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PubMed2002

Ligand/receptor signaling threshold (LIST) model accounts for gp130-mediated embryonic stem cell self-renewal responses to LIF and HIL-6.

We previously demonstrated that embryonic stem (ES) cell self-renewal required sustained signaling by leukemia inhibitory factor (LIF) in a concentration-dependent manner, allowing us to hypothesize that thresholds in ligand-receptor signaling modulate stem cell differentiation control. To test this hypothesis, we have experimentally and computationally compared the abilities of two gp130-signaling cytokines (LIF and Hyper-interleukin-6 [HIL-6]) to sustain ES cell self-renewal. Quantitative measurements of ES cell phenotypic markers (stage-specific embryonic antigen-1 and E-cadherin), functional assays (alkaline phosphatase activity and embryoid body formation efficiency), and transcription factor (Oct-4) expression over a range of LIF and HIL-6 concentrations demonstrated a superior ability of LIF to maintain ES cell pluripotentiality at higher concentrations (> or =500 pM). Additionally, we observed distinct qualitative differences in the ES cell self-renewal dose response profiles between the two cytokines. A computational model permitted calculation of the number of signaling complexes as a function of receptor expression, ligand concentration, and ligand/receptor-binding properties, generating predictions for the degree of self-renewal as a function of cytokine concentration by comparison of these calculated complex numbers to experimentally determined threshold cytokine concentrations. Model predictions, consistent with experimental data, indicated that differences in the potencies of these two cytokines were based primarily on differences in receptor-binding stoichiometries and properties. These results support a ligand/receptor signaling threshold model of ES cell fate modulation through appropriate types and levels of cytokine stimulation. Insights from these results may be more generally applicable to tissue-specific stem cells and could aid in the development of stem cell-based technologies.

Animals↗
PubMed1991

Modelling hearing thresholds in the elderly.

This paper concerns a linear mixed-effects repeated measures model in the analysis of a large data set with over 17,000 observations in a longitudinal study of pure-tone hearing perception in the elderly. The repeated measurements are described by fixed and random components in the model. The fixed effects include the age at entry, time of follow-up, a quadratic component in natural logarithm of frequency, a component to allow for participants with hearing impairments, as well as interaction terms between age and frequency and between impairment and frequency. The random factors include a term for subject, a time component and a frequency component. The analysis shows that hearing impaired individuals have similar patterns of hearing loss over time but, on average, have higher hearing thresholds than normal individuals. Estimation of the random effects in the model by restricted maximum likelihood (REML) using the Newton-Raphson method made possible the analysis of this large data set with speed and efficiency.

Aged↗
PubMed2000

Genetic parameters for reproductive traits of Holstein cattle in California and Minnesota.

Genetic parameters for five reproductive traits were estimated using data from 51,528 Holstein cows that were inseminated from April to September 1998 in 1717 herds in California and Minnesota. Nonreturn rate and veterinary-confirmed pregnancy rate at 60 and 90 d after insemination were evaluated using linear and threshold models, including an additive genetic effect for the cow being inseminated and a random environmental effect for the service bull. Interval from calving to first insemination was evaluated using a linear model, including an additive genetic effect for the cow being inseminated. Linear model heritability estimates for 60-d (90-d) nonreturn rate were 1.4% (1.5%) in California and 4.1% (2.7%) in Minnesota. Corresponding estimates for 60-d (90-d) confirmed pregnancy rate were 1.4% (2.3%) in California and 1.0% (2.0%) in Minnesota; the proportion of cows with veterinary data available 60 d after breeding was 86% in California and 55% in Minnesota. Threshold model heritability estimates were slightly higher than linear model estimates in California but were lower in Minnesota, presumably because 25% of the herd-season classes in Minnesota contained either all successes or all failures. Linear model repeatability estimates for the service bull effect on 60-d (90-d) nonreturn rate were 0.5% (0.4%) in California and 0.3% (0.3%) in Minnesota. Corresponding estimates for 60-d (90-d) confirmed pregnancy rates were 0.6% (0.2%) in California and 0.1% (0.4%) in Minnesota. Threshold model estimates were slightly higher than linear model estimates in both states. Heritability estimates for the interval from calving to first insemination were 5.8% in California and 6.1% in Minnesota. Despite the low parameter estimates, variation was present among animals, and it should be possible to identify sires that possess superior or inferior reproductive characteristics.

