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PubMed2002

Quality of life in advanced non-small-cell lung cancer: results of a Southwest Oncology Group randomized trial.

PURPOSE: The main purpose of this paper is to present the results of a randomized trial comparing the effects of two chemotherapy regimens on the Quality of life (QOL) of patients with advanced non-small-cell lung cancer (NSCLC). Trials in advanced stage disease represent an important treatment context for QOL assessment. A second purpose of this paper is to examine methods for handling the level of missing data commonly observed in the advanced stage disease context. METHODS: Patients were randomized to receive cisplatin plus vinorelbine or carboplatin plus paclitaxel. The QOL of 222 patients was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) prior to randomization; follow-up assessments occurred at 13 and 25 weeks. Three methods were used to analyze the QOL data: (1) cross-sectional analysis of four patient categories (improved, stable, missing, and declined) based on changes in the FACT-L score, (2) a mixed linear model, and (3) a pattern mixture model. The longitudinal analyses addressed two potential data biases. RESULTS: Questionnaire submission rates were 91% at baseline, 68% at 13 weeks, and 47% at 25 weeks. The cross-sectional and mixed linear model analyses did not show significant differences by treatment arm in patient-reported QOL. The pattern mixture model analysis, more appropriate given non-ignorable missing data, also found no statistically significant effect of treatment on patient QOL. CONCLUSION: We present a sensitivity analysis approach with multiple methods for analyzing treatment effects on patient QOL in the presence of substantial, non-ignorable missing data in an advanced stage disease clinical trial. We conclude that the two treatment arms did not differ statistically in their effects on patient QOL over a 25-week treatment period.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

Exploring contingency tables with correspondence analysis.

An algorithm for correspondence analysis is described and implemented in SAS/IML (SAS Institute, 1985a). The technique is shown, through the analysis of several biological examples, to supplement the log-linear models approach to the analysis of contingency tables, both in the model identification and model interpretation stages of analysis. A simple two-way contingency table of tumor data is analyzed using correspondence analysis. This example emphasises the relationships between the parameters of the log-linear model for the table and the graphical correspondence analysis results. The technique is also applied to a three-way table of survey data concerning ulcer patients to demonstrate applications of simple correspondence analysis to higher dimensional tables with fixed margins. Finally, the diets and foraging behaviors of birds of the Hubbard Brook Forest are each analyzed and then a simultaneous display of the two separate but related tables is constructed to highlight relationships between the tables.

Algorithms↗

PubMed2005

Short-term effects of treatment with 300 mg oral-dose diethylcarbamazine on nocturnally periodic Wuchereria bancrofti microfilaremia and antigenemia.

Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed.

Adolescent↗

PubMed2006

Structural kinetic modeling of metabolic networks.

To develop and investigate detailed mathematical models of metabolic processes is one of the primary challenges in systems biology. However, despite considerable advance in the topological analysis of metabolic networks, kinetic modeling is still often severely hampered by inadequate knowledge of the enzyme-kinetic rate laws and their associated parameter values. Here we propose a method that aims to give a quantitative account of the dynamical capabilities of a metabolic system, without requiring any explicit information about the functional form of the rate equations. Our approach is based on constructing a local linear model at each point in parameter space, such that each element of the model is either directly experimentally accessible or amenable to a straightforward biochemical interpretation. This ensemble of local linear models, encompassing all possible explicit kinetic models, then allows for a statistical exploration of the comprehensive parameter space. The method is exemplified on two paradigmatic metabolic systems: the glycolytic pathway of yeast and a realistic-scale representation of the photosynthetic Calvin cycle.

Computer Simulation↗

PubMedDate not supplied

A new algorithm for computing the parameters of linear compartment models in pharmacokinetics.

A new algorithm (FADHA) for computing pharmacokinetic parameter estimates has been developed. This technique is based on the simplex method which is used to minimize a nonlinear cost function. An important property of this program is that the convergence is ensured contrary to the well-known linear or nonlinear least-squares regression analysis which lead to a lack of convergence or to a false one. Two investigations of the comparative performances of FADHA program and other algorithms were undertaken (hexamethylmelamine and Piracetam pharmacokinetics). Least square analysis of data yielded biased estimates whereas FADHA estimates were unbiased and more precise. This new technique, takes into account all the possible observation errors and uses the concept of a weighting function rather than weights as such.

Altretamine↗

PubMed1991

Mean time parameters for generalized physiological flow models (semihomogeneous linear systems).

