Nonlinear relation between alcohol intake and high-density lipoprotein cholesterol level: results from the Copenhagen City Heart Study

BACKGROUND: It has been suggested that the level of high-density lipoprotein cholesterol (HDL-C) in the blood can be used as a marker of recent alcohol intake. However, before using HDL-C as a predictor of alcoholism, the relation between alcohol intake and HDL-C in the entire range of consumption must be explored. Most studies model the relation between alcohol intake and HDL-C linearly, although a threshold effect is expected. The objective of this study was to evaluate the shape of the relation between intake of alcohol and HDL-C and to determine whether there are differential effects of beer, wine, and spirits on HDL-C and whether they remain after adjusting for total alcohol. METHOD: The relation between alcohol intake and HDL-C was investigated by means of generalized additive models using data from the Copenhagen City Heart Study. RESULTS: A nonlinear effect of alcohol improved the model fit significantly, and the nonlinearity of alcohol was highly significant in both men and women. The relation was concave: HDL-C was stable in men and women who drank more than approximately 35 and 20 drinks per week, respectively. We found a significant nonlinear term of wine on HDL-C in men after adjustment for total alcohol intake. CONCLUSIONS: There was a concave relation between alcohol intake and HDL-C, indicating a threshold effect of alcohol on HDL-C. The association between wine and HDL-C in men after adjusting for total alcohol intake may be due to residual lifestyle confounding.     

22例肝移植患者他克莫司的群体药代动力学

目的:观察口服他克莫司(TAC)在肝移植患者中的群体药代动力学(PPK)特征,为调整用药方案和个体化给药提供科学依据. 方法:用非线性混合效应模型(NONMEM)程序分析前瞻性收集的22例肝移植患者254份TAC的稳态全血药物浓度样本.确定一级吸收二房室开放模型为PPK模型,估算清除率(CL/F)、中央室分布容积(V2)、室间清除率(Q)、外周室分布容积(V3)、吸收速率常数(Kα)及滞后时间(ALAG)的个体间变异用加法模型,个体自身变异(残差误差)用指数模型.定量评价剂量(DD)、年龄(AGE)、术后时间(POD)、血清肌酐(CR)、血清总胆红素(TBIL)和合并用药等固定效应(协变量)对TAC药代动力学参数的影响. 结果:CL/F、V2、Q、V3、Kα和ALAG的群体标准值分别为9.96L/h、85.9L、36.7L/h、351 L、2.53 h-1和0.242h.CL/F、V2和Q群体典型值的最终回归方程为(C)L/F=9.96×(DD/2)0.887×(AGE/32)-0.654×(POD/15)0.216、(V)2=85.9×(CR/40)0.674和(Q)=36.7×(TBIL/8)0.627.浓度实测值和个体预测值的平均绝对权重残差为(5.98±5.79)%. 结论:固定效应中剂量、年龄、术后时间对TAC的CL/F是有显著意义的协变量,而血清肌酐和血清总胆红素分别对V2和Q有显著影响.     

Population pharmacokinetics of topotecan: intraindividual variability in total drug

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.5 l per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of −2 ± 17%, and +5 ± 20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring. Received: 23 February 2000 / Accepted: 22 May 2000     

A Comparison of the Forecast Performance of Markov-switching and Threshold Autoregressive Models of US GNP

While there has been a great deal of interest in the modelling of non-linearities in economic time series, there is no clear consensus regarding the forecasting abilities of non-linear time-series models. We evaluate the performance of two leading non-linear models in forecasting post-war US GNP, the self-exciting threshold autoregressive model and the Markov-switching autoregressive model. Two methods of analysis are employed: an empirical forecast accuracy comparison of the two models, and a Monte Carlo study. The latter allows us to control for factors that may otherwise undermine the performance of the non-linear models.     

Reliability of traditional and fractal dimension measures of quiet stance center of pressure in young, healthy people

OBJECTIVES: To assess reliability of traditional and fractal dimension measures of quiet stance center of pressure (COP). DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: Thirty young healthy men (n=20) and women (n=10) (mean age, 23 y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: COP was recorded for 3 trials across 4 conditions: eyes open and eyes closed standing on firm and foam surfaces. Traditional COP variables--peak sway velocity and range of sway, both in the anteroposterior (AP) and mediolateral (ML) directions, and total excursion area, and fractal dimension of the COP in the AP and ML directions--were calculated. Reliability statistics were calculated. RESULTS: Range of sway (AP) was the most reliable traditional variable (intraclass correlation coefficient model 2,1 [ICC(2,1)] range -.28 to .72.). Peak sway velocity (AP) had poorest reliability (ICC(2,1) range, .05-.29). Only 1 of the traditional variables had excellent reliability; total excursion area (firm, eyes closed) (ICC(2,1)=.95). All bar 1 fractal dimension measures had excellent ICCs. Relative technical error of measurement ranged from 4% to 7% for the fractal dimension measures. Coefficients of variation were also very good, ranging from 1.8% to 6.7%. CONCLUSIONS: Fractal dimension measures were more reliable than traditional measures of COP. Although traditional measures are used extensively to assess COP, their reliability is questionable. Fractal dimension measures show promise to reliably quantify COP and warrant further investigation.     

