Estimating genetic covariance functions assuming a parametric correlation structure for environmental effects

A random regression model for the analysis of "repeated" records in animal breeding is described which combines a random regression approach for additive genetic and other random effects with the assumption of a parametric correlation structure for within animal covariances. Both stationary and non-stationary correlation models involving a small number of parameters are considered. Heterogeneity in within animal variances is modelled through polynomial variance functions. Estimation of parameters describing the dispersion structure of such model by restricted maximum likelihood via an "average information" algorithm is outlined. An application to mature weight records of beef cow is given, and results are contrasted to those from analyses fitting sets of random regression coefficients for permanent environmental effects.     

Use of the individual data of the a-bomb survivors for biologically based cancer models

All recent analyses of the data on solid cancer incidence of the atomic bomb survivors are corrected for migration and random dose errors. In the usual treatment with grouped data and regression calibration, the calibration of doses depends on the used dose response. For solid cancers, it usually is linear. Here, an individual likelihood is presented which works without further adjustment for all dose responses. When the same assumptions are made as in the usual Poisson regression, equivalent results are obtained. But, the individual likelihood has the potential to use more detailed models for dose errors and to estimate non-linear dose responses without recalibration. As an example for the potential of the individual data set for the analysis of risk at low doses, signals for a saturating bystander effect are investigated.     

Maximum likelihood estimation for cytogenetic dose-response curves

In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.     

Analysis of multi-type recurrent events in longitudinal studies; application to a skin cancer prevention trial

We consider the statistical modeling and analysis of replicated multi-type point process data with covariates. Such data arise when heterogeneous subjects experience repeated events or failures which may be of several distinct types. The underlying processes are modeled as nonhomogeneous mixed Poisson processes with random (subject) and fixed (covariate) effects. The method of maximum likelihood is used to obtain estimates and standard errors of the failure rate parameters and regression coefficients. Score tests and likelihood ratio statistics are used for covariate selection. A graphical test of goodness of fit of the selected model is based on generalized residuals. Measures for determining the influence of an individual observation on the estimated regression coefficients and on the score test statistic are developed. An application is described to a large ongoing randomized controlled clinical trial for the efficacy of nutritional supplements of selenium for the prevention of two types of skin cancer.     

Inference for the proportional hazards model with misclassified discrete-valued covariates

We consider the Cox proportional hazards model with discrete-valued covariates subject to misclassification. We present a simple estimator of the regression parameter vector for this model. The estimator is based on a weighted least squares analysis of weighted-averaged transformed Kaplan-Meier curves for the different possible configurations of the observed covariate vector. Optimal weighting of the transformed Kaplan-Meier curves is described. The method is designed for the case in which the misclassification rates are known or are estimated from an external validation study. A hybrid estimator for situations with an internal validation study is also described. When there is no misclassification, the regression coefficient vector is small in magnitude, and the censoring distribution does not depend on the covariates, our estimator has the same asymptotic covariance matrix as the Cox partial likelihood estimator. We present results of a finite-sample simulation study under Weibull survival in the setting of a single binary covariate with known misclassification rates. In this simulation study, our estimator performed as well as or, in a few cases, better than the full Weibull maximum likelihood estimator. We illustrate the method on data from a study of the relationship between trans-unsaturated dietary fat consumption and cardiovascular disease incidence.     

Estimation and comparison of changes in the presence of informative right censoring: conditional linear model

A general linear regression model for the usual least squares estimated rate of change (slope) on censoring time is described as an approximation to account for informative right censoring in estimating and comparing changes of a continuous variable in two groups. Two noniterative estimators for the group slope means, the linear minimum variance unbiased (LMVUB) estimator and the linear minimum mean squared error (LMMSE) estimator, are proposed under this conditional model. In realistic situations, we illustrate that the LMVUB and LMMSE estimators, derived under a simple linear regression model, are quite competitive compared to the pseudo maximum likelihood estimator (PMLE) derived by modeling the censoring probabilities. Generalizations to polynomial response curves and general linear models are also described.     