Animals↗
PubMed1993

Nonlinear mixed model analyses of five production disorders of dairy cattle.

A standardized threshold model was used to estimate herd variability and the impact of some risk factors on the incidence of retained placenta, metritis, ketosis, ovulatory dysfunction, and mastitis. Data consisted of records for 18,110 Swedish Red and White cows in 924 herds and 14,940 Swedish Friesian cows in 772 herds. Only first, second, and third party cows were included, and the breeds were analyzed separately. Herds were considered to be random effects, and variance components were estimated by the counterpart of REML for a threshold model. Estimated intraherd correlations varied from .04 to .18 and were lowest for the incidence of retained placenta (for both breeds) and highest for ketosis and ovulatory dysfunction for Swedish Red and White and Swedish Friesian breeds, respectively. Parity increased predicted lactational incidence risks for all disorders except metritis, but season of calving had no profound effect. Dystocia and stillbirth increased the risk of retained placenta; dystocia and retained placenta increased the risk of metritis. The risk of ketosis was not influence by any of the considered risk factor diseases, and the risk of mastitis was influenced only by retained placenta for Swedish Red and White cows. For both breeds, the risk of ovulatory dysfunction was increased by metritis and ketosis.

Animals↗
PubMed2005

Why are rare traits unilaterally expressed?: trait frequency and unilateral expression for cranial nonmetric traits in humans.

Based on an analysis of nonmetric trait databases from several large skeletal series in Northern Europe and South America, representing 27 bilateral traits, we report a predictable relationship between the frequency of nonmetric traits and the probability that they are expressed bilaterally. In a wider sampling of traits and populations, this study thus confirms the findings of an earlier study by Ossenberg ([1981] Am. J. Phys. Anthropol. 54:471-479), which reported the same relationship for two mandibular traits. This trend was previously explained by extending the multifactorial threshold model for discontinuous traits to incorporate either separate thresholds for unilateral or bilateral expression, or by a fuzzy threshold in which the probability of bilateral expression increases away from the median threshold value. We show that the trend is produced under the standard multifactorial threshold model for discontinuous traits simply if the within-individual or developmental instability variance remains relatively constant across the range of liability. Under this assumption, the number of individuals in which one side but not the other is pushed over the threshold for trait formation will be a larger proportion of the number of individuals expressing the trait when the trait frequency is low. As trait frequency increases, the significance of within-individual variance as a determinant of trait formation decreases relative to the genetic and among-individual environmental variance. These results have implications for interpreting nonmetric trait data as well as for understanding the prevalence of unilateral vs. bilateral expression of a wide variety of discontinuous traits, including dysmorphologies in humans.

Anthropology, Physical↗
PubMed1995

Cancer and non-cancer risk assessment: not so different if you consider mechanisms.

Default risk assessment procedures use threshold models for non-carcinogens and a non-threshold model for carcinogens. This a priori distinction reflects the fact that the default procedures do not consider mechanisms of action of specific chemicals. When mechanisms are considered, the distinction is not necessary. Starting with the premise that the goal of risk assessment is to identify actual risk for specific chemicals, three major, generic components of the overall mechanism translating exposure into a response of regulatory interest are identified. These are the specific mechanisms linking (1) exposure with dose to target tissue, (2) target tissue dose with short-term responses such as cytolethality or mutation, and (3) short-term responses with ensuing long-term responses such as cancer or cirrhosis. (Short-term responses may be regulatory end points of interest, or they may be intermediate steps on the way to longer-term sequelae). On-going research on formaldehyde and chloroform is described to illustrate how these three components of the overall mechanism can be examined experimentally and used in specific models. The impact of mechanism-based risk assessment on uncertainty is also considered. Uncertainty is a function of the extent to which the model used for risk assessment misspecifies the actual mechanism of action for the chemical in question. There is a trade-off between (a) mechanism-based models that may reduce uncertainty but are expensive and time-consuming to develop and (b) default models that are not chemical-specific but can be used with minimal data sets. Experience with mechanism-based risk assessment may allow modification of default procedures to minimize this trade-off. A future default procedure for carcinogen risk assessment might allow specification of mode of action. For example, while DNA reactive-carcinogens would still be assumed to have linear low-dose risk, carcinogens acting through purely cytotoxic mechanisms might be assumed to have sharply non-linear or even threshold dose-response curves.

