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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↗

Assessing the limitations of the Banister model in monitoring training.

The aim of this study was to carry out a statistical analysis of the Banister model to verify how useful it is in monitoring the training programmes of elite swimmers. The accuracy, the ill-conditioning and the stability of this model were thus investigated. The training loads of nine elite swimmers, measured over one season, were related to performances with the Banister model. First, to assess accuracy, the 95% bootstrap confidence interval (95% CI) of parameter estimates and modelled performances were calculated. Second, to study ill-conditioning, the correlation matrix of parameter estimates was computed. Finally, to analyse stability, iterative computation was performed with the same data but minus one performance, chosen at random. Performances were related to training loads for all participants (R(2) = 0.79 +/- 0.13, P < 0.05) and the estimation procedure seemed to be stable. Nevertheless, the range of 95% CI values of the most useful parameters for monitoring training was wide: t(a) = 38 (17, 59), t(f) = 19 (6, 32), t(n) = 19 (7, 35), t(g) = 43 (25, 61). Furthermore, some parameters were highly correlated, making their interpretation worthless. We suggest possible ways to deal with these problems and review alternative methods to model the training-performance relationships.

Adult↗

Long-term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content.

Quantal components of Schaffer collateral synaptic transmission recorded intracellularly from CA1 pyramidal cells were examined using 2 methods: simultaneous recordings of CA3-CA1 cell-pairs, and minimal electrical stimulation in stratum radiatum. Quantal parameters estimated by the method of failures and by a computer algorithm that optimized parameter estimates using deconvolution of background noise were highly correlated. EPSP-amplitude histograms of CA3-CA1 cell pairs (N = 10) and minimal electrical stimulation (N = 33) could be adequately described either by Poisson or binomial statistics, or by both, and exhibited similar estimates of unit quantal size (q) and mean quantal content (m). Paired-pulse stimulation with 50 msec between stimuli resulted in an expected facilitation in the EPSP amplitude and increase in m during the second response, as estimated by noise deconvolution, by the decrease in apparent failures, and by a decrease in the coefficient of variation of the EPSP. Tetanization of the Schaffer collaterals that induced long-term enhancement (LTE/LTP) of the population response was associated with an average increase in q for minimal-stimulation responses, with no significant change in any estimate of m. Taken together, these data indicate that, under the present experimental conditions, LTE is expressed as an increase in quantal size, rather than an increase in the number of quanta released per presynaptic impulse. Although this is not definitive evidence for a postsynaptic mechanism, these findings do further restrict the classes of possible presynaptic mechanisms that may be proposed to account for LTE expression.

Action Potentials↗

A solution to the problem of separation in logistic regression.

The phenomenon of separation or monotone likelihood is observed in the fitting process of a logistic model if the likelihood converges while at least one parameter estimate diverges to +/- infinity. Separation primarily occurs in small samples with several unbalanced and highly predictive risk factors. A procedure by Firth originally developed to reduce the bias of maximum likelihood estimates is shown to provide an ideal solution to separation. It produces finite parameter estimates by means of penalized maximum likelihood estimation. Corresponding Wald tests and confidence intervals are available but it is shown that penalized likelihood ratio tests and profile penalized likelihood confidence intervals are often preferable. The clear advantage of the procedure over previous options of analysis is impressively demonstrated by the statistical analysis of two cancer studies.

Breast Neoplasms↗

A quantitative framework for a multi-group model of Schistosomiasis japonicum transmission dynamics and control in Sichuan, China.

A quantitative framework is presented for the site-specific characterization of schistosomiasis transmission with the object of developing local control strategies. Central to the framework is a worm-burden model using ordinary differential equations of disease transmission in risk groups defined by residence and occupation. The model incorporates temperature- and precipitation-dependent seasonality of infectious stages, snail population dynamics, and seasonal patterns of human water contact specific to the local agricultural setting. The model's parameters are separated into two main subsets, those associated with the general biology of the parasite and its life cycle in the human and the snail and those associated with directly measurable features of disease status in the local population or relevant aspects of the local environment. In this regard, the model is structured and parameterized to take maximum advantage of data that can be collected in rural China by conventional methods. For example, it includes a statistical model for egg excretion to the environment by each risk group which is based on local population surveys of the prevalence and intensity of infection. The second element of the framework of analysis relates to the strategy for parameter estimation and calibration to local conditions. We propose a Bayesian approach in which parameter estimates are refined over time by methods employing extensive computer simulations. An early analysis of data collected between 1987 and 1989 in endemic villages near Xichang City in southwestern Sichuan provides encouragement that parametric uncertainty can be reduced to levels adequate to explore effective control strategies.