An augmented probit model for missing predictable covariates in quantal bioassay with small sample size

Summary Quantal bioassay experiments relate the amount or potency of some compound; for example, poison, antibody, or drug to a binary outcome such as death or infection in animals. For infectious diseases, probit regression is commonly used for inference and a key measure of potency is given by the ID_P , the amount that results in P% of the animals being infected. In some experiments, a validation set may be used where both direct and proxy measures of the dose are available on a subset of animals with the proxy being available on all. The proxy variable can be viewed as a messy reflection of the direct variable, leading to an errors‐in‐variables problem. We develop a model for the validation set and use a constrained seemingly unrelated regression (SUR) model to obtain the distribution of the direct measure conditional on the proxy. We use the conditional distribution to derive a pseudo‐likelihood based on probit regression and use the parametric bootstrap for statistical inference. We re‐evaluate an old experiment in 21 monkeys where neutralizing antibodies (nABs) to HIV were measured using an old (proxy) assay in all monkeys and with a new (direct) assay in a validation set of 11 who had sufficient stored plasma. Using our methods, we obtain an estimate of the ID₁ for the new assay, an important target for HIV vaccine candidates. In simulations, we compare the pseudo‐likelihood estimates with regression calibration and a full joint likelihood approach.     

Risk assessment for quantitative responses using a mixture model

A problem that frequently occurs in biological experiments with laboratory animals is that some subjects are less susceptible to the treatment than others. A mixture model has traditionally been proposed to describe the distribution of responses in treatment groups for such experiments. Using a mixture dose-response model, we derive an upper confidence limit on additional risk, defined as the excess risk over the background risk due to an added dose. Our focus will be on experiments with continuous responses for which risk is the probability of an adverse effect defined as an event that is extremely rare in controls. The asymptotic distribution of the likelihood ratio statistic is used to obtain the upper confidence limit on additional risk. The method can also be used to derive a benchmark dose corresponding to a specified level of increased risk. The EM algorithm is utilized to find the maximum likelihood estimates of model parameters and an extension of the algorithm is proposed to derive the estimates when the model is subject to a specified level of added risk. An example is used to demonstrate the results, and it is shown that by using the mixture model a more accurate measure of added risk is obtained.     

Inference for constrained estimation of tumor size distributions

SUMMARY: In order to develop better treatment and screening programs for cancer prevention programs, it is important to be able to understand the natural history of the disease and what factors affect its progression. We focus on a particular framework first outlined by Kimmel and Flehinger (1991, Biometrics, 47, 987-1004) and in particular one of their limiting scenarios for analysis. Using an equivalence with a binary regression model, we characterize the nonparametric maximum likelihood estimation procedure for estimation of the tumor size distribution function and give associated asymptotic results. Extensions to semiparametric models and missing data are also described. Application to data from two cancer studies is used to illustrate the finite-sample behavior of the procedure.     

Empirical Likelihood Semiparametric Regression Analysis for Longitudinal Data

A semiparametric regression model for longitudinal data is considered.The empirical likelihood method is used to estimate the regressioncoefficients and the baseline function, and to construct confidenceregions and intervals. It is proved that the maximum empiricallikelihood estimator of the regression coefficients achievesasymptotic efficiency and the estimator of the baseline functionattains asymptotic normality when a bias correction is made.Two calibrated empirical likelihood approaches to inferencefor the baseline function are developed. We propose a groupwiseempirical likelihood procedure to handle the inter-series dependencefor the longitudinal semiparametric regression model, and employbias correction to construct the empirical likelihood ratiofunctions for the parameters of interest. This leads us to provea nonparametric version of Wilks' theorem. Compared with methodsbased on normal approximations, the empirical likelihood doesnot require consistent estimators for the asymptotic varianceand bias. A simulation compares the empirical likelihood andnormal-based methods in terms of coverage accuracies and averageareas/lengths of confidence regions/intervals.     

