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Akaike's Information Criterion and Recent Developments in Information Complexity.

In this paper we briefly study the basic idea of Akaike's (1973) information criterion (AIC). Then, we present some recent developments on a new entropic or information complexity (ICOMP) criterion of Bozdogan (1988a, 1988b, 1990, 1994d, 1996, 1998a, 1998b) for model selection. A rationale for ICOMP as a model selection criterion is that it combines a badness-of-fit term (such as minus twice the maximum log likelihood) with a measure of complexity of a model differently than AIC, or its variants, by taking into account the interdependencies of the parameter estimates as well as the dependencies of the model residuals. We operationalize the general form of ICOMP based on the quantification of the concept of overall model complexity in terms of the estimated inverse-Fisher information matrix. This approach results in an approximation to the sum of two Kullback-Leibler distances. Using the correlational form of the complexity, we further provide yet another form of ICOMP to take into account the interdependencies (i.e., correlations) among the parameter estimates of the model. Later, we illustrate the practical utility and the importance of this new model selection criterion by providing several real as well as Monte Carlo simulation examples and compare its performance against AIC, or its variants. Copyright 2000 Academic Press.

Journal Article↗

Maximum likelihood analysis of rare binary traits under different modes of inheritance.

Maximum likelihood methodology was applied to determine the mode of inheritance of rare binary traits with data structures typical for swine populations. The genetic models considered included a monogenic, a digenic, a polygenic, and three mixed polygenic and major gene models. The main emphasis was on the detection of major genes acting on a polygenic background. Deterministic algorithms were employed to integrate and maximize likelihoods. A simulation study was conducted to evaluate model selection and parameter estimation. Three designs were simulated that differed in the number of sires/number of dams within sires (10/10, 30/30, 100/30). Major gene effects of at least one SD of the liability were detected with satisfactory power under the mixed model of inheritance, except for the smallest design. Parameter estimates were empirically unbiased with acceptable standard errors, except for the smallest design, and allowed to distinguish clearly between the genetic models. Distributions of the likelihood ratio statistic were evaluated empirically, because asymptotic theory did not hold. For each simulation model, the Average Information Criterion was computed for all models of analysis. The model with the smallest value was chosen as the best model and was equal to the true model in almost every case studied.

Algorithms↗

Efficient classification of complete parameter regions based on semidefinite programming.

BACKGROUND: Current approaches to parameter estimation are often inappropriate or inconvenient for the modelling of complex biological systems. For systems described by nonlinear equations, the conventional approach is to first numerically integrate the model, and then, in a second a posteriori step, check for consistency with experimental constraints. Hence, only single parameter sets can be considered at a time. Consequently, it is impossible to conclude that the "best" solution was identified or that no good solution exists, because parameter spaces typically cannot be explored in a reasonable amount of time. RESULTS: We introduce a novel approach based on semidefinite programming to directly identify consistent steady state concentrations for systems consisting of mass action kinetics, i.e., polynomial equations and inequality constraints. The duality properties of semidefinite programming allow to rigorously certify infeasibility for whole regions of parameter space, thus enabling the simultaneous multi-dimensional analysis of entire parameter sets. CONCLUSION: Our algorithm reduces the computational effort of parameter estimation by several orders of magnitude, as illustrated through conceptual sample problems. Of particular relevance for systems biology, the approach can discriminate between structurally different candidate models by proving inconsistency with the available data.

Algorithms↗

Pharmacokinetic modeling and absorbed dose estimation for chimeric anti-CEA antibody in humans.

