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PubMed2003

Using multiple drug exposure levels to optimize power in pharmacogenetic trials.

Large-scale pharmacogenetic trials testing tens to hundreds of thousands of single-nucleotide polymorphisms (SNPs) will become possible in the near future given rapidly decreasing costs of genotyping. Devising optimal designs for these trials will be a significant challenge. The author demonstrates how the level of drug exposure may strongly affect the power to detect true associations between genetic polymorphisms and drug response. An analytic model of drug response is described that is used to simulate pharmacogenetic trials. Analytical and numerical sensitivity analyses are performed on the model to demonstrate possible exposure-sensitivity behaviors. This model shows that the power to detect an association can be a nonlinear, nonmonotonic function of drug exposure. This model is further investigated using two clinical trial designs. The conclusion is that trial designs that use more than one drug exposure or dose will have an increased likelihood of discovering statistically significant pharmacogenetic associations.

Computer Simulation↗

PubMed2003

Investigation of time-dependency of intracranial brain shift and its relation to the extent of tumor removal using intra-operative MRI.

The object of the paper is to investigate intra-operative brainshift and its relation to the extent of tumor removal. Repeated T1w 3D datasets were acquired at different time points intra-operatively (T0; T1; T2...Tx) using a vertical open 0.5T MR scanner in six patients with intracranial tumor. An offline analysis with initial linear registration, intensity adjustment and finally nonlinear registration of the first versus subsequent time points (T0/T1; T0/T2...To/Tx) was performed, yielding a 3D displacement vector field that describes the brainshift. Brainshift was analysed qualitatively and quantitatively. A semi-automatic segmentation technique was used for calculation of the tumor size and the size of tumor remnants. Semi-automatic segmentation was reliable in all but two cases. Segmentation was difficult and unreliable in astrocytomas grade II. The shift basically followed gravity. The major shift reached levels up to 25 mm. Significant shift was observed at the first time point (T0). Intra-operative brainshift can be analysed qualitatively and also captured quantitatively. Neuronavigation that is based on pre-operatively acquired datasets is associated with a significant risk of surgical morbidity at a very early time point. Parallelisation on a workstation cluster may reduce computation time so that information about the displacement can facilitate updated navigation.

Adult↗

PubMed1999

Additive genetic relationships between heifer pregnancy and scrotal circumference in Hereford cattle.

The objective of this study was to determine an appropriate method for using yearling scrotal circumference observations and heifer pregnancy observations to produce EPD for heifer pregnancy. We determined the additive genetic effects of and relationship between scrotal circumference and heifer pregnancy for a herd of Hereford cattle in Solano, New Mexico. The binary trait of heifer pregnancy was defined as the probability of a heifer conceiving and remaining pregnant to 120 d, given that she was exposed at breeding. Estimates of heritability for heifer pregnancy and scrotal circumference were .138+/-.08 and .714+/-.132, respectively. Estimates of fixed effects for age of dam and age were significant for heifer pregnancy and bull scrotal circumference. The estimate of the additive genetic correlation between yearling heifer pregnancy and yearling bull scrotal circumference was .002+/-.45. Additional analyses included models with additive genetic groups for scrotal circumference EPD for heifer pregnancy or heifer pregnancy EPD for scrotal circumference to account for a potential nonlinear relationship between scrotal circumference and heifer pregnancy. Results support the development of a heifer pregnancy EPD because of a higher estimated heritability than previously reported. The development of a heifer pregnancy EPD would be an additional method for improving genetic merit for heifer fertility.

Aging↗

PubMed1992

[The use of multivariate mathematical methods in medical diagnostic systems--a model for the evaluation of cytological smears].

