Computer-aided calculation of dose response curves in behavioral pharmacology by using a nonlinear regression procedure

In a variety of behavioral pharmacological experiments drug induced graded responses can be recorded even if one animal can be tested only once. In this case the analysis of dose response relationships will be accompanied with theoretical and practical problems additional to those known for dose response curves in single subjects as well as for the all-or-none type of responses. An experimental design was considered where one quantitatively measurable response of each animal tested contributed to an average dose response relationship. Use was made of a four parameter model capable of fitting s-shaped dose response curves over the whole feasible dose range for solving this nonlinear regression problem. Two examples, the dose dependent increased locomotor activity induced by apomorphine and the inhibited locomotor activity after pimozide treatment, were given to demonstrate the use of the method described and to direct the reader's attention to the wide range of its possible applications.     

Nonlinear analysis of spatial vision using first-and-second-order volterra transfer functions measurement

The harmonic input method of nonlinear system identification is modified to allow the Volterra series approach to be used for psychophysical investigation of various aspects of human pattern vision in the spatial frequency domain. While it is well known that only one modulation transfer function provides a complete characterization of a linear system, a number of multidimensional transfer functions are needed to identify a nonlinear system. We have shown, that so far as the contrast sensitivity to sine-wave gratings may be used for an empirical estimate of the first-order modulation transfer function of the human visual system, the contrast sensitivity to difference harmonics may be used as an empirical estimate of the second-order modulation transfer function.

A difference harmonic arises from a mixture of two sine-wave gratings resulting from the nonlinearity of the visual system. Difference harmonic, experienced as some periodic beatlike structure, may still be observed if frequencies of the component gratings are higher than the maximum visual acuity.

The visibility of the low-frequency beatlike pattern produced by pairs of sine-wave gratings, which themselves are of spatial frequencies too high to be resolved, could be accounted for either by a difference frequency distortion product (Burton, 1973) or by a special beat detector (Derrington & Badcock, 1985). We found that increasing the contrast of one component grating may be compensated for by reducing the contrast of the other component grating, the beatlike pattern being at threshold. This is exactly what would be expected if the beatlike pattern is detected because of the difference harmonics produced by nonlinearity of the visual system.

We have determined contrast thresholds for the difference harmonics which occur between two unresolved different spatial frequencies. The contrast sensitivity function for difference harmonics was found to have a marked similarity both in the shape and position of peak sensitivity to the contrast sensitivity function for single sine-wave gratings. Another important characteristic of the contrast sensitivity function for difference harmonics is that it depends only on the frequency difference, Δf = f₁ − f₂, rather than on the value of either f₁ or f₂.

All this indicates that a difference harmonic arises from local nonlinearities in the visual system. More specifically, the visual system may be represented as a cascade system, composed of a linear system with transfer function O(f) followed by a nonlinear element, r(·), without spatial spread in cascade with another linear system with transfer function P(f). The nth order transfer function of this cascade system, H_n(f₁,...,f_n) can be expressed in the following way: H_n(f₁,...,f_n) = a_nO(f₁)P(f₁ + ... + f_n) where a_n is the nth coefficient in the Taylor series expansion for the nonlinear function r(·). It follows from this that the measurement of the first- and second-order transfer functions is sufficient to determine O(f) and P(f). We have derived the estimates of cO(f) and P(f) from contrast sensitivity functions for single sine-wave gratings and difference harmonics by the least squares method.     

Entwicklung eines Kreislaufmodells

Zusammenfassung Es wird ein Kreislaufmodell vorgestellt, das für in vitro-Studien der automatischen Steuerung von Blutpumpen zum Ersatz des Herzens entwickelt wurde. Die günstigsten Möglichkeiten zur automatischen Beeinflussung der Perfusionsflüsse mit einem Analogrechner über vorwiegend hämodynamische Meßgrößen sollen herausgefunden und dann bei Langzeitversuchen in vivo erprobt werden.

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Development of a circulation mock-up

Summary A circulation mock-up has been developed for in-vitro-studies of the automatic control of blood pumps for the replacement of the heart. The best control systems shall be found, which can serve to influencing the perfusion flow rates via an analog computer by hemodynamic signals. These control systems then will be tested during long term in-vivo experiments.

     

MODFIT: a pharmacokinetics computer program

This paper presents a computer program, MODFIT, written in FORTRAN, primarily for use on the Digital Equipment Company VAX series computers for the mathematical analysis of concentration-time data. Drug data generated from biological fluids and tissues may be fitted by a variety of different models. For many models, parameter starting estimates are program generated prior to automatic nonlinear regression analysis using a modified Davidon-Fletcher-Powell algorithm. The output of results is extensive and plotting facilities are available. Explicit and differential equation models may be fitted to single dose data and simulations using all models (single or repeat dose) may be employed to generate drug concentration-time data with plotting output. The package has been tested on numerous data with no problems regarding local function minima. Some comparisons with existing programs have been made and MODFIT compares well with respect to robustness, efficiency, and ease of use.     