UNLABELLED: The objective of this article was to model pharmacokinetic data from clinical diagnostic studies involving the 111In-labeled monoclonal antibody (MAb) chimeric T84.66, against carcinoembryonic antigen. Model-derived results based on the 111In-MAb blood, urine and digital imaging data were used to predict 90Y-MAb absorbed radiation doses and to guide treatment planning for future therapy trials. Fifteen patients with at least one carcinoembryonic antigen-positive lesion were evaluated. We report the kinetic parameter estimates and absorbed 111In-MAb dose and projected 90Y-MAb doses for each patient as well as describe our approach and rationale for modeling an extensive set of pharmacokinetic data. METHODS: The ADAPT II software package was used to create three- and five-compartment models of uptake against time in the patient population. The "best-fit" model was identified using ordinary least squares. Areas under the curve were calculated using the modeled curves and input into MIRDOSE3 to estimate absorbed radiation doses for each patient. RESULTS: A five-compartment model best described the liver, whole body, blood and urine data for a subcohort of nine patients with digital imaging data. A three-compartment model best described the blood and urine data for all 15 clinical patients accrued in the clinical trial. For the subcohort, the largest projected 90Y-MAb doses were delivered to the liver (mean, 24.78 rad/mCi; range, 15.02-37.07 rad/mCi), with red marrow estimates on the order of 3.32 rad/mCi (range, 1.24-5.55) of 90Y. Corresponding estimates for the 111In-MAb were 3.18 (range, 2.09-4.43) and 0.55 (range, 0.34-0.74), respectively. CONCLUSION: The three- and five-compartment models presented here were successfully used to represent the blood, urine and imaging data. This was evidenced by the small standard errors for the kinetic parameter estimates and R2 values close to 1. As planned future therapeutic trials will involve stem cell support to alleviate hematological toxicities, the development of an approach for estimating doses to other major organs is crucial.

Adult↗

Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes.

The stereoselective sulfoxidation of the pharmacologically active metabolite of sulindac, sulindac sulfide, was characterized in human liver, kidney, and cDNA-expressed enzymes. Kinetic parameter estimates (pH = 7.4) for sulindac sulfoxide formation in human liver microsomes (N = 4) for R- and S-sulindac sulfoxide were V(max) = 1.5 +/- 0.50 nmol/min/mg, K(m) = 15 +/- 5.1 microM; and V(max) = 1.1 +/- 0.36 nmol/min/mg, K(m) = 16 +/- 6.1 microM, respectively. Kidney microsomes (N = 3) produced parameter estimates (pH = 7.4) of V(max) = 0.9 +/- 0.29 nmol/min/mg, K(m) = 15 +/- 2.9 microM; V(max) = 0.5 +/- 0.21 nmol/min/mg, K(m) = 22 +/- 1.9 microM for R- and S-sulindac sulfoxide, respectively. In human liver and flavin-containing monooxygenase 3 (FMO3) the V(max) for R-sulindac sulfoxide increased 60-70% at pH = 8.5, but for S-sulindac sulfoxide was unchanged. In fourteen liver microsomal preparations, significant correlations occurred between R-sulindac sulfoxide formation and either immunoquantified FMO or nicotine N-oxidation (r = 0.88 and 0.83; P < 0.01). The R- and S-sulindac sulfoxide formation rate also correlated significantly (r = 0.85 and 0.75; P < 0.01) with immunoquantified FMO in thirteen kidney microsomal samples. Mild heat deactivation of microsomes reduced activity by 30-60%, and a loss in stereoselectivity was observed. Methimazole was a potent and nonstereoselective inhibitor of sulfoxidation in liver and kidney microsomes. n-Octylamine and membrane solubilization with lubrol were potent and selective inhibitors of S-sulindac sulfoxide formation. cDNA-expressed CYPs failed to appreciably sulfoxidate sulindac sulfide, and CYP inhibitors were ineffective in suppressing catalytic activity. Purified mini-pig liver FMO1, rabbit lung FMO2, and human cDNA-expressed FMO3 efficiently oxidized sulindac sulfide with a high degree of stereoselectivity towards the R-isomer, but FMO5 lacked catalytic activity. The biotransformation of the sulfide to the sulfoxide is catalyzed predominately by FMOs and may prove to be useful in characterizing FMO activity.

Animals↗

Properties of added variable plots in Cox's regression model.

The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.

Biometry↗

A three-compartment model of osmotic water exchange in the lung microvasculature.

