Isolation and probable functions of betaine esters in brain metabolism.
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Betaine↗
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Results for “Likelihood Functions”
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Estimating equations with nonignorably missing response data.
Troxel, Lipsitz, and Brennan (1997, Biometrics 53, 857-869) considered parameter estimation from survey data with nonignorable nonresponse and proposed weighted estimating equations to remove the biases in the complete-case analysis that ignores missing observations. This paper suggests two alternative modifications for unbiased estimation of regression parameters when a binary outcome is potentially observed at successive time points. The weighting approach of Robins, Rotnitzky, and Zhao (1995, Journal of the American Statistical Association 90, 106-121) is also modified to obtain unbiased estimating functions. The suggested estimating functions are unbiased only when the missingness probability is correctly specified, and misspecification of the missingness model will result in biases in the estimates. Simulation studies are carried out to assess the performance of different methods when the covariate is binary or normal. For the simulation models used, the relative efficiency of the two new methods to the weighting methods is about 3.0 for the slope parameter and about 2.0 for the intercept parameter when the covariate is continuous and the missingness probability is correctly specified. All methods produce substantial biases in the estimates when the missingness model is misspecified or underspecified. Analysis of data from a medical survey illustrates the use and possible differences of these estimating functions.
Biometry↗
Inferences on a life distribution by sampling from the ages or the ages at death.
Consider a system where units having independent and identically distributed lifetimes enter according to a nonhomogeneous Poisson process. After the unit's life in the system, the unit departs the system. For a fixed system time, this paper relates the units' common underlying life distribution with the distribution of the ages of units in the system, the distribution for the system life of units that departed the system and the distribution for the system life of units that have recently departed the system. Results can be used to estimate the underlying life distribution or a truncated version of that distribution based on the ages and/or most recent ages at death in both one sample and two sample situations. Results include a complete characterization of the possible distribution of the ages of those units in the system, how to estimate the underlying life distribution from the most recent ages at death, and how to test for an underlying monotone failure rate function based on independent samples from the ages and most recent ages at death. Two sample inferences that involve a likelihood ratio ordering make use of the results in Dykstra et al. (1995, J Amer Statisc Assoc 90(431):1030-1040), which provides the maximum likelihood estimators and a likelihood ratio test when the two distributions satisfy a likelihood ratio ordering. For the ages of the active units and the ages at death among the departed units, limits for their distributions and strong limiting results for their empirical distributions will be provided.
Biometry↗
Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.
Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.
Base Sequence↗
Evidence of positive Darwinian selection in Omp85, a highly conserved bacterial outer membrane protein essential for cell viability.
Omp85 is a highly conserved outer membrane protein found in all gram-negative bacteria. It is essential for bacterial cell viability and plays an integral function in the positioning and folding of other outer membrane proteins into the bacterial outer membrane. We have employed a maximum likelihood and a maximum parsimony approach to detect evidence of positive Darwinian selection in Omp85 homologues from 10 delta-proteobacteria and have identified 14 amino acid sites that show evidence of being under the influence of adaptive evolution. Interestingly all sites bar one are concentrated within surface loops of the protein that most likely interact with host immune response or the surrounding environment. Alternatively amino acids within membrane-spanning regions of the protein are found to be under purifying selection most likely as a result of structural constraints.
Bacterial Outer Membrane Proteins↗
EEG synchronisation during sleep-related epileptic seizures as a new tool to discriminate confusional arousals from paroxysmal arousals: preliminary findings.
