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PubMed1984

Maternal reproductive loss and cleft lip with or without cleft palate in human embryos.

Recognized spontaneous abortions in previous pregnancies were significantly more frequent in mothers of 87 Japanese embryos with cleft lip with or without cleft palate (CL(P] than in mothers of normal embryos. The number of prior pregnancies was found to be smaller in mothers of CL(P) embryos with additional defects, suggesting that unrecognized abortions might also occur more frequently in these women. The higher incidence of abortions was associated with more severe forms of CL(P), ie, CL(P) with associated anomalies rather than isolated CL(P), and bilateral rather than unilateral CL. These results are compatible with the "multifactorial two-threshold" model with a lower threshold beyond which the malformation occurs and a higher one beyond which the embryo dies. The present results are in contrast with the reduced spontaneous abortion rates in families of CL(P) probands reported previously. The reduced rates may be due to selection of those families in which CL(P) embryos escaped spontaneous abortion and survived to birth, although the effects of compensatory reproduction or maternal recall bias in postnatal data cannot be ruled out completely.

Abortion, Spontaneous↗
PubMed1992

Intraosseous versus intravenous epinephrine infusions in lambs: pharmacokinetics and pharmacodynamics.

Intraosseous and intravenous administrations of epinephrine were compared in newborn lambs. Plasma epinephrine levels were measured during each route of drug administration and used to calculate steady-state epinephrine clearance rate and to compare cardiovascular responses with plasma levels. Epinephrine was administered at a dose of 0.5 to 5 micrograms/kg/min. We observed first-order (linear) clearance kinetics by both routes of drug administration. The plasma epinephrine clearance rate was 186 +/- 17 ml/kg/min by the intraosseous route versus 174 +/- 11 ml/kg/min by the intravenous route. Dose responses were analyzed by computerized fit to a threshold model. The plasma epinephrine threshold, or lowest plasma level beyond which discernible increases in blood pressure occur, was slightly lower after intravenous than after intraosseous drug administration, 2.0 +/- 0.6 ng/ml versus 4.0 +/- 0.9 ng/ml of epinephrine. Both thresholds were within the ranges of plasma epinephrine levels that would be achieved at doses of 0.4 to 0.6 microgram/kg/min by either route. Other hemodynamic responses, including the maximum systolic blood pressure and degree of reflex bradycardia, were comparable. These results support the effectiveness of the intraosseous route for epinephrine administration.

Animals↗
PubMedDate not supplied

A complete enumeration and classification of two-locus disease models.

There are 512 two-locus, two-allele, two-phenotype, fully penetrant disease models. Using the permutation between two alleles, between two loci, and between being affected and unaffected, one model can be considered to be equivalent to another model under the corresponding permutation. These permutations greatly reduce the number of two-locus models in the analysis of complex diseases. This paper determines the number of nonredundant two-locus models (which can be 102, 100, 96, 51, 50, or 58, depending on which permutations are used, and depending on whether zero-locus and single-locus models are excluded). Whenever possible, these nonredundant two-locus models are classified by their property. Besides the familiar features of multiplicative models (logical AND), heterogeneity models (logical OR), and threshold models, new classifications are added or expanded: modifying-effect models, logical XOR models, interference and negative interference models (neither dominant nor recessive), conditionally dominant/recessive models, missing lethal genotype models, and highly symmetric models. The following aspects of two-locus models are studied: the marginal penetrance tables at both loci, the expected joint identity-by-descent (IBD) probabilities, and the correlation between marginal IBD probabilities at the two loci. These studies are useful for linkage analyses using single-locus models while the underlying disease model is two-locus, and for correlation analyses using the linkage signals at different locations obtained by a single-locus model.

Animals↗
PubMed2000

Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism.

