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[French evaluation of cardiac stimulation].

A national enquiry into the problems related to definitive cardiac pacemakers, carried out in 1975, has yielded certain essential findings: the number of first-time implantations of pacemakers has been increasing by about 20% per annum; 92% of electrodes are currently implanted by an endocavitary technique, thoracotomy having now practically been abandoned; 90% of pacemakers implanted in 1975 were threshold models, inhibited by a QRS complex; the indications have become progressively wider, and are essentially related with the various forms of bradycardia, most frequently those due to atrio--ventricular block. In 1976, we have now reached a figure of about 200 new implantations of pacemakers per million inhabitants; those using lithium are increasingly superceding the mercury and isotope models.

Aged↗

Some research needs in defibrillation and CPR.

The Fourth Purdue Conference on Cardiac Defibrillation and Cardiopulmonary Resuscitation identified needed defibrillation research, including an appropriate animal model, threshold validity, effects of polarity, and an easy-to-operate defibrillator. CPR research needs include better protocols, hemodynamics and survival studies, the role of pulmonary edema, re-examination of sudden death, and transchest pacing.

Animals↗

Tumor induction in BALB/c female mice after fission neutron or gamma irradiation.

This study was designed to examine the dose-response relationships for tumor induction after neutron irradiation in female BALB/c mice, with emphasis on the response in the dose range 0 to 50 rad. Tumors induced after radiation exposure included ovarian tumors, lung adenocarcinomas, and mammary adenocarcinomas. For comparison the dose responses for induction of these tumors after 137Cs gamma irradiation were also examined. As previously described for the female RFM mouse, the data for ovarian tumor induction after neutron and gamma irradiation were consistent with a threshold model. For lung and mammary tumors the dose-response curve after neutron irradiation appeared to "bend over" in the dose range 10 to 20 rad. The factors responsible for this bend-over and their relative contributions to the overall form of the dose-response relationship are not presently known. However, these data strongly indicate that extrapolation from data above 50 rad could result in a significant underestimate of risks. Further, it is clear that current models of neutron carcinogenesis are inadequate, since such a bend-over is not predicted at these low dose levels.

Adenocarcinoma↗

Community characteristics, women's education, and fertility in Peru.

Using data from the World Fertility Survey of 1977-78, this paper examines how community characteristics influence completed fertility in Peru. The analysis shows that community characteristics do not condition (interact with) the effects of mother's education in determining completed fertility. Rather, the effects of community characteristics are best described by a threshold model, which posits that below or above critical cut points, the effects on fertility of community (or individual) characteristics will diminish or increase. Empirical results showed that residence in communities with higher levels of access to the benefits of development decreased completed fertility beyond what one would have predicted on the basis of women's characteristics alone, and this effect was further amplified with increasing levels of development.

Educational Status↗

The genetics of urinary tract malformations.

In this discussion I have excluded consideration of the genetics of purely renal malformations, such as polycystic kidneys, and of functional disorders of the kidney. Systematic family studies are available for renal agenesis, duplication of the ureters, vesico-ureteric reflux (each probably due to maldevelopment of the ureteric bud), bladder exstrophy and hypospadias as isolated malformations. Renal agenesis has a birth frequency of about 1.2 in 10 000 and the proportion affected of sibs is about 3 per cent. Duplication of the ureter has a birth frequency of about 1 per cent and the proportion affected of sibs and parents of probands is about 12 per cent. Vesico-ureteral reflux also has a prevalence in early childhood of about 1 per cent and the proportion of sibs affected is about 10 per cent. Bladder exstrophy has a birth frequency of about 1 in 20 000 and perhaps about 1 per cent of sibs are affected. Hypospadias has a birth frequency in boys of about 1 in 300 and the proportion affected of brothers is about 10 per cent. Further family studies are needed of these malformations when they occur in isolation. Either the multifactorial threshold model or dominant inheritance with reduced penetrance and varied expressivity would fit the data available.

Bladder Exstrophy↗

["Hand clasping" and "arm folding". Population, hereditary, and neurophysiologic aspects].

The data have been obtained showing that the hand clasping does not constitute a hereditary trait. The frequency of R- and L-types makes nearly 50% in all age groups. Possible relation of this trait with left handedness on non-genetic basis is discussed. The frequency of R- and L-types of arm folding is age dependent. The association of this trait with brain motor asymmetry and asymmetry of finger dermatoglyphics has been established. The correlation calculated by means of the threshold model for multifactorial traits is significant in the pairs of monozygotic twins for T-type, and insignificant for L-type. This may reflect a non-uniform degree of hereditary effects on the function of left and right cerebral hemispheres.

Adult↗

Genetic analysis of Tourette syndrome suggesting major gene effect.