Automated pharmacokinetic analysis: Experiences of a user

Two curve-stripping and three nonlinear regression computer programs currently in use for automated pharmacokinetic analysis were tested alone and in combination on their suitability to solve a number of pharmacokinetic problems. The five programs, NONLIN, NONLINEAR, CFT3, ESTRIP, and RUGFIT (all non-commercial and readily available from the particular authors), were compared on these features: reliability, robustness, user convenience, and availability on macro or micro computers. The results show that if reliability and robustness are considered only, a combination of the curve-stripping program ESTRIP with the nonlinear regression program CFT3 operates better than the other combinations. This combination is even more attractive if, in addition, user convenience and availability on micro computers are taken into account.     

The relationship between the mass spectra of drugs and their biological activity—An application of artificial intelligence to chemistry

The mass spectra of a set of drugs consisting of sedatives and tranquilizers are analyzed and differentiated by pattern recognition methods, such as nonlinear mapping, K-nearest neighbors and Fisher discriminant. The mass spectral peaks are ranked, selected and weighed by the Fisher Ratio of each peak. The results indicate that it is possible to separate the two types of drugs and to predict the pharmacologic activity of “test” drugs with a high degree of accuracy. These general computer methods can be applied to other drugs or any data which requires separation into two classes.     

Parallel Cascade Recognition of Exon and Intron DNA Sequences

Many of the current procedures for detecting coding regions on human DNA sequences combine a number of individual techniques such as discriminant analysis and neural net methods. Recent papers have used techniques from nonlinear systems identification, in particular, parallel cascade identification (PCI), as one means for classifying protein sequences into their structure/function groups. In the present paper, PCI is used in a pilot study to distinguish exon (coding) from intron (noncoding; interspersed within genes) human DNA sequences. Only the first exon and first intron sequences with known boundaries in genomic DNA from the T-cell receptor locus were used for training. Then, the parallel cascade classifiers were able to achieve classification rates of about 89% on novel sequences in a test set, and averaged about 82% when results of a blind test were included. In testing over a much wider range of human nucleotide sequences, PCI classifiers averaged 83.6% correct classifications. These results indicate that parallel cascade classifiers may be useful components in future coding region detection programs. © 2002 Biomedical Engineering Society. PAC2002: 8715Cc, 8714Gg, 8715Aa     

Luminance mechanisms mediate the motion of red-green isoluminant gratings: the role of "temporal chromatic aberration"

In this paper we use a dynamic noise-masking paradigm to explore the nature of the mechanisms mediating the motion perception of drifting isoluminant red-green gratings. We compare contrast thresholds for the detection and direction discrimination of drifting gratings (1.5 cpd), over a range of temporal frequencies (0.5-9 Hz) in the presence of variable luminance or chromatic noise. In the first experiment, we used dynamic luminance noise to show that direction thresholds for red-green grating motion are masked by luminance noise over the entire temporal range tested, whereas detection thresholds are unaffected. This result indicates that the motion of nominally isoluminant red-green gratings is mediated by luminance signals. We suggest that stimulus-based luminance artifacts are not responsible for this effect because there is no masking of the detection thresholds. Instead we propose that chromatic motion thresholds for red-green isoluminant gratings are mediated by dynamic luminance artifacts that have an internal, physiological origin. We have termed these "temporal chromatic aberration". In the second experiment, we used dynamic chromatic noise masking to test for a chromatic contribution to red-green grating motion. We were unable to find conclusive evidence for a contribution of chromatic mechanisms to the chromatic grating motion, although a contribution at very high chromatic contrasts cannot be ruled out. Our results add to a growing body of evidence indicating the presence of dynamic, internal luminance artifacts in the motion of chromatic stimuli and we show that these occur even at very low temporal rates. Our results are compatible with our previous work indicating the absence of a chromatic mechanism for first order (quasi-linear) apparent motion [Vision Res. 40 (2000) 1993]. We conclude that previous conclusions based on the motion of chromatic red-green gratings should be reassessed to determine the contribution of dynamic luminance artifacts.