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Multivariate probit analysis: a neglected procedure in medical statistics.

The multivariate probit model is designed to regress a vector of correlated quantal variables on a mixture of continuous and discrete predictors. Various applications can be found in the biological, economical and psychosociological literature, but the method is not yet widely used in medical applications. We reintroduce this model thereby showing its usefulness in medical problems. Software for this model is, however, not widely available. We have written a PC program to select predictors and estimate parameters in the multivariate probit framework. The performance and characteristics of the program are briefly illustrated.

Mathematical Computing↗

Riemannian elasticity: a statistical regularization framework for non-linear registration.

In inter-subject registration, one often lacks a good model of the transformation variability to choose the optimal regularization. Some works attempt to model the variability in a statistical way, but the re-introduction in a registration algorithm is not easy. In this paper, we interpret the elastic energy as the distance of the Green-St Venant strain tensor to the identity, which reflects the deviation of the local deformation from a rigid transformation. By changing the Euclidean metric for a more suitable Riemannian one, we define a consistent statistical framework to quantify the amount of deformation. In particular, the mean and the covariance matrix of the strain tensor can be consistently and efficiently computed from a population of non-linear transformations. These statistics are then used as parameters in a Mahalanobis distance to measure the statistical deviation from the observed variability, giving a new regularization criterion that we called the statistical Riemannian elasticity. This new criterion is able to handle anisotropic deformations and is inverse-consistent. Preliminary results show that it can be quite easily implemented in a non-rigid registration algorithms.

Algorithms↗

Relative stabilities of nitrenium ions derived from heterocyclic amine food carcinogens: relationship to mutagenicity.

The bacterial mutagenicities of a wide variety of complex heteroaromatic amine mutagens and carcinogens present in cooked foods are approximately related to the stabilities of the corresponding nitrenium ions through equations of the kind: log(m) = a delta delta H + b. The stabilities of the nitrenium ions (delta delta H) were computed using the semiempirical AM1 molecular orbital procedure. Parallel calculations of the energies, charge distributions and geometries of simple model compounds provides a qualitative framework within which the stabilities of the nitrenium ions derived from the food carcinogens can be easily understood.

Amines↗

The cerebellum and VOR/OKR learning models.

Although one particular model of the cerebellum, as proposed by Marr and Albus, provides a formal framework for understanding how heterosynaptic plasticity of Purkinje cells might be used for motor learning, the physiological details remain largely an engima. Developments in computational neuroscience and artificial neural networks applied to real control problems are essential to understand fully how workspace errors associated with movement performances can be converted into motor-command errors, and how these errors can then be used as one kind of synaptic input by motor-learning algorithms that are based on biologically plausible rules involving heterosynaptic plasticity. These developments, as well as recent advances in the study of cellular mechanisms of synaptic plasticity, form the basis for the detailed computational models of cerebellar motor learning that have been proposed. These models provide hints toward resolving a long-standing controversy in the oculomotor literature regarding the sites of adaptive changes in the vestibuloocular reflex (VOR) and the optokinetic eye movement response (OKR), and suggest new experiments to elucidate general mechanisms of sensory motor learning.

Animals↗

Neuromodulation and cortical function: modeling the physiological basis of behavior.

Neuromodulators including acetylcholine, norepinephrine, serotonin, dopamine and a range of peptides alter the processing characteristics of cortical networks through effects on excitatory and inhibitory synaptic transmission, on the adaptation of cortical pyramidal cells, on membrane potential, on the rate of synaptic modification, and on other cortical parameters. Computational models of self-organization and associative memory function in cortical structures such as the hippocampus, piriform cortex and neocortex provide a theoretical framework in which the role of these neuromodulatory effects can be analyzed. Neuromodulators such as acetylcholine and norepinephrine appear to enhance the influence of synapses from afferent fibers arising outside the cortex relative to the synapses of intrinsic and association fibers arising from other cortical pyramidal cells. This provides a continuum between a predominant influence of external stimulation to a predominant influence of internal recall (extrinsic vs. intrinsic). Modulatory influence along this continuum may underlie effects described in terms of learning and memory, signal to noise ratio, and attention.

Acetylcholine↗

Systems modeling in support of evidence-based disaster planning for rural areas.

The objective of this communication is to introduce a conceptual framework for a study that applies a rigorous systems approach to rural disaster preparedness and planning. System Dynamics is a well-established computer-based simulation modeling methodology for analyzing complex social systems that are difficult to change and predict. This approach has been applied for decades to a wide variety of issues of healthcare and other types of service capacity and delivery, and more recently, to some issues of disaster planning and mitigation. The study will use the System Dynamics approach to create computer simulation models as "what-if" tools for disaster preparedness planners. We have recently applied the approach to the issue of hospital surge capacity, and have reached some preliminary conclusions--for example, on the question of where in the hospital to place supplementary nursing staff during a severe infectious disease outbreak--some of which we had not expected. Other hospital disaster preparedness issues well suited to System Dynamics analysis include sustaining employee competence and reducing turnover, coordination of medical care and public health resources, and hospital coordination with the wider community to address mass casualties. The approach may also be applied to preparedness issues for agencies other than hospitals, and could help to improve the interactions among all agencies represented in a community's local emergency planning committee. The simulation models will support an evidence-based approach to rural disaster planning, helping to tie empirical data to decision-making. Disaster planners will be able to simulate a wide variety of scenarios, learn responses to each and develop principles or best practices that apply to a broad spectrum of disaster scenarios. These skills and insights would improve public health practice and be of particular use in the promotion of injury and disease prevention programs and practices.