Data on Gilles de la Tourette syndrome are analyzed by multiple threshold models in inheritance that incorporate sex effect. The polygenic-multifactorial model is rejected. Single major locus inheritance can account for the data, although many of the occurrences of Tourette are due to nongenetic phenocopies. In both models, males and females share a common genetic environmental liability, but the less prevalent sex, that is, females, has a higher genetic loading for the disorder. The predicted population prevalences in the single major locus model are 2.3% for males and 0.8% for females. The implications for genetic and biological research in Tourette syndrome are discussed.

Female↗

Early exposure to otitis media: a preliminary investigation of behavioral outcome.

Factors that contribute to developmental vulnerability were examined in a 4-year follow-up of 31 children who, as infants, had participated in an investigation of the relationship between recurrent otitis media and developmental status. The children in this inner-city sample experienced significant decline in their language and developmental status regardless of their history with otitis media. Findings support a threshold model of risk, suggesting that otitis media does not necessarily pose an additional stress to the language and cognitive development of low-income, inner-city children. In keeping with theoretical models by Vygotsky and Rutter, maternal cognitive growth fostering facilitated children's language development by serving as a compensatory factor, counteracting the potential impact of recurrent otitis media.

Child↗

Should chloral hydrate be banned?

OBJECTIVE: Current federal regulations of potentially carcinogenic environmental chemicals are based on the assumption that risks for humans can be extrapolated from the effects of chronic high-dose exposure of rodents. It is assumed that all chemicals induce cancer by a genotoxic mechanism (direct interaction with DNA) and that humans metabolize chemicals by the same pathways as the test rodents. Trichloroethylene, a former medicine, is now regulated because of rodent studies. Its major metabolite, chloral hydrate, widely used as a sedative in both adults and children, is in danger of being banned by comparable studies. This paper assesses the safety of chloral hydrate. DESIGN: Analysis of the literature regarding the metabolic, toxicologic, and epidemiologic data on trichloroethylene and chloral hydrate. RESULTS: The dose-response relationship for carcinogenesis of chloral hydrate and other chemicals in its metabolic breakdown pathway is nonlinear in rodents: very high doses given chronically, sufficient to cause cellular necrosis, are necessary for induction of malignancies. In addition, epidemiologic data on people exposed to substantial amounts of trichloroethylene (which is metabolized to chloral hydrate) show no increase in mortality or cancers. CONCLUSIONS: The assumptions underlying current regulatory practices for environmental chemicals are not applicable to the medicinal use of chloral hydrate. Instead, a threshold model is appropriate. The data do not suggest the need to ban chloral hydrate as a medicine; however, possible modifications in its use are suggested.

Adult↗

Craniofacial morphology as a marker of predisposition to isolated cleft palate.

The etiology and pathogenesis of isolated cleft palate (CP) is largely unknown. Undoubtedly, bot genetic and environmental factors play a role in initiating this malformation. Although the predictions of the multifactorial threshold model have never been satisfied when subjected to statistical analysis, there is no a priori reason to dismiss the possibility that multiple genes may be segregating in CP families that give rise to specific and predictive phenotypes in the parents of CP offspring. We examined a sample composed of 52 parent pairs whose children were born with CP, as well as 75 normal controls with no family history of CP. Using anthropometric and roentgencephalometric methods, along with discriminant function analysis, we searched for craniofacial variables predictive of parents who were ¿at risk¿ for CP offspring. For fathers of CP children, 32 of the studied variables differed significantly from controls; for mothers of CP children 25 variables differed significantly from controls. These results support the hypothesis that there are characteristic morphometric signs in the craniofacies of the parents of children with CP. To confirm these findings, it will be necessary to prospectively ascertain the incidence of CP in the offspring of ¿at risk¿ parents and ¿not at risk¿ parents from families with and without a history of CP in other family members.

Adult↗

[Exposure to the technologists from radioactive patients during nuclear medicine studies].

In order to evaluate the exposure to the nuclear medicine technologists from patients who had been administrated with radiopharmaceuticals, we measured the exposure in 5 common diagnostic procedures (bone, lung, tumor scan, and brain, myocardial SPECT, n = 8 to 52) using a silicon semiconductor pocket dosimeter. We also measured the spatial dose rates at 5 cm, 50 cm, and 100 cm from skin surface of the patients (n = 10 to 21) using an ionization chamber, both 5 min after injection and right before the studies with the same procedures above. We further measured the spatial dose rate distributions around the patients in the 4 procedures (bone, renal, blood pool scan, and brain SPECT, n = 2 to 3). In results, the exposure to the technologists in each procedure was small (0.5, 0.5, 0.7, 1.6, and 0.3 muSv in each bone, lung, tumor scan, and brain, myocardial SPECT, respectively), compared with the dose limits of the medical workers. However, the dose-response relationships in cancer and hereditary effects, referred to as the stochastic effects, have been assumed linear and no threshold models; therefore, the exposure should be minimized. For this purpose, the measurements of spatial dose rates and spatial dose rate distributions were thought to be useful. The differences of these results among procedures were caused by the differences of dose distributions and physical and biological half lives of the radiopharmaceuticals. The results of the measurements in 7 consecutive weeks suggested that the direct measurement of the exposure using a high sensitive digital pocket dosimeter might result a reduced exposure to the technologists.

