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Phylogenetic Methods Meet Deep Learning.

Deep learning (DL) has been widely used in various scientific fields, but its integration into phylogenetics has been slower, primarily due to the complex nature of phylogenetic data. The studies that apply DL to sequencing data often limit analyses to four-taxon trees. Many of these studies serve as "proof of principle" and perform similarly to traditional phylogeny reconstruction methods. New ways of using training data, such as encoding with compact bijective ladderized vectors or transformers, enable the handling of much larger trees and genomic data sets. This short perspective focuses on the application of DL in phylogenetics, introducing prevalent DL architectures. We highlight potential problems in the field by discussing the risks of using simulation-based training data and emphasize the importance of reproducibility and robustness in computational estimates. Finally, we explore promising research areas, including the combination of phylogenetics and population genetics in DL, the analysis of neighbor dependencies, and the potential to significantly reduce computational cost compared to traditional methods. This perspective illustrates the potential of DL in complementing traditional phylogeny reconstruction methods and aiding the advancement of phylogenetic analysis, especially in performing computationally demanding tasks such as model selection or estimating branch support values.

Humans↗

A model for educational simulation of infant cardiovascular physiology.

Full-body patient simulators provide the technology and the environment necessary for excellent clinical education while eliminating risk to the patient. The extension of simulator-based training into management of basic and critical situations in complex patient populations is natural. We describe the derivation of an infant cardiovascular model through the redefinition of a complete set of parameters for an existing adult model. Specifically, we document a stepwise parameter estimation process, explicit simplifying assumptions, and sources for these parameters. The simulated vital signs are within the target hemodynamic variables, and the simulated systemic arterial pressure wave form and left ventricular pressure volume loop are realistic. The system reacts appropriately to blood loss, and incorporation of aortic stenosis is straightforward. This infant cardiovascular model can form the basis for screen-based educational simulations. The model is also an essential step in attaining a full-body, model-driven infant simulator.

Aging↗

The URO Mentor: development and evaluation of a new computer-based interactive training system for virtual life-like simulation of diagnostic and therapeutic endourological procedures.

OBJECTIVE: To overcome the current disadvantages of traditional training methods for ureterorenoscopy and percutaneous nephrolitholapaxy, using the URO Mentor (Simbionix, Tel Aviv, Israel) computer-assisted simulator. METHODS: The URO Mentor device for training and quality control in ureterorenoscopy was developed using virtual reality, multimedia technology and intelligent tutoring systems. The central software system features a proprietary visualization engine (the SVE) which allows real-time simulation by offering a high-level object-orientated application program interface (written in C++) available for use with either Microsoft, DirectX 7 or OpenGL as platforms. The SVE includes general procedures to allow two- (2D) and three-dimensional (3D) rendering, collision detection, collision correction, 3D morphing, 2D image manipulation, texture mapping, 'bump' mapping, video texture, X-ray rendering, special effects (blood, smoke, stone fragments and more) and reflections. RESULTS: The system allows a complete training session on a wide range of procedures by offering different types of cases and virtual patients, and features a full representation of the endourological procedures under direct vision and by using interactive fluoroscopy with a contrast agent. The supported tools include: baskets, graspers, intracorporal lithotripters, guidewires, catheters, stents, biopsy and dilatation devices. The endourological procedures that can be performed are lithotripsy, tumour resection, treatment of strictures and obstructions, stent placement and biopsies. CONCLUSION: The URO Mentor introduces a new generation of mannequin equipped with a special haptic device, providing trainees with an unparalleled life-like sensation while training for diagnostic and therapeutic endourological procedures. By bringing key advances into urological simulation (e.g. with the real-time X-ray renderer) and by integrating in a single system both high-quality simulation and learning tools, the URO Mentor provides new perspectives for computer-based urological training systems and methods.

Computer Simulation↗

Information encoding and computation with spikes and bursts.

Neurons compute and communicate by transforming synaptic input patterns into output spike trains. The nature of this transformation depends crucially on the properties of voltage-gated conductances in neuronal membranes. These intrinsic membrane conductances can enable neurons to generate different spike patterns including brief, high-frequency bursts that are commonly observed in a variety of brain regions. Here we examine how the membrane conductances that generate bursts affect neural computation and encoding. We simulated a bursting neuron model driven by random current input signal and superposed noise. We consider two issues: the timing reliability of different spike patterns and the computation performed by the neuron. Statistical analysis of the simulated spike trains shows that the timing of bursts is much more precise than the timing of single spikes. Furthermore, the number of spikes per burst is highly robust to noise. Next we considered the computation performed by the neuron: how different features of the input current are mapped into specific output spike patterns. Dimensional reduction and statistical classification techniques were used to determine the stimulus features triggering different firing patterns. Our main result is that spikes, and bursts of different durations, code for different stimulus features, which can be quantified without a priori assumptions about those features. These findings lead us to propose that the biophysical mechanisms of spike generation enables individual neurons to encode different stimulus features into distinct spike patterns.