Decision Making↗

Fiber tract-oriented statistics for quantitative diffusion tensor MRI analysis.

Quantitative diffusion tensor imaging (DTI) has become the major imaging modality to study properties of white matter and the geometry of fiber tracts of the human brain. Clinical studies mostly focus on regional statistics of fractional anisotropy (FA) and mean diffusivity (MD) derived from tensors. Existing analysis techniques do not sufficiently take into account that the measurements are tensors, and thus require proper interpolation and statistics of tensors, and that regions of interest are fiber tracts with complex spatial geometry. We propose a new framework for quantitative tract-oriented DTI analysis that systematically includes tensor interpolation and averaging, using nonlinear Riemannian symmetric space. A new measure of tensor anisotropy, called geodesic anisotropy (GA) is applied and compared with FA. As a result, tracts of interest are represented by the geometry of the medial spine attributed with tensor statistics (average and variance) calculated within cross-sections. Feasibility of our approach is demonstrated on various fiber tracts of a single data set. A validation study, based on six repeated scans of the same subject, assesses the reproducibility of this new DTI data analysis framework.

Algorithms↗

A deep learning framework for denoising and ordering scRNA-seq data using adversarial autoencoder with dynamic batching.

Single-cell RNA sequencing (scRNA-seq) provides high resolution of cell-to-cell variation in gene expression and offers insights into cell heterogeneity, differentiating dynamics, and disease mechanisms. However, technical challenges such as low capture rates and dropout events can introduce noise in data analysis. Here, we present a deep learning framework, called the dynamic batching adversarial autoencoder (DB-AAE), for denoising scRNA-seq datasets. First, we describe steps to set up the computing environment, training, and tuning. Then, we depict the visualization of the denoising results. For complete details on the use and execution of this protocol, please refer to Ko et al.1.

Deep Learning↗

Geometric and many-particle aspects of transmitter binding.

We investigate the various reactivity patterns possible when several transmitter molecules, released at one side of a synaptic gap, diffuse and bind reversibly to a single receptor at the other end. In the framework of a one-dimensional approximation, the complete time, reactivity, concentration and gap-width dependence are determined, using a rigorous theoretical and computational approach to the many-body aspects of this problem. The time dependence of the survival probability is found to consist of up to four phases. These include a short delay followed by gaussian, power-law, and exponential decay phases. A rigorous expression is derived for the long-time exponent and approximate expressions are obtained for describing the short-time gaussian phase.

Acetylcholine↗

Pulling smarties out of a bag: a Headed Records analysis of children's recall of their own past beliefs.

The work reported provides an information processing account of young children's performance on the Smarties task (Perner, J., Leekam, S.R., & Wimmer, H. 1987, Three-year-olds' difficulty with false belief: the case for a conceptual deficit. British Journal of Developmental Psychology, 5, 125-137). In this task, a 3-year-old is shown a Smarties tube and asked about the supposed contents. The true contents, pencils, is then revealed, and the majority of 3-year-olds cannot recall their initial belief that the tube contained Smarties. The theoretical analysis, based on the Headed Records framework (Morton, J., Hammersley, R.J., & Bekerian, D.A. 1985, Headed records: a model for memory and its failures, Cognition, 20, 1-23), focuses on the computational conditions that are required to resolve the Smarties task; on the possible limitations in the developing memory system that may lead to a computational breakdown; and on ways of bypassing such limitations to ensure correct resolution. The design, motivated by this analysis, is a variation on Perner's Smarties task. Instead of revealing the tube's contents immediately after establishing the child's beliefs about it, these contents were then transferred to a bag and a (false) belief about the bag's contents established. Only then were the true contents of the bag revealed. The same procedure (different contents) was carried out a week later. As predicted children's performance was better (a) in the 'tube' condition; and (b) on the second test. Consistent with the proposed analysis, the data show that when the computational demands imposed by the original task are reduced, young children can and do remember what they had thought about the contents of the tube even after its true contents are revealed.

Child, Preschool↗

A methodology for partitioning a vocabulary hierarchy into trees.