A bolus injection of hypertonic NaCl into the pulmonary arterial circulation of an isolated perfused dog lung causes the osmotic movement of water first into, and then out of the capillary. The associated changes in blood constituent concentrations and density are referred to as the osmotic transient (OT). Measurement of the sound conduction velocity of effluent blood during an OT is a highly sensitive way to monitor water movement between the vascular and extravascular spaces. It was our objective to develop a mathematical model that adequately describes this transient change in the sound conduction velocity and evaluate its application under conditions of homogeneous and heterogeneous capillary flow distributions. The model accounts for osmotic water exchange between the capillary and two parallel extravascular compartments, and includes as parameters the osmotic conductances (sigmaK1 ,sigmaK2) of the two compartments. The osmotic conductance parameters incorporate the filtration coefficient for water and reflection coefficient for salt for the two pathways of water exchange. The partition of total extravascular lung water (EVLW) between the two extravascular compartments is a third parameter of the model. The homogeneous model parameter estimates (per gram wet lung weight +/-95% confidence limits) from the best-fit analysis of a typical curve were sigmaK1=2.15 +/-0.07, sigmaK2 = 0.03 + 0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)] and V1 = 23.83+/-0.12 ml, with a coefficient of variation (CV) of 0.08. The heterogeneous parameter estimates for a capillary transit time distribution with mean transit time (MTTc) = 1.72 s, and relative dispersion (RDc) = 0.35 were KI = 2.38+/-0.05, or K2 = 0.03+/-0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)], V1 = 23.91+/-0.08 ml, and CV=0.05. EVLW was 42.1 ml for both models. We conclude that the three-compartment mathematical model adequately describes a typical OT under both homogeneous and heterogeneous blood flow assumptions.

Animals↗

A theoretical discussion of the use of the Lineweaver-Burk plot to estimate kinetic parameters of intestinal transport in the presence of unstirred water layers.

Transport of a solute molecule from the bulk phase in the intestinal lumen into the mucosal cells is determined by the rate of movement of the solute molecule across two barriers, the unstirred water layers (UWL) and the microvillus membrane. Failure to account for the effect of the resistance offered by the UWL introduces significant errors into the estimate of kinetic constants of carrier-mediated transport, and these errors may be further magnified by the use of the Lineweaver-Burk plot. This study was under taken to determine use of this plot under conditions that depict the effect of varying the effective resistance of the UWL, the distribution of transport sites along the villus (fn), the passive permeability coefficient (P), the maximal transport rate (Jdm), and the Michaelis constant (Km). Theoretical curves derived from a new equation demonstrate that (1) the Lineweaver-Burk plot is linear under only a limited number of conditions, and even then may lead to serous over- or under-estimation of Jdm and Km; (2) failure to correct for passive permeation may give rise to additional quantitative discrepancies between the true and apparent values of Jdm and Km; and (3) the qualitative characteristics of a carrier-mediated intestinal transport system may be ascertained only after correction for the contribution of passive permeation, and after correction for the effective resistance of the UWL.

Biological Transport↗

Confirmatory factor analysis of the Wechsler Memory Scale-III.

The latent structure of the Wechsler Memory Scale-III was analyzed by confirmatory factor analysis using the covariance matrix based on the 11 primary subtests from the standardization sample. Omnibus fit indexes and individual parameter estimates were examined. Of the five models evaluated, a three-factor model (working memory, auditory memory, and visual memory) provided the best fit for the standardization sample (NNFI = .98, RMSEA = .05, GFI = .98, BIC = 429.42). Models that proposed separate immediate and delayed memory constructs were hampered by inadmissible parameter estimates that signaled model specification errors. R2 values for the Faces subtests were uniformly low for all five models that suggested that this subtest has insufficient commonality with the visual memory construct.

Factor Analysis, Statistical↗

Population pharmacokinetics of raltitrexed in patients with advanced solid tumours.

AIMS: To investigate the population pharmacokinetics of raltitrexed in patients with advanced solid tumours and to identify patient covariates contributing to the interpatient variability in the pharmacokinetics of raltitrexed. METHODS: Patient covariate and concentration-time data were collected from patients receiving 0.1-4.5 mg m(-2) raltitrexed during the early clinical trials of raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate population mean estimates for clearance (CL) and central volume of distribution (V). The relationship between individual estimates of the pharmacokinetic parameters and patient covariates was examined and the influence of significant covariates on the population parameter estimates and their variance was investigated using stepwise multiple linear regression. The performance of the developed model was tested using an independent validation dataset. All patient data were pooled in the total cohort to refine the population pharmacokinetic model for raltitrexed. RESULTS: three-compartment pharmacokinetic model was used to fit the concentration-time data of raltitrexed. Estimated creatinine clearance (CL(CR)) was found to influence significantly the CL of raltitrexed and explained 35% of variability in this parameter, whilst body weight (WT) and serum albumin concentrations (ALB) accounted for 56% of the variability in V. Satisfactory prediction (mean prediction error 0.17 micro g l(-1) and root mean square prediction error 4.99 micro g l(-1)) of the observed raltitrexed concentrations was obtained in the model validation step. The final population mean estimates were 2.17 l h(-1)[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI 6.02, 6.70) for CL and V, respectively. Interpatient variability in the pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential covariates were included in the final model. The following covariate relationships with raltitrexed parameters were described by the final population model: CL (l h(-1)) = 0.54 + 0.02 CL(CR) (ml min(-1)) and V (l) = 6.64 + 0.08 WT (kg) - 0.16 ALB (g l(-1)). CONCLUSIONS: A population pharmacokinetic model has been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic parameters of raltitrexed are markedly influenced by the patient's renal function, body weight and serum albumin levels, which may be taken into account in dose individualization. The use of influential covariates to guide anticancer dosage selection may result in less variability in drug exposure and potentially a better clinical outcome.

