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PubMed2025

WinPCA: a package for windowed principal component analysis.

SUMMARY: With chromosomal reference genomes and population-scale whole genome-sequencing becoming increasingly accessible, contemporary studies often include characterizations of the genomic landscape as it varies along chromosomes, commonly termed genome scans. While traditional summary statistics like FST and dXY between pre-assigned populations remain integral to characterizing the genomic divergence profile, PCA differs by providing single-sample resolution, thereby supporting the identification of polymorphic inversions, introgression and other types of divergent sequence that may not be fully aligned with global population structure. Here, we introduce WinPCA, a user-friendly package to compute, polarize and visualize genetic principal components in windows along the genome. To accommodate low-coverage whole genome-sequencing datasets, WinPCA can optionally make use of PCAngsd methods to compute principal components in a genotype likelihood framework. WinPCA accepts variant data in either VCF or BEAGLE format and can generate rich plots for interactive data exploration and downstream presentation. AVAILABILITY AND IMPLEMENTATION: WinPCA is implemented in Python and freely available at https://github.com/MoritzBlumer/winpca and https://doi.org/10.5281/zenodo.15614979.

Software↗
PubMed2005

Structural basis of biological nitrogen fixation.

Biological nitrogen fixation is mediated by the nitrogenase enzyme system that catalyses the ATP dependent reduction of atmospheric dinitrogen to ammonia. Nitrogenase consists of two component metalloproteins, the MoFe-protein with the FeMo-cofactor that provides the active site for substrate reduction, and the Fe-protein that couples ATP hydrolysis to electron transfer. An overview of the nitrogenase system is presented that emphasizes the structural organization of the proteins and associated metalloclusters that have the remarkable ability to catalyse nitrogen fixation under ambient conditions. Although the mechanism of ammonia formation by nitrogenase remains enigmatic, mechanistic inferences motivated by recent developments in the areas of nitrogenase biochemistry, spectroscopy, model chemistry and computational studies are discussed within this structural framework.

Ammonia↗
PubMed2000

Renormalization-group approach to the vulcanization transition

The vulcanization transition-the cross-link-density-controlled equilibrium phase transition from the liquid to the amorphous solid state-is explored analytically from a renormalization-group perspective. The analysis centers on a minimal model which has previously been shown to yield a rich and informative picture of vulcanized matter at the mean-field level, including a connection with mean-field percolation theory (i.e., random graph theory). This minimal model accounts for both the thermal motion of the constituents and the quenched random constraints imposed on their motion by the cross-links, as well as particle-particle repulsion which suppresses density fluctuations and plays a pivotal role in determining the symmetry structure (and hence properties) of the model. A correlation function involving fluctuations of the amorphous solid order parameter, the behavior of which signals the vulcanization transition, is examined, its physical meaning is elucidated, and the associated susceptibility is constructed and analyzed. A Ginzburg criterion for the width (in cross-link density) of the critical region is derived and is found to be consistent with a prediction due to de Gennes. Inter alia, this criterion indicates that the upper critical dimension for the vulcanization transition is 6. Certain universal critical exponents characterizing the vulcanization transition are computed, to lowest nontrivial order, within the framework of an expansion around the upper critical dimension. This expansion shows that the connection between vulcanization and percolation extends beyond mean-field theory, surviving the incorporation of fluctuations in the sense that pairs of physically analogous quantities (one percolation related and one vulcanization related) are found to be governed by identical critical exponents, at least to first order in the departure from the upper critical dimension (and presumably beyond). The relationship between the present approach to vulcanized matter and other approaches, such as those based on gelation-percolation ideas, is explored in the light of this connection. To conclude, some expectations for how the vulcanization transition is realized in two dimensions, developed with H. E. Castillo, are discussed.

Journal Article↗
PubMed2004

Dissipation and tunneling in quantum Hall bilayers.

We discuss the interplay between transport and intrinsic dissipation in quantum Hall bilayers, within the framework of a simple thought experiment. We compute, for the first time, quantum corrections to the semiclassical dynamics of this system. This allows us to reinterpret tunneling measurements on these systems. We find a strong peak in the zero-temperature tunneling current that arises from the decay of Josephson-like oscillations into incoherent charge fluctuations. In the presence of an in-plane field, resonances in the tunneling current develop an asymmetric line shape.

Journal Article↗
PubMed2003

Open capture-recapture models with heterogeneity: I. Cormack-Jolly-Seber model.