Controlled medical vocabularies are useful in application areas such as medical information systems and decision-support systems. However, such vocabularies are large and complex, and working with them can be daunting. It is important to provide a means for orienting vocabulary designers and users to the vocabulary's contents. We describe a methodology for partitioning a vocabulary based on an IS-A hierarchy into small meaningful pieces. The methodology uses our disciplined modeling framework to refine the IS-A hierarchy according to prescribed rules in a process carried out by a user in conjunction with the computer. The partitioning of the hierarchy implies a partitioning of the vocabulary. We demonstrate the methodology with respect to a complex sample of the MED, an existing medical vocabulary.

Models, Theoretical↗

A Web-based program for implementing evidence-based patient safety recommendations.

BACKGROUND: In response to increasing national concerns about medical safety, product developers from a health services research and software group recently created a commercial Web-based program to address a wide variety of patient safety issues in the acute care setting. They also wanted to provide a program with credible, referenced, and up-to-date content, not just a technology infrastructure for reporting errors. SAFETY OPTIMIZER: This Web-based program, which has evolved over time, now features seven modules for assessing organizational risk and for implementing strategies to reduce risk. The Literature Module features detailed synopses that are graded and organized into summary statements to provide recommendations for improving patient safety. The Implementation/Tracking Module includes numerous risk-reduction strategies. The Incident Reporting Module enables the collection of data at the point of care on a variety of incidents, using either paper-based or on-line forms. Other modules offer opportunities to assess adherence to JCAHO patient safety standards, forecast the benefits of certain evidence-based guidelines, evaluate staff competency, and obtain information from a variety of key safety Web sites. EXPERIENCE TO DATE: The program is in use at more than 30 health care organization facilities and systems. It is still too early to provide quantitative data on the impact of this program on patient safety. CONCLUSIONS: It is hoped that vendor solutions such as the one described in this article will help organizations develop a practical and effective framework for addressing the wide range of issues in patient safety.

Clinical Competence↗

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

Angiotensin-Converting Enzyme Inhibitors↗

Halo substituent effects on intramolecular cycloadditions involving furanyl amides.

Intramolecular Diels-Alder reactions involving a series of N-alkenyl-substituted furanyl amides were investigated. Stable functionalized oxanorbornenes were formed in high yield upon heating at 80-110 degrees C. The cycloaddition reactions include several bromo-substituted furanyl amides, and these systems were found to proceed at a much faster rate and in higher yield than without substitution. This effect was observed by incorporating a halogen in the 3- or 5-position of the furan ring and appears to be general. The origin of increased cycloaddition rates for halo-substituted furans has been investigated with quantum mechanical calculations. The success of these reactions is attributed to increases in reaction exothermicities; this both decreases activation enthalpies and increases barriers to retrocycloadditions. Halogen substitution on furan increases reactant energy and stabilizes the product, which is attributed to the preference of electronegative halogens to be attached to a more highly alkylated and therefore more electropositive framework.

Amides↗

On the information-theoretical meaning of Hill's parametric evenness.

The degree to which abundances are divided equitably among community species or evenness is a basic property of any biological community. Several evenness indices have been proposed to summarize community structure. However, despite their potential applicability in ecological research, none seems to be generally preferred. In this paper we show that, unlike other evenness indices without any clear information-theoretical meaning, Hill's parametric diversity measure E(alpha,0) has an immediate relation to Rényi's generalized information. Therefore, E(alpha,0) might be adequate for summarizing community structure within the context of a general theoretical framework of diversity analysis based on information theory.

Ecology↗

Topological units of environmental signal processing in the transcriptional regulatory network of Escherichia coli.

Recent evidence indicates that potential interactions within metabolic, protein-protein interaction, and transcriptional regulatory networks are used differentially according to the environmental conditions in which a cell exists. However, the topological units underlying such differential utilization are not understood. Here we use the transcriptional regulatory network of Escherichia coli to identify such units, called origons, representing regulatory subnetworks that originate at a distinct class of sensor transcription factors. Using microarray data, we find that specific environmental signals affect mRNA expression levels significantly only within the origons responsible for their detection and processing. We also show that small regulatory interaction patterns, called subgraphs and motifs, occupy distinct positions in and between origons, offering insights into their dynamical role in information processing. The identified features are likely to represent a general framework for environmental signal processing in prokaryotes.

Computer Simulation↗

The importance of healthy communities of higher education.

A framework for understanding issues that contribute to vibrant and healthy communities of higher education is presented. The focus is on how individual and community health relate to institutional missions, purposes, and goals. This framework may be applied to 2-year and 4-year colleges and universities whether they are public, private, research, teaching, sectarian, religious, residential, or computer institutions. The following questions are addressed: Why should colleges maintain healthy communities? How do we define health in colleges and universities? Why is this important for society? What are the key responsibilities in fostering healthy educational communities? Who is responsible for assuring that this happens? What added value do personal and community health yield for institutions of higher education? Readers are provided with a rationale for assessing the role and importance of individual and community health in their campus environments; engaging students, faculty, and staff in discussions about these issues; and determining whether more thorough, systematic, and intensive community health assessments or interventions are needed in their campus settings.

Health↗