Adult↗

Breastfeeding patterns and exposure to suboptimal breastfeeding among children in developing countries: review and analysis of nationally representative surveys.

BACKGROUND: Suboptimal breastfeeding is associated with higher mortality among infants and young children in the developing world. We describe patterns in 'exclusive breastfeeding' and 'any breastfeeding' rates and quantify exposure to suboptimal breastfeeding among children aged two years or younger in developing countries. METHODS: We reviewed nationally representative surveys that collected data on breastfeeding rates in 94 developing countries. Surveys were categorized by completeness and comprehensiveness of data. Complete and comprehensive data were analysed with minimum chi-square regression. With a fitting procedure, estimated parameters were used to impute missing observations for incomplete or non-comprehensive surveys. Breastfeeding indicators were calculated and are reported for 135 developing countries by UN region. RESULTS: Amongst infants aged six months or younger in the developing world, the prevalence of exclusive breastfeeding is 39% and the prevalence of no breastfeeding is 5.6%. The prevalence of continued breastfeeding is 86% and 68% for infants and children aged 6-11 and 12-23 months, respectively, in the developing world. Imputation expands population coverage of indicators, especially for infants. Breastfeeding trends are highly linear and estimated parameters defining the age-specific attrition hazard are robust. Survey-reported rates, particularly for exclusive breastfeeding, appear to have systematic upward bias, and exposure estimates must be considered conservative. CONCLUSIONS: Compliance with breastfeeding recommendations in developing countries is low, and more attention should be given to increasing breastfeeding - especially exclusive breastfeeding - and to monitoring trends. Although the introduction of more standardized and better validated survey instruments is desirable, since data coverage, completeness and comprehensiveness are extensive, global exposure assessment is relatively robust. Moreover, the regularity of breastfeeding patterns show existing survey data capture real biological and social phenomena. Our method for the analysis of breastfeeding rates provides a potent tool for summarizing trends, validating observations, translating and extrapolating indicators (as well as projecting and imputing estimates when necessary) and should support more effective child health monitoring.

Age Factors↗

Estimating the parameters in the Cox model when covariate variables are measured with error.

The Cox proportional hazards model is commonly used to model survival data as a function of covariates. Because of the measuring mechanism or the nature of the environment, covariates are often measured with error and are not directly observable. A naive approach is to use the observed values of the covariates in the Cox model, which usually produces biased estimates of the true association of interest. An alternative strategy is to take into account the error in measurement, which may be carried out for the Cox model in a number of ways. We examine several such approaches and compare and contrast them through several simulation studies. We introduce a likelihood-based approach, which we refer to as the semiparametric method, and show that this method is an appealing alternative. The methods are applied to analyze the relationship between survival and CD4 count in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

Detection of two-component mixtures of lognormal distributions in grouped, doubly truncated data: analysis of red blood cell volume distributions.

