Parameter Sensitivity Analysis in Electrophysiological Models Using Multivariable Regression

Computational models of electrical activity and calcium signaling in cardiac myocytes are important tools for understanding physiology. The sensitivity of these models to changes in parameters is often not well-understood, however, because parameter evaluation can be a time-consuming, tedious process. I demonstrate here what I believe is a novel method for rapidly determining how changes in parameters affect outputs. In three models of the ventricular action potential, parameters were randomized, repeated simulations were run, important outputs were calculated, and multivariable regression was performed on the collected results. Random parameters included both maximal rates of ion transport and gating variable characteristics. The procedure generated simplified, empirical models that predicted outputs resulting from new sets of input parameters. The linear regression models were quite accurate, despite nonlinearities in the mechanistic models. Moreover, the regression coefficients, which represent parameter sensitivities, were robust, even when parameters were varied over a wide range. Most importantly, a side-by-side comparison of two similar models identified fundamental differences in model behavior, and revealed model predictions that were both consistent with, and inconsistent with, experimental data. This new method therefore shows promise as a tool for the characterization and assessment of computational models. The general strategy may also suggest methods for integrating traditional quantitative models with large-scale data sets obtained using high-throughput technologies.     

基于心脏电生理模型的心律失常机制研究进展

揭示发病机制是心律失常诊断、治疗、药物研发和设备设计的关键.整合当前在心脏分子生物学、生物化学、生理学及解剖学方面的最新成果,构建从离子通道、心肌细胞、心肌纤维、心肌组织、心脏器官到躯体各个层次的多尺度多模态心脏电生理模型,用于系统研究微观局部变化发生、发展、转化为宏观心律失常表现的过程,将彻底改变传统从基因突变、蛋白质表达、细胞电生理、临床表现单独研究心律失常的方式,实现微观与宏观研究的统一,使心脏电生理模型成为系统研究心律失常发病机制的有力手段.本文综述了心脏电生理模型的构建方法和研究进展,讨论了多尺度心脏电生理模型在揭示心律失常机制研究中的作用和地位,给出了基于心脏电生理模型心律失常研究的挑战和重要发展方向.     

Distance-Based Analysis with Quantile Regression Models

Statistics in Biosciences - Non-standard structured, multivariate data are emerging in many research areas, including genetics and genomics, ecology, and social science. Suitably defined pairwise...     

Functional Mixed-Effect Models for Electrophysiological Responses

In electro/psychophysiological experiments, linear mixed-effect modeling is an effective statistical technique for data repeatedly observed from the same experimental participants or stimulus items. This review describes the application of mixed-effect modeling to functional responses, in particular those observed in event-related EEG or MEG experiments, using a discrete wavelet transform. The technique is illustrated with a design with several covariates, and procedures for generating posterior samples and computing a Bayesian false discovery rate are described. Neirofiziologiya/Neurophysiology, Vol. 41, No. 1, pp. 79–87, January–February, 2009.     

Sexual-Selection Models for Exaggerated Traits are Useful but Constraining

SYNOPSIS. Science is driven by productive hypotheses and technology,but these may sometimes limit the questions posed. For instance,Fisherian runaway sexual selection and related hypotheses havehelped us understand the evolution of exaggerated visual sexualdimorphism. Species with indistinguishable sexes, however, mayuse different behavioral mechanisms when pairing and thus possessdifferent adaptations. In the monomorphic Midas cichlid (Amphilophuscitrinellum), females chose large aggressive males in a restrainedsituation, as sexual selection predicts, but males did not choose.The nuchal hump of males swells coincidently with pair formation.However, overly large humps were shunned by females while thenormal— size hump facilitated sex recognition. This speciesis polychromatic, and pairs mate assortatively by color in Nicaragua.Some have suggested the Midas cichlid might therefore show howsexual selection produces explosive speciation of cichlids inAfrica. All females, however, are biased toward normal—colormales. The color of gold morphs modulates aggressive responsesof the other fish. All else equal, the benefit to gold in afight equals 15% more weight than the opponent. Pair formationsucceeds best when the typically smaller female of a pair isrelatively more aggressive than the male. The pair combination,gold male with normal female, is difficult to produce; makingthe female the same size as the male removes the disability.Pair formation is a negotiated process in which the male teststhe aggressiveness of the female relative to self. That putsthe behavioral mechanisms of the male and female in conflict.     

