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Estimation of multivariate frailty models using penalized partial likelihood.

There exists a growing literature on the estimation of gamma distributed multiplicative shared frailty models. There is, however, often a need to model more complicated frailty structures, but attempts to extend gamma frailties run into complications. Motivated by hip replacement data with a more complicated dependence structure, we propose a model based on multiplicative frailties with a multivariate log-normal joint distribution. We give a justification and an estimation procedure for this generally structured frailty model, which is a generalization of the one presented by McGilchrist (1993, Biometrics 49, 221-225). The estimation is based on Laplace approximation of the likelihood function. This leads to estimating equations based on a penalized fixed effects partial likelihood, where the marginal distribution of the frailty terms determines the penalty term. The tuning parameters of the penalty function, i.e., the frailty variances, are estimated by maximizing an approximate profile likelihood. The performance of the approximation is evaluated by simulation, and the frailty model is fitted to the hip replacement data.

Biometry↗

Generalized gamma frailty model.

In this article, we present a frailty model using the generalized gamma distribution as the frailty distribution. It is a power generalization of the popular gamma frailty model. It also includes other frailty models such as the lognormal and Weibull frailty models as special cases. The flexibility of this frailty distribution makes it possible to detect a complex frailty distribution structure which may otherwise be missed. Due to the intractable integrals in the likelihood function and its derivatives, we propose to approximate the integrals either by Monte Carlo simulation or by a quadrature method and then determine the maximum likelihood estimates of the parameters in the model. We explore the properties of the proposed frailty model and the computation method through a simulation study. The study shows that the proposed model can potentially reduce errors in the estimation, and that it provides a viable alternative for correlated data. The merits of proposed model are demonstrated in analysing the effects of sublingual nitroglycerin and oral isosorbide dinitrate on angina pectoris of coronary heart disease patients based on the data set in Danahy et al. (sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977; 55:381-387).

Angina Pectoris↗

Generalized proportional hazards model based on modified partial likelihood.

The proportional hazards (Cox) model is generalized by assuming that at any moment the ratio of hazard rates is depending not only on values of covariates but also on resources used until this moment. Relations with generalized multiplicative, frailty and linear transformation models are considered. A modified partial likelihood function is proposed, and properties of the estimators are investigated.

Humans↗

The consistency of the posterior probability of linkage.

When searching for trait loci along the genome, properly incorporating prior genomic information into the analysis will almost certainly increase the chance of success. Recently, we devised a method that utilizes such prior information in the mapping of trait genes for complex disorders (Vieland, 1998; Wang el al. 1999; Vieland et al. 2000). This method uses the posterior probability of linkage (PPL) based on the admixture model as a measure of linkage information. In this paper, we study the consistency of the PPL. It is shown that, as the number of pedigrees increases, the PPL converges in probability to 1 when there is linkage between the marker and a trait locus, and converges to 0 otherwise. This conclusion is shown to be true for general pedigrees and trait models, even, when the likelihood functions are based on misspecified trait models. As part of the effort to prove this conclusion, it is shown that when there is no linkage, the maximum likelihood estimator of the recombination fraction in the admixture model is asymptotically 0.5, even when the admixture model misrepresents the true model.

Computer Simulation↗

Simultaneous iterative reconstruction for emission and attenuation images in positron emission tomography.

The quality of the attenuation correction strongly influences the outcome of the reconstructed emission scan in positron emission tomography. Usually the attenuation correction factors are calculated from the transmission and blank scan and thereafter applied during the reconstruction on the emission data. However, this is not an optimal treatment of the available data, because the emission data themselves contain additional information about attenuation: The optimal treatment must use this information for the determination of the attenuation correction factors. Therefore, our purpose is to investigate a simultaneous emission and attenuation image reconstruction using a maximum likelihood estimator, which takes the attenuation information in the emission data into account. The total maximum likelihood function for emission and transmission is used to derive a one-dimensional Newton-like algorithm for the calculation of the emission and attenuation image. Log-likelihood convergence, mean differences, and the mean of squared differences for the emission image and the attenuation correction factors of a mathematical thorax phantom were determined and compared. As a result we obtain images improved with respect to log likelihood in all cases and with respect to our figures of merit in most cases. We conclude that the simultaneous reconstruction can improve the performance of image reconstruction.

Algorithms↗

Maximum likelihood estimation of a stochastic integrate-and-fire neural encoding model.

