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Gene expression data analysis with a dynamically extended self-organized map that exploits class information.

MOTIVATION: Currently the most popular approach to analyze genome-wide expression data is clustering. One of the major drawbacks of most of the existing clustering methods is that the number of clusters has to be specified a priori. Furthermore, by using pure unsupervised algorithms prior biological knowledge is totally ignored Moreover, most current tools lack an effective framework for tight integration of unsupervised and supervised learning for the analysis of high-dimensional expression data and only very few multi-class supervised approaches are designed with the provision for effectively utilizing multiple functional class labeling. RESULTS: The paper adapts a novel Self-Organizing map called supervised Network Self-Organized Map (sNet-SOM) to the peculiarities of multi-labeled gene expression data. The sNet-SOM determines adaptively the number of clusters with a dynamic extension process. This process is driven by an inhomogeneous measure that tries to balance unsupervised, supervised and model complexity criteria. Nodes within a rectangular grid are grown at the boundary nodes, weights rippled from the internal nodes towards the outer nodes of the grid, and whole columns inserted within the map The appropriate level of expansion is determined automatically. Multiple sNet-SOM models are constructed dynamically each for a different unsupervised/supervised balance and model selection criteria are used to select the one optimum one. The results indicate that sNet-SOM yields competitive performance to other recently proposed approaches for supervised classification at a significantly reduced computational cost and it provides extensive exploratory analysis potentiality within the analysis framework. Furthermore, it explores simple design decisions that are easier to comprehend and computationally efficient.

Algorithms↗

Computational Science and Engineering Online (CSE-Online): a cyber-infrastructure for scientific computing.

With the expansion of the Internet and World Wide Web (or the Web), research environments have changed dramatically. As a result, the need to be able to efficiently and securely access information and resources from remote computer systems is becoming even more critical. This paper describes the development of an extendable integrated Web-accessible simulation environment for computational science and engineering called Computational Science and Engineering Online (CSE-Online; http://cse-online.net). CSE-Online is based on a unique client-server software architecture that can distribute the workload between the client and server computers in such a way as to minimize the communication between the client and server, thus making the environment less-sensitive to network instability. Furthermore, the new software architecture allows the user to access data and resources on one or more remote servers as well as on the computing grid while having the full capability of the Web-services collaborative environment. It can be accessed anytime and anywhere from a Web browser connected to the network by either a wired or wireless connection. It has different modes of operations to support different working environments and styles. CSE-Online is evolving into middleware that can provide a framework for accessing and managing remote data and resources including the computing grid for any domain, not necessarily just within computational science and engineering.

Engineering↗

Creating and simulating skeletal muscle from the visible human data set.

Simulation of the musculoskeletal system has important applications in biomechanics, biomedical engineering, surgery simulation, and computer graphics. The accuracy of the muscle, bone, and tendon geometry as well as the accuracy of muscle and tendon dynamic deformation are of paramount importance in all these applications. We present a framework for extracting and simulating high resolution musculoskeletal geometry from the segmented visible human data set. We simulate 30 contact/collision coupled muscles in the upper limb and describe a computationally tractable implementation using an embedded mesh framework. Muscle geometry is embedded in a nonmanifold, connectivity preserving simulation mesh molded out of a lower resolution BCC lattice containing identical, well-shaped elements, leading to a relaxed time step restriction for stability and, thus, reduced computational cost. The muscles are endowed with a transversely isotropic, quasi-incompressible constitutive model that incorporates muscle fiber fields as well as passive and active components. The simulation takes advantage of a new robust finite element technique that handles both degenerate and inverted tetrahedra.

Algorithms↗

A model for rouleaux pattern formation of red blood cells.

Human red blood cells (RBCs) in a solution form rouleaux patterns under various conditions. The degree of rouleaux formation depends on, for example, the concentration and molecular weight of added large molecules. We present a two-dimensional discrete cellular space model in which an RBC is represented by a rectangle and differential adhesion is assumed among the longer (a-site), the shorter (b-site) sides of the rectangle and the solvent. The total sum of the adhesion energy is assumed to guide the step-by-step change of the model cell configuration and also define absolutely stable patterns. We compare the set of absolutely stable patterns and cell aggregate patterns for both actual and computer-simulated cases to obtain the basic validity of our framework. Then we proceed to assess the effects of added high polymers to the adhesion parameters. We first note that under suitable conditions, decrease in a-site-solvent affinity is necessary to have complex patterns rather than increase of a-a affinity. The hypothesis that addition of high polymers reduce the a-site-solvent affinity is concomitant with a newly proposed osmotic stress theory. The parameter fitting results for the experimental phase change curves can also be interpreted as supporting more the new theory than existing traditional explanations.

