Extreme value modelling of laboratory safety data from clinical studies

Most clinical studies collect several safety‐related laboratory variables. Generally, it is the extreme values of these variables that indicate potential safety issues. We illustrate the novel application of extreme value modelling to such data, with the aim of predicting the incidence of severe adverse drug reactions. By applying the methods to a clinical trial data set, we identify a dose–response relationship and use Bayesian techniques to identify a potential safety concern by making predictions from the fitted model, despite the small sample size. Copyright © 2012 John Wiley & Sons, Ltd.     

Polytomous logistic model for matched pairs case-control design:studies with covariates

Pair-wise matched case-control design is commonly used in epidemiological analysis for estimating odds ratios. In the most simplest situation, each subject is classified according to a binary outcome and the factor of interest being a two-level factor. Binary logistic models have beenfound to be very useful for studying such relationship. In our earlier studies we have shown that polytomous logistic model can be used for estimating odds ratios when the exposure of prime interest assumes multiple levels. In this paper, using the above model, we estimate the odds ratios for the possible levels of risk factor of interest adjusting for covariates which were notincluded in the matching process. An illustrative example is presented and discussed.     

Multivariate extreme value modelling of laboratory safety data from clinical studies

Generally, in the interpretation of clinical safety laboratory data, it is extreme values that indicate potential safety issues. We illustrate the application of multivariate extreme value modelling to such data. Applying the methods to a clinical trial dataset, we find unexpected extremal relationships that have potentially important implications for the interpretation of such data. Copyright © 2012 John Wiley & Sons, Ltd.     

Semiparametric methods for evaluating the covariate-specific predictiveness of continuous markers in matched case-control studies

To assess the value of a continuous marker in predicting the risk of a disease, a graphical tool called the predictiveness curve has been proposed. It characterizes the marker's predictiveness, or capacity to risk stratify the population by displaying the distribution of risk endowed by the marker. Methods for making inference about the curve and for comparing curves in a general population have been developed. However, knowledge about a marker's performance in the general population only is not enough. Since a marker's effect on the risk model and its distribution can both differ across subpopulations, its predictiveness may vary when applied to different subpopulations. Moreover, information about the predictiveness of a marker conditional on baseline covariates is valuable for individual decision making about having the marker measured or not. Therefore, to fully realize the usefulness of a risk prediction marker, it is important to study its performance conditional on covariates. In this article, we propose semiparametric methods for estimating covariate-specific predictiveness curves for a continuous marker. Unmatched and matched case-control study designs are accommodated. We illustrate application of the methodology by evaluating serum creatinine as a predictor of risk of renal artery stenosis.     

Three centuries of categorical data analysis: Log-linear models and maximum likelihood estimation

The common view of the history of contingency tables is that it begins in 1900 with the work of Pearson and Yule, but in fact it extends back at least into the 19th century. Moreover, it remains an active area of research today. In this paper we give an overview of this history focussing on the development of log-linear models and their estimation via the method of maximum likelihood. Roy played a crucial role in this development with two papers co-authored with his students, Mitra and Marvin Kastenbaum, at roughly the mid-point temporally in this development. Then we describe a problem that eluded Roy and his students, that of the implications of sampling zeros for the existence of maximum likelihood estimates for log-linear models. Understanding the problem of non-existence is crucial to the analysis of large sparse contingency tables. We introduce some relevant results from the application of algebraic geometry to the study of this statistical problem.     

On modelling data from degradation sample paths over time

This paper is mainly concerned with modelling data from degradation sample paths over time. It uses a general growth curve model with Box‐Cox transformation, random effects and ARMA(p, q) dependence to analyse a set of such data. A maximum likelihood estimation procedure for the proposed model is derived and future values are predicted, based on the best linear unbiased prediction. The paper compares the proposed model with a nonlinear degradation model from a prediction point of view. Forecasts of failure times with various data lengths in the sample are also compared.     

Cumulative logit models for matched pairs case-control design: Studies with covariates

Binary as well as polytomous logistic models have been found useful for estimating odds ratios when the exposure of prime interest assumes unordered multiple levels under matched pair case-control design. In our earlier studies, we have shown the use of a polytomous logistic model for estimating cumulative odds ratios when the exposure of prime interest assumes multiple ordered levels under matched pair case-control design. In this paper, using the above model, we estimate the covariate adjusted cumulative odds ratios, in the case of an ordinal multiple level exposure variable under a pairwise matched case-control retrospective design. An approach, based on asymptotic distributional results, is also described to investigate whether or not the response categories are distinguishable with respect to the cumulative odds ratios after adjusting the effect of covariates. An illustrative example is presented and discussed.     