We examine a cascade encoding model for neural response in which a linear filtering stage is followed by a noisy, leaky, integrate-and-fire spike generation mechanism. This model provides a biophysically more realistic alternative to models based on Poisson (memoryless) spike generation, and can effectively reproduce a variety of spiking behaviors seen in vivo. We describe the maximum likelihood estimator for the model parameters, given only extracellular spike train responses (not intracellular voltage data). Specifically, we prove that the log-likelihood function is concave and thus has an essentially unique global maximum that can be found using gradient ascent techniques. We develop an efficient algorithm for computing the maximum likelihood solution, demonstrate the effectiveness of the resulting estimator with numerical simulations, and discuss a method of testing the model's validity using time-rescaling and density evolution techniques.

Algorithms↗

A Matlab function to estimate choice model parameters from paired-comparison data.

Tversky (1972) has proposed a family of models for paired-comparison data that generalize the Bradley-Terry-Luce (BTL) model and can, therefore, apply to a diversity of situations in which the BTL model is doomed to fail. In this article, we present a Matlab function that makes it easy to specify any of these general models (EBA, Pretree, or BTL) and to estimate their parameters. The program eliminates the time-consuming task of constructing the likelihood function by hand for every single model. The usage of the program is illustrated by several examples. Features of the algorithm are outlined. The purpose of this article is to facilitate the use of probabilistic choice models in the analysis of data resulting from paired comparisons.

Algorithms↗

Iterative reconstruction for attenuation correction in positron emission tomography: maximum likelihood for transmission and blank scan.

The quality of the attenuation correction strongly influences the outcome of the reconstructed emission scan in positron emission tomography. The calculation of the attenuation correction factors must take into account the Poisson nature of the radioactive decay process, because-for a reasonable scan duration-the transmission measurements contain lines of response with low count numbers in the case of large attenuation factors. Our purpose in this study is to investigate a maximum likelihood estimator for attenuation correction factor calculation in positron emission tomography, which incorporates the Poisson nature of the radioactive decay into transmission and blank measurement. Therefore, the correct maximum likelihood function is used to derive two estimators for the calculation of the attenuation coefficient image and the corresponding attenuation correction factors depending on the measured blank and transmission data. Log likelihood convergence, mean differences, and the mean of squared differences for the attenuation correction factors of a mathematical thorax phantom were determined and compared. The algorithms yield adequate attenuation correction factors, however, the algorithm taking the noise in the blank scan into account can perform better for noisy blank scans. We conclude that maximum likelihood-including blank likelihood-is advantageous to reconstruct attenuation correction factors for low statistic blank and good statistic transmission data. For normal blank and transmission statistics the implementation of the statistical nature of the blank is not mandatory.

Biophysical Phenomena↗

A likelihood approach to populations samples of microsatellite alleles.

This paper presents a likelihood approach to population samples of microsatellite alleles. A Markov chain recursion method previously published by GRIFFITHS and TAVARE is applied to estimate the likelihood function under different models of microsatellite evolution. The method presented can be applied to estimate a fundamental population genetics parameter theta as well as parameters of the mutational model. The new likelihood estimator provides a better estimator of theta in terms of the mean square error than previous approaches. Furthermore, it is demonstrated how the method may easily be applied to test models of microsatellite evolution. In particular it is shown how to compare a one-step model of microsatellite evolution to a multi-step model by a likelihood ratio test.

Alleles↗

Directly modelling matched case-control data.

Matching in case-control studies is a situation in which one wishes to make inferences about a parameter of interest in the presence of nuisance parameters. The usual approach is to apply a conditional likelihood. A bivariate latent class log-linear model for binomial responses is shown to yield a standard likelihood identical to the usual conditional one. This extension of the Rasch model for binary responses gives consistent estimates and a suitable likelihood function for cases matched with any fixed number of controls.

Age Factors↗

Application of the complex multivariate normal distribution to crystallographic methods with insights into multiple isomorphous replacement phasing.

Probabilistic methods involving maximum-likelihood parameter estimation have become a powerful tool in computational crystallography. At the centre of these methods are the relevant probability distributions. Here, equations are developed based on the complex multivariate normal distribution that generalize the distributions currently used in maximum-likelihood model and heavy-atom refinement. In this treatment, the effects of various sources of error in the experiment are considered separately and allowance is made for correlations among sources of error. The multivariate distributions presented are closely related to the distributions previously derived in ab initio phasing and can be applied to many different aspects of a crystallographic structure-determination process including model refinement, density modification, heavy-atom phasing and refinement or combinations of them. The underlying probability distributions for multiple isomorphous replacement are re-examined using these techniques. The re-analysis requires the underlying assumptions to be made explicitly and results in a variance term that, unlike those previously used for maximum-likelihood multiple isomorphous replacement phasing, is expressed explicitly in terms of structure-factor covariances. Test cases presented show that the newly derived multiple isomorphous replacement likelihood functions perform satisfactorily compared with currently used programs.