Computer Simulation↗

Elimination of response latency variability in neuronal spike trains.

Neuronal activity in the mammalian cortex exhibits a considerable amount of trial-by-trial variability. This may be reflected by the magnitude of the activity as well as by the response latency with respect to an external event, such as the onset of a sensory stimulus, or a behavioral event. Here we present a novel nonparametric method for estimating trial-by-trial differences in response latency from neuronal spike trains. The method makes use of the dynamic rate profile for each single trial and maximizes their total pairwise correlation by appropriately shifting all trials in time. The result is a new alignment of trials that largely eliminates the variability in response latency and provides a new internal trigger that is independent of experiment time. To calibrate the method, we simulated spike trains based on stochastic point processes using a parametric model for phasic response profiles. We illustrate the method by an application to simultaneous recordings from a pair of neurons in the motor cortex of a behaving monkey. It is demonstrated how the method can be used to study the temporal relation of the neuronal response to the experiment, to investigate whether neurons share the same dynamics, and to improve spike correlation analysis. Differences between this and other previously published methods are discussed.

Action Potentials↗

"Practicing" medicine without risk: students' and educators' responses to high-fidelity patient simulation.

PURPOSE: To understand the responses of medical students and educators to high-fidelity patient simulation, a new technology allowing "practice without risk." METHOD: Pilot groups of students (n = 27) and educators (n = 33) were exposed to a simulator session, then surveyed with multiple-choice and open-ended questions. Open-ended comments were transcribed and coded. They were analyzed for recurring themes and tested for inter-rater agreement. An independent focus group subsequently performed higher-level thematic analysis. RESULTS: Overall, 85% of the students rated the session excellent and 85% of the educators rated it excellent or very good. Over 80% of both groups thought that simulator-based training should be required for all medical students. Analytic categories derived from written comments were: Overall Assessment (i.e., "generally good experience"); Process Descriptors (i.e., "very realistic"); Teaching Utility (i.e., "broad educational tool"); Pedagogic Efficacy (i.e., "promotes critical thinking"); and Goals for Future Use (i.e., "more practice sessions"). Thirty percent of students and 38% of educators were impressed by the realism of the simulator, and they (37% and 25%, respectively) identified the ability to "practice" medicine as the primary advantage of simulation. The focus group rated cost as the major current disadvantage (66%). CONCLUSIONS: Students' and educators' responses to high-fidelity patient simulation were very positive. The ability to practice without risk must be weighed against the cost of this new technology.

Attitude of Health Personnel↗

Impact of the endoscopic sinus surgical simulator on operating room performance.

OBJECTIVES/HYPOTHESIS: The aim of this study is to evaluate an endoscopic sinus surgical simulator (ESS) as a training device and to introduce a methodology to assess its impact on actual operating room performance. STUDY DESIGN: Prospective evaluation of the endoscopic sinus surgical simulator as a trainer. METHODS: Ten junior and senior ear, nose and throat residents served as subjects, some of whom had prior training with the simulator. The evaluation team collected several measures, which were analyzed for a statistical correlation, including simulator scores, operating room performance rating, ratings of videotaped operating room procedures, and surgical competency rating. RESULTS: These findings suggest the ESS simulator positively affects initial operating room performance across all measures as judged by senior surgeons rating anonymous videotapes of those procedures. The two simulation-trained residents were rated consistently better than the other two residents across all measures. These differences approached statistical significance for two items: anterior ethmoidectomy (P =.06; P <.05) and surgical confidence (P =.09; P <.05). In addition, the 3 subjects with the highest overall scores on the competency evaluation also had 3 of the 4 highest cumulative simulation times. CONCLUSIONS: The endoscopic sinus surgical simulator is a valid training device and appears to positively impact operating room performance among junior otolaryngology residents.

Clinical Competence↗

Identification of connectivity in neural networks.