Functional Regression Models for Epistasis Analysis of Multiple Quantitative Traits

To date, most genetic analyses of phenotypes have focused on analyzing single traits or analyzing each phenotype independently. However, joint epistasis analysis of multiple complementary traits will increase statistical power and improve our understanding of the complicated genetic structure of the complex diseases. Despite their importance in uncovering the genetic structure of complex traits, the statistical methods for identifying epistasis in multiple phenotypes remains fundamentally unexplored. To fill this gap, we formulate a test for interaction between two genes in multiple quantitative trait analysis as a multiple functional regression (MFRG) in which the genotype functions (genetic variant profiles) are defined as a function of the genomic position of the genetic variants. We use large-scale simulations to calculate Type I error rates for testing interaction between two genes with multiple phenotypes and to compare the power with multivariate pairwise interaction analysis and single trait interaction analysis by a single variate functional regression model. To further evaluate performance, the MFRG for epistasis analysis is applied to five phenotypes of exome sequence data from the NHLBI’s Exome Sequencing Project (ESP) to detect pleiotropic epistasis. A total of 267 pairs of genes that formed a genetic interaction network showed significant evidence of epistasis influencing five traits. The results demonstrate that the joint interaction analysis of multiple phenotypes has a much higher power to detect interaction than the interaction analysis of a single trait and may open a new direction to fully uncovering the genetic structure of multiple phenotypes.     

Methods for Checking Assumptions in Regression Models

The usual assumptions in regression analysis are: The setup is true; the random errors are uncorre-lated (and normally distributed); and the data contain no outliers. Reasoning known recommendations to check these assumptions by inspection of the residuals new proposals are discussed and illustrated by an example.     

甘蔗蔗汁品质性状的回归分析及模型

本文对47份不同甘蔗基因型的蔗汁品质性状进行简单回归和逐步回归分析.结果表明,蔗汁蔗糖分(Suc)与锤度(BX)、温度校正后锤度(BX′)、蔗汁旋光读数(0Z)以及转光度(pol)之间均呈线性回归,简单回归模型均达极显著水平(P＜0.01),决定系数(R2)分别为0.9393、0.9199、0.9861及0.9839.通过逐步回归分析和残差分析建立多重线性回归方程为Suc=0.05706 0.21488BX 0.181030Z,方差分析表明多重线性回归模型达极显著水平(P＜0.01),决定系数为0.9931.t测验表明,蔗汁蔗糖分的模型预测值与实测值间的差异不显著,相对误差平均为0.49%.     

自制起搏电极在心脏电生理实验中的应用研究

本文探索了自制起搏电极在心脏电生理研究中的应用,通过选择适当的材料,分为三部分制作电极：极片部分、起搏器接口部分、焊封与绝缘。最后,将电极缝合于犬的心脏进行起搏。结论是自制起搏电极应用于动物实验进行心脏电生理的研究是可行的。     

Hemodialysis Water Parameters as Predisposing Factors for Anemia in Patients in Dialytic Treatment: Application of Mixed Regression Models

Biological Trace Element Research - Contamination by metals and microbiological agents in hemodialysis water can cause clinical intercurrences in hemodialysis patients. Evaluating and assuring...     

Merging Spline Approximations with Analysis of Nonlinear Regression Models

The paper outlines a method of analysis of intricically non-linear regression functions. The nonlinear model is first approximated by a cubic spline function. Thereafter, the standard methods of analysis in linear models are applied to obtain estimates and test statistics.     

Compound Regression Models for Ordered Categorical Data

A general class of sequential models for the analysis of ordered categorical variables is developed and discussed. The models apply if the ordinal response may be subdivided into two or more meaningful sets of response categories. The parametrization explicitly makes use of this subdivision. The models furnish a linear alternative to non-linear models which incorporate a scale parameter. They are shown to be special cases of multivariate generalized linear models. Applications are discussed with the use of several examples.     