Adult↗

Low-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3H 10T1/2 cells.

We have previously shown that chronic exposure of plateau-phase C3H 10 T1/2 cells to (60)Co gamma radiation at doses as low as 10 cGy protected the cells against neoplastic transformation by a subsequent large acute radiation exposure. We have also shown that this induced resistance to neoplastic transformation correlated with an increased ability to repair radiation-induced chromosome breaks. We now show that a single exposure of quiescent cells to doses as low as 0.1 cGy also reduces the risk of neoplastic transformation, from the spontaneous level to a rate three- to fourfold below that level. Higher doses, up to 10 cGy at the same dose rate (0.24 cGy/min), did not reduce the neoplastic transformation frequency further. This protective effect was seen only in irradiated cells that were allowed to incubate at 37 degrees C before release from contact inhibition. Cells released into low-density subcultures immediately after irradiation had unchanged neoplastic transformation frequencies. These results demonstrate that low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation. If similar processes are induced in human cells, the results also suggest that a single low dose, at background or occupational exposure levels, may in some circumstances reduce rather than increase cancer risk, a conclusion inconsistent with the linear no-threshold model of cancer risk from radiation.

Animals↗

Genetics of type 1 diabetes.

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda s = 2.5). It is recognised that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda s = 1.25), cannot account for all of the observed clustering of disease in families (lambda s = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33), IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. The results suggest that the clustering of type 1 diabetes in families is due to the sharing of alleles at multiple loci, and that the as yet unidentified environmental factors are not causing clustering, but instead appear to influence the overall penetrance of genetically programmed susceptibility. The data are consistent with a polygenic threshold model for the inheritance of type 1 diabetes.

Animals↗

An examination of the genetic relationship between bipolar and unipolar illness in an epidemiological sample.

In an epidemiologic sample of female-female twin pairs, we previously reported analyses of lifetime major depression. Because lifetime mania was not assessed, we could not differentiate unipolar from bipolar illness. Having completed such an evaluation in this sample, we now examine three questions: (i) does removing bipolar cases from our cohort substantially alter estimates for the heritability of major depression?; (ii) does our epidemiologic data support a familial relationship between major depression and mania?; and (iii) do our results for major depression and mania suggest that the two disorders are caused by the same underlying liability? We find that (i) the heritability of major depression declines only trivially if cases with a history of mania are removed; (ii) mania in one twin predicts major depression in her cotwin-suggesting a familial/genetic relationship between major depression and mania; and (iii) a multiple threshold model fits our data well, consistent with the hypothesis that unipolar and bipolar disorders are points on a continuum of a single liability of illness. The validity of these results are tempered by the small number of bipolar cases detected, as expected from the low base rate of mania in general population samples.

Adult↗

Ionizing radiation and cancer risk: evidence from epidemiology.

Epidemiological studies provide the primary data on the carcinogenic effects of radiation in humans. Much of what is known has come from studies of the atomic bomb survivors, and to a lesser extent from patients receiving radiotherapy. These studies demonstrate that exposure to moderate to high doses of radiation increases the risk of cancer in most organs. For all solid cancers combined, cancers of the thyroid, breast and lung, and leukemia, risk estimates are fairly precise, and associations have been found at relatively low doses (<0.2 Gy). Associations between radiation and cancers of the salivary glands, stomach, colon, bladder, ovary, central nervous system and skin have also been reported, but the relationships are not as well quantified. Associations between radiation and cancers of the liver and esophagus, and to a lesser extent multiple myeloma and non-Hodgkin's lymphoma, have been reported in a few studies, but results are inconsistent. Chronic lymphocytic leukemia, Hodgkin's disease, and cancers of the pancreas, prostate, testis and cervix have rarely been linked to radiation exposure. A linear no-threshold model adequately describes the dose-response relationship for solid cancers, although at extremely high doses the risk appears to flatten out. Because few populations have been followed until the end of life, the temporal patterns of risk are not completely known. An increased risk, however, does continue for several decades. In contrast, radiation-related leukemias begin to occur shortly (2-3 years) after exposure and, at least in the A-bomb survivors, a linear-quadratic dose response seems to fit the data better than a pure linear model. Radiation does not act entirely in isolation. It can interact with other carcinogens, e.g. tobacco or chemotherapeutic agents, and with host factors such as age at exposure, gender or reproductive history. Interactions with medical interventions or with certain heritable mutations have also been suggested. While the studies of high-dose exposures are essential for understanding the overall biological consequences of radiation exposure, the public is more concerned about the long-term health effects from protracted exposures at low doses. Unfortunately, the inherent limitations of epidemiology make it extremely difficult to directly quantify health risks from these exposures. While most epidemiological data are compatible with linear extrapolations from exposures at high doses or high dose rates, they cannot entirely exclude other possibilities. As the field of epidemiology advances, understanding more about the health effects of prolonged and low-dose exposures will be the next challenge.