Animals↗

Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients.

OBJECTIVE: To describe the factors affecting pharmacokinetics of telmisartan, an angiotensin II receptor antagonist, a population pharmacokinetic (PPK) model has been developed based upon the data collected from healthy volunteers and hypertensive patients. METHODS: A total of 1566 plasma samples were collected from 20 healthy volunteers and 129 hypertensive patients, together with the demographic background. The data were analyzed by the NONMEM program using two-compartment model with first-order absorption. The robustness of the obtained PPK model was validated by the bootstrapping resampling method. RESULTS: The oral clearance (CL/F) was found to be associated with age, dose and alcohol consumption, but neither related to serum creatinine nor smoking history. The volume of distribution for the central compartment was related to age and dose, and the volume of distribution for the peripheral compartment was related to body weight and gender. The absorption rate constant (Ka) and the absorption lag time were described as function of dose. The CL/F decreased with advanced age. The CL/F decreased and Ka increased with higher dose, reflecting the super-proportional increase in the plasma levels of telmisartan. The AUC and C(max) values predicted by the present PPK model were well consistent with the observed values. The means of parameter estimates obtained with 200 bootstrap replicates were within 95-111% of the final parameter estimates from the original data set. CONCLUSION: A PPK model for telmisartan developed here well described the individual variability and exposure, and robustness of the model has been validated by the bootstrapping method.

Journal Article↗

Study of the lactation curve in dairy cattle on farms in central Mexico.

Accurate knowledge of lactation curves has an important relevance to management and research of dairy production systems. A number of equations have been proposed to describe the lactation curve, the most widely applied being the gamma equation. The objective of this work was to compare and evaluate candidate functions for their predictive ability in describing lactation curves from central Mexican dairy cows reared under 2 contrasting management systems. Five equations were considered: Gaines (exponential decay), Wood (gamma equation), Rook (Michaelis-Menten xexponential), and 2 more mechanistic ones (Dijkstra and Pollott). A database consisting of 701 and 1283 records of cows in small-scale and intensive systems, respectively, was used in the analysis. Before analysis, the database was divided into 6 groups representing first, second, and third and higher parity cows in both systems. In all cases except second and above parity cows in small-scale systems, all models improved on the Gaines equation. The Wood equation explained much of the variation, but its parameters do not have direct biological interpretation. Although the Rook equation fitted the data well, some of the parameter estimates were not significant. The Dijkstra equation consistently gave better predictions, and its parameters were usually statistically significant and lend themselves to physiological interpretation. As such, the differences between systems and parity could be explained due to variations in theoretical initial milk production at parturition, specific rates of secretory cell proliferation and death, and rate of decay, all of which are parameters in the model. The Pollott equation, although containing the most biology, was found to be over-parameterized and resulted in nonsignificant parameter estimates. For central Mexican dairy cows, the Dijkstra equation was the best option to use in describing the lactation curve.

Animals↗

Genetic analysis of manic-depressive illness.

Two threshold models, a single locus model, and two combined models are fitted to data on familial incidence of bipolar affective disorder in 194 nuclear families ascertained through a bipolar proband. The relative fit of alternative transmission models is tested by a likelihood ratio chi-square with the degrees of freedom defined by the difference in the number of parameters estimated by each model. All parameters are estimated by the method of maximum likelihood. The simplest threshold model, permitting only a single background familial correlation, is found to provide a statistically poorer fit than any of the alternative models, and may be rejected as a model for the etiology of bipolar affective disorder. The four remaining models are statistically indistinguishable. It is suggested, however, that the involvement of a major locus in the etiology of this disorder deserves further scrutiny since any of the models incorporating a major locus, with or without a multifactorial background, are consistently associated with greater likelihoods than the complex threshold model. It is also noted that diagnostic criteria are critical in the analysis. In the present study, relatives of probands are considered affected if a diagnosis of bipolar or unipolar affective disorder is present. When only bipolar relatives are considered affected, none of the transmission models may be rejected. Finally, the results of these analyses are found to be independent of the ascertainment parameter.