Using quantile averages in matched observational studies

In two observational studies, one investigating the effects of minimum wage laws on employment and the other of the effects of exposures to lead, an estimated treatment effect's sensitivity to hidden bias is examined. The estimate uses the combined quantile averages that were introduced in 1981 by B. M. Brown as simple, efficient, robust estimates of location admitting both exact and approximate confidence intervals and significance tests. Closely related to Gastwirth's estimate and Tukey's trimean, the combined quantile average has asymptotic efficiency for normal data that is comparable with that of a 15% trimmed mean, and higher efficiency than the trimean, but it has resistance to extreme observations or breakdown comparable with that of the trimean and better than the 15% trimmed mean. Combined quantile averages provide consistent estimates of an additive treatment effect in a matched randomized experiment. Sensitivity analyses are discussed for combined quantile averages when used in a matched observational study in which treatments are not randomly assigned. In a sensitivity analysis in an observational study, subjects are assumed to differ with respect to an unobserved covariate that was not adequately controlled by the matching, so that treatments are assigned within pairs with probabilities that are unequal and unknown. The sensitivity analysis proposed here uses significance levels, point estimates and confidence intervals based on combined quantile averages and examines how these inferences change under a range of assumptions about biases due to an unobserved covariate. The procedures are applied in the studies of minimum wage laws and exposures to lead. The first example is also used to illustrate sensitivity analysis with an instrumental variable.     

ARIMA modelling of birth data

In this article the fitting of ARIMA models to time series relating to the births at Edendale Hospital in Natal, South Africa, over a 16-year period is discussed. The model (011)X(011)12 provides andexcellent fit to the monthly totals of mothers delivered but serious discrepancies between estimates of the moving average parameters obtained by the method of unconditional least squares using various statistical computer packages were observed. These can be ascribed to the fact that certain of the packages use the method of backcasting to calculate the unconditional sum-of-squares function in the estimation procedure and this approach breaks down for values of the moving average parameters close to the invertibility boundary. A simulation study to compare the different methods of estimation for the model (011) X (011)12 and to assess the seriousness of discrepancies in the ULS estimates is described. ARIMA models which provided the best fit to the series of monthly totals of caesarean sections performed, breechs births and instrumental deliveries are non-seasonal and reflect a dependence of present on past observations. In contrast the series involving stillbirths and neonatal deaths are white noise indicating that perinatal deaths are random events.     

Joint modelling of longitudinal binary data and survival data

The medical costs in an ageing society substantially increase when the incidences of chronic diseases, disabilities and inability to live independently are high. Healthy lifestyles not only affect elderly individuals but also influence the entire community. When assessing treatment efficacy, survival and quality of life should be considered simultaneously. This paper proposes the joint likelihood approach for modelling survival and longitudinal binary covariates simultaneously. Because some unobservable information is present in the model, the Monte Carlo EM algorithm and Metropolis-Hastings algorithm are used to find the estimators. Monte Carlo simulations are performed to evaluate the performance of the proposed model based on the accuracy and precision of the estimates. Real data are used to demonstrate the feasibility of the proposed model.     

Multilevel modelling of complex survey data

Summary.  Multilevel modelling is sometimes used for data from complex surveys involving multistage sampling, unequal sampling probabilities and stratification. We consider generalized linear mixed models and particularly the case of dichotomous responses. A pseudolikelihood approach for accommodating inverse probability weights in multilevel models with an arbitrary number of levels is implemented by using adaptive quadrature. A sandwich estimator is used to obtain standard errors that account for stratification and clustering. When level 1 weights are used that vary between elementary units in clusters, the scaling of the weights becomes important. We point out that not only variance components but also regression coefficients can be severely biased when the response is dichotomous. The pseudolikelihood methodology is applied to complex survey data on reading proficiency from the American sample of the 'Program for international student assessment' 2000 study, using the Stata program gllamm which can estimate a wide range of multilevel and latent variable models. Performance of pseudo-maximum-likelihood with different methods for handling level 1 weights is investigated in a Monte Carlo experiment. Pseudo-maximum-likelihood estimators of (conditional) regression coefficients perform well for large cluster sizes but are biased for small cluster sizes. In contrast, estimators of marginal effects perform well in both situations. We conclude that caution must be exercised in pseudo-maximum-likelihood estimation for small cluster sizes when level 1 weights are used.     