Analytical and experimental methods are provided for estimating synaptic connectivities from simultaneous recordings of multiple neurons. The results are based on detailed, yet flexible neuron models in which spike trains are modeled as general doubly stochastic point processes. The expressions derived can be used with nonstationary or stationary records, and can be readily extended from pairwise to multineuron estimates. Furthermore, we show analytically how the estimates are improved as more neurons are sampled, and derive the appropriate normalizations to eliminate stimulus-related correlations. Finally, we illustrate the use and interpretation of the analytical expressions on simulated spike trains and neural networks, and give explicit confidence measures on the estimates.

Animals↗

Effects of certain training parameters on detection of simulated breast cancer.

Forty-two female subjects, constituting 14 groups, palpated a silicone breast model in a lump detection task. Three variables, number of trials (amount of practice), search pattern requirement (restricted vs. unrestricted), and the presence or absence of lumps, were manipulated according to 3 x 2 x 2 design. The effect of all modes of practice on detection performance in posttest 1 was evidenced by an increase in percent of lumps detected and a decrease in detection threshold, but no form of practice was superior to the others. Following posttest 1 a brief search-training procedure was administered to 39 subjects which further lowered detection threshold, increased percent of lumps detected, and increased trial duration in posttest 2. The results indicate the effectiveness of the training procedure for improving detection ability and suggest the need for a more complex model to determine more specifically the effects of the practice models employed.

Adolescent↗

Estimation of premotor synaptic drives to simulated abducens motoneurons for control of eye position.

The firing rate of an abducens motoneuron (AbMN) is linearly related to eye position with slope K, above recruitment threshold theta. Within the AbMN population K increases as theta increases. It is possible that these properties depend on the synaptic drives generated by the major premotor inputs to AbMNs, namely position-vestibular-pause (PVP) cells and eye and head velocity (EHV) cells in the medial vestibular nucleus, and eye-position and burst-position cells in the nucleus prepositus hypoglossi (NPH). Premotor inputs to AbMNs were therefore modelled by a two-layer net, in which the output nodes represented the AbMNs (with fixed intrinsic properties) and the input nodes the three classes of premotor units ( n=20/class). Conjugate eye-position commands were used to generate the firing rates in premotor units found experimentally. The output of the net was compared with observed AbMN firing rates, and the resultant error used to adjust the magnitude and sign of the connection weights between premotor units and AbMNs. To provide additional constraints on permitted weights, the net was also trained under simulated smooth pursuit, cancellation of the vestibular-ocular reflex, and the vestibulo-ocular reflex itself (all at 0.5 Hz). Since the projections of EHV cells have not been clearly characterized, two versions of the model were trained, corresponding to different assumptions about these projections. In both versions, position-related AbMN firing rates were derived mainly from an excitatory drive from PVP cells and an inhibitory drive from NPH cells with the opposite ON direction. Variation in AbMN threshold theta and position sensitivity K depended on the strength of the drive from the NPH: the stronger the drive, the higher both K and theta. This arrangement was observed in six variants of the basic model with different parameter values, and in a simplified form (constant PVP drive and varying NPH drive) was able to generate qualitatively the observed relationship between K and theta even in the absence of input from EHV cells. It appears to be a robust mechanism for producing the experimentally observed variation in position-related firing of AbMNs, even without a contribution from their intrinsic properties, and predicts that local blocking of the inhibitory drive from cells in the NPH should lower both the position threshold and sensitivity of an individual AbMN. The model also indicates that if EHV cells have ipsilateral inhibitory projections, as has been proposed on the basis of their similarity with cells receiving input from the flocculus, then their role in eye-position control would reinforce that of cells in the NPH.

Abducens Nerve↗

Virtual ureteroscopy predicts ureteroscopic proficiency of medical students on a cadaver.

PURPOSE: Training on a virtual reality (VR) simulator has been shown to improve the performance of VR endoscopic tasks by novice endoscopists. However, to our knowledge the translation of VR skills into clinical endoscopic proficiency has not been demonstrated. We established criterion validity for a VR ureteroscopy simulator by evaluating VR trained subjects in a cadaver model. MATERIALS AND METHODS: A total of 32 participants, including 16 medical students and 16 urology residents, were evaluated at baseline on a VR ureteroscopy simulator (Uromentor, Simbionix, Lod, Israel), performing simple diagnostic ureteroscopy. The students then underwent 5 hours of supervised training on the simulator. Two weeks later all participants were reevaluated (VR2) on the simulator when repeating the initial task. Each participant was then assessed on the performance of a similar diagnostic ureteroscopy in a male cadaver. RESULTS: In medical students VR2 and cadaver performances correlated closely for several measured parameters (total time for task completion and overall global ratings score). In contrast, there was little correlation between the 2 performances in residents. Indeed, performance on the cadaver correlated more closely with the training level than VR2 scores. Despite VR training medical students were unable to perform cadaver ureteroscopy comparably to residents. CONCLUSIONS: For novice endoscopists performance on the simulator after training predicted operative (cadaver) performance and, thus, it may be useful for the education and assessment of physicians in training. However, VR training is unable to override the impact of clinical training, although it may help shorten the learning curve early in training.