We have examined the statistical requirements for the detection of mixtures of two lognormal distributions in doubly truncated data when the sample size is large. The expectation-maximization algorithm was used for parameter estimation. A bootstrap approach was used to test for a mixture of distributions using the likelihood ratio statistic. Analysis of computer simulated mixtures showed that as the ratio of the difference between the means to the minimum standard deviation increases, the power for detection also increases and the accuracy of parameter estimates improves. These procedures were used to examine the distribution of red blood cell volume in blood samples. Each distribution was doubly truncated to eliminate artifactual frequency counts and tested for best fit to a single lognormal distribution or a mixture of two lognormal distributions. A single population was found in samples obtained from 60 healthy individuals. Two subpopulations of cells were detected in 25 of 27 mixtures of blood prepared in vitro. Analyses of mixtures of blood from 40 patients treated for iron-deficiency anemia showed that subpopulations could be detected in all by 6 weeks after onset of treatment. To determine if two-component mixtures could be detected, distributions were examined from untransfused patients with refractory anemia. In two patients with inherited sideroblastic anemia a mixture of microcytic and normocytic cells was found, while in the third patient a single population of microcytic cells was identified. In two family members previously identified as carriers of inherited sideroblastic anemia, mixtures of microcytic and normocytic subpopulations were found. Twenty-five patients with acquired myelodysplastic anemia were examined. A good fit to a mixture of subpopulations containing abnormal microcytic or macrocytic cells was found in two. We have demonstrated that with large sample sizes, mixtures of distributions can be detected even when distributions appear to be unimodal. These statistical techniques provide a means to characterize and quantify alterations in erythrocyte subpopulations in anemia but could also be applied to any set of grouped, doubly truncated data to test for the presence of a mixture of two lognormal distributions.

Adolescent↗

Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials.

PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.

Adult↗

Experimental designs for estimating the parameters of the Michaelis-Menten equation from progress curves of enzyme-catalyzed reactions.

When the progress curve for an enzyme catalysed reaction follows the integrated Michaelis-Menten equation, the maximum velocity and Michaelis constant can be determined from a single such curve. In this paper, an experimental design for collecting the data is proposed which is close to optimum in the sense that it produces the smallest standard error in the estimate of the Michaelis constant. This design involves choosing an initial substrate concentration which is approx. two or three times the value of the Michaelis constant.

Catalysis↗

Survival tests with Chironomus riparius exposed to spiked sediments can profit from DEBtox model.

DEBtox model is a biologically based model used to analyse aquatic toxicity data (The analysis of aquatic toxicity data, VU University Press, Amsterdam, The Netherlands, 1996, 149pp.). To date, it has not been used to analyse sediment survival tests, mainly because this would require daily counting of survivors, which is difficult for benthic organisms. In the present study, we adapted survival toxicity tests with the midge Chironomus riparius to permit survival data analysis with DEBtox. To validate the adaptation proposed, we exposed organisms to two chemicals, copper and methiocarb. We exposed larvae of second, third and fourth instar to different concentrations of the tested compounds and two different diets to assess the influence of diet and instar on DEBtox parameter estimates. Daily counting of organisms did not affect survival and did not lead to much more effort when compared to usual tests. Moreover, the analysis profited much from use of the DEBtox model. It was possible, with only survival data to estimate and validate the kinetics of the compounds, to predict survival during the recovery of exposed organisms and to assess the influence of food availability on toxicity. Food availability did not influence methiocarb toxicity, but copper was more toxic to food-limited organisms when a threshold concentration was exceeded. Comparison of parameters estimate also helped in understanding the differences in toxicity responses between instars. For the two compounds we studied, the difference was entirely explained by differences in threshold values.

Animals↗

Using reproductive value to estimate key parameters in density-independent age-structured populations.

The dynamics of reproductive value are used to provide a simple derivation of Tuljapurkar's approximation for the long-run growth rate and environmental variance of lnN, in a density-independent age-structured population in a random environment. With no environmental autocorrelation, the dynamics of total population size, N, generally shows time lags and autocorrelation caused by life history, which may strongly bias estimates of environmental variance obtained by ignoring age structure. In contrast, the total reproductive value, V, is Markovian and obeys a first-order autoregressive process. This suggests a simple method for estimating the environmental variance, and avoiding potentially large bias due to age-structure fluctuations, by converting a multivariate time series of age structure to a univariate time series of lnV. We illustrate the method by estimating the long-run growth rate and the environmental variance in an exponentially growing population of Bighorn Sheep.

Age Distribution↗

Ion channels. Preventing artifacts and reducing errors in single-channel analysis.

The power of single-channel analysis techniques has rapidly expanded during the past few years, giving investigators increased ability to identify models and estimate parameters while reducing error and artifacts. At present, however, there is no single best method, as even the most advanced techniques have various limitations which depend on the experimental data and models being examined. Consequently, for the examined models and experimental data, the most critical part of single-channel analysis is to estimate errors and evaluate the ability of the methods used to discriminate among possible gating mechanisms. The magnitudes of the errors and the ability to identify models and estimate parameters depend on the models being examined as well as the experimental conditions and data. Consequently, the evaluation of the errors associated with each method needs to be repeated when the experimental data and examined models change.

Artifacts↗