature was increased at constant relative humidity. The point at which the core temperature began to increase was defined as the inflection point. The environmental temperature recorded 5 min before the inflection point was used to calculate the critical WBGT for each ensemble. A three-way analysis of variance with ensemble by humidity protocol interactions and a multiple comparison test were used to make comparisons among the mean values. Only the vapor-barrier ensemble (Tychem QC) demonstrated an interaction with humidity level. The following CAFs are proposed: Cotton Coveralls (0 degrees C-WBGT), Tyvek 1424 Coveralls (+1), NexGen Coveralls (+2), and Tychem QC Coveralls (+10).

Adult↗

An ENSEMBLE machine learning approach for the prediction of all-alpha membrane proteins.

MOTIVATION: All-alpha membrane proteins constitute a functionally relevant subset of the whole proteome. Their content ranges from about 10 to 30% of the cell proteins, based on sequence comparison and specific predictive methods. Due to the paucity of membrane proteins solved with atomic resolution, the training/testing sets of predictive methods for protein topography and topology routinely include very few well-solved structures mixed with a hundred proteins known with low resolution. Moreover, available predictors fail in predicting recently crystallised membrane proteins (Chen et al., 2002). Presently the number of well-solved membrane proteins comprises some 59 chains of low sequence homology. It is therefore possible to train/test predictors only with the set of proteins known with atomic resolution and evaluate more thoroughly the performance of different methods. RESULTS: We implement a cascade-neural network (NN), two different hidden Markov models (HMM), and their ensemble (ENSEMBLE) as a new method. We train and test in cross validation the three methods and ENSEMBLE on the 59 well resolved membrane proteins. ENSEMBLE scores with a per-protein accuracy of 90% for topography and 71% for topology, outperforming the best single method of 7 and 5 percentage points, respectively. When tested on a low resolution set of 151 proteins, with no homology with the 59 proteins, the per-protein accuracy of ENSEMBLE is 76% for topography and 68% for topology. Our results also indicate that the performance of ENSEMBLE is higher than that of the best predictors presently available on the Web.

Algorithms↗

An artificial neural network ensemble to predict disposition and length of stay in children presenting with bronchiolitis.

BACKGROUND: Artificial neural networks apply complex non-linear functions to pattern recognition problems. An ensemble is a 'committee' of neural networks that usually outperforms single neural networks. Bronchiolitis is a common manifestation of viral lower respiratory tract infection in infants and toddlers. OBJECTIVE: To train artificial neural network ensembles to predict the disposition and length of stay in children presenting to the Emergency Department with bronchiolitis. METHODS: A specifically constructed database of 119 episodes of bronchiolitis was used to train, validate, and test a neural network ensemble. We used EasyNN 7.0 on a 200 Mhz pentium PC with a maths co-processor. The ensemble of neural networks constructed was subjected to fivefold validation. Comparison with actual and predicted dispositions was measured using the kappa statistic for disposition and the Kaplan-Meier estimations and log rank test for predictions of length of stay. RESULTS: The neural network ensembles correctly predicted disposition in 81% (range 75-90%) of test cases. When compared with actual disposition the neural network performed similarly to a logistic regression model and significantly better than various 'dumb machine' strategies with which we compared it. The prediction of length of stay was poorer, 65% (range 60-80%), but the difference between observed and predicted lengths of stay were not significantly different. CONCLUSION: Artificial neural network ensembles can predict disposition for infants and toddlers with bronchiolitis; however, the prediction of length of hospital stay is not as good.

Bronchiolitis↗

Inequivalence of statistical ensembles in single molecule measurements.

We study the role of fluctuations in single molecule experimental measurements of force-extension (f-zeta) curves. We use the worm-like chain (WLC) model to bring out the connection between the Helmholtz ensemble characterized by the free energy [F(zeta)] and the Gibbs ensemble characterized by the free energy [G(f)] . We consider the rigid rod limit of the WLC model as an instructive special case to bring out the issue of ensemble inequivalence. We point out the need for taking into account the free energy of transition when one goes from one ensemble to another. We also comment on the "phase transition" noticed in an isometric setup for semiflexible polymers and propose a realization of its thermodynamic limit. We present general arguments which rule out nonmonotonic force-extension curves in some ensembles and note that these do not apply to the isometric ensemble.

Journal Article↗

Ensembling local learners through multimodal perturbation.