Males are at least four times more likely to develop autism than females. Among relatives with a broader autistic phenotype, males predominate too. Autism is a highly heritable disorder, yet genome scans have not revealed any predisposing loci on the sex chromosomes. A nongenetic explanation for male vulnerability, such as exposure to prenatal androgens, is unlikely for a variety of reasons. A novel genetic mechanism that resolves many of the outstanding difficulties is outlined here. The imprinted-X liability threshold model hypothesizes that the threshold for phenotypic expression of many autistic characteristics is influenced by an imprinted X-linked gene(s) that is protective in nature. Imprinted genes are known to play an important role in normal fetal and behavioral development. The gene is expressed only on the X-chromosome that is inherited from the father and raises the threshold for phenotypic expression. It is normally silenced when transmitted maternally. Because only females have a paternal X-chromosome, the threshold for phenotypic expression is higher in them than in males. Evidence for the existence of the genetic locus was found in a study of females with X-monosomy (Turner's syndrome) in which females had either a single paternal or maternal X-chromosome. Identifying the sites of action of this X-linked gene could lead to the discovery of autosomal loci that confer more directly a predisposition to autism.

Autistic Disorder↗
PubMed2004

Genetic analysis of litter size, parturition length, and birth assistance requirements in primiparous sows using a joint linear-threshold animal model.

The aim of this study was to investigate whether selection for number of live born piglets has led to prolonged parturition and increased requirement for birth assistance, resulting in increased numbers of stillborn piglets. Data were collected from 6,718 primiparous Norwegian Landrace sows farrowing between 2001 and 2003. The need for birth assistance was recorded as a binary response. Physical intervention in the birth of piglets and/or hormonal treatment by the farmer was recorded as birth assistance. The duration of the parturition was analyzed as a binary trait (<4 h and >4 h). The statistical model used for analysis included contemporary groups of herd-year, litter breed, season of farrowing, parity in which the sow was born, a regression on the age of sow at farrowing, an additive genetic effect, and a service sire effect. A full Bayesian approach via Gibbs sampling was adopted to estimate the genetic relationships between these four traits. A total chain length of 100,000 iterations was run. The first 10,000 samples were discarded as burn-in, and the remaining 90,000 iterations were retained without thinning for post-Gibbs analysis. The highest direct heritability was estimated for the number of live-born piglets (h2 = 0.07), followed by the duration of farrowing (h2 = 0.05), the need for birth assistance (h2 = 0.05), and the number of stillborn piglets (h2 = 0.04). The genetic correlations revealed that the number of live and stillborn piglets was uncorrelated; however, the number of live piglets born had a moderate genetic correlation to the need for birth assistance (rg = 0.24 +/- 0.01) and duration of farrowing (rg = -0.20 +/- 0.01), whereas the number of stillborn piglets was highly correlated to the need for birth assistance (rg = 0.74 +/- 0.01) and the duration of parturition (rg = 0.66 +/- 0.01). The duration of farrowing and the need for birth assistance were genetically highly correlated (rg = 0.89 +/- 0.00). For all traits, the service sire variance was approximately one quarter in magnitude compared with its respective genetic variance. The results showed that selection for the number of live born piglets is not expected to influence the number of stillborn piglets. Increasing the number of live piglets born through selection should have a slight negative effect on farrowing duration and a minor increase in the need for birth assistance. Sows with a high genetic potential for birth assistance and prolonged parturition were more likely to give birth to greater numbers of stillborn piglets.

Animals↗
PubMed1999

Risk estimation for multifactorial diseases. A report of the International Commission on Radiological Protection.