Random-effects models for serial observations with binary response

This paper presents a general mixed model for the analysis of serial dichotomous responses provided by a panel of study participants. Each subject's serial responses are assumed to arise from a logistic model, but with regression coefficients that vary between subjects. The logistic regression parameters are assumed to be normally distributed in the population. Inference is based upon maximum likelihood estimation of fixed effects and variance components, and empirical Bayes estimation of random effects. Exact solutions are analytically and computationally infeasible, but an approximation based on the mode of the posterior distribution of the random parameters is proposed, and is implemented by means of the EM algorithm. This approximate method is compared with a simpler two-step method proposed by Korn and Whittemore (1979, Biometrics 35, 795-804), using data from a panel study of asthmatics originally described in that paper. One advantage of the estimation strategy described here is the ability to use all of the data, including that from subjects with insufficient data to permit fitting of a separate logistic regression model, as required by the Korn and Whittemore method. However, the new method is computationally intensive.     

Bayesian semiparametric modeling for matched case-control studies with multiple disease states

We present a Bayesian approach to analyze matched "case-control" data with multiple disease states. The probability of disease development is described by a multinomial logistic regression model. The exposure distribution depends on the disease state and could vary across strata. In such a model, the number of stratum effect parameters grows in direct proportion to the sample size leading to inconsistent MLEs for the parameters of interest even when one uses a retrospective conditional likelihood. We adopt a semiparametric Bayesian framework instead, assuming a Dirichlet process prior with a mixing normal distribution on the distribution of the stratum effects. We also account for possible missingness in the exposure variable in our model. The actual estimation is carried out through a Markov chain Monte Carlo numerical integration scheme. The proposed methodology is illustrated through simulation and an example of a matched study on low birth weight of newborns (Hosmer, D. A. and Lemeshow, S., 2000, Applied Logistic Regression) with two possible disease groups matched with a control group.     

Quasi-likelihood estimation for relative risk regression models

For a prospective randomized clinical trial with two groups, the relative risk can be used as a measure of treatment effect and is directly interpretable as the ratio of success probabilities in the new treatment group versus the placebo group. For a prospective study with many covariates and a binary outcome (success or failure), relative risk regression may be of interest. If we model the log of the success probability as a linear function of covariates, the regression coefficients are log-relative risks. However, using such a log-linear model with a Bernoulli likelihood can lead to convergence problems in the Newton-Raphson algorithm. This is likely to occur when the success probabilities are close to one. A constrained likelihood method proposed by Wacholder (1986, American Journal of Epidemiology 123, 174-184), also has convergence problems. We propose a quasi-likelihood method of moments technique in which we naively assume the Bernoulli outcome is Poisson, with the mean (success probability) following a log-linear model. We use the Poisson maximum likelihood equations to estimate the regression coefficients without constraints. Using method of moment ideas, one can show that the estimates using the Poisson likelihood will be consistent and asymptotically normal. We apply these methods to a double-blinded randomized trial in primary biliary cirrhosis of the liver (Markus et al., 1989, New England Journal of Medicine 320, 1709-1713).     

Zipf's law in importance of genes for cancer classification using microarray data

Using a measure of how differentially expressed a gene is in two biochemically/phenotypically different conditions, we can rank all genes in a microarray dataset. We have shown that the falling-off of this measure (normalized maximum likelihood in a classification model such as logistic regression) as a function of the rank is typically a power-law function. This power-law function in other similar ranked plots are known as the Zipf's law, observed in many natural and social phenomena. The presence of this power-law function prevents an intrinsic cutoff point between the "important" genes and "irrelevant" genes. We have shown that similar power-law functions are also present in permuted dataset, and provide an explanation from the well-known chi(2) distribution of likelihood ratios. We discuss the implication of this Zipf's law on gene selection in a microarray data analysis, as well as other characterizations of the ranked likelihood plots such as the rate of fall-off of the likelihood.     