Animals↗
PubMed2003

Evaluation of six multinomial models of conscious and unconscious processes with the recall-recognition paradigm.

Six multinomial processing-tree models (W. H. Batchelder & D. M. Riefer, 1999), which include parameters representing conscious and unconscious memory processes, were tested using the recall-recognition paradigm. Data from 2 experiments were fit equally well by 3 of the 6 models. One model recognition was an extension of the generate-recognize model (L. L. Jacoby, 1998), and another was an extension of the non-high-threshold model (D. M. McBride & B. A. Dosher, 1999). The 3rd model was the source evaluation model (D. M. McBride & B. A. Dosher, 1999). Values of the parameters of 2 of these 3 models, excepting the non-high-threshold model, responded to experimental manipulations in accordance with the meaning of the parameters. The equivalence of models with regard to goodness-of-fit tests is discussed as is how experiments can be designed to demonstrate the superiority of one model over another. The potential usefulness of these models in the study of amnesia is considered.

Attention↗
PubMed1989

Anaerobic threshold estimation by statistical modelling.

Anaerobic threshold (AT) is usually estimated as a change point problem by visual analysis of the cardiorespiratory response to incremental dynamic exercise. In this study, two phase linear (TPL) models of the linear-linear and linear-quadratic type were used for the estimation of AT. The correlation coefficient between the classical and statistical approaches was 0.88, and 0.89 after outlier exclusion. The TPL models provide a simple method for estimating AT that can be easily implemented using a digital computer for the automatic pattern recognition of AT.

Anaerobic Threshold↗
PubMed1994

The evolution of dimorphic traits: predicting the genetic correlation between environments.

Many traits vary in a dichotomous manner, although the underlying genetic determination is polygenic. The genetic basis of such dimorphic traits can be analyzed using the threshold model, in which it is assumed that there is a continuously distributed underlying character and the phenotype is determined by whether the character is above or below a threshold. Threshold traits frequently vary with environmental variables such as photoperiod, temperature and density. This effect can be accounted for using a threshold model in which (1) there is a critical value of the environmental variable at which a genotype switches to the alternate morph, and (2) switch (threshold) points are normally distributed in the population. I term this the environmental threshold (ET) model. I show that the ET model predicts that across environments differing in only one factor the genetic correlation will be 1. This prediction is supported by data from three wing dimorphic insects. Evidence is presented that the genetic correlation between environments differing in two components (temperature and photoperiod) is less than 1.

Animals↗
PubMed1992

Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 3. Noncancer mortality based on the revised doses (DS86).

Deaths in the RERF Life Span Study (LSS) sample have been determined for the years 1950-1985 and an analysis of cancer mortality with the revised DS86 doses has been described separately. In this report, we examine the relationship to dose of deaths from all diseases other than cancer. Although the evidence is still limited, there seems to be an excess risk from noncancer death at high doses (2 or 3 Gy and over). Statistically, a pure quadratic or a linear-threshold model [the estimated threshold dose is 1.4 Gy (0.6-2.8 Gy)] is found to fit better than a simple linear or linear-quadratic model. This increase in noncancer mortality is statistically demonstrable, generally, after 1965 and among the younger survivors (less than 40 at the time of the bombing), suggesting a sensitivity for this age group. For specific causes of death, an excess in relative risk at the high dose level, that is, 2 Gy or more, is seen in circulatory and digestive diseases. The relative risk is, however, much smaller than that for cancer. These findings, based as they are on death certificates, have their limitations. Most significant, perhaps, is the possible erroneous attribution of radiation-related cancer deaths to other causes. At present, the contribution such errors may make to the apparent increase in non-cancer deaths at the higher doses cannot be estimated as rigorously as is obviously desirable. However, even now, this increase does not appear to be fully explicable in terms of errors in classification. Further follow-up of mortality in this LSS cohort as well as disease revealed by the biennial physical examinations of the morbidity subsample (Adult Health Study) of the LSS cohort will be needed to confirm this suggestion of a radiation-related increase in mortality from causes other than cancer, and to determine whether it results in a demonstrable life shortening among the heavily exposed A-bomb survivors.