The methods of the multivariate mathematics have been applied in several studies to increase the diagnostic reliability of medical decision support system. In the recent years some new algorithms for decision support (fuzzy logic) and for pattern recognition (neural nets), both specified by nonlinearity, were developed. This paper provides results for the application of this methods in the area of quantitative cytology and the comparison with the traditional classifiers. 21 normal, 15 dysplastic, 23 malignant, Feulgen stained gastric imprint smears were analysed on a Leitz Miamed DNA equipment. The determination of mean DNA content, the 2c deviation index (2cDI), 5c Exceeding rate (RcER), G1,S,G2 phase fraction ratios, cell nucleus area, form factor was performed. The discriminant analysis classified correctly the 95.6% of malignant cases, 86.7% of dysplasias, and 80.7% normal cases. Our diagnostic system using fuzzy logic made the diagnostic borders fine tuneable, and reliable. The back propagation neural net could classify all three diagnostic groups above 95% correctly. The application of nonlinear computational methods made the diagnostic system more reliable. The application of these algorithms are encouraged.

Algorithms↗

PubMed2000

Nonlinear analysis of continuous ECG during sleep I. Reconstruction.

In recent years evidence has accumulated that ECG signals are of a nonlinear nature. It has been recognized that strictly periodic cardiac rhythms are not accompanied by healthy conditions but, on the contrary, by pathological states. Therefore, the application of methods from nonlinear system theory for the analysis of ECG signals has gained increasing interest. Crucial for the application of nonlinear methods is the reconstruction (embedding) of the time series in a phase space with appropriate dimension. In this study continuous ECG signals of 12 healthy subjects recorded during different sleep stages were analysed. Proper embedding dimension was determined by application of two techniques the false nearest neighbours method and the saturation of the correlation dimension. Results for the ECG signals were compared with findings for simulated data (quasiperiodic dynamics, Lorenz data, white noise) and for phase randomized surrogates. Findings obtained with the two approaches suggest that embedding dimensions from 6 to 8 may be regarded as suitable for the topologically proper reconstruction of ECG signals.

Adult↗

PubMed2003

Vibrational and quantum-chemical study of push-pull chromophores for second-order nonlinear optics from rigidified thiophene-based pi-conjugating spacers.

Two types of push-pull chromophores built around thiophene-based pi-conjugating spacers rigidified by either covalent bonds or noncovalent intramolecular interactions have been analysed by means of IR and Raman spectroscopical measurements in the solid state as well as in a variety of solvents. Comparison of the Raman features of NLO-phores based on a covalently rigidified dithienylene (DTE) spacer with those of their open chain DTE analogues shows that the bridging of the central double bond of DTE with the nearest beta-positions of the thienyl units through two ethylene bridges significantly improves the intramolecular charge transfer. This also occurs for NLO-phores based on a 2,2'-bi(3,4-ethylenedioxythiophene) (BEDOT) spacer as compared with their corresponding parent compounds based on an unsubstituted bithiophene (BT) spacer. For NLO-phores based on a BEDOT spacer, noncovalent intramolecular interactions between sulfur and oxygen atoms are responsible for the rigidification of the spacer. The Raman spectra of these NLO-phores obtained in the form of solutes in dilute solutions reveal two different behaviours: i) chromophores based on covalently bridged or open chain DTE spacers display Raman spectral profiles in solution quite similar to those of the corresponding solids, with a very little dependence on the polarity of the solvent, while ii) larger spectral changes are noticed for NLO-phores built around BEDOT or BT spacers on going from solids to solutions. In the second case, spectral changes must be ascribed not solely to conformational distortions of the donor and acceptor end groups with respect to the pi-conjugated backbone mean-square-plane (as for the DTE-based NLO-phores) but also to distortions of the thienyl units of the pi-conjugating spacer from coplanarity. The insertion of vinylenic bridges between the thienyl units of the pi-conjugating spacer and between the spacer and the donor and acceptor end groups is a suitable strategy to reach a fairly large intramolecular charge transfer both in polar and nonpolar solvents. Density functional theory (DFT) calculations have been carried out to assign the relevant electronic and vibrational features and to derive useful information about the molecular structure of these NLO-phores.

Journal Article↗

PubMed2004

The temporal representation of speech in a nonlinear model of the guinea pig cochlea.