Biometry↗

Counting the cost: estimating the economic benefit of pedophile treatment programs.

OBJECTIVE: The principal objective of this paper is to identify the economic costs and benefits of pedophile treatment programs incorporating both the tangible and intangible cost of sexual abuse to victims. METHOD: Cost estimates of cognitive behavioral therapy programs in Australian prisons are compared against the tangible and intangible costs to victims of being sexually abused. Estimates are prepared that take into account a number of problematic issues. These include the range of possible recidivism rates for treatment programs; the uncertainty surrounding the number of child sexual molestation offences committed by recidivists; and the methodological problems associated with estimating the intangible costs of sexual abuse on victims. RESULTS: Despite the variation in parameter estimates that impact on the cost-benefit analysis of pedophile treatment programs, it is found that potential range of economic costs from child sexual abuse are substantial and the economic benefits to be derived from appropriate and effective treatment programs are high. CONCLUSIONS: Based on a reasonable set of parameter estimates, in-prison, cognitive therapy treatment programs for pedophiles are likely to be of net benefit to society. Despite this, a critical area of future research must include further methodological developments in estimating the quantitative impact of child sexual abuse in the community.

Australia↗

Ground water model calibration using pilot points and regularization.

Use of nonlinear parameter estimation techniques is now commonplace in ground water model calibration. However, there is still ample room for further development of these techniques in order to enable them to extract more information from calibration datasets, to more thoroughly explore the uncertainty associated with model predictions, and to make them easier to implement in various modeling contexts. This paper describes the use of "pilot points" as a methodology for spatial hydraulic property characterization. When used in conjunction with nonlinear parameter estimation software that incorporates advanced regularization functionality (such as PEST), use of pilot points can add a great deal of flexibility to the calibration process at the same time as it makes this process easier to implement. Pilot points can be used either as a substitute for zones of piecewise parameter uniformity, or in conjunction with such zones. In either case, they allow the disposition of areas of high and low hydraulic property value to be inferred through the calibration process, without the need for the modeler to guess the geometry of such areas prior to estimating the parameters that pertain to them. Pilot points and regularization can also be used as an adjunct to geostatistically based stochastic parameterization methods. Using the techniques described herein, a series of hydraulic property fields can be generated, all of which recognize the stochastic characterization of an area at the same time that they satisfy the constraints imposed on hydraulic property values by the need to ensure that model outputs match field measurements. Model predictions can then be made using all of these fields as a mechanism for exploring predictive uncertainty.

Calibration↗

Low power? Use two-dimensional confidence regions as a graphical method for depicting uncertainty.

Prospective studies of rare outcomes, such as HIV seroconversion or obsessive-compulsive disorder, can often result in small sample sizes with limited power for detecting associations. For this reason, it is useful to develop graphical procedures that enable researchers to depict uncertainty around parameter estimates and examine the direction of association when statistical power is low. Classical procedures include the reporting of confidence intervals, which typically are derived from asymptotic normality of parameters estimated using large samples. In this paper, we present a likelihood-based procedure for the estimation of the confidence region of two parameters from a conditional logistic regression of a nested case-control study with a relatively small number of cases. Graphical depiction of the confidence regions provides an easily comprehensible procedure to quantify the uncertainty of the estimation based on small samples.

Adult↗

Positron emission tomographic measurement of blood-to-brain and blood-to-tumour transport of 82Rb. II: Clinical data and validation of technique.

Computer simulations and error analysis of a simple two-compartment, passive-diffusion exchange model for 82Rb across the blood-brain-barrier (BBB) have demonstrated the feasibility of obtaining useful estimates of unidirectional rate constant (K1) and tissue-blood water volume (Vb) in vivo using dynamic positron tomography (PET). The coefficients of variation (CV) in parameter estimates for 20 studies on ten patients are shown to have mean values of 10% for tumour K1 and Vb, 6% for normal brain Vb and 30% for normal brain K1. Ten test-retest studies show a very high correlation (R2 greater than 0.88) between the estimated parameter values. Apparent tissue blood volume (Vb) estimates obtained from 82Rb studies underestimate the blood volumes obtained by single-breath C15O studies by approximately 15%. In normal brain the extraction of rubidium (E) is small (less than 10%), and gives rise to a linear relationship between K1 and permeability-surface area product (PS). In tumour, however, E is larger (greater than 30%), and results in a non-linear relationship between these values. For both tumour and normal brain, K1 was found to be independent of regional cerebral blood flow (rCBF). The data from these clinical studies are in agreement with the predictions of the computer simulations and suggest the suitability of 82Rb/PET in the quantification of BBB functional changes.

