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Modeling longitudinal data with nonignorable dropouts using a latent dropout class model.

In longitudinal studies with dropout, pattern-mixture models form an attractive modeling framework to account for nonignorable missing data. However, pattern-mixture models assume that the components of the mixture distribution are entirely determined by the dropout times. That is, two subjects with the same dropout time have the same distribution for their response with probability one. As that is unlikely to be the case, this assumption made lead to classification error. In addition, if there are certain dropout patterns with very few subjects, which often occurs when the number of observation times is relatively large, pattern-specific parameters may be weakly identified or require identifying restrictions. We propose an alternative approach, which is a latent-class model. The dropout time is assumed to be related to the unobserved (latent) class membership, where the number of classes is less than the number of observed patterns; a regression model for the response is specified conditional on the latent variable. This is a type of shared-parameter model, where the shared "parameter" is discrete. Parameter estimates are obtained using the method of maximum likelihood. Averaging the estimates of the conditional parameters over the distribution of the latent variable yields estimates of the marginal regression parameters. The methodology is illustrated using longitudinal data on depression from a study of HIV in women.

Analysis of Variance↗

Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs.

AIMS: To create a general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs. METHODS: Physiological data for neonates, 0.5-, 1-, 2-, 5-, 10- and 15-year-old children, and adults, of both sexes were compiled from the literature. The data comprised body weight and surface area, organ weights, vascular and interstitial spaces, extracellular body water, organ blood flows, cardiac output and glomerular filtration rate. Tissue: plasma partition coefficients were calculated from rat data and unbound fraction (f u) of the drug in human plasma, and age-related changes in unbound intrinsic hepatic clearance were estimated from CYP1A2 and CYP2E1 (theophylline) and CYP3A4 (midazolam) activities in vitro. Volume of distribution (V dss), total and renal clearance (CL and CL R) and elimination half-life (t(1/2)) were estimated by PBPK modelling, as functions of age, and compared with literature data. RESULTS: The predicted V dss of theophylline was 0.4-0.6 l kg(-1) and showed only a modest change with age. The median prediction error (MPE) compared with literature data was 3.4%. Predicted total CL demonstrated the time-course generally reported in the literature. It was 20 ml h(-1) kg(-1) in the neonate, rising to 73 ml h(-1) kg(-1) at 5 years and then decreasing to 48 ml h(-1) kg(-1) in the adult. Overall, the MPE was - 4.0%. Predicted t(1/2) was 18 h in the neonate, dropping rapidly to 4.6-7.2 h from 6 months onwards, and the MPE was 24%. The predictions for midazolam were also in good agreement with literature data. V dss ranged between 1.0 and 1.7 l kg(-1) and showed only modest change with age. CL was 124 ml h(-1) kg(-1) in the neonate and peaked at 664 ml h(-1) kg(-1) at 5 years before decreasing to 425 ml h(-1) kg(-1) in the adult. Predicted t(1/2) was 6.9 h in the neonate and attained 'adult' values of 2.5-3.5 h from 1 year onwards. CONCLUSIONS: A general PBPK model for the prediction of drug disposition over the age range neonate to young adult is presented. A reference source of physiological data was compiled and validated as far as possible. Since studies of pharmacokinetics in children present obvious practical and ethical difficulties, one aim of the work was to utilize maximally already available data. Prediction of the disposition of theophylline and midazolam, two model drugs with dissimilar physicochemical and pharmacokinetic characteristics, yielded results that generally tallied with literature data. Future use of the model may demonstrate further its strengths and weaknesses.

Adolescent↗

Modelling and role-modelling: integrating nursing theory into practice.

This article contrasts two clinical cases using a relatively new paradigm and theory, modelling and role-modelling. The concepts and linkages from modelling and role-modelling are presented and are the basis for analysing the outcomes of of two patients. The case study approach communicates an understanding of the theory modelling and role-modelling and assists nurses to develop expertise in its use.