This report reviews data on naturally-occurring multifactorial diseases and develops a mathematical model to predict the impact of radiation-induced mutations on the frequencies of these diseases in the population. It provides an outline of the aetiological features and examples of multifactorial diseases, interpreted to arise as a result of the joint action of genetic and environmental factors. Examples include common congenital abnormalities (such as neural tube defects, cardiovascular malformations, cleft lip+/-palate etc.) and chronic diseases (such as coronary heart disease, essential hypertension, diabetes mellitus etc.). These diseases are not readily explained on the basis of simple mendelian patterns of inheritance. The report considers the concepts and models used to explain the inheritance patterns of multifactorial diseases with particular emphasis on the multifactorial threshold model (MTM) of disease liability. The MTM is useful for predicting risk to relatives of those affected from information on their population frequencies. In these predictions, the heritability (h(2)) provides a measure of the relative importance of transmissible genetic effects in the overall phenotypic variation. Conceptual differences between mendelian and multifactorial diseases are discussed. The genetic basis of a multifactorial disease is that a genetically susceptible individual may or may not develop the disease depending on the interaction of a number of risk factors, both genetic and environmental. Three chronic multifactorial disease entities are reviewed in depth, viz. diabetes mellitus, essential hypertension, and coronary heart disease. The report considers briefly mechanistic population genetic models developed to explain polygenic variation. The basic conclusion is that the concepts of liability and threshold (underlying the MTM model) and that of mutation-selection balance (from population genetic models) together provide a basis for developing a model for assessing the impact of radiation-induced mutations on the frequencies of multifactorial diseases in the population.The mutation component (MC) of genetic diseases quantifies the responsiveness of the genetic component of a disease to an increase in mutation rate (e.g. after radiation exposure). This report integrates the concepts of liability and threshold (from the MTM model) and of mutation-selection equilibrium (from mechanistic population genetic models) into the 'Finite Locus Threshold Model' (FLTM) for estimating MC for multifactorial diseases and the relationship between MC and h(2) of these diseases. Computer simulation studies illustrate the effects of one-time or a permanent increase in mutation rate on MC for multifactorial diseases.Finally, the report addresses the estimation of the radiation risk of multifactorial diseases. A formal revision of the estimates of risk of multifactorial diseases (and also of mendelian diseases) contained in the 1990 Recommendations of ICRP, Publication 60, must await the results of studies currently underway. While future genetic risk estimates are likely to be lower than those in current use, until the new ones become available, those provided in Publication 60 may be regarded as being adequate for use in radiological protection- they are unlikely to underestimate risk.

Abnormalities, Radiation-Induced↗
PubMed2002

Exploration of threshold analysis in the relation between stressful life events and preterm delivery.

Biologic evidence suggests that the hormones activated by stress affect gestational length, but the results of epidemiologic investigations are inconsistent. The authors of this paper know of no threshold models that have been studied; these models assume that stress does not affect preterm delivery until a certain amount of stress has been experienced but that each unit of stress above the threshold adds to the risk of preterm delivery. By using standard logistic regression, the authors compared threshold and nonthreshold models of the relation between number of stressful life events and preterm delivery in 11 US states. They used data on 1990-1995 births from the Pregnancy Risk Assessment Monitoring System. The risk of preterm delivery among multiparas who gave birth in 1990-1993 increased 7% for each event over five they experienced, but no relation was found for 1994-1995 births. Among primiparas who gave birth in 1994-1995, the risk increased 5% for each event over two, but no relation was found for 1990-1993 births. These results suggest that a threshold model may fit the relation between stress and preterm delivery better than one with no threshold. However, the inconsistent results are difficult to reconcile with a biologic threshold in the relation between stress and preterm delivery.

Adult↗
PubMed1992

A threshold result for an epidemiological model.

A threshold parameter R0 is identified for an SIRS epidemiological model which has nonlinear incidence and a distributed delay for transfer out of the removed class. For R0 less than 1, the disease free equilibrium is proved to be the global attractor for all solutions.

Communicable Diseases↗
PubMed2002

Effects of dinoseb on the life cycle of Daphnia magna: modeling survival time and a proposal for an alternative to the no-observed-effect concentration.