Cell Adhesion↗

Healthcare compunetics.

Changes in life expectancy, healthy life expectancy and health seeking behaviour are having an impact on the demand for care. Such changes could occur across the whole population, or for specific groups. Changes for specific groups will be particularly affected by policy initiatives, while both these and wider changes will be affected by people's levels of engagement with their health and the health service itself. Levels of education, income and media coverage of health issues are also important. These factors could also encourage an increase in people caring for themselves and their families or community. People are now expecting a patient-centred service with safe high quality treatment, comfortable accommodation services, fast access and an integrated joined-up system. The uptake of integrated Information and Communication technologies (ICT) will be crucial. Healthcare Compunetics, the combination of computing and networking customised for medical and care, will provide the common policy and framework for combined multi-disciplinary research, development, implementation and usage.

Artificial Intelligence↗

Phylogenomic subsampling and upsampling for efficient evolutionary analyses of big data.

Long runtimes, high memory demands, and reliance on high-performance computing impede phylogenomic analyses. We review a scalable phylogenomic subsampling with upsampling (PSU) framework, in which small subsamples of sites from a concatenated alignment are expanded by upsampling before inference, and the resulting analyses are then aggregated to obtain evolutionary estimates. PSU harnesses the fact that the computational cost of maximum likelihood analysis is strongly influenced by the number of distinct site patterns in the concatenated alignment, whereas statistical power depends primarily on the amount of evolutionary information represented by the total number of sites and substitutions. By reducing the former while restoring the latter through upsampling, PSU can approximate many full-data analyses at substantially lower computational cost. Analysis of simulated and empirical datasets shows that PSU can accurately estimate bootstrap support values, select the optimal substitution model, test evolutionary hypotheses, and infer branch lengths, divergence times, and associated uncertainty measures, while reducing runtime and memory requirements by orders of magnitude. PSU also provides distributions of inferred clade support across independent subsamples, enabling detection of conflicting phylogenetic signals that may remain hidden in conventional bootstrap analysis. Automated tuning of subsample size, the number of subsamples, and the number of upsampling replicates make PSU practical across diverse datasets. We suggest that PSU is a general strategy for scalable phylogenomic inference using a broad range of statistical methods. By enabling analyses of genome-scale alignments on commodity hardware, PSU broadens research access and reduces environmental and infrastructural costs of big-data phylogenomics.

confidence limits↗

transFusion: a novel comprehensive platform for integration analysis of single-cell and spatial transcriptomics.

MOTIVATION: Understanding spatial organization, intercellular interactions, and regulatory networks within the spatial context of tissues is crucial for uncovering complex biological processes and disease mechanisms. Spatial transcriptomics technologies have revolutionized this field by enabling the spatially resolved profiling of gene expression. 10× Visium has emerged as the predominant spatial technology, but its low resolution and the complexity of integrating multimodal datasets present significant analytical challenges, particularly for researchers with limited computational and statistical expertise. Current spatial transcriptomics analysis platforms generally fall short of effectively integrating multimodal data and maximizing the utility of spatial information-such as uncovering complex cellular spatial dependencies, multimodal gradient patterns, and spatial coexpression of ligand-receptor pairs and regulatory networks related to disease or biological states-thereby limiting their ability to provide comprehensive end-to-end analytical workflows when analyzing 10× Visium data. RESULTS: To address these limitations, we developed transFusion, a novel, advanced web-based platform specializing in the most comprehensive and effective integration analysis of scRNA-seq and 10× Visium spatial transcriptomics data. transFusion offers 12 key functions, from basic visualization to advanced analyses, including intercellular dependency analysis, ligand-receptor coexpression identification and visualization, and spatial multimodal gradient variation patterns. Two case studies were used to demonstrate transFusion's capabilities in exploring tissue architecture, intercellular communication, dependency networks, and multimodal gradient variation patterns with minimal computational skills and statistical expertise. transFusion provides a flexible and powerful framework for multimodal data integration analysis. AVAILABILITY AND IMPLEMENTATION: transFusion is freely available at https://github.com/WQLin8/transFusion.

Spatial Transcriptomics↗

A framework for comprehensive health terminology systems in the United States: development guidelines, criteria for selection, and public policy implications. ANSI Healthcare Informatics Standards Board Vocabulary Working Group and the Computer-Based Patient Records Institute Working Group on Codes and Structures.