Confusional arousals, paroxysmal arousals (as part of the nocturnal frontal lobe epilepsy) and normal arousals and awakenings from NREM sleep are frequently a challenge for differential diagnosis. In this article we describe the course of synchronisation between different EEG channels during nocturnal seizures in 3 patients with sleep-related epileptic seizures and in 1 patient with sleep terrors. The functional interactions between the different EEG channels during the nocturnal seizures were analysed by means of the so-called synchronisation likelihood (SL). SL is a measure of the dynamical (linear and nonlinear) interdependencies between a time series (EEG channel) and one or more other time series. The main results of our study are the confirmation of a significant increase in EEG synchronisation during sleep-related seizures and the indication that clinically similar ictal motor patterns might be generated by different neurophysiological mechanisms, characterised by different patterns of synchronisation involving multiple or single frequency bands. This new approach might be useful to differentiate motor seizures, emerging from NREM sleep, from parasomnias (arousal disorders) when both ictal and interictal EEGs are uninformative.
Adult↗
Health practices that predict recovery from functional limitations in older adults.
BACKGROUND: Although previous studies show the benefits of certain health behaviors in reducing physical disability in older people, their effects on functional limitation, an antecedent of disability, are not well established. This study aims to identify health behavioral practices that affect recovery from functional limitations in older adults. METHODS: A total of 312 community-dwelling adults aged 65 and older with functional limitations were examined in 2002 for functional recovery in 2003. Functional limitations were measured by self-reports of difficulty performing upper- and lower-body movements. Positive health practices included regular physical activity, normal body mass index (BMI), periodic medical checkups, and moderate alcohol consumption. Logistic regression models were fitted to identify individual as well as combined health practices that predict functional recovery, adjusting for sociodemographic and health-related covariates. RESULTS: Although each of the positive health practices was significantly associated with functional recovery in the bivariate analyses, only physical activity continued to be a strong independent predictor in the multivariate analysis. The likelihood of functional recovery tended to increase with the number of health practices adopted by the elderly. Physical activity, in combination with normal BMI, proved to be one of the most influential health practice profiles, resulting in a high percentage of functional recovery. CONCLUSIONS: Health behaviors, especially physical activity, contribute to an older person's functional independence. The benefit of an increased number of health practices on recovery from functional limitations suggests that targeting multiple behavioral risks may help delay the onset of disability in later life.
Aged↗
Uses of the EM algorithm in the analysis of data on HIV/AIDS and other infectious diseases.
The analysis of data on infectious diseases is a natural setting for applications of the EM algorithm, because the infection process is only partially observable. Difficulties in determining the expectation at the E step have been side-stepped by adopting pragmatic models which reflect only part of the mechanism that generates the data. In the HIV/AIDS context the EM algorithm has helped in the reconstruction of the unobserved HIV infection curve, the so-called backprojection problem, as well as in the estimation of the distribution for the incubation period until AIDS, in estimating the infectivity of HIV in partnerships and in estimating parameters describing the decline in the immune system. There is a need for smooth estimates of functions in these applications, suggesting the use of the EMS algorithm or use of the EM algorithm to maximize a penalized likelihood. For data on other infectious diseases the application of the EM algorithm has so far been restricted to analyses of data on the size of outbreaks in a sample of households.
Acquired Immunodeficiency Syndrome↗
Using evolutionary methods to study G-protein coupled receptors.
A novel method to analyze evolutionary change is presented and its application to the analysis of sequence data is discussed. The investigated method uses phylogenetic trees of related proteins with an evolutionary model in order to gain insight about protein structure and function. The evolutionary model, based on amino acid substitutions, contains adjustable parameters related to amino acid and sequence properties. A maximum likelihood approach is used with a phylogenetic tree to optimize these parameters. The model is applied to a set of Muscarinic receptors, members of the G-protein coupled receptor family. Here we show that the optimized parameters of the model are able to highlight the general structural features of these receptors.
Animals↗
Smooth centile curves for skew and kurtotic data modelled using the Box-Cox power exponential distribution.