Risk assessment is in urgent need of more accurate toxic effect endpoints than those currently in use, especially for low concentrations. Often such endpoints are estimated by analysis of variance, linear interpolation, or smoothing. As these statistical methods are not always satisfactory, some authors have proposed to describe the entire dose-response curves by fully formalized parametric regression models whose parameters have toxicological meaning. These models allow a better evaluation of pollutant effects, including inter- and extrapolation to any other than the measured effect values. Following this line, a four-parameter logistic regression model (standard model) was fitted to survival data of Daphnia magna under pesticide (dinoseb) stress. The heterogeneity of the variance was taken into account with a both-sides logarithmic transformation. Besides the standard model, a hormesis and a threshold model were tested too. These two others models have been described in the literature and might better represent the dose-response function we are looking for. All three models showed a good fit to our data, and the statistics gave no hints as to which model is the most appropriate. As no evidence was seen for hormesis or for the existence of a threshold concentration, we used the simplest, namely, the standard model, for most of our calculations. Model calculations allow the quantification of the effects on individuals' longevity as well as on mean survival time of the population. We used them to define a no-effect value, the statistical-no-effect concentration (SNEC). The SNEC is based on the confidence bands of the modeled regression and represents the highest value for which an effect is statistically not different from the control. The SNEC is an alternative to classical endpoints, like the no-observed-effect concentration (NOEC) or the low-effect concentrations (e.g., EC10, EC5, EC1).

2,4-Dinitrophenol↗
PubMed2001

Statistical characteristics of climbing fiber spikes necessary for efficient cerebellar learning.

Mean firing rates (MFRs), with analogue values, have thus far been used as information carriers of neurons in most brain theories of learning. However, the neurons transmit the signal by spikes, which are discrete events. The climbing fibers (CFs), which are known to be essential for cerebellar motor learning, fire at the ultra-low firing rates (around 1 Hz), and it is not yet understood theoretically how high-frequency information can be conveyed and how learning of smooth and fast movements can be achieved. Here we address whether cerebellar learning can be achieved by CF spikes instead of conventional MFR in an eye movement task, such as the ocular following response (OFR), and an arm movement task. There are two major afferents into cerebellar Purkinje cells: parallel fiber (PF) and CF, and the synaptic weights between PFs and Purkinje cells have been shown to be modulated by the stimulation of both types of fiber. The modulation of the synaptic weights is regulated by the cerebellar synaptic plasticity. In this study we simulated cerebellar learning using CF signals as spikes instead of conventional MFR. To generate the spikes we used the following four spike generation models: (1) a Poisson model in which the spike interval probability follows a Poisson distribution, (2) a gamma model in which the spike interval probability follows the gamma distribution, (3) a max model in which a spike is generated when a synaptic input reaches maximum, and (4) a threshold model in which a spike is generated when the input crosses a certain small threshold. We found that, in an OFR task with a constant visual velocity, learning was successful with stochastic models, such as Poisson and gamma models, but not in the deterministic models, such as max and threshold models. In an OFR with a stepwise velocity change and an arm movement task, learning could be achieved only in the Poisson model. In addition, for efficient cerebellar learning, the distribution of CF spike-occurrence time after stimulus onset must capture at least the first, second and third moments of the temporal distribution of error signals.

Action Potentials↗
PubMed2003

Bivariate analysis of liability to clinical mastitis and to culling in first-lactation cows.

Records taken on 13,070 first-lactation daughters of 250 Norwegian Cattle sires were used to examine associations between susceptibility to clinical mastitis and to culling. Clinical mastitis was defined as a binary trait, whereas culling was treated as either binary (culled or not culled) or continuous (length of opportunity period) for two sampling periods (120 or 300 d of lactation). Two Bayesian models were employed; 1) a bivariate threshold model with both mastitis and culling as binary traits, and 2) a bivariate model with mastitis as a threshold binary variable and time to culling as Gaussian. The heritability of liability to clinical mastitis was not affected by either the length of sampling period (120 vs. 300 d) or by whether culling (binary) or length of opportunity period was the second trait in the bivariate analysis. The posterior mean (standard deviation) of heritability of liability to clinical mastitis was 0.06 to 0.07 (0.02) in all analyses. The heritability estimate of length of opportunity period was less than 0.001. Culling (threshold trait) in first lactation had a low heritability, but a high genetic correlation with clinical mastitis. The posterior means (standard deviation) for heritability of liability to culling were 0.01 (0.006) for 120 d and 0.02 (0.009) for 300 d, and the posterior means (standard deviation) of the genetic correlation between liability to clinical mastitis and to culling were 0.48 (0.24) and 0.53 (0.21) for 120 and 300 d, respectively.

