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The power of iterated generalized least squares (GLS) method to detect direct relationships in the analysis of correlated quantitative traits.

We examined the power of the stepwise iterated generalized least squares (GLS) method by modeling the relationship between quantitative traits and other variables using the simulated data for Problem 2A. The comparison between the generating model provided by the workshop and the results of the stepwise iterated GLS model showed that this method could be used as a first step in identifying the underlying model for genetic data. The estimated covariance matrices also provide useful information about the genetic properties of the traits.

Computer Simulation↗

Intracardiac electrogram parameters, electrode surface area and pacer input impedance: their correlations.

Small surface area electrodes are accused of sensing defects which were related to alterations that they induce in the endocardiac electrograms. Since several factors affect the cardiac signal coming from electrode to sensing circuit, i.e. electrode surface area, electrode-tissue interface, pacemaker input impedance and sensing amplifier pass-band, Authors present their studies performed on 252 implanted electrodes of various type. Study was carried out by connecting in parallel to the recorder a variable resistor in order to simulate different pacer input impedances. The results showed a significant reduction in RS amplitude when recorder was paralleled with resistor values lower than 40 K. Slew rates showed a similar behaviours since RS steep tract did not change his duration with load, while total QRS duration is reduced. High speed analysis has shown that the RS segment is not linear in about 40% of cases: the main tract is used for calculations. The most significant attenuations and distortions of endocardial electrogram were observed with smallest electrodes and lowest resistances parallel connected: in these cases the sensing impedance at the electrode-tissue interface appears to be between 3 to 5 K ohms. The results suggest that the most of the alledged sensing faults experienced in the past were probably due to small tip electrodes connected to low input impedance generators or to impending failure situations. The AA. conclude that the main question does not concerne a true electrode inefficiency but a wrongly chosen pacemaker-electrode combination, i.e. small tip electrode connected with old generator models. To avoid the evaluation error, it would be instrumental that the pacemaker manufacturers would specify input characteristics of their generators. So, the implanting clinician becomes able to exactly evaluate the true signal arriving to the sensing circuit by connecting in parallel with the recorder input a resistor whose value approximates the input resistance of the generator to be implanted.

Cardiac Pacing, Artificial↗

Testing models of female reproductive migratory behaviour and population structure in the Caribbean hawksbill turtle, Eretmochelys imbricata, with mtDNA sequences.

Information on the reproductive behaviour and population structure of female hawksbill turtles, Eretmochelys imbricata, is necessary to define conservation priorities for this highly endangered species. Two hypotheses to explain female nest site choice, natal homing and social facilitation, were tested by analyzing mtDNA control region sequences of 103 individuals from seven nesting colonies in the Caribbean and western Atlantic. Under the social facilitation model, newly mature females follow older females to a nesting location, and subsequently use this site for future nesting. This model generates an expectation that female lineages will be homogenized among regional nesting colonies. Contrary to expectations of the social facilitation model, mtDNA lineages were highly structured among western Atlantic nesting colonies. These analyses identified at least 6 female breeding stocks in the Caribbean and western Atlantic and support a natal homing model for recruitment of breeding females. Reproductive populations are effectively isolated over ecological time scales, and recovery plans for this species should include protection at the level of individual nesting colonies.

Animals↗

Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer.