Age Factors↗
PubMedDate not supplied

Genetic parameters for litter size in sheep: natural versus hormone-induced oestrus.

The litter size in Suffolk and Texel-sheep was analysed using REML and Bayesian methods. Litters born after hormonal induced oestrus and after natural oestrus were treated as different traits in order to estimate the genetic correlation between the traits. Explanatory variables were the age of the ewe at lambing, period of lambing, a year*flock-effect, a permanent environmental effect associated with the ewe, and the additive genetic effect. The heritability estimates for litter size ranged from 0.06 to 0.13 using REML in bi-variate linear models. Transformation of the estimates to the underlying scale resulted in heritability estimates from 0.12 to 0.17. Posterior means of the heritability of litter size in the Bayesian approach with bi-variate threshold models varied from 0.05 to 0.18. REML estimates of the genetic correlations between the two types of litter size ranged from 0.57 to 0.64 in the Suffolk and from 0.75 to 0.81 in the Texel. The posterior means of the genetic correlation (Bayesian analysis) were 0.40 and 0.44 for the Suffolk and 0.56 and 0.75 for the Texel in the sire and animal model respectively. A bivariate threshold model seems appropriate for the genetic evaluation of prolificacy in the breeds concerned.

Animals↗
PubMed2004

Induced hippocampal neuron protection in an optimized gerbil ischemia model: insult thresholds for tolerance induction and altered gene expression defined by ischemic depolarization.

Preconditioning of hippocampal CA1 neurons was evaluated in a gerbil model of transient global ischemia using extracellular recording of DC potential shifts characteristic of ischemic depolarization to precisely define the duration of both priming and test insults. Brief ischemia resulting in depolarizations of 2.5 to 3.5 minutes consistently induced maximal tolerance (95% protection) against subsequent challenges 2 days later with an approximate doubling of the insult duration required for complete CA1 neuron loss from 6 to 12 minutes depolarization when evaluated 1 week after the test insult. Significant protection persisted at 2 months survival, although the apparent injury threshold regressed to approximately 8 minutes, indicating delayed progression of injury after longer test insults. In situ hybridization was used to evaluate depolarization thresholds for induction of mRNAs encoding the 70 kDa heat shock/stress protein, hsp72, as well as several immediate-early genes (c-fos, c-jun, junB, and junD). Immediate-early genes were prominently expressed after short insults inducing tolerance, whereas appreciable hsp72 induction only occurred after insults approaching the threshold for neuron injury. These results establish an ischemic preconditioning model with the predictability needed for mechanistic studies and demonstrate that prior transcriptional activation of the postischemic heat shock response is not required for expression of delayed tolerance.

Animals↗
PubMed1988

Genetic analysis of dystocia and calf mortality in Israeli-Holsteins by threshold and linear models.

Calvings of 106,751 Israeli Holstein heifers were analyzed for dystocia and calf mortality, scored dichotomously, and a composite trait, scored trichotomously. Dystocia was also studied with 146,973 second and third parity records. Models fitted included herd-year-season, sex of calf, calving age, calving month, sire of cow, sire of calf, and groups of sire of cow and of calf. Herd-year-season, sire of cow and calf, and residuals were random with diagonal variance-covariance matrices. Herd-year-season variance was assume to be 10% of the residual component. Other variance components were estimated by REML for linear models and by the counterpart of REML for threshold models. Heritability estimates were two to five times greater in threshold than in linear models, but correlations between corresponding sire evaluations were all greater than .9. Linear model sire evaluations were skewed positively, whereas threshold model evaluations had symmetrical distributions. Heritability for dystocia was greater in first than in later parities. Correlations between first and later parity sire evaluations were less than .5. Thus, the genetic control of dystocia seems to be different for heifers and cows. Correlations between sire of cow and calf evaluations were less than .3. Correlations between dystocia and calf mortality evaluations were about .7.