Nonlinear intravascular ultrasound contrast imaging

Nonlinear contrast agent imaging with intravascular ultrasound (IVUS) is investigated using a prototype IVUS system and an experimental small bubble contrast agent. The IVUS system employed a mechanically scanned single element transducer and was operated at a 20 MHz transmit frequency (F20) for second harmonic imaging (H40), and at a 40 MHz transmit frequency (F40) for subharmonic imaging (SH20). Characterization experiments were performed with agent and tissue phantom signals acquired during transducer rotation. The suppression of transmit frequency tissue signals was achieved using a combination of pulse-inversion and bandpass filtering. H40 was found to improve the contrast-to-tissue signal ratio (CTR) by up to 22 dB relative to F20, but suffered from tissue propagation harmonics at higher pressures (>0.3 MPa). SH20 was also shown to be possible at a range of pressures (approximately 0.25 to 1.8 MPa), with tissue signals suppressed to near the noise floor. Coronary phantom experiments demonstrated the detection of agent in 1 mm diameter vessels outside a larger 4 mm diameter vessel in which the IVUS catheter was situated. These results suggest the feasibility of harmonic IVUS contrast imaging, which may have applications in coronary lumen boundary detection and vasa vasorum imaging.     

MATLAB软件在非线性药动学参数估算中的应用

目的:利用MATLAB软件拟合非线性药动学参数。方法:采用MATLAB软件的非线性回归拟合二室模型血管外给药的药-时数据。结果:MATLAB非线性算法与3p97软件拟合得到的药动学参数一致,通过实例验证了其处理非线性药动学问题的有效性。结论:MATLAB回归分析计算准确、方便、简单,并能显示直观的拟合曲线图,适用于估算非线性药室模型的药动学参数。     

冷却剂参数对铣槽喷管低周疲劳寿命的影响

采用有限体积流固耦合计算方法、非线性有限元热结构耦合分析方法和局部应变法研究大面积比铣槽喷管三维再生冷却槽道在循环工作条件下的热结构变形与低周疲劳寿命,并对比分析了冷却剂质量流量与入口温度对铣槽喷管疲劳使用寿命的影响。计算结果表明,铣槽喷管热结构响应呈现复杂的三维效应,应变较大位置主要分布在与肋连接的内衬区域,喷管中部的残余应变量最大;冷却槽道低周疲劳寿命分布和热结构响应基本一致,最小寿命位于喷管中部与肋相连的内衬区域燃气侧;随冷却剂质量流量增加,铣槽喷管低周疲劳寿命不断提高;随冷却剂入口温度增加喷管尾部低周疲劳寿命值不断降低,而喷管中前部的低周疲劳寿命值却不断提高,当冷却剂入口温度为280K左右时,本文的铣槽喷管总体使用寿命达到最大。      

Comparison of Model-Based Tests and Selection Strategies to Detect Genetic Polymorphisms Influencing Pharmacokinetic Parameters

We evaluate by simulation three model-based methods to test the influence of a single nucleotide polymorphism on a pharmacokinetic parameter of a drug: analysis of variance (ANOVA) on the empirical Bayes estimates of the individual parameters, likelihood ratio test between models with and without genetic covariate, and Wald tests on the parameters of the model with covariate. Analyses are performed using the FO and FOCE method implemented in the NONMEM software. We compare several approaches for model selection based on tests and global criteria. We illustrate the results with pharmacokinetic data on indinavir from HIV-positive patients included in COPHAR 2-ANRS 111 to study the gene effect prospectively. Only the tests based on the EBE obtain an empirical type I error close to the expected 5%. The approximation made with the FO algorithm results in a significant inflation of the type I error of the LRT and Wald tests.     

非线性粘弹性方程的EQrot1非协调有限元分析

针对非线性粘弹性方程,在半离散和全离散格式下给出EQrot1非协调有限元逼近.由于该单元的相容误差(O(h2)阶)比插值误差(O(h)阶)高一阶,可得到在H1模意义下的O(h2)阶超逼近结果,并利用插值后处理技术导出整体超收敛.进而,基于该单元的渐近展开式,构造新的插值后处理算子和外推格式,给出O(h4)阶的外推结果.最后,运用与以往文献不同的方法得到全离散逼近格式的最优误差估计.     

My Career as a Pharmacometrician and Commentary on the Overlap Between Statistics and Pharmacometrics in Drug Development

As part of a series of articles celebrating the American Statistical Association's 175th anniversary in 2014, this article provides a historical perspective of key statistical contributions to pharmacometrics (the design, modeling, and analysis of experiments involving complex dynamic systems) as well as a commentary on the author's career as a pharmaceutical industry statistician and pharmacometrician. Individuals with training in various academic disciplines including pharmacokinetics, pharmacology, engineering, and statistics, to name a few, have pursued careers as pharmacometricians. While pharmacometrics has benefitted greatly from advances in statistical methodology, there continues to be tension and skepticism between biostatisticians and pharmacometricians as they apply their expertise to drug development problems. This article explores some of the root causes for this tension and provides some suggestions for improving collaborations between statisticians and pharmacometricians. The article concludes with a plea for more statisticians to consider careers as pharmacometrics practitioners.