This note gives expressions for recirculation mean time parameters of the disposition kinetics of particles in a semihomogeneous stationary linear system. In such a system each compartment may have an arbitrary single-pass disposition function, rather than a known parametric (usually monoexponential) one. Such systems provide a generalization of physiological flow models. Given observations of arterial blood concentrations and tissue amounts, and making the additional assumptions that (i) the fraction of total blood flow exiting each tissue that goes to each other tissue is constant and known, and (ii) the fraction of drug entering each tissue that is eliminated to the outside is constant and known, the input to each tissue can be known, and therefore both its total blood flow and its single-pass disposition function can be estimated. Recirculation mean time parameters can be computed from these estimates. Application to real thiopental data is presented as an example.

Mathematical Computing↗

PubMed2006

Climate cycles and forecasts of cutaneous leishmaniasis, a nonstationary vector-borne disease.

BACKGROUND: Cutaneous leishmaniasis (CL) is one of the main emergent diseases in the Americas. As in other vector-transmitted diseases, its transmission is sensitive to the physical environment, but no study has addressed the nonstationary nature of such relationships or the interannual patterns of cycling of the disease. METHODS AND FINDINGS: We studied monthly data, spanning from 1991 to 2001, of CL incidence in Costa Rica using several approaches for nonstationary time series analysis in order to ensure robustness in the description of CL's cycles. Interannual cycles of the disease and the association of these cycles to climate variables were described using frequency and time-frequency techniques for time series analysis. We fitted linear models to the data using climatic predictors, and tested forecasting accuracy for several intervals of time. Forecasts were evaluated using "out of fit" data (i.e., data not used to fit the models). We showed that CL has cycles of approximately 3 y that are coherent with those of temperature and El Niño Southern Oscillation indices (Sea Surface Temperature 4 and Multivariate ENSO Index). CONCLUSIONS: Linear models using temperature and MEI can predict satisfactorily CL incidence dynamics up to 12 mo ahead, with an accuracy that varies from 72% to 77% depending on prediction time. They clearly outperform simpler models with no climate predictors, a finding that further supports a dynamical link between the disease and climate.

Animals↗

PubMed1997

Two-stage method of estimation for general linear growth curve models.

We extend the linear random-effects growth curve model (REGCM) (Laird and Ware, 1982, Biometrics 38, 963-974) to study the effects of population covariates on one or more characteristics of the growth curve when the characteristics are expressed as linear combinations of the growth curve parameters. This definition includes the actual growth curve parameters (the usual model) or any subset of these parameters. Such an analysis would be cumbersome using standard growth curve methods because it would require reparameterization of the original growth curve. We implement a two-stage method of estimation based on the two-stage growth curve model used to describe the response. The resulting generalized least squares (GLS) estimator for the population parameters is consistent, asymptotically efficient, and multivariate normal when the number of individuals is large. It is also robust to model misspecification in terms of bias and efficiency of the parameter estimates compared to maximum likelihood with the usual REGCM. We apply the method to a study of factors affecting the growth rate of salmonellae in a cubic growth model, a characteristic that cannot be analyzed easily using standard techniques.

Animals↗

PubMed2003

Studying parents and grandparents to assess genetic contributions to early-onset disease.

Suppose DNA is available from affected individuals, their parents, and their grandparents. Particularly for early-onset diseases, maternally mediated genetic effects can play a role, because the mother determines the prenatal environment. The proposed maximum-likelihood approach for the detection of apparent transmission distortion treats the triad consisting of the affected individual and his or her two parents as the outcome, conditioning on grandparental mating types. Under a null model in which the allele under study does not confer susceptibility, either through linkage or directly, and when there are no maternally mediated genetic effects, conditional probabilities for specific triads are easily derived. A log-linear model permits a likelihood-ratio test (LRT) and allows the estimation of relative penetrances. The proposed approach is robust against genetic population stratification. Missing-data methods permit the inclusion of incomplete families, even if the missing person is the affected grandchild, as is the case when an induced abortion has followed the detection of a malformation. When screening multiple markers, one can begin by genotyping only the grandparents and the affected grandchildren. LRTs based on conditioning on grandparental mating types (i.e., ignoring the parents) have asymptotic relative efficiencies that are typically >150% (per family), compared with tests based on parents. A test for asymmetry in the number of copies carried by maternal versus paternal grandparents yields an LRT specific to maternal effects. One can then genotype the parents for only the genes that passed the initial screen. Conditioning on both the grandparents' and the affected grandchild's genotypes, a third log-linear model captures the remaining information, in an independent LRT for maternal effects.

Age of Onset↗

PubMedDate not supplied

Control of a nonsquare drug infusion system: A simulation study.