Animals↗
PubMed1994

UV-B-laser-induced DNA damage in lymphocytes observed by single-cell gel electrophoresis.

Human lymphocytes from a cell culture were irradiated with 12 mJ pulses (524 J m-2) of an XeCl excimer laser (308 nm). DNA strand breaks were analysed with the "comet assay", a single-cell method. The DNA damage of individual cells could be investigated depending on the energy and the irradiated volume. DNA damage could be detected already after a single laser pulse of 12 mJ. Since the irradiation time is short compared with the DNA repair time, DNA damage is solely dependent on the total number of photons. A quantitative evaluation of the number of damaged cells vs. number of photons can be best explained by a detection threshold model. The calculated threshold is 1.25 x 10(8) photons cell-1. From this and the principal sensitivity of the comet assay, one can estimate that the upper limit for DNA damaging efficiency is 400,000 photons.

Cells, Cultured↗
PubMed1997

Single neuron model with recurrent excitation: response to slow periodic modulation.

The influence of a recurrent excitatory connection on the response of three neuron models to slow periodic modulation is analyzed. The models are the graded response model and the threshold model with and without adaptation. Lissajous displays of the system's output (discharge rate) as a function of the instantaneous input value show hysteresis in all three models. Hence, the outputs are different depending on whether the input is increasing or decreasing. Recurrent excitation increases the width of the hysteresis with (i) the frequency of the periodic modulation, (ii) the transmission delay of the recurrent connection, and (iii) the connection strength.

Action Potentials↗
PubMedDate not supplied

An evaluation of the anticonvulsant effects of vitamin E.

The anticonvulsant effects of D-alpha-tocopherol (vitamin E) were studied in 4 animal seizure models: the Metrazol threshold model (MET), the maximal electroshock model (MES), the kindling model (well-established seizures), and the ferrous chloride model. Vitamin E failed to antagonize seizures in the MES, MET, or the kindling models. It was, however, able to significantly delay the onset of electrographic seizures in the intracerebral ferrous chloride model. Thus, vitamin E shows activity in the ferrous chloride model, but not in the animal models commonly used to screen for anticonvulsant drug actions.

Animals↗
PubMed2026

PEStimate: predicting offspring disease risk after polygenic embryo screening.

MOTIVATION: Polygenic embryo screening (PES) is a new, controversial technology, whereby human in vitro fertilization embryos are screened for their genetic risk of complex, polygenic diseases. PES aims to reduce the disease burden in offspring by prioritizing the selection of low-risk embryos. However, given that polygenic diseases are usually late-onset, PES outcomes must be estimated by epidemiological modeling. The liability threshold model has been previously used to predict outcomes. However, predictions rely on complex sets of equations, some of which require numerical integration or simulation. Further, previous models failed to account for the possibility that the selected embryo will not be born. RESULTS: Here, we present PEStimate, a freely available online app for predicting PES outcomes when screening for a single disease. PEStimate predicts the offspring risk with and without PES, as well as generates plots of the risk reduction versus key parameters. Users can adjust the number of available embryos, the live birth rate, the disease prevalence, the accuracy of the genetic risk predictor, the embryo selection method, the genetic risk of parents, and the disease status of parents, siblings, uncles/aunts, and grandparents of the embryos. Our model includes, for the first time, the possibility of embryo implantation failure, showing that risk reductions have been previously overestimated. PEStimate provides geneticists, healthcare professionals, patients, and other stakeholders with a necessary tool for examining the impact of PES and weighing its potential benefits against possible personal and societal harms. AVAILABILITY AND IMPLEMENTATION: PEStimate: https://polygenicembryo.shinyapps.io/pestimate. Source code: https://github.com/Lirazk/PEStimate.

Humans↗