Latent class regression on latent factors

In the research of public health, psychology, and social sciences, many research questions investigate the relationship between a categorical outcome variable and continuous predictor variables. The focus of this paper is to develop a model to build this relationship when both the categorical outcome and the predictor variables are latent (i.e. not observable directly). This model extends the latent class regression model so that it can include regression on latent predictors. Maximum likelihood estimation is used and two numerical methods for performing it are described: the Monte Carlo expectation and maximization algorithm and Gaussian quadrature followed by quasi-Newton algorithm. A simulation study is carried out to examine the behavior of the model under different scenarios. A data example involving adolescent health is used for demonstration where the latent classes of eating disorders risk are predicted by the latent factor body satisfaction.     

Statistical methods for analysis of radiation effects with tumor and dose location-specific information with application to the WECARE study of asynchronous contralateral breast cancer

Summary .  Methods for the analysis of individually matched case-control studies with location-specific radiation dose and tumor location information are described. These include likelihood methods for analyses that just use cases with precise location of tumor information and methods that also include cases with imprecise tumor location information. The theory establishes that each of these likelihood based methods estimates the same radiation rate ratio parameters, within the context of the appropriate model for location and subject level covariate effects. The underlying assumptions are characterized and the potential strengths and limitations of each method are described. The methods are illustrated and compared using the WECARE study of radiation and asynchronous contralateral breast cancer.     

Semiparametric regression for periodic longitudinal hormone data from multiple menstrual cycles

We consider semiparametric regression for periodic longitudinal data. Parametric fixed effects are used to model the covariate effects and a periodic nonparametric smooth function is used to model the time effect. The within-subject correlation is modeled using subject-specific random effects and a random stochastic process with a periodic variance function. We use maximum penalized likelihood to estimate the regression coefficients and the periodic nonparametric time function, whose estimator is shown to be a periodic cubic smoothing spline. We use restricted maximum likelihood to simultaneously estimate the smoothing parameter and the variance components. We show that all model parameters can be easily obtained by fitting a linear mixed model. A common problem in the analysis of longitudinal data is to compare the time profiles of two groups, e.g., between treatment and placebo. We develop a scaled chi-squared test for the equality of two nonparametric time functions. The proposed model and the test are illustrated by analyzing hormone data collected during two consecutive menstrual cycles and their performance is evaluated through simulations.     

Functional Generalized Linear Models with Images as Predictors

Summary .  Functional principal component regression (FPCR) is a promising new method for regressing scalar outcomes on functional predictors. In this article, we present a theoretical justification for the use of principal components in functional regression. FPCR is then extended in two directions: from linear to the generalized linear modeling, and from univariate signal predictors to high-resolution image predictors. We show how to implement the method efficiently by adapting generalized additive model technology to the functional regression context. A technique is proposed for estimating simultaneous confidence bands for the coefficient function; in the neuroimaging setting, this yields a novel means to identify brain regions that are associated with a clinical outcome. A new application of likelihood ratio testing is described for assessing the null hypothesis of a constant coefficient function. The performance of the methodology is illustrated via simulations and real data analyses with positron emission tomography images as predictors.     

Latent variable models for longitudinal data with multiple continuous outcomes

Multiple outcomes are often used to properly characterize an effect of interest. This paper proposes a latent variable model for the situation where repeated measures over time are obtained on each outcome. These outcomes are assumed to measure an underlying quantity of main interest from different perspectives. We relate the observed outcomes using regression models to a latent variable, which is then modeled as a function of covariates by a separate regression model. Random effects are used to model the correlation due to repeated measures of the observed outcomes and the latent variable. An EM algorithm is developed to obtain maximum likelihood estimates of model parameters. Unit-specific predictions of the latent variables are also calculated. This method is illustrated using data from a national panel study on changes in methadone treatment practices.     

多维协变量具有测量误差的结构回归模型

提出具有测量误差的结构回归模型,研究可交换条件下多维协变量的测量误差对平均处理效应估计的影响,在没有其它的附加条件下,尽管大多数模型参数不可识别,平均处理效应仍可识别,由于平均处理效应的极大似然估计求解困难,建议在实际中使用拟极大似然估计作为替代。