Ensemble learning algorithms train multiple component learners and then combine their predictions. In order to generate a strong ensemble, the component learners should be with high accuracy as well as high diversity. A popularly used scheme in generating accurate but diverse component learners is to perturb the training data with resampling methods, such as the bootstrap sampling used in bagging. However, such a scheme is not very effective on local learners such as nearest-neighbor classifiers because a slight change in training data can hardly result in local learners with big differences. In this paper, a new ensemble algorithm named Filtered Attribute Subspace based Bagging with Injected Randomness (FASBIR) is proposed for building ensembles of local learners, which utilizes multimodal perturbation to help generate accurate but diverse component learners. In detail, FASBIR employs the perturbation on the training data with bootstrap sampling, the perturbation on the input attributes with attribute filtering and attribute subspace selection, and the perturbation on the learning parameters with randomly configured distance metrics. A large empirical study shows that FASBIR is effective in building ensembles of nearest-neighbor classifiers, whose performance is better than that of many other ensemble algorithms.

Algorithms↗

The significance of neural ensemble codes during behavior and cognition.

The development of techniques to record from populations of neurons has made it possible to ask questions concerning the encoding of task-relevant information in awake, behaving animals. The issue of how groups of neurons within different brain structures register and retrieve representations of behaviorally significant events can now be addressed using multineuron-recording techniques. This review examines recent studies employing simultaneous recording of ten or more individual neurons in the mammalian brain. A major issue discussed is whether ensemble information content reconstructed from single-neuron recordings may be underestimated if compared to ensembles where those same neurons were recorded simultaneously. The mechanics of ensemble information encoding in the hippocampus is illustrated from population statistical analyses of ensemble activity during performance of a delay task. Detailed descriptions of methods of extracting ensemble information, as well as cross-correlational analyses, are discussed in the context of emergent issues regarding interpretation of ensemble data.

Animals↗

Statistical Viewer: a tool to upload and integrate linkage and association data as plots displayed within the Ensembl genome browser.

BACKGROUND: To facilitate efficient selection and the prioritization of candidate complex disease susceptibility genes for association analysis, increasingly comprehensive annotation tools are essential to integrate, visualize and analyze vast quantities of disparate data generated by genomic screens, public human genome sequence annotation and ancillary biological databases. We have developed a plug-in package for Ensembl called "Statistical Viewer" that facilitates the analysis of genomic features and annotation in the regions of interest defined by linkage analysis. RESULTS: Statistical Viewer is an add-on package to the open-source Ensembl Genome Browser and Annotation System that displays disease study-specific linkage and/or association data as 2 dimensional plots in new panels in the context of Ensembl's Contig View and Cyto View pages. An enhanced upload server facilitates the upload of statistical data, as well as additional feature annotation to be displayed in DAS tracts, in the form of Excel Files. The Statistical View panel, drawn directly under the ideogram, illustrates lod score values for markers from a study of interest that are plotted against their position in base pairs. A module called "Get Map" easily converts the genetic locations of markers to genomic coordinates. The graph is placed under the corresponding ideogram features a synchronized vertical sliding selection box that is seamlessly integrated into Ensembl's Contig- and Cyto- View pages to choose the region to be displayed in Ensembl's "Overview" and "Detailed View" panels. To resolve Association and Fine mapping data plots, a "Detailed Statistic View" plot corresponding to the "Detailed View" may be displayed underneath. CONCLUSION: Features mapping to regions of linkage are accentuated when Statistic View is used in conjunction with the Distributed Annotation System (DAS) to display supplemental laboratory information such as differentially expressed disease genes in private data tracks. Statistic View is a novel and powerful visual feature that enhances Ensembl's utility as valuable resource for integrative genomic-based approaches to the identification of candidate disease susceptibility genes. At present there are no other tools that provide for the visualization of 2-dimensional plots of quantitative data scores against genomic coordinates in the context of a primary public genome annotation browser.

Chromosome Mapping↗

Coding of sound-source location by ensembles of cortical neurons.