A model predictive control strategy was developed and tested on a nonlinear canine circulatory model for the regulation of hemodynamic variables under critical care conditions. Different patient conditions such as congestive heart failure, post-operative hypertension, and sepsis shock were studied in closed-loop simulations. The model predictive controller, which uses a different linear model depending on the patient condition, allowed constraints to be explicitly enforced. The controller was initially tuned on the basis of a linear plant model, then tested on the nonlinear physiological model; the simulations demonstrated the ability to handle constraints, such as drug dosage specifications, commonly desired by critical care physicians.

Animals↗

PubMed1994

Variations in maximum amplitude of facial expressions between and within normal subjects.

Definitive proof of efficacy of preventions and therapeutic interventions, and of risk factors in lower motor neuron facial paralyses continue to be confounded by the lack of repeatable quantitative measures of outcome. Clinical and research experience with human facial expression repeatedly demonstrates wide variations between subjects. To our knowledge, little information is available to isolate and describe the differences in dynamic facial expression between and within normal subjects. The purpose of this study is to use a statistical model to analyze the components of the observed variations of maximum amplitude measurement of image change during normal human subject facial expressions. Seventeen consecutive normal adult human subjects with no current or past evidence of facial nerve or ear disease were studied. Videotapes of command facial expressions were taken using specific and standardized conditions. The tapes were analyzed using a new computer-assisted image-change analysis program capable of generating dimensional data for the maximum amplitude of expression. These data were statistically analyzed using a General Linear Model with Nested variables to isolate and define component variations and errors. The General Linear Model predicted 88% of the observed total variation (p < 0.05).* A model performance this high suggests that most of the important independent variables were being studied. The major component of the variations was the difference among (between) subjects. Seventy-seven percent of the predicted variation was due to this difference (p < 0.05). Little of the variation (1%) seemed to be within-subjects. Test-retest agreement was acceptable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Lennard-Jones sticks: a new model for linear molecules.

We consider the anisotropic interaction between two line segments consisting of a homogeneous distribution of Lennard-Jones centers. The potential energy of such a pair cannot be expressed in closed form. However, we show that it may be approximated in a way that renders this intuitively appealing model competitive both for simulations and theory.

Journal Article↗

PubMed2001

Optimal design for linear interpolation of curves.

Non-parametric procedures are often used for the analysis of pharmacokinetic trials. Fewer design procedures are available for non-parametric estimation than for parametric estimation. Linear interpolation is widely used for curve estimation in pharmacokinetic trials, where often only sparse sampling is feasible. Current design procedures for smoothing or local fit are not suitable as they are based on asymptotic properties and the bias of the estimate is ignored. This paper proposes optimal designs that minimize the mean squared error of linear interpolation. Optimal designs for three situations are considered. The first situation is single curve estimation based on an ordinary non-linear model. The second is estimating several curves in a non-linear mixed model setting using an average mean squared error as the design criterion. The third situation is destructive sampling where estimating the average curve is the main purpose. In the first situation, the design results in the best linear interpolation when the variance is constant. For the destructive sampling design, an algorithm based on approximations is proposed. This algorithm can be programmed in a common statistical package. Numerical examples are used to illustrate the design procedure.

Algorithms↗

PubMed1978

The relation between arterial viscoelasticity and wave propagation in the canine femoral artery in vivo.

The influence of arterial dimensions and viscoelasticity on pulse wave propagation has been expressed in many theoretical models of blood flow in arteries, but few experimental tests of these theories in vivo have been reported. The measurements required for such tests include not only the arterial viscoelasticity, diameter, and wall thickness, but also the true propagation coefficients and impedances, for comparison with the values "predicted" by solution of the model equations. We made such measurements in 16 experiments on the femoral artery in nine anesthetized dogs. A two-point pressure and flow technique was used to measure wave propagation, and an ultrasonic micrometer was used to measure vessel diameter as a function of time and pressure. Measured attenuation constants ranged from 0.010 at 1.3 Hz to 0.075 at 12.7 Hz, and were more than twice as large as those predicted by two representative linear models. True phase velocity, which increased from 6.71 m/sec at 1.3 Hz to 10.54 m/sec at 12.7 Hz, agreed closely with the values computed by the Cox model but were lower than those given by the Jager model. The resistive, but not the reactive, component of longitudinal impedance was significantly greater than predicted by the models at all frequencies. The experiments do not identify the source of these discrepancies. The use of linear models to calculate pulsatile blood flow from pressure gradients in relatively small vessels, or to calculate attenuation and characteristic impedance from arterial viscoelasticity in vessels of any size, produces significant errors.

Animals↗

PubMed1992

Accounting for the correlation between fellow eyes in regression analysis.