The Box-Cox power exponential (BCPE) distribution, developed in this paper, provides a model for a dependent variable Y exhibiting both skewness and kurtosis (leptokurtosis or platykurtosis). The distribution is defined by a power transformation Y(nu) having a shifted and scaled (truncated) standard power exponential distribution with parameter tau. The distribution has four parameters and is denoted BCPE (mu,sigma,nu,tau). The parameters, mu, sigma, nu and tau, may be interpreted as relating to location (median), scale (approximate coefficient of variation), skewness (transformation to symmetry) and kurtosis (power exponential parameter), respectively. Smooth centile curves are obtained by modelling each of the four parameters of the distribution as a smooth non-parametric function of an explanatory variable. A Fisher scoring algorithm is used to fit the non-parametric model by maximizing a penalized likelihood. The first and expected second and cross derivatives of the likelihood, with respect to mu, sigma, nu and tau, required for the algorithm, are provided. The centiles of the BCPE distribution are easy to calculate, so it is highly suited to centile estimation. This application of the BCPE distribution to smooth centile estimation provides a generalization of the LMS method of the centile estimation to data exhibiting kurtosis (as well as skewness) different from that of a normal distribution and is named here the LMSP method of centile estimation. The LMSP method of centile estimation is applied to modelling the body mass index of Dutch males against age.
Adolescent↗
Noise analysis of MAP-EM algorithms for emission tomography.
The ability to theoretically model the propagation of photon noise through PET and SPECT tomographic reconstruction algorithms is crucial in evaluating the reconstructed image quality as a function of parameters of the algorithm. In a previous approach for the important case of the iterative ML-EM (maximum-likelihood-expectation-maximization) algorithm, judicious linearizations were used to model theoretically the propagation of a mean image and a covariance matrix from one iteration to the next. Our analysis extends this approach to the case of MAP (maximum a posteriori)-EM algorithms, where the EM approach incorporates prior terms. We analyse in detail two cases: a MAP-EM algorithm incorporating an independent gamma prior, and a one-step-late (OSL) version of a MAP-EM algorithm incorporating a multivariate Gaussian prior, for which familiar smoothing priors are special cases. To validate our theoretical analyses, we use a Monte Carlo methodology to compare, at each iteration, theoretical estimates of mean and covariance with sample estimates, and show that the theory works well in practical situations where the noise and bias in the reconstructed images do not assume extreme values.
Algorithms↗
Estimating data transformations in nonlinear mixed effects models.
A routine practice in the analysis of repeated measurement data is to represent individual responses by a mixed effects model on some transformed scale. For example, for pharmacokinetic, growth, and other data, both the response and the regression model are typically transformed to achieve approximate within-individual normality and constant variance on the new scale; however, the choice of transformation is often made subjectively or by default, with adoption of a standard choice such as the log. We propose a mixed effects framework based on the transform-both-sides model, where the transformation is represented by a monotone parametric function and is estimated from the data. For this model, we describe a practical fitting strategy based on approximation of the marginal likelihood. Inference is complicated by the fact that estimation of the transformation requires modification of the usual standard errors for estimators of fixed effects; however, we show that, under conditions relevant to common applications, this complication is asymptotically negligible, allowing straightforward implementation via standard software.
Arginine↗
Estimation and inference for a spline-enhanced population pharmacokinetic model.
This article is motivated by an application where subjects were dosed three times with the same drug and the drug concentration profiles appeared to be the lowest after the third dose. One possible explanation is that the pharmacokinetic (PK) parameters vary over time. Therefore, we consider population PK models with time-varying PK parameters. These time-varying PK parameters are modeled by natural cubic spline functions in the ordinary differential equations. Mean parameters, variance components, and smoothing parameters are jointly estimated by maximizing the double penalized log likelihood. Mean functions and their derivatives are obtained by the numerical solution of ordinary differential equations. The interpretation of PK parameters in the model and its flexibility are discussed. The proposed methods are illustrated by application to the data that motivated this article. The model's performance is evaluated through simulation.
Biometry↗
Monitoring epidemiologic surveillance data using hidden Markov models.