Probasin (PB) gene product is prostate-specific, epithelial cell in origin, and androgen-regulated. A large 12-kb promoter fragment of the PB gene (LPB) was linked to the simian virus 40 (SV40) large T antigen (Tag) deletion mutant (that removes the expression of the small t antigen) to deliver consistently high levels of transgene expression to the transgenic mouse prostate. Seven male founders, their male offspring, and all the male offspring from two female founders developed at least prostatic epithelial cell hyperplasia by 10 weeks of age, indicating that the incidence of transformation was 100%. Tumorigenesis in the LPB-Tag animals progressed in a manner similar to that observed in the human prostate. Initially, multifocal proliferating lesions were detected in the prostatic epithelium, which continued to progress into hyperplasia involving the entire epithelium and then low-grade dysplasia. Reactive stromal proliferation was induced and continued to develop throughout the progression to high-grade dysplasia, carcinoma in situ, and adenocarcinoma. Immunohistochemical studies indicated that most stromal cells stained positively for both androgen receptor and smooth muscle alpha-actin, suggesting that stromal overgrowth largely represented mesenchymal cells that had differentiated into smooth muscle cells. Epithelial cell transformation was accompanied by the down-regulation of differentiated function, as suggested by the loss of dorsolateral prostate-specific secretory proteins. Tumor growth was regarded as androgen-dependent because tumors regressed in animals castrated at 11 weeks of age, and androgen treatment restored both epithelial/stromal cell ratio and tumor growth. Furthermore, small populations of prostatic epithelial cells in castrated animals continued to proliferate, suggesting the potential for androgen-independent growth. Although prostatic metastasis to other organs was not observed, local invasion was detected. In summary, the LPB-Tag animal model is unique in that it is the only model generated with the Tag alone, thereby eliminating any influences of the small t antigen on prostate tumor formation. Moreover, this model undergoes molecular changes similar to those found in human prostate including: (a) the multi-focal nature of tumorigenesis, (b) the progressive histopathologic changes from low- to high-grade dysplasia similar to human prostatic intraepithelial neoplasia, (c) stimulation of reactive stromal proliferation, and (d) the androgen-dependent growth of the primary tumor. Thus, the LPB-Tag prostate tumor model will be useful for studying the sequential mechanisms underlying the development of multistep tumorigenesis.

Androgen-Binding Protein↗

Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer.

Probasin (PB) gene product is prostate-specific, epithelial cell in origin, and androgen-regulated. A large 12-kb promoter fragment of the PB gene (LPB) was linked to the simian virus 40 (SV40) large T antigen (Tag) deletion mutant (that removes the expression of the small t antigen) to deliver consistently high levels of transgene expression to the transgenic mouse prostate. Seven male founders, their male offspring, and all the male offspring from two female founders developed at least prostatic epithelial cell hyperplasia by 10 weeks of age, indicating that the incidence of transformation was 100%. Tumorigenesis in the LPB-Tag animals progressed in a manner similar to that observed in the human prostate. Initially, multifocal proliferating lesions were detected in the prostatic epithelium, which continued to progress into hyperplasia involving the entire epithelium and then low-grade dysplasia. Reactive stromal proliferation was induced and continued to develop throughout the progression to high-grade dysplasia, carcinoma in situ, and adenocarcinoma. Immunohistochemical studies indicated that most stromal cells stained positively for both androgen receptor and smooth muscle alpha-actin, suggesting that stromal overgrowth largely represented mesenchymal cells that had differentiated into smooth muscle cells. Epithelial cell transformation was accompanied by the down-regulation of differentiated function, as suggested by the loss of dorsolateral prostate-specific secretory proteins. Tumor growth was regarded as androgen-dependent because tumors regressed in animals castrated at 11 weeks of age, and androgen treatment restored both epithelial/stromal cell ratio and tumor growth. Furthermore, small populations of prostatic epithelial cells in castrated animals continued to proliferate, suggesting the potential for androgen-independent growth. Although prostatic metastasis to other organs was not observed, local invasion was detected. In summary, the LPB-Tag animal model is unique in that it is the only model generated with the Tag alone, thereby eliminating any influences of the small t antigen on prostate tumor formation. Moreover, this model undergoes molecular changes similar to those found in human prostate including: (a) the multi-focal nature of tumorigenesis, (b) the progressive histopathologic changes from low- to high-grade dysplasia similar to human prostatic intraepithelial neoplasia, (c) stimulation of reactive stromal proliferation, and (d) the androgen-dependent growth of the primary tumor. Thus, the LPB-Tag prostate tumor model will be useful for studying the sequential mechanisms underlying the development of multistep tumorigenesis.

Androgen-Binding Protein↗

Comparison of spike-triggered functional MRI BOLD activation and EEG dipole model localization.