Analysis of Variance↗
PubMed1989

Models for genetic analysis of dystocia and calf mortality.

Calvings of 106,750 Israeli Holstein heifers were analyzed for dystocia and calf mortality, which were scored dichotomously. 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 calf. Herd-year-season, sire of cow and of calf, and residuals were random with diagonal variance-covariance matrices. Traits were analyzed with and without a herd-year-season effect, and dystocia was analyzed separately for male and female calvings and with both sexes combined. Variance components were estimated by REML for linear models and by the counterpart of REML for threshold models. Heritability estimates were two to four times larger in threshold than in linear models, but correlations between corresponding sire evaluations were all greater than .9. Correlations between evaluations computed with and without herd-year-season effects were .9 for sire of calf evaluations for dystocia and greater than .97 for all other evaluations. Correlations between sire evaluations computed separately for male and female calvings were between .3 and .7. Thus, calving difficulty is expressed differently in male and female calvings. Genetic trends were unfavorable for dystocia but favorable for calf mortality. Phenotypic trends were curvilinear with maxima in 1982 and 1983 for calf mortality and dystocia.

Age Factors↗
PubMed1991

A transducer model for contrast perception.

Multiple channel models of visual function proposed to date have been either threshold models or suprathreshold models. The transition between detection and perception of contrast which involves the gradual disappearance of spatial response pooling has not been addressed. We propose a model that allows us to simulate contrast detection, contrast perception and the gradual disappearance of spatial response pooling with contrast. The model successfully predicts thresholds and perceived contrast functions for several multiple component stimuli.

Calibration↗
PubMed1980

[Expanded model of lambda phage ontogeny].

An enlarged threshold model of regulatory system of development of lambda phage (RSDP lambda-2) is built. It includes 15 synthetic blocks of proteins and mRNAs and 4 blocks corresponding to the ontogenetic processes: two-stage replication, integration and exclusion of phage genome, formation of aggregates of regulatory proteins, regulation of bacterial lysis. By means of computer simulation of the RSDP lambda-2 model, the dynamics of concentrations of all main proteins, respective fractions of mRNAs and DNA are described in lytic and lysogenic regimens of phage ontogenesis. The results obtained are in a good agreement with available experimental data. The dependence of portion (%) of lysogenic responses on the mean multiplicity n of phage infection of bacterial culture, is built. This curve has a maximum point in accordance with experimental data of Kourilsky [10].

Bacteriophage lambda↗
PubMed1991

Genetic analysis of dystocia in dairy cattle.

Breeding values and genetic parameters for dystocia were estimated in Normande and Holstein breeds. Dystocia scores were related to an underlying continuous variable via a threshold model. The underlying linear model included the effects of calving season, sex of calf by parity of dam, sire of calf, grandsire of calf, dam within maternal grandsire and herd-year effects. Typical results were found for the environmental effects, with a strong influence of dam parity on dystocia, a strong influence of sex of calf, and a small effect of calving season. Herd-year variances were 32 and 40% of the residual variance in the Normande and Holstein breeds, respectively. Heritabilities for the Normande (Holstein) breed were .08 (.07) for direct effects and .11 (.07) for maternal effects. Correlations between sire and grandsire effects were .51 and .36 for the Normande and Holstein breeds, respectively. The corresponding correlations between direct and maternal effects were .15 and -.09. The results of this study show that a complete model for dystocia including the threshold concept and maternal effects can be applied for routine evaluation of dairy AI bulls. Maternal effects are important, and they should be considered in dystocia analysis, especially if nonrandom mating is present. Selection for reducing dystocia in calf and cow effects are not antagonistic.

Animals↗