The analysis of routinely collected surveillance data is an important challenge in public health practice. We present a method based on a hidden Markov model for monitoring such time series. The model characterizes the sequence of measurements by assuming that its probability density function depends on the state of an underlying Markov chain. The parameter vector includes distribution parameters and transition probabilities between the states. Maximum likelihood estimates are obtained with a modified EM algorithm. Extensions are provided to take into account trend and seasonality in the data. The method is demonstrated on two examples: the first seeks to characterize influenza-like illness incidence rates with a mixture of Gaussian distributions, and the other, poliomyelitis counts with mixture of Poisson distributions. The results justify a wider use of this method for analysing surveillance data.
Disease Outbreaks↗
An adjustment to improve the bivariate survivor function repaired NPMLE.
We recently proposed a representation of the bivariate survivor function as a mapping of the hazard function for truncated failure time variates. The representation led to a class of estimators that includes van der Laan's repaired nonparametric maximum likelihood estimator (NPMLE) as an important special case. We proposed a Greenwood-like variance estimator for the repaired NPMLE but found somewhat poor agreement between the empirical variance estimates and these analytic estimates for the sample sizes and bandwidths considered in our simulation study. The simulation results also confirmed those of others in showing slightly inferior performance for the repaired NPMLE compared to other competing estimators as well as a sensitivity to bandwidth choice in moderate sized samples. Despite its attractive asymptotic properties, the repaired NPMLE has drawbacks that hinder its practical application. This paper presents a modification of the repaired NPMLE that improves its performance in moderate sized samples and renders it less sensitive to the choice of bandwidth. Along with this modified estimator, more extensive simulation studies of the repaired NPMLE and Greenwood-like variance estimates are presented. The methods are then applied to a real data example.
Likelihood Functions↗
Improvement of domain linker prediction by incorporating loop-length-dependent characteristics.
Protein dissection into structural domains that can fold in isolation is an important issue in both functional and structural proteomics. Here, we analyzed inter- and intradomain loop sequences (respectively named domain linker and nonlinker loops) and computed a domain linker likelihood score, which was used for developing a domain boundary prediction protocol. The analysis confirmed our previous results indicating that the amino acid composition in terms of glycine, proline, aspartic acid, asparagine, lysine, and histidine significantly differs between linker and nonlinker loops. However, a detailed examination revealed that the amino acid composition bias actually depends on the loop length. Indeed, significant frequency deviations were observed for glycine, proline, and aspartic acid in short linker and nonlinker loops, whereas deviations were observed for aspartic acid, proline, asparagine, and lysine in long linker and nonlinker loops. Finally, we incorporated this loop-length-dependent amino acid composition bias in a simple linker prediction protocol, which predicted linkers with a 40.6% specificity and a 36.1% sensitivity. These figures are 4.4 and 2.4% higher than those obtained with our former prediction protocol that does not incorporate loop-length-dependent characteristics. This result should have practical significance for experimental protein dissection, since the probability of obtaining a stably folding structural domain by randomly dissecting a protein sequence is estimated to be 12.6%.
Algorithms↗
Effects of psychoeducational intervention for married patients with bipolar disorder and their spouses.
The relative benefit of adding a structured psychoeducational intervention to standard medication treatment for married patients with bipolar disorder and their spouses was assessed. Patients were randomly assigned to receive either medication management or medication management plus a marital intervention with their spouses for an 11-month period. Patients' symptoms, functioning, and adherence to their medication regimens were measured at study entry and at 11 months. Significant effects favoring the combined treatments were observed for overall patient functioning but not for symptom levels. The marital intervention was associated with improved medication adherence. Combined psychosocial and medication treatment does not affect patients' symptom levels beyond the effects of medication alone, but it does result in significant incremental gains in overall patient functioning.
Bipolar Disorder↗
Fitting a psychometric function to price judgments: an analysis of consumers' discounted prices.
We examined a psychometric function of price judgment, comparing the mental ruler model, which predicted inverted S-shaped psychometric function, with a power function. Subjects, 102 citizens living in Japan, were asked to rate satisfaction with specified discounted prices. Analysis indicated that predictions of the mental ruler model gave a better fit than those of the power function.
Adolescent↗