Adult↗

Virtual patients in clinical medicine.

Virtual Patients are an essential component of medical virtual reality. Most work to date has been dedicated to virtual patients in surgery. However, virtual patients also have a strong potential in clinical medicine, where they can be used as visual interfaces to knowledge-based systems in various simulation and training applications. In this paper, we describe the implementation of a virtual patient in the field of cardiac emergencies and propose directions to extend the development of virtual patients towards the integration of multiple physiological sub-systems.

Clinical Medicine↗

Physiological stimuli evoke two forms of endocytosis in bovine chromaffin cells.

1. Exocytosis and endocytosis were measured following single, or trains of, simulated action potentials (sAP) in bovine adrenal chromaffin cells. Catecholamine secretion was measured by oxidative amperometry and cell membrane turnover was measured by voltage clamp cell capacitance measurements. 2. The sAPs evoked inward Na(+) and Ca(2+) currents that were statistically identical to those evoked by native action potential waveforms. On average, a single secretory granule underwent fusion following sAP stimulation. An equivalent amount of membrane was then quickly internalised (tau = 560 ms). 3. Stimulation with sAP trains revealed a biphasic relationship between cell firing rate and endocytic activity. At basal stimulus frequencies (single to 0.5 Hz) cells exhibited a robust membrane internalisation that then diminished as firing increased to intermediate levels (1.9 and 6 Hz). However at the higher stimulation rates (10 and 16 Hz) endocytic activity rebounded and was again able to effectively maintain cell surface near pre-stimulus levels. 4. Treatment with cyclosporin A and FK506, inhibitors of the phosphatase calcineurin, left endocytosis characteristics unaltered at the lower basal stimulus levels, but blocked the resurgence in endocytosis seen in control cells at higher sAP frequencies. 5. Based on these findings we propose that, under physiological electrical stimulation, chromaffin cells internalise membrane via two distinct pathways that are separable. One is prevalent at basal stimulus frequencies, is lessened with increased firing, and is insensitive to cyclosporin A and FK506. A second endocytic form is activated by increased firing frequencies, and is selectively blocked by cyclosporin A and FK506.

Action Potentials↗

Dynamics of neuronal firing correlation: modulation of "effective connectivity".

1. We reexamine the possibilities for analyzing and interpreting the time course of correlation in spike trains simultaneously and separably recorded from two neurons. 2. We develop procedures to quantify and properly normalize the classical joint peristimulus time scatter diagram. These allow separation of the "raw" correlation into components caused by direct stimulus modulations of the single-neuron firing rates and those caused by various types of interaction between the two neurons. 3. A newly developed significance test ("surprise") is applied to evaluate such inferences. 4. Application of the new procedures to simulated spike trains allowed the recovery of the known circuitry. In particular, it proved possible to recover fast stimulus-locked modulations of "effective connectivity," even if they were masked by strong direct stimulus modulations of individual firing rates. These procedures thus present a clearly superior alternative to the commonly used "shift predictor." 5. Adopting a model-based approach, we generalize the classical measures for quantifying a direct interneuronal connection ("efficacy" and "contribution") to include possible stimulus-locked time variations. 6. Application of the new procedures to real spike trains from several different preparations showed that fast stimulus-locked modulations of "effective connectivity" also occur for real neurons.

Animals↗

Estimating the temporal interval entropy of neuronal discharge.