We studied six patients with localization-related epilepsy, frequent interictal epileptiform discharges, and positive spike-triggered blood oxygen level-dependent functional MRI (BOLD-fMRI) findings. EEG source analysis solutions based on 64-channel EEG recorded in a separate session outside the scanner were obtained using dipole models and compared to the BOLD localization. The BOLD and structural images were coregistered, allowing the measurement of distances between the generator models and BOLD activation(s) and structural lesion when present. In all cases dipole models could be found that explained a sufficient amount of the data and that were anatomically concordant with the BOLD localization. In the five cases with structural abnormality visible on T1 scans, the BOLD activation overlapped or was in close proximity to the abnormality. The overall mean distance between the main moving dipole and the center of the nearest BOLD activation was 3.5 and 2.2 cm for the negative and positive peaks, respectively, including one case of a deep BOLD activation, in which the distance was 5 cm. In conclusion, the degree of agreement between the BOLD and EEG source localization indicates that the combination of these two noninvasive techniques offers the possibility of advancing the study of the generators of epileptiform electrical activity.

Adult↗

PRISM-G: an interpretable privacy scoring framework for assessing risk in synthetic human genome data.

MOTIVATION: Synthetic genomic data promises broader data access, but unresolved privacy risks remain a major concern. Existing evaluations often rely on similarity-based metrics that measure proximity between real and synthetic genomes, overlooking additional mechanisms through which genomic information may leak. RESULTS: We introduce PRISM-G, a model-agnostic framework that quantifies privacy exposure in synthetic genomic data across three complementary components: proximity to real genomes in genetic-coordinate space, replay of familial or population-structure patterns, and trait-linked exposure through rare variants and membership-inference signals. These components are normalized and combined through a risk-averse aggregation into a single 0-100 PRISM-G score. By pairing PRISM-G with downstream utility metrics, the framework also enables analysis of privacy-utility trade-offs across generative models. We evaluated PRISM-G on synthetic cohorts generated by a generative adversarial network (GAN), a restricted Boltzmann machine (RBM), and a logic-based SAT solver (Genomator). Our results show that privacy vulnerabilities arise along different axes across models and marker densities, demonstrating that a single similarity-based metric is insufficient to characterize genomic privacy risk. AVAILABILITY AND IMPLEMENTATION: The source code of PRISM-G is available at https://github.com/alejocrojo09/prismg.

Humans↗

A molecular modeling analysis of the binding interactions between the okadaic acid class of natural product inhibitors and the Ser-Thr phosphatases, PP1 and PP2A.

We have proposed computer-generated models of the catalytic subunits of the serine-threonine protein phosphatases PP1 and PP2A complexed with their endogenous substrate phospho-DARPP-32, and several known naturally occurring inhibitors. This study is part of an overall effort to elucidate the signal transduction pathways in which PP1 and PP2A may play an important role.

Amino Acid Sequence↗

Fast generation of stereolithographic models.

In this paper we present a work-in-progress method for fast and efficient generation of stereolithographic models. The overall approach is embedded in our general software framework Julius, which runs on high-end-graphic systems as well as on low-level PCs. The design of the support structures needed for the stereolithographic process will allow semiautomatic generation of the model. We did produce support structures for stereolithographic models with this fast data processing pipeline and will show future perspectives in this paper.

Computer Graphics↗

[Use of voxel-oriented femur models for stress analysis. Generation, calculation and validation of CT-based FEM models].

A means of interfacing computed tomography with the finite element method for the analysis of stress distribution in human femurs is described. With the aid of data transfer and image processing programs, three-dimensional voxel models of four macerated and a fresh-frozen cadaveric femur were generated from CT data sets. The underlying basic principle is direct generation of model elements from one or more adjacent CT-voxels, which are characterised by their coordinates and local absorption coefficients. A new algorithm was used for smoothing the edges of the model. All the models were analysed with respect to their stress distribution under different load situations, and the results were compared with the data of a parallel study utilizing the strain-gauge technique. Using the method of linear regression, a high correlation (coefficient of determination r2: 0.80-0.91) was found between the calculated and experimentally measured principal stresses at the surface of the bones.