Adolescent↗

Parameter optimisation of real-time control strategies for urban wastewater systems.

Real-time control (RTC) of wastewater systems has been a topic of research and application for over two decades. Attempts so far have mainly focused on one of the parts of the urban wastewater system: either the sewer system, or the treatment plant or the river. Approaches to integrate these subsystems and considering them jointly for control purposes have been pursued only recently. Control of the systems aims at pursuing one (or several concomitant) objectives, which are expressed, for example, in terms of overflow volumes, loads, effluent concentrations, receiving water quality or monetary costs, to name just a few. This paper provides a general and formal definition of the problem to define a real time control algorithm for a given urban wastewater system. A general mathematical optimization problem is formulated, which describes the task of finding an (in some sense) optimum control algorithm. Since this optimization problem is, in the general case, highly non-linear with only limited information available about the objective function itself, optimization methods appropriate for this type of problem are identified. Here, the similarity of the problem to find a control algorithm and of the parameter estimation problem common in mathematical modelling becomes apparent. Hence, methods (and problems encountered) in parameter estimation can be transferred to the problem of determining optimum RTC algorithms. This parallelism is outlined in the paper. As an application of the parameterisation and optimization of control strategies, integrated control of an urban wastewater system is discussed. Since the analysis of integrated control as just described poses certain requirements on a simulation engine, a novel modelling tool, called SYNOPSIS, is utilized here. This simulation tool, comprising of modules simulating water quantity and quality processes in all parts of the urban wastewater system, is embedded into a suite of optimization procedures. An integrated RTC algorithm for the urban wastewater system is formulated, the parameters of which are optimized using various global optimization routines. Comparison of their efficiency indicates good performance for the Controlled Random Search and for the genetic algorithms. The findings suggest that integrated control can indeed lead to an increase in performance of the urban wastewater system. These results appear to be encouraging and justify further work. Areas for further development are identified in the final section of the paper.

Algorithms↗

The effect of transducer characteristics on the estimation of Nakagami paramater as a function of scatterer concentration.

The effect of transducer characteristics on the sensitivity of the Nakagami parameter to detect the variation of scatterer concentrations was studied. The rationale for this study stems from our pilot results which showed that the Nakagami parameters, estimated using a nonfocused transducer were not as sensitive as those of measurements using a commercial ultrasonic scanner in previous reports. This discrepancy may be attributed to the effects of transducer characteristics relative to the size of the resolution cell as verified by measurements of phantoms and 2-D computer simulations. The Nakagami parameter as a function of scatterer concentration was calculated using backscattered signals acquired from the scattering medium of different scatterer concentrations ranging from 2 to 32 scatterers/mm(3) using both 5 MHz nonfocused and focused transducers. Experimental and simulation results obtained from the nonfocused transducer represent that their respective Nakagami parameters increased from 1.17 to 1.31 and from 0.82 to 1.01 corresponding to the increase of scatterer concentrations. For the results obtained from the focused transducer, their average Nakagami parameters increased from 0.27 to 0.72 and from 0.33 to 0.81. These consistent results demonstrated that Nakagami parameter estimated using a focused transducer tends to be more sensitive than that by a nonfocused transducer to detect the variation of low scatterer concentration. This difference is fully due to the effect of transducer characteristics associated with the effective number of scatterers in the resolution cell.

Computer Simulation↗

Reliability of pharmacodynamic analysis by logistic regression: a computer simulation study.