Adaptation, Psychological↗

gamma-Hydroxybutyrate model of generalized absence seizures: further characterization and comparison with other absence models.

gamma-Hydroxybutyrate (GHB) produces a constellation of EEG and behavioral events that respond selectively to antiabsence antiepileptic drugs. The GHB-induced seizure was quantitated in the presence of three other absence seizure models: pentylenetetrazole, systemic penicillin, and the flash evoked afterdischarge (FEAD). Penicillin and pentylenetetrazole produced a significant prolongation of GHB-induced seizure in a dose-dependent fashion. This potentiation of GHB seizure was observed when these compounds were given either before administration of gamma-butyrolactone (GBL), the prodrug of GHB, or at the onset of GHB-induced seizure. Photic stimulation given in a manner to produce FEAD also resulted in a significant prolongation of GHB-induced seizure. All of these maneuvers lowered the threshold to GHB seizure, but none interfered with the brain kinetics of GHB in the animals treated with GBL. Ethosuximide pretreatment significantly shortened the GHB seizure and overcame the potentiating effect of penicillin and pentylenetetrazole in this model. These data confirm the GHB-treated animal as a model of generalized absence seizure. The GHB model meets appropriate criteria for an absence seizure model and compares favorably with other models of absence currently in use.

Animals↗

Models of hepatic drug clearance: discrimination between the 'well stirred' and 'parallel-tube' models.

The predictive ability of two models of hepatic drug clearance are compared. The 'parallel-tube' model predicts that the steady-state drug concentration following constant rate oral administration increases with increase in hepatic blood flow. The 'well-stirred' model predicts that this parameter is not sensitive to changes in hepatic blood flow. Using the steady-state reservoir drug concentration as the discriminatory index, the predictions of the models were tested in a recirculating isolated perfused rat liver system with lignocaine and pethidine, both of which are highly extracted, as test drugs. The steady-state reservoir concentration of both drugs was found to be constant when flow through the liver was increased from 10 ml min-1 to 15 ml min-1. The experimental findings indicate that the 'well-stirred' model more accurately describes the elimination of highly cleared drugs with perturbations of flow than does the 'parallel-tube' model.

Animals↗

A model experiment to study sonic boom propagation through turbulence. Part III: validation of sonic boom propagation models.

In previous papers, we have shown that model experiments are successful in simulating the propagation of sonic booms through the atmospheric turbulent boundary layer. The results from the model experiment, pressure wave forms of spark-produced N waves and turbulence characteristics of the plane jet, are used to test various sonic boom models for propagation through turbulence. Both wave form distortion models and rise time prediction models are tested. Pierce's model [A. D. Pierce, "Statistical theory of atmospheric turbulence effects on sonic boom rise times," J. Acoust. Soc. Am. 49, 906-924 (1971)] based on the wave front folding mechanism at a caustic yields an accurate prediction for the rise time of the mean wave form after propagation through the turbulence.

Aircraft↗

Binaural processing model based on contralateral inhibition. I. Model structure.

This article presents a quantitative binaural signal detection model which extends the monaural model described by Dau et al. [J. Acoust. Soc. Am. 99, 3615-3622 (1996)]. The model is divided into three stages. The first stage comprises peripheral preprocessing in the right and left monaural channels. The second stage is a binaural processor which produces a time-dependent internal representation of the binaurally presented stimuli. This stage is based on the Jeffress delay line extended with tapped attenuator lines. Through this extension, the internal representation codes both interaural time and intensity differences. In contrast to most present-day models, which are based on excitatory-excitatory interaction, the binaural interaction in the present model is based on contralateral inhibition of ipsilateral signals. The last stage, a central processor, extracts a decision variable that can be used to detect the presence of a signal in a detection task, but could also derive information about the position and the compactness of a sound source. In two accompanying articles, the model predictions are compared with data obtained with human observers in a great variety of experimental conditions.

Attention↗

A cancer survival model that takes sociodemographic variations in "normal" mortality into account: comparison with other models.