Biomechanical Phenomena↗

Dynamics of membrane excitability determine interspike interval variability: a link between spike generation mechanisms and cortical spike train statistics.

We propose a biophysical mechanism for the high interspike interval variability observed in cortical spike trains. The key lies in the nonlinear dynamics of cortical spike generation, which are consistent with type I membranes where saddle-node dynamics underlie excitability (Rinzel & Ermentrout, 1989). We present a canonical model for type I membranes, the theta-neuron. The theta-neuron is a phase model whose dynamics reflect salient features of type I membranes. This model generates spike trains with coefficient of variation (CV) above 0.6 when brought to firing by noisy inputs. This happens because the timing of spikes for a type I excitable cell is exquisitely sensitive to the amplitude of the suprathreshold stimulus pulses. A noisy input current, giving random amplitude "kicks" to the cell, evokes highly irregular firing across a wide range of firing rates; an intrinsically oscillating cell gives regular spike trains. We corroborate the results with simulations of the Morris-Lecar (M-L) neural model with random synaptic inputs: type I M-L yields high CVs. When this model is modified to have type II dynamics (periodicity arises via a Hopf bifurcation), however, it gives regular spike trains (CV below 0.3). Our results suggest that the high CV values such as those observed in cortical spike trains are an intrinsic characteristic of type I membranes driven to firing by "random" inputs. In contrast, neural oscillators or neurons exhibiting type II excitability should produce regular spike trains.

Algorithms↗

Simulation studies of self-associating systems; discrimination between specific and isodesmic associations.

The possibilities of discriminating between definite and indefinite (isodesmic) modes of self-association are explored by fitting the different models to stimulated data, using non-linear least-squares curve-fitting to determine the fitting parameters for real and impostor models. It was found that over an extensive range of values for the equilibrium constant of a non-ideal isodesmic generating model, only a non-ideal monomer-dimer-tetramer-octamer was a successful impostor model. Some criteria for rejecting inappropriate models are discussed.

Binding Sites↗

"True" color surface anatomy: mapping the Visible Human to patient-specific CT data.

The mapping of "true" color and texture information into traditional medical imaging modality data can add considerable information and aid in diagnostics. One of the goals of this work has been to create CT color lookup tables for all visually well-defined structures in the Visible Human male cryosection data set which then can be used to color patient-specific CT data. The primary goal has been to develop a method for stripping textures from a volumetric data set for polygonal models and non-uniform rational B-spline (NURBS) models generated from a volumetric data set. It is believed that these methods can eventually be used to provide clinicians with 3D models with physiologically accurate color textures.

Anatomy, Cross-Sectional↗

Determination of total dietary fiber of intact cereal food products by near-infrared reflectance.

Near-infrared reflectance spectra of cereal food products were acquired with a commercial dual-diode-array (Si, InGaAs) spectrometer customized to allow rapid acquisition of scans of intact breakfast cereals, snack foods, whole grains, and milled products. Substantial gains in the performance of multivariate calibration models generated from these data were obtained by a computational strategy that systematically analyzed the performance of various spectral windows. The calibration model based on 137 cereal food products determined the total dietary fiber (TDF) content of a test set of 45 intact diverse cereal food products with root-mean-squared error of cross-validation of between 1.8 and 2.0% TDF, relative to the laborious enzymatic-gravimetric reference method. The calibration performance is adequate to estimate TDF over the range of values found in diverse types of cereal food products (0.7-50.1%). The method requires no sample preparation and is relatively unaffected by specimen moisture content.

Calibration↗

Caregiving Effectiveness Model evolution to a midrange theory of home care: a process for critique and replication.

A clinically relevant model, grounded in nursing theory, has evolved to become a midrange theory. This article describes the processes used to derive, validate, revise, and test the Caregiving Effectiveness Model. Testing of this midrange theory used prospective longitudinal research with family members caring for patientsrequiring lifelong, complex, technology-based home care. It presents the conceptual critiques and statistical procedures and discusses derivation of model-generated nursing interventions and implications for use of these validation processes in developing nursing knowledge. The article summarizes limitations of the model and presents recommendations for future research.