The temporal representation of speechlike stimuli in the auditory-nerve output of a guinea pig cochlea model is described. The model consists of a bank of dual resonance nonlinear filters that simulate the vibratory response of the basilar membrane followed by a model of the inner hair cell/auditory nerve complex. The model is evaluated by comparing its output with published physiological auditory nerve data in response to single and double vowels. The evaluation includes analyses of individual fibers, as well as ensemble responses over a wide range of best frequencies. In all cases the model response closely follows the patterns in the physiological data, particularly the tendency for the temporal firing pattern of each fiber to represent the frequency of a nearby formant of the speech sound. In the model this behavior is largely a consequence of filter shapes; nonlinear filtering has only a small contribution at low frequencies. The guinea pig cochlear model produces a useful simulation of the measured physiological response to simple speech sounds and is therefore suitable for use in more advanced applications including attempts to generalize these principles to the response of human auditory system, both normal and impaired.

Animals↗

PubMed1993

Ninety-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette: DNA adducts and alveolar macrophage cytogenetics.

To study the genotoxic effects of subchronic exposure to environmental tobacco smoke, Sprague-Dawley rats were exposed to 0, 0.1, 1.0, and 10 mg total particulate matter (TPM)/m3 of aged and diluted sidestream smoke (ADSS) from 1R4F reference cigarettes 6 hr per day, 5 days a week for 13 weeks. DNA from lung, heart, larynx, bladder, and liver was tested for adduct formation by the 32P-postlabeling assay after 28 (except bladder) and 90 days of exposure and 90 days after cessation of exposure. In addition, alveolar macrophages from animals exposed for 28 or 90 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any tissue in any of the animals exposed to 0.1 or 1.0 mg TPM/m3. However, increased levels of DNA adducts with diagonal radioactive zones were observed in lung, heart, and larynx DNA of animals exposed to the highest concentration of ADSS (10 mg TPM/m3). Adduct analyses with varying amounts of DNA from lungs of mid- and high-exposure animals clearly indicate that the dose-response for DNA adduct formation is nonlinear. The adduct levels were highest after 90 days of exposure and were significantly reduced in all target tissues 90 days after cessation of exposure. Chromosomal aberrations in alveolar macrophages were not elevated in any group after 28 or 90 days of exposure. These results indicate a no-observed-effect-level (NOEL) of at least 1.0 mg/m3 for DNA adduct formation in lung, heart, and larynx, and a NOEL of at least 10 mg/m3 for the induction of chromosome aberrations in alveolar macrophages, under the conditions of this study.

Administration, Inhalation↗

PubMed1998

Nonlinear Variation in Simulated Complex Pattern Development.

Simulated spore walls manufactured from colloidal polystyrene latex, cyclohexane and water demonstrate a range of structure comparable with that occurring within the walls of Selaginella megaspores. Initial investigation of the relationship between the initiation parameters of the self-assembling simulation and its ultimate structure imply a nonlinear relationship. It is suggested that such self-assembly processes result in structure that cannot be directly mapped onto an equivalent genetic coding and that phylogenetic analyses based on self-assembled structure may differ in its conclusions from that based on DNA sequences.Copyright 1998 Academic Press Limited

Journal Article↗

PubMed2006

Validation of a clinical finite element model of the human lumbosacral spine.

Very few finite element models on the lumbosacral spine have been reported because of its unique biomechanical characteristics. In addition, most of these lumbosacral spine models have been only validated with rotation at single moment values, ignoring the inherent nonlinear nature of the moment-rotation response of the spine. Because a majority of lumbar spine surgeries are performed between L4 and S1 levels, and the confidence in the stress analysis output depends on the model validation, the objective of the present study was to develop a unique finite element model of the lumbosacral junction. The clinically applicable model was validated throughout the entire nonlinear range. It was developed using computed tomography scans, subjected to flexion and extension, and left and right lateral bending loads, and quantitatively validated with cumulative variance analyses. Validation results for each loading mode and for each motion segment (L4-L5, L5-S1) and bisegment (L4-S1) are presented in the paper.