Health care in the United States has become an information-intensive industry, yet electronic health records represent patient data inconsistently for lack of clinical data standards. Classifications that have achieved common acceptance, such as the ICD-9-CM or ICD, aggregate heterogeneous patients into broad categories, which preclude their practical use in decision support, development of refined guidelines, or detailed comparison of patient outcomes or benchmarks. This document proposes a framework for the integration and maturation of clinical terminologies that would have practical applications in patient care, process management, outcome analysis, and decision support. Arising from the two working groups within the standards community--the ANSI (American National Standards Institute) Healthcare Informatics Standards Board Working Group and the Computer-based Patient Records Institute Working Group on Codes and Structures--it outlines policies regarding 1) functional characteristics of practical terminologies, 2) terminology models that can broaden their applications and contribute to their sustainability, 3) maintenance attributes that will enable terminologies to keep pace with rapidly changing health care knowledge and process, and 4) administrative issues that would facilitate their accessibility, adoption, and application to improve the quality and efficiency of American health care.

Delivery of Health Care↗

Synthesis of generalized algorithms for the fast computation of synaptic conductances with Markov kinetic models in large network simulations.

Markovkinetic models constitute a powerful framework to analyze patch-clamp data from single-channel recordings and model the dynamics of ion conductances and synaptic transmission between neurons. In particular, the accurate simulation of a large number of synaptic inputs in wide-scale network models may result in a computationally highly demanding process. We present a generalized consolidating algorithm to simulate efficiently a large number of synaptic inputs of the same kind (excitatory or inhibitory), converging on an isopotential compartment, independently modeling each synaptic current by a generic n-state Markov model characterized by piece-wise constant transition probabilities. We extend our findings to a class of simplified phenomenological descriptions of synaptic transmission that incorporate higher-order dynamics, such as short-term facilitation, depression, and synaptic plasticity.

Algorithms↗

A framework for considering business models.

Information technology (IT) such as computerized physician order entry, computer-based decision support and alerting systems, and electronic prescribing can reduce medical errors and improve the quality of health care. However, the business value of these systems is frequently questioned. At present a number of barriers exist to realizing the potential of IT to improve quality of care. Some of these barriers are: the ineffectiveness of existing error reporting systems, low investment in IT infrastructure, legal impediments to reforms, and the difficulty in demonstrating a sufficient return on investment to justify expenditures for quality improvement. This paper provides an overview of these issues, a framework for considering business models, and examples of successful implementations of IT to improve quality of patient care.

Information Management↗

Large vortex-like structure of dipole field in computer models of liquid water and dipole-bridge between biomolecules.

We propose a framework to describe the cooperative orientational motions of water molecules in liquid water and around solute molecules in water solutions. From molecular dynamics (MD) simulation a new quantity "site-dipole field" is defined as the averaged orientation of water molecules that pass through each spatial position. In the site-dipole field of bulk water we found large vortex-like structures of more than 10 A in size. Such coherent patterns persist more than 300 ps although the orientational memory of individual molecules is quickly lost. A 1-ns MD simulation of systems consisting of two amino acids shows that the fluctuations of site-dipole field of solvent are pinned around the amino acids, resulting in a stable dipole-bridge between side-chains of amino acids. The dipole-bridge is significantly formed even for the side-chain separation of 14 A, which corresponds to five layers of water. The way that dipole-bridge forms sensitively depends on the side-chain orientations and thereby explains the specificity in the solvent-mediated interactions between biomolecules.

Amino Acids↗

Describing multiple levels of abstraction in the metabolism.

We discuss some central issues that arise in the computer representation of the metabolism and its subsystems. We provide a framework for the representation of metabolites and bioreactions at multiple levels of detail. The framework is based on defining an explicit linear mapping of metabolites and reactions from one level of detail to another. A simple reaction mechanism serves as an illustration and shows the emergence of the concept of a catalyst from metabolic abstraction levels.

Catalysis↗

Novel formulation of nonlocal electrostatics.

The accurate modeling of the dielectric properties of water is crucial for many applications in physics, computational chemistry, and molecular biology. This becomes possible in the framework of nonlocal electrostatics, for which we propose a novel formulation allowing for numerical solutions for the nontrivial molecular geometries arising in the applications mentioned before. Our approach is based on the introduction of a secondary field psi, which acts as the potential for the rotation free part of the dielectric displacement field D. For many relevant models, the dielectric function of the medium can be expressed as the Green's function of a local differential operator. In this case, the resulting coupled Poisson (-Boltzmann) equations for psi and the electrostatic potential phi reduce to a system of coupled partial differential equations. The approach is illustrated by its application to simple geometries.

Biopolymers↗

Phase retrieval from noisy data based on minimization of penalized I-divergence.

We study noise artifacts in phase retrieval based on minimization of an information-theoretic discrepancy measure called Csiszár's I-divergence. We specifically focus on adding Poisson noise to either the autocorrelation of the true image (as in astronomical imaging through turbulence) or the squared Fourier magnitudes of the true image (as in x-ray crystallography). Noise effects are quantified via various error metrics as signal-to-noise ratios vary. We propose penalized minimum I-divergence methods to suppress the observed noise artifacts. To avoid computational difficulties arising from the introduction of a penalty, we adapt Green's one-step-late approach for use in our minimum I-divergence framework.