BACKGROUND: Many pharmacologic studies record data as binary yes-or-no variables, and analysis is performed using logistic regression. This study investigates the accuracy of estimation of the drug concentration associated with a 50% probability of drug effect (C50) and the term describing the steepness of the concentration-effect relation (gamma). METHODS: The authors developed a technique for simulating pharmacodynamic studies with binary yes-or-no responses. Simulations were conducted assuming either that each data point was derived from the same patient or that data were pooled from multiple patients in a population with log-normal distributions of C50 and gamma. Coefficients of variation were calculated. The authors also determined the percentage of simulations in which the 95% confidence intervals contained the true parameter value. RESULTS: The coefficient of variation of parameter estimates decreased with increasing n and gamma. The 95% confidence intervals for C50 estimation contained the true parameter value in more than 90% of the simulations. However, the 95% confidence intervals of gamma did not contain the true value in a substantial number of simulations of data from multiple patients. CONCLUSION: The coefficient of variation of parameter estimates may be as large as 40-50% for small studies (n < or = 20). The 95% confidence intervals of C50 almost always contain the true value, underscoring the need for always reporting confidence intervals. However, when data from multiple patients is naively pooled, the estimates of gamma may be biased, and the 95% confidence intervals may not contain the true value.

Algorithms↗

Estimation of parameters of deleterious mutations in partial selfing or partial outcrossing populations and in nonequilibrium populations.

The Deng-Lynch method was developed to estimate the rate and effects of deleterious genomic mutations (DGM) in natural populations under the assumption that populations are either completely outcrossing or completely selfing and that populations are at mutation-selection (M-S) balance. However, in many plant and animal populations, selfing or outcrossing is often incomplete in that a proportion of populations undergo inbreeding while the rest are outcrossing. In addition, the degrees of deviation of populations from M-S balance are often not known. Through computer simulations, we investigated the robustness and the applicability of the Deng-Lynch method under different degrees of partial selfing or partial outcrossing and for nonequilibrium populations approaching M-S balance at different stages. The investigation was implemented under constant, variable, and epistatic mutation effects. We found that, generally, the estimation by the Deng-Lynch method is fairly robust if the selfing rate (S) is <0.10 in outcrossing populations and if S > 0.8 in selfing populations. The estimation may be unbiased under partial selfing with variable and epistatic mutation effects in predominantly outcrossing populations. The estimation is fairly robust in nonequilibrium populations at different stages approaching M-S balance. The dynamics of populations approaching M-S balance under various parameters are also studied. Under mutation and selection, populations approach balance at a rapid pace. Generally, it takes 400-2000 generations to reach M-S balance even when starting from homogeneous individuals free of DGM. Our investigation here provides a basis for characterizing DGM in partial selfing or outcrossing populations and for nonequilibrium populations.

Genetics, Population↗

A modular neural network architecture for pattern classification based on different feature sets.

We propose a novel connectionist method for the use of different feature sets in pattern classification. Unlike traditional methods, e.g., combination of multiple classifiers and use of a composite feature set, our method copes with the problem based on an idea of soft competition on different feature sets developed in our earlier work. An alternative modular neural network architecture is proposed to provide a more effective implementation of soft competition on different feature sets. The proposed architecture is interpreted as a generalized finite mixture model and, therefore, parameter estimation is treated as a maximum likelihood problem. An EM algorithm is derived for parameter estimation and, moreover, a model selection method is proposed to fit the proposed architecture to a specific problem. Comparative results are presented for the real world problem of speaker identification.

Humans↗

Population dynamics of nitrifying bacteria in an aquatic ecosystem.

In a space environment such as Space Shuttle or Space Station, animal experiments with aquatic species in a closed system pose a crucial problem in maintaining their water quality for a long term. In nature, ammonia as an animal wastes is converted by nitrifying bacteria to nitrite or nitrate compounds, which usually become nitrogen sources for plants. Thus an application of the biological reactor with such bacteria attached on some filters has been suggested and experimentally studied for efficient waste managements of ammonia. Although some successful results were reported (Kozu et al. 1995, Nagaoka et al. 1998, Nakamura et al. 1997, 1998) in the space applications, purely empirical approaches have so far been taken to develop a biological filter having a stable nitrifying activity. In this study, we constructed a mathematical model to deal with the dynamics of the ammonia nitrifying processes in a biological reactor. The model describes population dynamics of the ammonia-oxidizing bacteria and the nitrite-oxidizing bacteria cultivated on the same filter. We estimated parameters involved in the model using the experimental data. The result shows that these estimated parameters could be applied to general cases and that the two bacteria are in a symbiotic relationship; they can better perform when both coexist, as has been empirically recognized. Based on the model analysis, we discuss how to prepare a high performance biological filter.

Ammonia↗