Adult↗

PubMed1985

A model of the strain-induced B-Z transition.

The B-to-Z transition in supercoiled circular DNA is modeled as a strain-induced nonlinear excitation process. Using a model, in which DNA is regarded as a chain of units with a bistable energy function along the twisting coordinate together with a harmonic inter-unit interaction, we show that a Z region and the accompanying two B-Z junctions of finite width appear naturally as a solution of nonlinear equations, when the strain exceeds a critical value. We examine the B-Z transition behaviour as a function of twist under various situations. We also analyse available experimental results on B-Z transition in supercoiled plasmid with G-C insertions by this mechanistic model in order to estimate the magnitude of model parameters. The energy barrier of the B-Z transition is estimated to be of the order of 1 kcal/mole per base pair. The analysis shows that if the length of the insertion is less than a certain value, the entire insertion converts to Z form at a transition point, but if the insertion is much longer, the B-Z transition exhibits a different behavior, in which part of the insertion flips to Z form and the Z region expands linearly upon changing linking number.

DNA↗

PubMed1989

Beta skin dose determination using TLDs, Monte-Carlo calculations, and extrapolation chamber.

The beta doses produced by 90Sr-Y and 204 Tl beta sources were determined using three methods: Monte-Carlo calculations, measurements with TLDs, and measurements with an extrapolation chamber. Excellent agreement was obtained by all three methods, except a TLD nonlinear response to beta s was observed, which gives doses approximately 20% high for the 90Sr-Y source and 5% low for the 204Tl source. Also, analyses performed with low-energy beta s using these methods can determine errors in shield thickness covering TLD elements. Direct measurement of skin dose is not possible by the TLDs because the minimum shield thickness for the elements is 13 mg cm-2. A thinner shield for the elements must be used or the data must be extrapolated. Presently, thinner shields for TLD elements are not available, and the thick shields can lead to significant errors in skin dose when exposed to low-energy beta s.

Filtration↗

PubMed1993

Detecting chaos in a noisy time series.

We propose a new method for detecting low-dimensional chaotic time series when there is dynamical noise present. The method identifies the sign of the largest Liapunov exponent and thus the presence or absence of chaos. It also shows when it is possible to assign a value to the exponent. This approach can work for short time series of only 500 points. We analyse several real time series including chickenpox and measles data from New York City. For model systems it correctly identifies important spatial scales at which noise and nonlinear effects are important. We propose a further technique for estimating the level of noise in real time series if it is difficult to detect by the former method.

Biology↗

PubMed2006

GENTEX, a general multiscale model for in vivo tissue exchanges and intraorgan metabolism.

Endothelial cells lining myocardial capillaries not only impede transport of blood solutes to the contractile cells, but also take up and release substrates, competing with myocytes. Solutes permeating this barrier exhibit concentration gradients along the capillary. This paper introduces a generic model, GENTEX, to characterize blood-tissue exchanges. GENTEX is a whole organ model of the vascular network providing intraorgan flow heterogeneity and accounts for substrate transmembrane transport, binding and metabolism in erythrocytes, plasma, endothelial cells, interstitial space and cardiomyocytes. The model is tested here for the analysis of multiple tracer indicator dilution data on purine nucleoside metabolism in the isolated Krebs-Henseleit-perfused non-working hearts. It has been also used for analysing NMR contrast data for regional myocardial flows and for positron emission tomographic studies of cardiac receptor kinetics. The facilitating transporters, binding sites and enzymatic reactions are nonlinear elements and allow competition between substrates and a reaction sequence of up to five substrate-product reactions in a metabolic network. Strategies for application start with experiment designs incorporating inert reference tracers. For the estimation of endothelial and sarcolemmal permeability-surface area products and metabolism of the substrates and products, model solutions were optimized to fit the data from pairs of tracer injections (of either inosine or adenosine, plus the reference tracers) injected under the same circumstances a few minutes later. The results provide a self-consistent description of nucleoside metabolism in a beating well-perfused rabbit heart, and illustrate the power of the model to fit multiple datasets simultaneously.