In open population capture-recapture studies, it is usually assumed that similar animals (e.g., of the same sex and age group) have similar survival rates and capture probabilities. These assumptions are generally perceived to be an oversimplification, and they can lead to incorrect model selection and biased parameter estimates. Allowing for individual variability in survival and capture probabilities among apparently similar animals is now becoming possible, due to advances in closed population models and improved computing power. This article presents a flexible framework of likelihood-based models which allow for individual heterogeneity in survival and capture rates. Heterogeneity is modeled using finite mixtures, which have enough flexibility of distribution shape to accommodate a wide variety of different patterns of individual variation. The models condition on the first capture of each animal, and include as a special case the Cormack-Jolly-Seber model. Model selection is done either using Akaike's information criterion or by likelihood ratio tests, making available checks of different influences on survival rates. Bias in parameter estimates is reduced by including individual heterogeneity. Model selection and bias reduction are important in population studies and for making informed management decisions.

Animals↗
PubMed1972

The role of operational research in clinical chemistry.

This paper begins with a critical examination of the published account (Carruthers, 1970) of a pioneering study of simulation in a clinical chemistry laboratory. It next considers the basic requirements for the formal mathematical description of such a laboratory: these include the setting of criteria, the resource and input variates, and the definition of success by means of criterion variates. Investigation of criterion variates can be by direct measurement, or by a theoretical approach which may include simulation. The aims of simulation are discussed and an attempt to simulate the operation of a large clinical chemistry laboratory is described. The difficulty of constructing an overall measure of efficiency is considered in relation to improving performance within an existing framework, to evaluating new equipment such as computers on-line to laboratory apparatus, and to inter-laboratory comparisons of performance. It is concluded that complex operational research techniques, including simulation, have little to offer at least for the present, and may even lead to misleading conclusions.

Chemistry, Clinical↗
PubMed2004

Thirty years of computational autopoiesis: a review.

Computational autopoiesis--the realization of autopoietic entities in computational media--holds an important and distinctive role within the field of artificial life. Its earliest formulation by Francisco Varela, Humberto Maturana, and Ricardo Uribe was seminal in demonstrating the use of an artificial, computational medium to explore the most basic question of the abstract nature of living systems--over a decade in advance of the first Santa Fe Workshop on Artificial Life. The research program it originated has generated substantive demonstrations of progressively richer, lifelike phenomena. It has also sharply illuminated both conceptual and methodological problems in the field. This article provides an integrative overview of the sometimes disparate work in this area, and argues that computational autopoiesis continues to provide an effective framework for addressing key open problems in artificial life.

Artificial Intelligence↗
PubMed1985

Risk assessment extrapolations and physiological modeling.

The process of assessing the risk associated with human exposure to environmental chemicals inevitably relies on a number of assumptions, estimates and rationalizations. One of the more challenging aspects of risk assessment involves the need to extrapolate beyond the range of conditions used in experimental animal studies to predict anticipated human risks. The most obvious extrapolation required is that from the tested animal species to humans; but others are also generally required, including extrapolating from high dose to low dose, from one route of exposure to another and from one exposure timeframe to another. Several avenues are available for attempting these extrapolations, ranging from the assumption of strict correspondence of dose to the use of statistical correlations. One promising alternative for conducting more scientifically sound extrapolations is that of using physiologically based pharmacokinetic models that contain sufficient biological detail to allow pharmacokinetic behavior to be predicted for widely different exposure scenarios. In recent years, successful physiological models have been developed for a variety of volatile and nonvolatile chemicals, and their ability to perform the extrapolations needed in risk assessment has been demonstrated. Techniques for determining the necessary biochemical parameters are readily available, and the computational requirements are now within the scope of even a personal computer. In addition to providing a sound framework for extrapolation, the predictive power of a physiologically based pharmacokinetic model makes it a useful tool for more reliable dose selection before beginning large-scale studies, as well as for the retrospective analysis of experimental results.

Animals↗
PubMed2006

Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution II: dynamics.

BACKGROUND: To accurately describe gene expression and computationally model animal transcriptional networks, it is essential to determine the changing locations of cells in developing embryos. RESULTS: Using automated image analysis methods, we provide the first quantitative description of temporal changes in morphology and gene expression at cellular resolution in whole embryos, using the Drosophila blastoderm as a model. Analyses based on both fixed and live embryos reveal complex, previously undetected three-dimensional changes in nuclear density patterns caused by nuclear movements prior to gastrulation. Gene expression patterns move, in part, with these changes in morphology, but additional spatial shifts in expression patterns are also seen, supporting a previously proposed model of pattern dynamics based on the induction and inhibition of gene expression. We show that mutations that disrupt either the anterior/posterior (a/p) or the dorsal/ventral (d/v) transcriptional cascades alter morphology and gene expression along both the a/p and d/v axes in a way suggesting that these two patterning systems interact via both transcriptional and morphological mechanisms. CONCLUSION: Our work establishes a new strategy for measuring temporal changes in the locations of cells and gene expression patterns that uses fixed cell material and computational modeling. It also provides a coordinate framework for the blastoderm embryo that will allow increasingly accurate spatio-temporal modeling of both the transcriptional control network and morphogenesis.