Crystallography, X-Ray↗

Estimation of weights and validation: a marginal likelihood approach.

The estimation of weights is quite an important aspect of the restrained refinement of macromolecular structures and related procedures such as the estimation of coordinate errors and structure validation using geometrical criteria. In principle, the method of maximum likelihood can be used for estimation of both atomic and weighting parameters. However, the low observation-to-parameter ratio in macromolecular refinement makes this kind of estimate of weighting parameters seriously biased; thus, the weighting parameters have traditionally been estimated separately from atomic parameters using a special technique, such as minimizing the free R factor. However, the variance of the latter estimate is large, as only a small portion of all data is used. In this work, an estimator of weights is proposed which is based on an approximation of a marginal likelihood function of the weighting parameters and which uses all the X-ray data. There is a known true value for the overall scaling coefficient for distance variances in restrained refinement and therefore the (maximum-likelihood) estimator for this coefficient may be used as a validation statistic.

Crystallography, X-Ray↗

Parameter estimation in longitudinal studies with outcome-dependent follow-up.

In many observational studies, individuals are measured repeatedly over time, although not necessarily at a set of prespecified occasions. Instead, individuals may be measured at irregular intervals, with those having a history of poorer health outcomes being measured with somewhat greater frequency and regularity; i.e., those individuals with poorer health outcomes may have more frequent follow-up measurements and the intervals between their repeated measurements may be shorter. In this article, we consider estimation of regression parameters in models for longitudinal data where the follow-up times are not fixed by design but can depend on previous outcomes. In particular, we focus on general linear models for longitudinal data where the repeated measures are assumed to have a multivariate Gaussian distribution. We consider assumptions regarding the follow-up time process that result in the likelihood function separating into two components: one for the follow-up time process, the other for the outcome process. The practical implication of this separation is that the former process can be ignored when making likelihood-based inferences about the latter; i.e., maximum likelihood (ML) estimation of the regression parameters relating the mean of the longitudinal outcomes to covariates does not require that a model for the distribution of follow-up times be specified. As a result, standard statistical software, e.g., SAS PROC MIXED (Littell et al., 1996, SAS System for Mixed Models), can be used to analyze the data. However, we also demonstrate that misspecification of the model for the covariance among the repeated measures will, in general, result in regression parameter estimates that are biased. Furthermore, results of a simulation study indicate that the potential bias due to misspecification of the covariance can be quite considerable in this setting. Finally, we illustrate these results using data from a longitudinal observational study (Lipshultz et al., 1995, New England Journal of Medicine 332, 1738-1743) that explored the cardiotoxic effects of doxorubicin chemotherapy for the treatment of acute lymphoblastic leukemia in children.

Adolescent↗

A stochastic formulation of the gompertzian growth model for in vitro bactericidal kinetics: parameter estimation and extinction probability.

Time-kill curves have frequently been employed to study the antimicrobial effects of antibiotics. The relevance of pharmacodynamic modeling to these investigations has been emphasized in many studies of bactericidal kinetics. Stochastic models are needed that take into account the randomness of the mechanisms of both bacterial growth and bacteria-drug interactions. However, most of the models currently used to describe antibiotic activity against microorganisms are deterministic. In this paper we examine a stochastic differential equation representing a stochastic version of a pharmacodynamic model of bacterial growth undergoing random fluctuations, and derive its solution, mean value and covariance structure. An explicit likelihood function is obtained both when the process is observed continuously over a period of time and when data is sampled at time points, as is the custom in these experimental conditions. Some asymptotic properties of the maximum likelihood estimators for the model parameters are discussed. The model is applied to analyze in vitro time-kill data and to estimate model parameters; the probability of the bacterial population size dropping below some critical threshold is also evaluated. Finally, the relationship between bacterial extinction probability and the pharmacodynamic parameters estimated is discussed.

Anti-Bacterial Agents↗

An EM algorithm for mapping binary disease loci: application to fibrosarcoma in a four-way cross mouse family.