We examined the coding of sound-source location by ensembles of neurons in the auditory cortex. Broadband noise bursts were presented from loudspeakers throughout 360 degrees in the horizontal plane. Sound levels varied from 20 to 40 dB above neural thresholds. We recorded temporal spike patterns simultaneously at 16 recording sites in area A2 of alpha-chloralose-anesthetized cats. Spike patterns of individual units varied in spike counts and in spike timing as a function of sound-source location. Ensembles of up to 19 units recorded simultaneously demonstrated additional location sensitivity in the form of relative spike counts and relative spike timing among neurons. We used an artificial neural network (ANN) algorithm to recognize ensemble spike patterns and, thereby, to infer the locations of sound sources. The ANN could estimate stimulus locations based on ensemble responses to single-stimulus presentations. Median errors (MEs) averaged 49.2 +/- 11.9 degrees (mean +/- SD; n = 34; chance level, 90 degrees ). The ANN maintained better-than-chance performance even when input spike patterns were expressed as relative spike counts across units (i.e., no information available from absolute spike counts of individual units; ME, 63.0 +/- 11.8 degrees ) or when spike latencies were represented as time relative to the first spike for each trial (i.e., no external time reference available; ME, 54.3 +/- 12.4 degrees ). The ANN performance improved monotonically as the sizes of ensemble patterns were increased by combining patterns across the entire unit sample. The performance by ensembles of 128 units approached the level of localization performance of behaving cats.

Action Potentials↗

The organization of spatial coding in the hippocampus: a study of neural ensemble activity.

Neural activity was recorded from local groups of hippocampal single units in rats performing a spatial-memory task. The organization of functional correlates in these neural ensembles was investigated by examining the spatial relationships among the place fields of single units in each ensemble. The distance and overlap between place fields were determined together with the tuning of cellular activity to behavioral variables, including direction, speed, and turning angle during movements within place fields. The place fields of recorded neural ensembles were significantly clustered: closer in space and considerably more overlapped than chance when compared statistically with Monte Carlo simulations. Just as single units often have significant firing in more than one distinct location in the environment (subfields), the ensembles had multiple and distinct clusters of overlapping subfields. In addition, proximity and overlap between place fields were significantly, but weakly, correlated with similarity in optimal movement tuning parameters. These results suggest that the hippocampus maintains a local organization with respect to place fields despite having no apparent large-scale isomorphism with the spatial environment. The organization of multiple, clustered place fields with correlated movement tuning properties in small neural ensembles suggests the existence of functional neural ensembles serving to encode multiple sensory and behavioral aspects of a place or event. Such an organization is similar to that observed for neocortical association areas afferent to the hippocampal system.

Animals↗

[Structural organization and connections of cell ensembles of the olfactory bulb of the cat brain].

The cat cerebral olfactory tubercle (OT) includes into its composition certain cellular ensembles distinguished by means of morphological criteria. The ensembles consist of three cellular components: clusters of granular neurons (islands of Calleja), pyramid-like neurons of the layer II, situating along the periphery of the islands, and groupings made by polygonal and spindle-like neurons of the layer III. Morphometrical analysis of every of the three cellular complex components has been carried out. About 7-10 islands of Calleja are situated on the OT territory, which makes nearly 75% of the whole surface of the OT. Neuronal composition of the cellular ensembles has been studied by Golgi method. Varieties of long and short axonal neurons, included into the ensemble composition, have been characterized. Presence of projections of the macrocellular neurons of the layer III (a part of the third component of the ensemble) has been revealed in the posterior part of the lateral hypothalamus and in the field of Forel H1. Possible role of the cellular ensembles is discussed for ensuring various functions of the OT.

Animals↗

Improving the ensemble average of visual evoked potentials. II. Simulations and experiments.

Ensemble averaging is generally used for the estimation of Evoked Potentials. This paper deals with the assessment of correction procedures for the time variability of the ensemble components, this time variability reduces the improvement of the signal-to-noise ratio (SNR) by averaging. Evoked potentials were estimated by ensemble averaging, synchronized to a periodic stimulus. It is assumed that VEP-instability is partly caused by time-variability of the evoked potentials. Two time-variate models were used, from which procedures were derived to correct the single VEP-responses prior to ensemble averaging. The models are: (1) variation in response delay (jitter), (2) variable compression/expansion of the time scale of the response (wow). The Spectral Phase Difference method was applied to estimate both the delay time jitter and the wow factor of single responses with respect to a template (conventional ensemble average). The effects of the devised correction on the average VEP waveform and on the SNR of the ensemble were investigated by using data from realistic simulations and from experiments (n = 23) with a number of healthy human volunteers (n = 17). Jitter- and wow-corrections were effective on simulations with time variability due to delay time jitter and time scale distortion (wow), respectively. Both wow- and jitter correction of the single responses improved the SNR of the VEP measurements significantly and to the same amount. A combined wow-jitter approach resulted in significantly better results than the exclusive application of jitter- or wow correction.

Computer Simulation↗