Animals↗
PubMed2002

The IUPS Physiome Project. International Union of Physiological Sciences.

Modern medicine is currently benefiting from the development of new genomic and proteomic techniques, and also from the development of ever more sophisticated clinical imaging devices. This will mean that the clinical assessment of a patient's medical condition could, in the near future, include information from both diagnostic imaging and DNA profile or protein expression data. The Physiome Project of the International Union of Physiological Sciences (IUPS) is attempting to provide a comprehensive framework for modelling the human body using computational methods which can incorporate the biochemistry, biophysics and anatomy of cells, tissues and organs. A major goal of the project is to use computational modelling to analyse integrative biological function in terms of underlying structure and molecular mechanisms. To support that goal the project is establishing web-accessible physiological databases dealing with model-related data, including bibliographic information, at the cell, tissue, organ and organ system levels. This paper discusses the development of comprehensive integrative mathematical models of human physiology based on patient-specific quantitative descriptions of anatomical structures and models of biophysical processes which reach down to the genetic level.

Biophysics↗
PubMed2004

Strong collaboration sets QI program apart.

Quality initiatives are not viewed in silos, but in a global, hospitalwide framework. All new physicians must learn the computer system--and treat nurses with respect. Facility participates in as many state, regional, and national benchmark projects as possible.

California↗
PubMed1996

Computer-assisted clinimetric tool for the study of facial expression: a pilot validity study.

Clinimetrics is the measurement of clinical phenomena; more specifically, it is mensuration, the act of acquiring and labeling basic raw data that is used to describe or measure symptoms, signs, and other distinctly clinical phenomena. Over the last 5 years, a new computer method for measuring facial expression has been developed. Refinement and validation of this technique are necessary before clinical applications are appropriate. Four hundred fifty data points from two human observers and the computed method were compared with one another by using indices of location, dispersion, and association within the framework of the logical construct of validity. These results suggest that the computed method is valid. This new method may be nearly ready for clinical applications as a primary or adjunctive clinimetric tool.

Adult↗
PubMed2006

Mathematical modeling of cancer progression and response to chemotherapy.

The complex, constantly evolving and multifaceted nature of cancer has made it difficult to identify unique molecular and pathophysiological signatures for each disease variant, consequently hindering development of effective therapies. Mathematical modeling and computer simulation are tools that can provide a robust framework to better understand cancer progression and response to chemotherapy. Successful therapeutic agents must overcome biological barriers occurring at multiple space and time scales and still reach targets at sufficient concentrations. A multiscale computer simulator founded on the integration of experimental data and mathematical models can provide valuable insights into these processes and establish a technology platform for analyzing the effectiveness of chemotherapeutic drugs, with the potential to cost-effectively and efficiently screen drug candidates during the drug-development process.

Antineoplastic Agents↗
PubMed2004

An integrative neural network for detecting inertial motion and head orientation.

The ability to navigate in the world and execute appropriate behavioral responses depends critically on the contribution of the vestibular system to the detection of motion and spatial orientation. A complicating factor is that otolith afferents equivalently encode inertial and gravitational accelerations. Recent studies have demonstrated that the brain can resolve this sensory ambiguity by combining signals from both the otoliths and semicircular canal sensors, although it remains unknown how the brain integrates these sensory contributions to perform the nonlinear vector computations required to accurately detect head movement in space. Here, we illustrate how a physiologically relevant, nonlinear integrative neural network could be used to perform the required computations for inertial motion detection along the interaural head axis. The proposed model not only can simulate recent behavioral observations, including a translational vestibuloocular reflex driven by the semicircular canals, but also accounts for several previously unexplained characteristics of central neural responses such as complex otolith-canal convergence patterns and the prevalence of dynamically processed otolith signals. A key model prediction, implied by the required computations for tilt-translation discrimination, is a coordinate transformation of canal signals from a head-fixed to a spatial reference frame. As a result, cell responses may reflect canal signal contributions that cannot be easily detected or distinguished from otolith signals. New experimental protocols are proposed to characterize these cells and identify their contributions to spatial motion estimation. The proposed theoretical framework makes an essential first link between the computations for inertial acceleration detection derived from the physical laws of motion and the neural response properties predicted in a physiologically realistic network implementation.

Acceleration↗
PubMed1994

Further improvement in methods of group-to-group sequence alignment with generalized profile operations.