STUDY OBJECTIVES: Sociodemographic differentials in cancer survival have occasionally been studied by using a relative survival approach, where all cause mortality among persons with a cancer diagnosis is compared with that among similar persons without such a diagnosis ("normal" mortality). One should ideally take into account that this "normal" mortality not only depends on age, sex, and period, but also various other sociodemographic variables. However, this has very rarely been done. A method that permits such variations to be considered is presented here, as an alternative to an existing technique, and is compared with a relative survival model where these variations are disregarded and two other methods that have often been used. DESIGN, SETTING, AND PARTICIPANTS: The focus is on how education and marital status affect the survival from 12 common cancer types among men and women aged 40-80. Four different types of hazard models are estimated, and differences between effects are compared. The data are from registers and censuses and cover the entire Norwegian population for the years 1960-1991. There are more than 100 000 deaths to cancer patients in this material. MAIN RESULTS AND CONCLUSIONS: A model for registered cancer mortality among cancer patients gives results that for most, but not all, sites are very similar to those from a relative survival approach where educational or marital variations in "normal" mortality are taken into account. A relative survival approach without consideration of these sociodemographic variations in "normal" mortality gives more different results, the most extreme example being the doubling of the marital differentials in survival from prostate cancer. When neither sufficient data on cause of death nor on variations in "normal" mortality are available, one may well choose the simplest method, which is to model all cause mortality among cancer patients. There is little reason to bother with the estimation of a relative-survival model that does not allow sociodemographic variations in "normal" mortality beyond those related to age, sex, and period. Fortunately, both these less data demanding models perform well for the most aggressive cancers.

Adult↗

Modeling evolution at the protein level using an adjustable amino acid fitness model.

An adjustable fitness model for amino acid site substitutions is investigated. This model, a generalization of previously developed evolutionary models, has several distinguishing characteristics: it separately accounts for the processes of mutation and substitution, allows for heterogeneity among substitution rates and among evolutionary constraints, and does not make any prior assumptions about which sites or characteristics of proteins are important to molecular evolution. While the model has fewer adjustable parameters than the general reversible mtREV model, when optimized it outperforms mtREV in likelihood analysis on protein-coding mitochondrial genes. In addition, the optimized fitness parameters of the model show correspondence to some biophysical characteristics of amino acids.

Amino Acid Substitution↗

Can we model nitric oxide biotransport? A survey of mathematical models for a simple diatomic molecule with surprisingly complex biological activities.

Nitric oxide (NO) is a remarkable free radical gas whose presence in biological systems and whose astonishing breadth of physiological and pathophysiological activities have only recently been recognized. Mathematical models for NO biotransport, just beginning to emerge in the literature, are examined in this review. Some puzzling and paradoxical properties of NO may be understood by modeling proposed mechanisms with known parameters. For example, it is not obvious how NO can survive strong scavenging by hemoglobin and still be a potent vasodilator. Recent models do not completely explain how tissue NO can reach effective levels in the vascular wall, and they point toward mechanisms that need further investigation. Models help to make sense of extremely low partial pressures of NO exhaled from the lung and may provide diagnostic information. The role of NO as a gaseous neurotransmitter is also being understood through modeling. Studies on the effects of NO on O2 transport and metabolism, also reviewed, suggest that previous mathematical models of transport of O2 to tissue need to be revised, taking the biological activity of NO into account.

Animals↗

Analysis of longitudinal data: the integration of theoretical model, temporal design, and statistical model.

This article argues that ideal longitudinal research is characterized by the seamless integration of three elements: (a) a well-articulated theoretical model of change observed using (b) a temporal design that affords a clear and detailed view of the process, with the resulting data analyzed by means of (c) a statistical model that is an operationalization of the theoretical model. Two general varieties of theoretical models are considered: models in which the time-related change of primary interest is continuous, and those in which it is characterized by movement between discrete states. In addition, two general types of temporal designs are considered: the longitudinal panel design and the intensive longitudinal design. For each general category of theoretical models, some of the analytic possibilities available for longitudinal panel designs and for intensive longitudinal designs are discussed. The article concludes with brief discussions of two issues particularly relevant to longitudinal research--missing data and measurement--and a few words about exploratory research.

Humans↗

A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building.