Animals↗

PubMed2006

Experimental support of the scaling rule for demographic stochasticity.

A scaling rule of ecological theory, accepted but lacking experimental confirmation, is that the magnitude of fluctuations in population densities due to demographic stochasticity scales inversely with the square root of population numbers. This supposition is based on analyses of models exhibiting exponential growth or stable equilibria. Using two quantitative measures, we extend the scaling rule to situations in which population densities fluctuate due to nonlinear deterministic dynamics. These measures are applied to populations of the flour beetle Tribolium castaneum that display chaotic dynamics in both 20-g and 60-g habitats. Populations cultured in the larger habitat exhibit a clarification of the deterministic dynamics, which follows the inverse square root rule. Lattice effects, a deterministic phenomenon caused by the discrete nature of individuals, can cause deviations from the scaling rule when population numbers are small. The scaling rule is robust to the probability distribution used to model demographic variation among individuals.

Animals↗

PubMed2002

Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study.

PURPOSE: Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer. PATIENTS AND METHODS: A cohort of 512 women without known diabetes, who had early-stage (T1 to T3, N0 to N1, and M0) breast cancer, was assembled and observed prospectively. Information on traditional prognostic factors and body size was collected, and fasting blood was obtained. RESULTS: Fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest (> 51.9 pmol/L) versus the lowest (< 27.0 pmol/L) insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some evidence to suggest that the association of insulin with breast cancer outcomes may be nonlinear. Insulin was correlated with body mass index (Spearman r = 0.59, P <.001), which, in turn, was associated with distant recurrence and death (P <.001). In multivariate analyses that included fasting insulin and available tumor- and treatment-related variables, adjusted hazard ratios for the upper versus lower insulin quartile were 2.1 (95% CI, 1.2 to 3.6) and 3.3 (95% CI, 1.5 to 7.0) for distant recurrence and death, respectively. CONCLUSION: Fasting insulin level is associated with outcome in women with early breast cancer. High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.

Adult↗

PubMed2004

Dynamical analysis reveals individuality of locomotion in goldfish.

Goldfish swimming was analysed quantitatively to determine if it exhibits distinctive individual spatio-temporal patterns. Due to the inherent variability in fish locomotion, this hypothesis was tested using five nonlinear measures, complemented by mean velocity. A library was constructed of 75 trajectories, each of 5 min duration, acquired from five fish swimming in a constant and relatively homogeneous environment. Three nonlinear measures, the 'characteristic fractal dimension' and 'Richardson dimension', both quantifying the degree to which a trajectory departs from a straight line, and 'relative dispersion', characterizing the variance as a function of the duration, have coefficients of variation less than 7%, in contrast to mean velocity (30%). A discriminant analysis, or classification system, based on all six measures revealed that trajectories are indeed highly individualistic, with the probability that any two trajectories generated from different fish are equivalent being less than 1%. That is, the combination of these measures allows a given trajectory to be assigned to its source with a high degree of confidence. The Richardson dimension and the 'Hurst exponent', which quantifies persistence, were the most effective measures.

Animals↗

PubMed2001

Temperature, routine activities, and domestic violence: a reanalysis.

It was hypothesized that base rate differences in the number of complaints made during daylight and nighttime hours were responsible for a previously reported, nonlinear relationship between temperature and domestic violence. This hypothesis was tested by subjecting calls for service in 1987 and 1988 in Minneapolis, to moderator-variable regression analyses with controls for time of day, day of the week, season, and their interactions as well as linear trend, major holidays, public school closings, the first day of the month, and other weather variables. Temporal variables explained 75% of the variance in calls for service. As hypothesized, the base rate artifact was responsible for an apparent downturn in violence at high temperatures: Fewer complaints were received during afternoon hours, because they happen to be the warmest time of the day. The results were interpreted in terms of routine activity theory.

Adult↗