It has previously been shown that rigorous optimization of alignment between two groups of sequences in the sense of minimal sum of pairs (SP) score with a linear gap-weighting function can be achieved by an extended version of the dynamic programming algorithm. The major drawback of this algorithm was that the computation time grows in proportion to the product of the numbers (M and N) of sequences comprising the two groups. A new algorithm presented in this paper achieves the same rigorous alignment in a time complexity much less dependent on the sizes of the groups. Examinations with many groups of sequences indicated that the new algorithm runs faster than the earlier one when M x N > 6-10, approximately 10 times faster when M x N approximately 200, and > 100 times faster when M x N > 2500. This computational acceleration facilitates application of the algorithm to alignment of large groups, especially in the framework of iterative refinement strategies.

Algorithms↗
PubMed2002

Theory, abstraction and design in medical informatics.

OBJECTIVE: To analyze the scientific and engineering components of Medical Informatics. A clear characterization of these components should be undertaken to categorize different areas of Medical Informatics and create a research agenda for the future. METHODS: We have adapted a classical ACM and IEEE report on computing to analyze Medical Informatics from three different viewpoints: Theory, Abstraction, and Design. RESULTS: We suggest that Medical Informatics can be considered from these three perspectives: (1) Theory, from which medical informaticians formally characterize the properties of the objects of study, creating new theories or using and adapting existing theories (e.g., from mathematics), (2) Abstraction, from which medical informaticians deal with all aspects of medical information and create new abstractions, methods, and technology-independent models, which can be experimentally verified, and (3) Design, from which medical informaticians develop systems or act as information brokers or advisors between medical and technology professionals, to improve the quality of computer applications in medicine. CONCLUSION: Based on this framework, we suggest that Medical Informatics has an independent scientific character, different from other applied informatics areas. Finally, we analyze these three perspectives using data mining in medicine.

Medical Informatics↗
PubMed2004

Towards quality control for DNA microarrays.

We present a framework for detecting probes in oligonucleotide microarrays that may add significant error to measurements in hybridization experiments. Four types of so-called degenerate probe behavior are considered: secondary structure formation, self-dimerization, cross-hybridization, and dimerization. The framework uses a well-established model for computing the free energy of nucleic acid sequence hybridization and a novel method for the detection of patterns in hybridization experiment data. Our primary result is the identification of unique patterns in hybridization experiment data that are shown to correlate with each type of degenerate probe behavior. A support function for identifying degenerate probes from a large set of hybridization experiments is given and some preliminary experimental results are given for the Affymetrix HuGeneFL GeneChip. Finally, we show a strong relationship between the Affymetrix discrimination measure for a probe and the free-energy estimate from theoretical models of hybridization. In particular, probes on the HuGeneFL GeneChip with high free-energy estimates (weak hybridization) have almost always approximately zero discrimination. The framework can be applied to any Affymetrix oligonucleotide array, and the software is made freely available to the community.

Base Sequence↗
PubMed2001

Computing diffusion rates in T2-dark hematomas and areas of low T2 signal.

BACKGROUND AND PURPOSE: It has been suggested that restricted diffusion is present within hematomas with intact red cell membranes; however, computing apparent diffusion coefficient (ADC) values in areas of low T2 signal can be problematic. Our purpose was to show the pitfalls of measuring diffusion within hematomas with intracellular blood products and to present a framework based on the properties of expected values for computing ADC values from regions with signal intensities close to that of the background noise (ie, T2-dark hematomas). METHODS: Twelve patients with intracranial hematomas who had undergone diffusion imaging were retrospectively identified during a 2-year period (four intracellular oxyhemoglobin, seven intracellular deoxyhemoglobin, one intracellular methemoglobin). Regions of interest were drawn on the hematomas, the contralateral white matter, and over the background. ADC values were computed using a variety of methods: 1) using expected values incorporating the variance of the background, 2) computing the mean of the regions of interest before taking the natural log, 3) masking negative values, and 4) masking the background at 0.5% increments from 0.5 to 5.5% and including the masked voxels (an intrinsically flawed method). Two-tailed Student's t test was performed between the white matter and the hematoma ADC values. RESULTS: There was no statistically significant difference between the hematomas and the white matter for methods 1 through 3 (P = .14, P = .23, and P = .83, respectively). Only method 4 revealed a statistically significant difference, beginning at 0.5% masking (P = .04) and becoming progressively more significant with increased masking (P = 4.14 x 10(-7) at 5.5% masking). The effect of masking was limited to the T2-dark hematomas. CONCLUSION: There is no restriction of diffusion for in vivo hematomas with intracellular blood products. The T2 blackout effect for T2-dark hematomas on diffusion-weighted images should not be interpreted as fast diffusion. The method of expected values can be used to obtain measurements for regions with signal intensities near the background noise. Using literature values for RBC self-diffusion, we computed lower limits of diffusion for hematomas with intracellular blood products to be 0.3 x 10(-3) mm2/s.

Cerebral Hemorrhage↗