A model of Sr metabolism was developed by using plasma and urinary Sr kinetic data obtained in groups of postmenopausal women who received four different oral doses of Sr and collected during the Sr administration period (25 days) and for 28 days after cessation of treatment. A nonlinear compartmental formalism that is appropriate for study of non-steady-state kinetics and allows dissociation of variables pertaining to Sr metabolism (system 1) from those indirectly operating on it (system 2) was used. At each stage of model development, the dose-dependent model response was fitted to the four sets of data considered simultaneously (1 set per dose). A seven-compartment model with internal Sr distribution and intestinal, urinary, and bone metabolic pathways was selected. It includes two kinds of nonlinearities: those accounting for saturable intestinal and bone processes, which behave as intrinsic nonlinearities because they are directly dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which suggest the cooperative involvement of plasma Sr changes in modulating some intestinal and bone mineral metabolic pathways. With the set of identified parameter values, the initial steady-state model predictions are relevant to known physiology, and some peculiarities of model behavior for long-term Sr administration were simulated.

Female↗

Alternative to hand-tuning conductance-based models: construction and analysis of databases of model neurons.

Conventionally, the parameters of neuronal models are hand-tuned using trial-and-error searches to produce a desired behavior. Here, we present an alternative approach. We have generated a database of about 1.7 million single-compartment model neurons by independently varying 8 maximal membrane conductances based on measurements from lobster stomatogastric neurons. We classified the spontaneous electrical activity of each model neuron and its responsiveness to inputs during runtime with an adaptive algorithm and saved a reduced version of each neuron's activity pattern. Our analysis of the distribution of different activity types (silent, spiking, bursting, irregular) in the 8-dimensional conductance space indicates that the coarse grid of conductance values we chose is sufficient to capture the salient features of the distribution. The database can be searched for different combinations of neuron properties such as activity type, spike or burst frequency, resting potential, frequency-current relation, and phase-response curve. We demonstrate how the database can be screened for models that reproduce the behavior of a specific biological neuron and show that the contents of the database can give insight into the way a neuron's membrane conductances determine its activity pattern and response properties. Similar databases can be constructed to explore parameter spaces in multicompartmental models or small networks, or to examine the effects of changes in the voltage dependence of currents. In all cases, database searches can provide insight into how neuronal and network properties depend on the values of the parameters in the models.

Algorithms↗

Modeling neural mechanisms for genesis of respiratory rhythm and pattern. I. Models of respiratory neurons.

The general objectives of our research, presented in this series of papers, were to develop a computational model of the brain stem respiratory neural network and to explore possible neural mechanisms that provide the genesis of respiratory oscillations and the specific firing patterns of respiratory neurons. The present paper describes models of single respiratory neurons that have been used as the elements in our network models of the central respiratory pattern generator presented in subsequent papers. The models of respiratory neurons were developed in the Hodgkin-Huxley style employing both physiological and biophysical data obtained from brain stem neurons in mammals. Two single respiratory neuron models were developed to match the two distinct firing behaviors of respiratory neurons described in vivo: neuron type I shows an adapting firing pattern in response to synaptic excitation, and neuron type II shows a ramp firing pattern during membrane depolarization after a period of synaptic inhibition. We found that a frequency ramp firing pattern can result from intrinsic membrane properties, specifically from the combined influence of calcium-dependent K(AHP)(Ca), low-threshold Ca(T) and K(A) channels. The neuron models with these ionic channels (type II) demonstrated ramp firing patterns similar to those recorded from respiratory neurons in vivo. Our simulations show that K(AHP)(Ca) channels in combination with high-threshold Ca(L) channels produce spike frequency adaptation during synaptic excitation. However, in combination with low-threshold Ca(T) channels, they cause a frequency ramp firing response after release from inhibition. This promotes a testable hypothesis that the main difference between the respiratory neurons that adapt (for example, early inspiratory, postinspiratory, and decrementing expiratory) and those that show ramp firing patterns (for example, ramp inspiratory and augmenting expiratory) consists of a ratio between the two types of calcium channels: Ca(L) channels predominate in the former and Ca(T) channels in the latter respiratory neuron types. We have analyzed the dependence of adapting and ramp firing patterns on maximal conductances of different ionic channels and values of synaptic drive. The effect of adjusting specific membrane conductances and synaptic interactions revealed plausible neuronal mechanisms that may underlie modulatory effects on respiratory neuron firing patterns and network performances. The results of computer simulation provide useful insight into functional significance of specific intrinsic membrane properties and their interactions with phasic synaptic inputs for a better understanding of respiratory neuron firing behavior.