To better understand the role of timing in the function of the nervous system, we have developed a methodology that allows the entropy of neuronal discharge activity to be estimated from a spike train record when it may be assumed that successive interspike intervals are temporally uncorrelated. The so-called interval entropy obtained by this methodology is based on an implicit enumeration of all possible spike trains that are statistically indistinguishable from a given spike train. The interval entropy is calculated from an analytic distribution whose parameters are obtained by maximum likelihood estimation from the interval probability distribution associated with a given spike train. We show that this approach reveals features of neuronal discharge not seen with two alternative methods of entropy estimation. The methodology allows for validation of the obtained data models by calculation of confidence intervals for the parameters of the analytic distribution and the testing of the significance of the fit between the observed and analytic interval distributions by means of Kolmogorov-Smirnov and Anderson-Darling statistics. The method is demonstrated by analysis of two different data sets: simulated spike trains evoked by either Poissonian or near-synchronous pulsed activation of a model cerebellar Purkinje neuron and spike trains obtained by extracellular recording from spontaneously discharging cultured rat hippocampal neurons.

Action Potentials↗

Spike sorting based on automatic template reconstruction with a partial solution to the overlapping problem.

A new method for spike sorting is proposed which partly solves the overlapping problem. Principal component analysis and subtractive clustering techniques are used to estimate the number of neurons contributing to multi-unit recording. Spike templates (i.e. waveforms) are reconstructed according to the clustering results. A template-matching procedure is then performed. Firstly all temporally displaced templates are compared with the spike event to find the best-fitting template that yields the minimum residue variance. If the residue passes the chi(2)-test, the matching procedure stops and the spike event is classified as the best-fitting template. Otherwise the spike event may be an overlapping waveform. The procedure is then repeated with all possible combinations of two templates, three templates, etc. Once one combination is found, which yields the minimum residue variance among the combinations of the same number of component templates and makes the residue pass the chi(2)-test, the matching procedure stops. It is unnecessary to check the remaining combinations of more templates. Consequently, the computational effort is reduced and the over-fitting problem can be partly avoided. A simulated spike train was used to assess the performance of the proposed method, which was also applied to a real recording of chicken retina ganglion cells.

Action Potentials↗

The design and testing of a force feedback dental simulator.

The Iowa Dental Surgical Simulator is a haptic simulator to train dental students in the haptic skills of dentistry. The initial design emphasizes the detection of carious lesions. This work describes the software and implementation of the prototype system, the design tradeoffs' and the technical issues associated with haptic and graphics subsystems. The work also describes the current system performance, including a formal evaluation by practicing dentists and performance measures. A discussion of the limitations of the current system is followed by an analysis of opportunities to improve the quality of the simulator. The results should be of interest to designers of medical haptic simulation systems and other simulation designers.

Biophysical Phenomena↗

Trials of teaching methods in basic life support (3): comparison of simulated CPR performance after first training and at 6 months, with a note on the value of re-training.

A randomised controlled trial comparing staged teaching of cardiopulmonary resuscitation (CPR) with conventional training provided the additional opportunity to investigate skill acquisition and retention in those attending conventional CPR classes. All subjects were tested immediately after their first instruction period and again at 6-9 months at an unheralded home visit. We were able to assess how far performance was related to poor acquisition of skills and how far it was related to skill decay. Out of 262 subjects who were randomised to receive conventional CPR instruction, 166 were available for home testing at 6-9 months. An invitation to attend for re-training had been accepted by 39 of them. The remaining 127 who attended only a single class comprise the principal study group, with additional comparative observations on the smaller re-trained cohort. Important failings were observed in the acquisition of skills in all modalities tested after the initial instruction. These were particularly marked in skills related to ventilation. Immediately after a class, 68% of trainees performed an effective check of breathing, but only 33% opened the airway as taught and no more than 18% provided an ideal ventilation volume. The technique of chest compression was also less than ideal. Although 80% of subjects placed their hands in an acceptable position, compression to an adequate depth and an adequate rate of compression were achieved by 54 and 63%, respectively. Seventy-eight percent demonstrated a careful approach, and 46% remembered to call for help. A carotid pulse check was simulated by 61% of trainees. When tested 6-9 months later, skill deterioration from this baseline was observed in all modalities tested except for the ventilation volume. The skill decay was significant (P<0.05) for the careful approach, performing an effective breathing check, the carotid pulse check, placing the hands in an acceptable position for chest compression, and compressing at an optimal rate. The minority who attended for re-training showed a trend to protection against skill decay for seven of the ten variables, compared with those who had attended only one training session. This improvement was significant for only two of them, but all were relatively small with limited practical value. Many who attend conventional CPR classes fail to acquire the necessary skills, and the skills that are acquired decline appreciably over the subsequent 6-9 months. The value of conventional re-training was modest in this study of community volunteers.

Adult↗