Bayesian modelling of spatial compositional data

Compositional data are vectors of proportions, specifying fractions of a whole. Aitchison (1986) defines logistic normal distributions for compositional data by applying a logistic transformation and assuming the transformed data to be multi- normal distributed. In this paper we generalize this idea to spatially varying logistic data and thereby define logistic Gaussian fields. We consider the model in a Bayesian framework and discuss appropriate prior distributions. We consider both complete observations and observations of subcompositions or individual proportions, and discuss the resulting posterior distributions. In general, the posterior cannot be analytically handled, but the Gaussian base of the model allows us to define efficient Markov chain Monte Carlo algorithms. We use the model to analyse a data set of sediments in an Arctic lake. These data have previously been considered, but then without taking the spatial aspect into account.     

New approaches for censored longitudinal data in joint modelling of longitudinal and survival data,with application to HIV vaccine studies

In HIV vaccine studies, longitudinal immune response biomarker data are often left-censored due to lower limits of quantification of the employed immunological assays. The censoring information is important for predicting HIV infection, the failure event of interest. We propose two approaches to addressing left censoring in longitudinal data: one that makes no distributional assumptions for the censored data—treating left censored values as a “point mass” subgroup—and the other makes a distributional assumption for a subset of the censored data but not for the remaining subset. We develop these two approaches to handling censoring for joint modelling of longitudinal and survival data via a Cox proportional hazards model fit by h-likelihood. We evaluate the new methods via simulation and analyze an HIV vaccine trial data set, finding that longitudinal characteristics of the immune response biomarkers are highly associated with the risk of HIV infection.

     

Analyzing propensity matched zero-inflated count outcomes in observational studies

Determining the effectiveness of different treatments from observational data, which are characterized by imbalance between groups due to lack of randomization, is challenging. Propensity matching is often used to rectify imbalances among prognostic variables. However, there are no guidelines on how appropriately to analyze group matched data when the outcome is a zero-inflated count. In addition, there is debate over whether to account for correlation of responses induced by matching and/or whether to adjust for variables used in generating the propensity score in the final analysis. The aim of this research is to compare covariate unadjusted and adjusted zero-inflated Poisson models that do and do not account for the correlation. A simulation study is conducted, demonstrating that it is necessary to adjust for potential residual confounding, but that accounting for correlation is less important. The methods are applied to a biomedical research data set.     

An estimated‐score approach for dealing with missing covariate data in matched case–control studies

Matched case–control designs are commonly used in epidemiological studies for estimating the effect of exposure variables on the risk of a disease by controlling the effect of confounding variables. Due to retrospective nature of the study, information on a covariate could be missing for some subjects. A straightforward application of the conditional logistic likelihood for analyzing matched case–control data with the partially missing covariate may yield inefficient estimators of the parameters. A robust method has been proposed to handle this problem using an estimated conditional score approach when the missingness mechanism does not depend on the disease status. Within the conditional logistic likelihood framework, an empirical procedure is used to estimate the odds of the disease for the subjects with missing covariate values. The asymptotic distribution and the asymptotic variance of the estimator when the matching variables and the completely observed covariates are categorical. The finite sample performance of the proposed estimator is assessed through a simulation study. Finally, the proposed method has been applied to analyze two matched case–control studies. The Canadian Journal of Statistics 38: 680–697; 2010 © 2010 Statistical Society of Canada     

Exact tests for matched pairs:studies with covariates

In prospective or retrospective studies with matched pairs one often wishes to control for covariates other than those used in the matching process.Large sample procedures assuming a logistic model are available for this problem.The present paper presents some exact permutation tests which are uniformly most powerful unbiased within a large class of tests.     

Models for survival data from cancer prevention studies

Summary. We propose a new parametric survival model for cancer prevention studies. The formulation of the model is in the spirit of stochastic modelling of the occurrences of tumours through two stages: initiation of an undetected tumour and promotion of the tumour to a detectable cancer. Several novel properties of the model proposed are derived. In addition, we examine the relationship of our model with the existing lagged regression model of Zucker and Lakatos. Also, we bridge the difference between two distinct stochastic modelling methods for cancer data, one used primarily for cancer therapeutic trials and the other used for cancer prevention trials.