Case-Control Studies↗

Potential accuracy of genetic evaluation for calving difficulty with incomplete data on calving difficulty and/or birth weight using a bivariate threshold-linear animal model.

The purpose of this study was to evaluate the potential loss of accuracy in direct and maternal predicted breeding values (PBV) for calving difficulty (CD) with different levels of missing records of CD and/or birth weight (BW), using a bivariate threshold-linear animal model. Data obtained from the American Gelbvieh Association included 84,420 first-parity records with both CD and BW available. The final pedigree file included 178,858 animals. The model included fixed calf-sex-dam-age, random herd-year-season, and animal direct and maternal effects. Different levels of missing observations for CD and BW were obtained by randomly deleting 0, 25, 50, 75, and 100% of records for both traits in various combinations. Correlation estimates between PBV for CD obtained with complete and incomplete data were used to measure the changes in PBV for different levels of missing records. Reported correlations are means of three replicates. The results suggest that the information on direct and maternal PBV provided by CD records is more reliable than the information provided by BW records. The difference was especially large when a high proportion of CD records were missing. Correlations above 0.96 and 0.95 for direct and maternal PBV, respectively, when missing 25% or 0% of the CD or BW records suggest that small changes would be predicted with a low proportion incomplete data. For genetic prediction of popular sires (with > 100 pogeny), a higher proportion of missing records could be tolerated. The results suggest that the bivariate threshold-linear animal model is useful for routine genetic evaluation of CD with incomplete field data.

Journal Article↗

Semiquantitative assessment of myocardial perfusion using magnetic resonance imaging: evaluation of appropriate thresholds and segmentation models.

RATIONALE AND OBJECTIVES: The aim of the study was to determine optimal thresholds for semiquantitative perfusion parameters and to evaluate the influence of different segmentation models in detecting malperfused regions. MATERIAL AND METHODS: In 6 healthy subjects and 13 patients with coronary artery disease, contrast-enhanced first-pass perfusion imaging was performed using a SR-TrueFISP-sequence. Thresholds for semiquantitative parameters were established, and different segmentation models of the left ventricular myocardium were tested. The standard of reference for patient studies was single photon emission computed tomography. RESULTS: Optimal thresholds were determined in healthy subjects for the perfusion parameters upslope, AUC, and peak SI of mv-0.5*std, mv-1.5*std, and mv-1.0*std, respectively. Using the optimal threshold for each parameter/segmentation combination sensitivities and specificities of stress studies were between 66% and 93% and 77% and 92%, respectively. Subdivision of radial segments into subendo/subepicardial segments increased sensitivities for perfusion deficits. CONCLUSIONS: Subdivision of radial myocardial segments is essential in analysis of magnetic resonance first-pass perfusion series. Semiquantitative perfusion parameters possess different sensitivities for the detection of perfusion deficits.

Adult↗

A statistical model predicting the seizure threshold for right unilateral ECT in 106 patients.

Titration of the electroconvulsive therapy (ECT) stimulus to the patient's convulsive threshold is the only way to directly assess the patient's seizure threshold. This technique is presently practiced by 39% of ECT providers, according to a recent survey. Because multiple variables influence the seizure threshold in patients, multivariate statistical methods may provide a useful strategy to determine which variables exert the most influence on convulsive threshold. A multivariate ordinal logistic model of seizure threshold was developed on an experimental group of 66 consecutive patients undergoing titrated right unilateral (RUL) ECT for major depression. The accuracy of the model was cross-validated on a second group of 40 patients undergoing similar RUL ECT procedures. The final multivariate ordinal logistic regression model for the seizure threshold level (STL) was significant (Likelihood ratio chi 2 = 54.115; p < 0.0001:R2 = 0.313). Increasing age, African-American race, and longer inion-nasion distances (p < 0.06) predicted higher STL. Female gender was associated with a lower STL. The ability of the final model to accurately predict STL for the validation group was fair (pairwise correlation was 0.576; p < 0.001). The model did well for predicting lower STL, but fared poorly for higher STL. In conclusion, modeling STL may help establish the relative contribution of variables thought to be important to seizure threshold. However, STL models remain impractical for clinical applications in estimating seizure threshold at this time, and empirical stimulus titration should be used.

Adult↗