Many diseases show dichotomous phenotypic variation but do not follow a simple Mendelian pattern of inheritance. Variances of these binary diseases are presumably controlled by multiple loci and environmental variants. A least-squares method has been developed for mapping such complex disease loci by treating the binary phenotypes (0 and 1) as if they were continuous. However, the least-squares method is not recommended because of its ad hoc nature. Maximum Likelihood (ML) and Bayesian methods have also been developed for binary disease mapping by incorporating the discrete nature of the phenotypic distribution. In the ML analysis, the likelihood function is usually maximized using some complicated maximization algorithms (e.g. the Newton-Raphson or the simplex algorithm). Under the threshold model of binary disease, we develop an Expectation Maximization (EM) algorithm to solve for the maximum likelihood estimates (MLEs). The new EM algorithm is developed by treating both the unobserved genotype and the disease liability as missing values. As a result, the EM iteration equations have the same form as the normal equation system in linear regression. The EM algorithm is further modified to take into account sexual dimorphism in the linkage maps. Applying the EM-implemented ML method to a four-way-cross mouse family, we detected two regions on the fourth chromosome that have evidence of QTLs controlling the segregation of fibrosarcoma, a form of connective tissue cancer. The two QTLs explain 50-60% of the variance in the disease liability. We also applied a Bayesian method previously developed (modified to take into account sex-specific maps) to this data set and detected one additional QTL on chromosome 13 that explains another 26% of the variance of the disease liability. All the QTLs detected primarily show dominance effects.

Algorithms↗

Statistical estimation of parameters in a disease transmission model: analysis of a Cryptosporidium outbreak.

Population dynamic models, commonly used tools in the study of epidemics and other complex population processes, are implicit non-linear mathematical equations. Inference based on such models can be difficult due to the problems associated with high dimensional parameters that may be non-identified and complex likelihood functions that are difficult to maximize. To address a problem of non-identifiability due to collinearity of parameter estimates in a mathematical model of the 1993 Milwaukee Cryptosporidium parvum outbreak, we examined the utility of a constrained profile likelihood approach. This method was used to study two parameters of interest from the mathematical model: (i). the rate of secondary transmission; (ii). the proportional increase in primary transmission due to water treatment failure. The estimated values of these parameters were shown to depend strongly on poorly understood aspects of Cryptosporidium epidemiology such as asymptomatic proportion and the population immune status. Our analysis demonstrated that the combination of a disease transmission model and a constrained profile likelihood procedure provides an effective approach for inference and estimation of important parameters regulating infectious disease outbreaks.

Animals↗

The additive genetic gamma frailty model for linkage analysis of age-of-onset variation.

Age of onset is a key factor in the linkage analysis of many complex diseases. Current methods in nonparametric linkage analysis are mainly concentrated on the affected relative pairs or affected family members with age of onset information either ignored or taken into account by specifying age-dependent penetrances for liability classes. On the other hand, gamma frailty models were developed in the biostatistics literature to model familial aggregation of age of onset. However, these frailty models cannot be used directly for linkage analysis. This paper extends the gamma frailty model by incorporating inheritance vector information and provides a semiparametric approach for linkage testing. For a given inheritance vector at the putative disease locus, we construct an additive genetic gamma frailty for each individual within a nuclear family and use the Cox proportional hazard model to model age of onset. We derive the conditional hazard ratio parameter for sib pairs and define a likelihood ratio based LOD score statistic under our model. The EM algorithm is used for estimating the parameters and the maximum likelihood functions. Simulated data sets are used to illustrate these new statistical methods.

Age Factors↗

Effects of implicit parameters in segregation analysis.

In human genetic analysis, data are collected through the so-called 'ascertainment procedure'. Statistically this sampling scheme can be thought of as a multistage sampling method. At the first stage, one or several probands are ascertained. At the subsequent stages, a sequential sampling scheme is applied. Sampling in such a way is virtually a nonrandom procedure, which, in most cases, causes biased estimation which may be intractable. This paper focuses on the underlying causes of the intractability problem of ascertained genetic data. Three types of parameters, i.e. target, design and nuisance parameters, are defined as the essences to formulate the true likelihood of a set of data. These parameters are also classified into explicit or implicit parameters depending on whether they can be expressed explicity in the likelihood function. For ascertained genetic data, a sequential scheme is regarded as an implicit design parameter, and a true pedigree structure as an implicit nuisance parameter. The intractability problem is attributed to loss of information of any implicit parameter in likelihood formulation. Several approaches to build a likelihood for estimation of the segregation ratio when only an observed pedigree structure is available are proposed.

Female↗