Adaptation, Physiological↗

A componential model of human interaction with graphs: 1. Linear regression modeling.

Task analyses served as the basis for developing the Mixed Arithmetic-Perceptual (MA-P) model, which proposes (1) that people interacting with common graphs to answer common questions apply a set of component processes--searching for indicators, encoding the value of indicators, performing arithmetic operations on the values, making spatial comparisons among the indicators, and responding; and (2) that the type of graph and user's task determine the combination and order of the components applied (i.e., the processing steps). Two experiments investigated the prediction that response time will be linearly related to the number of processing steps according to the MA-P model. Subjects used line graphs, scatter plots, and stacked bar graphs to answer comparison questions and questions requiring arithmetic calculations. A one-parameter version of the model (with equal weights for all components) and a two-parameter version (with different weights for arithmetic and nonarithmetic processes) accounted for 76%-85% of individual subjects' variance in response time and 61%-68% of the variance taken across all subjects. The discussion addresses possible modifications in the MA-P model, alternative models, and design implications from the MA-P model.

Computer Graphics↗

Gaussian process modeling in conjunction with individual patient simulation modeling: a case study describing the calculation of cost-effectiveness ratios for the treatment of established osteoporosis.

Individual patient-level models can simulate more complex disease processes than cohort-based approaches. However, large numbers of patients need to be simulated to reduce 1st-order uncertainty, increasing the computational time required and often resulting in the inability to perform extensive sensitivity analyses. A solution, employing Gaussian process techniques, is presented using a case study, evaluating the cost-effectiveness of a sample of treatments for established osteoporosis. The Gaussian process model accurately formulated a statistical relationship between the inputs to the individual patient model and its outputs. This model reduced the time required for future runs from 150 min to virtually-instantaneous, allowing probabilistic sensitivity analyses-to be undertaken. This reduction in computational time was achieved with minimal loss in accuracy. The authors believe that this case study demonstrates the value of this technique in handling 1st- and 2nd-order uncertainty in the context of health economic modeling, particularly when more widely used techniques are computationally expensive or are unable to accurately model patient histories.

Alendronate↗

An optimisation model for regional integrated solid waste management I. Model formulation.

Increased environmental concerns and the emphasis on material and energy recovery are gradually changing the orientation of MSW management and planning. In this context, the application of optimisation techniques have been introduced to design the least cost solid waste management systems, considering the variety of management processes. This study presents a model that was developed and applied to serve as a solid waste decision support system for MSW management taking into account both socio-economic and environmental considerations. The model accounts for solid waste generation rates, composition, collection, treatment, disposal as well as potential environmental impacts of various MSW management techniques. The model follows a linear programming formulation with the framework of dynamic optimisation. The model can serve as a tool to evaluate various MSW management alternatives and obtain the optimal combination of technologies for the handling, treatment and disposal of MSW in an economic and environmentally sustainable way. The sensitivity of various waste management policies will be also addressed. The work is presented in a series of two papers: (I) model formulation, and (II) model application and sensitivity analysis.

Conservation of Natural Resources↗

An optimisation model for regional integrated solid waste management II. Model application and sensitivity analyses.

Increased environmental concerns and the emphasis on material and energy recovery are gradually changing the orientation of MSW management and planning. In this context, the application of optimisation techniques have been introduced to design the least cost solid waste management systems, considering the variety of management processes (recycling, composting, anaerobic digestion, incineration, and landfilling), and the existence of uncertainties associated with the number of system components and their interrelations. This study presents a model that was developed and applied to serve as a solid waste decision support system for MSW management taking into account both socio-economic and environmental considerations. The model accounts for solid waste generation rates, composition, collection, treatment, disposal as well as potential environmental impacts of various MSW management techniques. The model follows a linear programming formulation with the framework of dynamic optimisation. The model can serve as a tool to evaluate various MSW management alternatives and obtain the optimal combination of technologies for the handling, treatment and disposal of MSW in an economic and environmentally sustainable way. The sensitivity of various waste management policies is also addressed. The work is presented in a series of two papers: (I) model formulation, and (II) model application and sensitivity analysis.

Conservation of Natural Resources↗