不育男性精浆锌与其它精液参数的回归分析

对２２３例男性不育患者的精浆锌进行了测定,并用回归分析的方法研究了精浆锌与其它精液参数的关系．结果显示：精浆锌与精液ｐＨ、精子存活率之间存在显著的线性回归（Ｐ＜０．０１）,而精浆锌与精子密度、前向运动精子百分率、精子畸型率具有显著的曲线回归（Ｐ＜０．０１）．     

A Comparison of Regression Models for Small Counts

ABSTRACT Count data with means <2 are often assumed to follow a Poisson distribution. However, in many cases these kinds of data, such as number of young fledged, are more appropriately considered to be multinomial observations due to naturally occurring upper truncation of the distribution. We evaluated the performance of several versions of multinomial regression, plus Poisson and normal regression, for analysis of count data with means <2 through Monte Carlo simulations. Simulated data mimicked observed counts of number of young fledged (0, 1, 2, or 3) by California spotted owls (Strix occidentalis occidentalis). We considered size and power of tests to detect differences among 10 levels of a categorical predictor, as well as tests for trends across 10-year periods. We found regular regression and analysis of variance procedures based on a normal distribution to perform satisfactorily in all cases we considered, whereas failure rate of multinomial procedures was often excessively high, and the Poisson model demonstrated inappropriate test size for data where the variance/mean ratio was <1 or >1.2. Thus, managers can use simple statistical methods with which they are likely already familiar to analyze the kinds of count data we described here.     

An Attempt to Infer the Electrophysiological Functions of Some Intracellular Structures in Cardiac Cells by an Electronic Analogue

A circuit which simulates the electrical conduction characteristics of the neuron has been modified by the addition of a feedback loop to simulate the electrical properties of some of the "specialized" tissues of the mammalian heart. It is suggested that there is similar electrical feedback in the muscle cells which is responsible for their electrical properties, and possible relationships between the feedback and observed structures are discussed.     

Regression Smoothers for Estimating Parameters of Growth Analyses

The objective of regression smoothers is to obtain predictedvalues of a dependent variable and its first derivative fromempirical data without having to assume any particular functionalrelationship between the dependent and independent variables.An early variant of this type of analysis, specifically naturalB-splines, was first applied to growth analyses by Parsons andHunt in 1981 (Annals of Botany 48 : 341–352, 1981). Theobject of this paper is to describe and evaluate two recentadvances in this area (cubic spline smoothers and loess smoothers)in the context of plant growth analysis and compare them tonaturalB -splines. The accuracies of these methods are evaluatedusing simulated data of a type that normally causes difficultieswith other methods. A bootstrap procedure is described thatimproves the estimate of the optimal smoother parameter. Itis shown that these smoothers can capture even subtle changesin relative growth rate. The method is then applied to growthdata ofHolcus lanatus. B -splines; cubic spline smoothers; growth analyses; Holcus lanatus ; loess; relative growth rate; RGR     

Electrophysiological Evidence for Intrinsic Pacemaker Currents in Crayfish Parasol Cells

I used sharp intracellular electrodes to record from parasol cells in the semi-isolated crayfish brain to investigate pacemaker currents. Evidence for the presence of the hyperpolarization-activated inward rectifier potassium current was obtained in about half of the parasol cells examined, where strong, prolonged hyperpolarizing currents generated a slowly-rising voltage sag, and a post-hyperpolarization rebound. The amplitudes of both the sag voltage and the depolarizing rebound were dependent upon the strength of the hyperpolarizing current. The voltage sag showed a definite threshold and was non-inactivating. The voltage sag and rebound depolarization evoked by hyperpolarization were blocked by the presence of 5–10 mM Cs²⁺ ions, 10 mM tetraethyl ammonium chloride, and 10 mM cobalt chloride in the bathing medium, but not by the drug ZD 7288. Cs⁺ ions in normal saline in some cells caused a slight increase in mean resting potential and a reduction in spontaneous burst frequency. Many of the neurons expressing the hyperpolarization-activated inward potassium current also provided evidence for the presence of the transient potassium current I_A, which was inferred from experimental observations of an increased latency of post-hyperpolarization response to a depolarizing step, compared to the response latency to the depolarization alone. The latency increase was reduced in the presence of 4-aminopyridine (4-AP), a specific blocker of I_A. The presence of 4-AP in normal saline also induced spontaneous bursting in parasol cells. It is conjectured that, under normal physiological conditions, these two potassium currents help to regulate burst generation in parasol cells, respectively, by helping to maintain the resting membrane potential near a threshold level for burst generation, and by regulating the rate of rise of membrane depolarizing events leading to burst generation. The presence of post-burst hyperpolarization may depend upon I_A channels in parasol cells.     

Goodness of Fit Tests for Proportional Hazards Regression Models

We present a test of goodness of fit for the proportional hazard regression model. The test is based on a score statistic for testing against local mixture alternatives. Contrary to the findings of several other authors, we detect a significant lack of fit in Freireich's leukemia data.