Regression techniques that appropriately use all available eyes have infrequently been applied in the ophthalmologic literature, despite advances both in the development of statistical models and in the availability of computer software to fit these models. We considered the general linear model and polychotomous logistic regression approaches of Rosner and the estimating equation approach of Liang and Zeger, applied to both linear and logistic regression. Methods were illustrated with the use of two real data sets: (1) impairment of visual acuity in patients with retinitis pigmentosa and (2) overall visual field impairment in elderly patients evaluated for glaucoma. We discuss the interpretation of coefficients from these models and the advantages of these approaches compared with alternative approaches, such as treating individuals rather than eyes as the unit of analysis, separate regression analyses of right and left eyes, or utilization of ordinary regression techniques without accounting for the correlation between fellow eyes. Specific advantages include enhanced statistical power, more interpretable regression coefficients, greater precision of estimation, and less sensitivity to missing data for some eyes. We concluded that these models should be used more frequently in ophthalmologic research, and we provide guidelines for choosing between alternative models.

Adolescent↗

PubMed2004

Linear polyenes: models for the spectroscopy and photophysics of carotenoids.

We have developed procedures for synthesizing dimethyl polyenes using living polymerization techniques and have initiated investigations of the spectroscopic properties of these molecules. Purification using high-performance liquid chromatography (HPLC) of the polyene mixtures resulting from the syntheses promises to provide all-trans polyenes with a wide range in the number of conjugated double bonds. Low temperature optical measurements on these model systems, both in glasses and in n-alkane mixed crystals, yield absorption and fluorescence spectra with considerably higher vibronic resolution than the spectra currently available for carotenoids with comparable conjugation lengths. The dimethyl polyenes thus allow a more precise exploration of the electronic properties of long, linearly conjugated systems. These studies can be used to verify the existence of low-lying singlet states predicted by theory and recently invoked to explain low-resolution fluorescence, Raman excitation spectra, and the transient absorption spectroscopy of carotenoids. Steady state and time-resolved optical studies of the dimethyl series will be used to better understand the energies and dynamics of the low energy electronic states relevant to the photochemistry and photobiology of all linearly conjugated systems.

Carotenoids↗

PubMed2004

Generic biomass functions for Norway spruce in Central Europe--a meta-analysis approach toward prediction and uncertainty estimation.

To facilitate future carbon and nutrient inventories, we used mixed-effect linear models to develop new generic biomass functions for Norway spruce (Picea abies (L.) Karst.) in Central Europe. We present both the functions and their respective variance-covariance matrices and illustrate their application for biomass prediction and uncertainty estimation for Norway spruce trees ranging widely in size, age, competitive status and site. We collected biomass data for 688 trees sampled in 102 stands by 19 authors. The total number of trees in the "base" model data sets containing the predictor variables diameter at breast height (D), height (H), age (A), site index (SI) and site elevation (HSL) varied according to compartment (roots: n = 114, stem: n = 235, dry branches: n = 207, live branches: n = 429 and needles: n = 551). "Core" data sets with about 40% fewer trees could be extracted containing the additional predictor variables crown length and social class. A set of 43 candidate models representing combinations of lnD, lnH, lnA, SI and HSL, including second-order polynomials and interactions, was established. The categorical variable "author" subsuming mainly methodological differences was included as a random effect in a mixed linear model. The Akaike Information Criterion was used for model selection. The best models for stem, root and branch biomass contained only combinations of D, H and A as predictors. More complex models that included site-related variables resulted for needle biomass. Adding crown length as a predictor for needles, branches and roots reduced both the bias and the confidence interval of predictions substantially. Applying the best models to a test data set of 17 stands ranging in age from 16 to 172 years produced realistic allocation patterns at the tree and stand levels. The 95% confidence intervals (% of mean prediction) were highest for crown compartments (approximately +/- 12%) and lowest for stem biomass (approximately +/- 5%), and within each compartment, they were highest for the youngest and oldest stands, respectively.

Biomass↗

PubMed2004

Quantifying patterns in the evolution of reproductive isolation.

We present a likelihood-based statistical method for examining the pattern or rate of evolution of reproductive isolation. The method uses large empirical datasets to estimate, for a given clade, the average duration of two phases in the divergence of populations. The first phase is a lag phase and refers to the period during which lineages diverge but no detectable reproductive isolation evolves. The second is an accumulation phase, referring to the period during which the magnitude of reproductive isolation between diverging lineages increases. The pattern of evolution is inferred from the relative durations of these two phases. Results of analyses of postzygotic isolation data indicate significant differences among taxa in the pattern of evolution of postzygotic isolation that are consistent with predictions based on genetic differences among these groups. We also examine whether the evolution of postzygotic isolation is best explained by either of two models for the rate of accumulation: a linear model or a quadratic function as may be suggested by recent studies. Our analysis indicates that the appropriateness of either model varies among taxa.

Animals↗