Algorithms↗

Porphyrin distortion from resonance Raman intensities of out-of-plane modes: Computation and modeling of N-methylmesoporphyrin, a ferrochelatase transition state analog.

Resonance Raman spectra of porphyrins are computed with DFT/CIS methodology to monitor out-of-plane distortions. A framework is established for assessing protein-induced distortion of porphyrin bound to a ferrochealatase antibody. Tests on undistorted porphyrins give good agreement with the experimental intensity pattern of in-plane modes for free-base porphine (FBP) and mesorporphyrin IX free base (MP). The computed spectrum of N-methylmesoporphyrin (NMP), in which the methyl-substituted pyrrole ring is tilted 32 degrees from the mean porpyrin plane, also gives reasonable agreement with experiment and reveals activation of out-of-plane (oop) vibrational modes. To model oop distortions systematically, an artificial molecule, FBP-X8, was constructed, in which the H atoms attached to the FBP pyrrole Cb atoms are replaced by heavy substituents, as in physiological porphyrins. Oop mode enhancements are computed for FBP-X8 by displacing it along the canonical distortion coordinates: doming, saddling, ruffling and waving. When FBP-X8 is constrained to the NMP porphyrin geometry, normal coordinate decomposition reveals significant contributions also from modes higher in frequency than the canonical modes, and they contribute importantly to the computed RR intensities. NMP-constrained FBP-X8 gives a reasonable facsimile of the NMP RR spectrum, but better results are obtained with a full computation of MP, constrained in the same way; thus the physiological substituents have significant influence on the RR spectra, over and above their effective masses. Attention focuses on a mode analogous to gamma 15 in 4-fold symmetric porphyrins, which is a kind of saddling mode. This mode is selectively enhanced in NMP-constrained MP; a corresponding RR band is induced upon binding MP to a ferrochelatase antibody.

Computer Simulation↗

A clinical perspective of accelerated statistical reconstruction.

Although the potential benefits of maximum likelihood reconstruction have been recognised for many years, the technique has only recently found widespread popularity in clinical practice. Factors which have contributed to the wider acceptance include improved models for the emission process, better understanding of the properties of the algorithm and, not least, the practicality of application with the development of acceleration schemes and the improved speed of computers. The objective in this article is to present a framework for applying maximum likelihood reconstruction for a wide range of clinically based problems. The article draws particularly on the experience of the three authors in applying an acceleration scheme involving use of ordered subsets to a range of applications. The potential advantages of statistical reconstruction techniques include: (a) the ability to better model the emission and detection process, in order to make the reconstruction converge to a quantitative image, (b) the inclusion of a statistical noise model which results in better noise characteristics, and (c) the possibility to incorporate prior knowledge about the distribution being imaged. The great flexibility in adapting the reconstruction for a specific model results in these techniques having wide applicability to problems in clinical nuclear medicine.

Algorithms↗

The evaluation of expert diagnostic systems. How to assess outcomes and quality parameters?

Improvement of the quality in health care and the assessment of health outcomes of medical technologies have attracted an increasing attention in the implementation phases. In this paper 10 recent evaluation studies are reviewed to investigate to what extent they reflect the structure, process, and outcome of the conceptual framework. It is found that all the evaluation studies focus on structure measures. But if computer programs to support medical decision making are to be considered in the planning process of the health care system, the evaluation studies must strive to evaluate process and outcomes measures as well. A proposal for a framework for this kind of exploratory and evaluative research is outlined.

Diagnosis, Computer-Assisted↗

Creating an interactive Web-based e-learning course: a practical introduction for radiologists.

With the development of e-learning and its ability to provide rich animated content rapidly to a wide audience, new methods for teaching medical imaging have evolved. E-learning tools allow building of learner-focused structured courses. Standards such as shareable content object reference model (SCORM) or Aviation Industry Computer-based Training Committee (AICC) guidelines and recommendations provide the framework required to combine text, images, videos, animations, and quizzes for learning assessment, even if each of these elements is created with different software. The main features to consider when choosing a learning management system are content management, assessment and reporting tools, customization options, course delivery, administration, and security. The tools for building a Web-based course with pages containing text, images, videos, and Flash animations are now accessible to any radiologist. Open-source learning management systems and content authoring software are available at no cost. The authors developed e-MRI.com, a free Web-based e-learning course with interactive animations and simulations, self-tests, and clinical cases to demonstrate the potential of the latest advances in e-learning and pedagogy applied to magnetic resonance imaging physics.

Computer-Assisted Instruction↗