Adaptation, Psychological↗

Improving the quality of the NCQA (National Committee for Quality Assurance) Annual Member Health Care Survey Version 1.0.

The National Committee for Quality Assurance (NCQA) developed a standardized survey instrument in 1995 designed to measure enrollee satisfaction with the care and services received from health plans across the United States. After the survey was administered for a large number of health plans and thousands of responses were received, some areas for survey improvement have emerged. The objective of this research was to evaluate the NCQA Annual Member Health Care Survey Version 1.0 (the standard form) relative to an alternate survey form created in cooperation with the HMO Group, Maritz Marketing Research, Inc., and Healthcare Research Systems, Ltd. The alternate form of the NCQA survey was constructed to test several theories of measurement improvement via rewording of items, reordering of items, deletion of items, and addition of items. The most important findings of the research project are reported herein. Ten geographically dispersed member health maintenance organizations (HMOs) of The HMO Group took part in the project. A split-half design was used to test the standard and alternate survey forms concurrently. Surveys were administered by using the NCQA-recommended mail methodology of survey and cover letter, reminder card, and second survey. Assuming a 50% response rate, a target of 400 responses (200 for each survey form) per HMO was planned. The window for responding was allowed to remain open 4 weeks beyond the mailing of the second survey to achieve the desired response rate. A total of 4,056 responses were collected (2,022 for the standard form and 2,034 for the alternate form). It was found that the addition of "No Experience" and "No Opinion" response options to the majority of satisfaction items reduced the random error associated with informed responses and produced statistically significant higher correlations with the global satisfaction items relative to the standard form items. Only four of the eight Short Form 12 summary scales, General Health, Reported Health Transition, Mental Health, and Social Functioning, were useful for adjusting data (covariation). The entire set of comorbidities (chronic disease checklist) could be eliminated without losing significant data adjustment capability. The multiple linear regression models generated by using the global satisfaction items on the alternate form had higher adjusted R2 values than the standard-form models. The alternate-form item Overall Value correlated highly with cost items and general satisfaction item, making it a useful global satisfaction variable for predictive modeling.

Health Care Surveys↗

A lumped parameter model of left ventricular filling-pressure waveforms.

Assessment of left-ventricular function and quantification of valve stenosis are important in clinical practice as well as in physiological research. This paper describes a mathematical model of diastolic ventricular filling and flow across the mitral valve. The model primarily consists of a system of three first-order, non-linear ordinary differential equations. The equations are solved in MATLAB using the ode45 command. The model generates pressure versus time waveforms for the atrium and ventricle, and flow versus time waveforms for mitral valve flow. Comparisons between model outputs and in-vivo data collected in two porcine experiments show excellent agreement.

Diastole↗

Modeling helix-turn-helix protein-induced DNA bending with knowledge-based distance restraints.

A crucial element of many gene functions is protein-induced DNA bending. Computer-generated models of such bending have generally been derived by using a presumed bending angle for DNA. Here we describe a knowledge-based docking strategy for modeling the structure of bent DNA recognized by a major groove-inserting alpha-helix of proteins with a helix-turn-helix (HTH) motif. The method encompasses a series of molecular mechanics and dynamics simulations and incorporates two experimentally derived distance restraints: one between the recognition helix and DNA, the other between respective sites of protein and DNA involved in chemical modification-enabled nuclease scissions. During simulation, a DNA initially placed at a distance was "steered" by these restraints to dock with the binding protein and bends. Three prototype systems of dimerized HTH DNA binding were examined: the catabolite gene activator protein (CAP), the phage 434 repressor (Rep), and the factor for inversion stimulation (Fis). For CAP-DNA and Rep-DNA, the root mean square differences between model and x-ray structures in nonhydrogen atoms of the DNA core domain were 2.5 A and 1.6 A, respectively. An experimental structure of Fis-DNA is not yet available, but the predicted asymmetrical bending and the bending angle agree with results from a recent biochemical analysis.

Base Sequence↗