Exact maximum likelihood for incomplete data from a correlated gaussian process

In many situations in which a variable is measured at locations in time or space the observed data can be regarded as incomplete, the missing data sites perhaps completing a regular pattern such as a rectangular grid. In this paper general methods not dependent on the sequential nature of time are considered for estimating the parameters of Gaussian processes. An example is given.     

Multivariate Linear Regression Model with Elliptically Contoured Distributed Errors and Monotone Missing Dependent Variables

In this article, the multivariate linear regression model is studied under the assumptions that the error term of this model is described by the elliptically contoured distribution and the observations on the response variables are of a monotone missing pattern. It is primarily concerned with estimation of the model parameters, as well as with the development of the likelihood ratio test in order to examine the existence of linear constraints on the regression coefficients. An illustrative example is presented for the explanation of the results.     

The impact of missing data on the results of a schizophrenia study

Missing data pose a serious challenge to the integrity of randomized clinical trials, especially of treatments for prolonged illnesses such as schizophrenia, in which long‐term impact assessment is of great importance, but the follow‐up rates are often no more than 50%. Sensitivity analysis using Bayesian modeling for missing data offers a systematic approach to assessing the sensitivity of the inferences made on the basis of observed data. This paper uses data from an 18‐month study of veterans with schizophrenia to demonstrate this approach. Data were obtained from a randomized clinical trial involving 369 patients diagnosed with schizophrenia that compared long‐acting injectable risperidone with a psychiatrist's choice of oral treatment. Bayesian analysis utilizing a pattern‐mixture modeling approach was used to validate the reported results by detecting bias due to non‐random patterns of missing data. The analysis was applied to several outcomes including standard measures of schizophrenia symptoms, quality of life, alcohol use, and global mental status. The original study results for several measures were confirmed against a wide range of patterns of non‐random missingness. Robustness of the conclusions was assessed using sensitivity parameters. The missing data in the trial did not likely threaten the validity of previously reported results. Copyright © 2014 John Wiley & Sons, Ltd.     

Regression Analysis of Length‐biased and Right‐censored Failure Time Data with Missing Covariates

Length‐biased and right‐censored failure time data arise from many fields, and their analysis has recently attracted a great deal of attention. Two examples of the areas that often produce such data are epidemiological studies and cancer screening trials. In this paper, we discuss regression analysis of such data in the presence of missing covariates, for which no established inference procedure seems to exist. For the problem, we consider the data arising from the proportional hazards model and propose two inverse probability weighted estimation procedures. The asymptotic properties of the resulting estimators are established, and the extensive simulation study conducted for the evaluation of the proposed methods suggests that they work well for practical situations.     

Testing the proportional odds assumption in multiply imputed ordinal longitudinal data

A popular choice when analyzing ordinal data is to consider the cumulative proportional odds model to relate the marginal probabilities of the ordinal outcome to a set of covariates. However, application of this model relies on the condition of identical cumulative odds ratios across the cut-offs of the ordinal outcome; the well-known proportional odds assumption. This paper focuses on the assessment of this assumption while accounting for repeated and missing data. In this respect, we develop a statistical method built on multiple imputation (MI) based on generalized estimating equations that allows to test the proportionality assumption under the missing at random setting. The performance of the proposed method is evaluated for two MI algorithms for incomplete longitudinal ordinal data. The impact of both MI methods is compared with respect to the type I error rate and the power for situations covering various numbers of categories of the ordinal outcome, sample sizes, rates of missingness, well-balanced and skewed data. The comparison of both MI methods with the complete-case analysis is also provided. We illustrate the use of the proposed methods on a quality of life data from a cancer clinical trial.     

Choice of estimand and analysis methods in diabetes trials with rescue medication

The analysis of clinical trials aiming to show symptomatic benefits is often complicated by the ethical requirement for rescue medication when the disease state of patients worsens. In type 2 diabetes trials, patients receive glucose‐lowering rescue medications continuously for the remaining trial duration, if one of several markers of glycemic control exceeds pre‐specified thresholds. This may mask differences in glycemic values between treatment groups, because it will occur more frequently in less effective treatment groups. Traditionally, the last pre‐rescue medication value was carried forward and analyzed as the end‐of‐trial value. The deficits of such simplistic single imputation approaches are increasingly recognized by regulatory authorities and trialists. We discuss alternative approaches and evaluate them through a simulation study. When the estimand of interest is the effect attributable to the treatments initially assigned at randomization, then our recommendation for estimation and hypothesis testing is to treat data after meeting rescue criteria as deterministically ‘missing’ at random, because initiation of rescue medication is determined by observed in‐trial values. An appropriate imputation of values after meeting rescue criteria is then possible either directly through multiple imputation or implicitly with a repeated measures model. Crucially, one needs to jointly impute or model all markers of glycemic control that can lead to the initiation of rescue medication. An alternative for hypothesis testing only are rank tests with outcomes from patients ‘requiring rescue medication’ ranked worst, and non‐rescued patients ranked according to final visit values. However, an appropriate ranking of not observed values may be controversial. Copyright © 2015 John Wiley & Sons, Ltd.     

Clinical utility estimation for assay cutoffs in early phase oncology enrichment trials

Predictive enrichment strategies use biomarkers to selectively enroll oncology patients into clinical trials to more efficiently demonstrate therapeutic benefit. Because the enriched population differs from the patient population eligible for screening with the biomarker assay, there is potential for bias when estimating clinical utility for the screening eligible population if the selection process is ignored. We write estimators of clinical utility as integrals averaging regression model predictions over the conditional distribution of the biomarker scores defined by the assay cutoff and discuss the conditions under which consistent estimation can be achieved while accounting for some nuances that may arise as the biomarker assay progresses toward a companion diagnostic. We outline and implement a Bayesian approach in estimating these clinical utility measures and use simulations to illustrate performance and the potential biases when estimation naively ignores enrichment. Results suggest that the proposed integral representation of clinical utility in combination with Bayesian methods provide a practical strategy to facilitate cutoff decision‐making in this setting. Copyright © 2015 John Wiley & Sons, Ltd.     

Application of a predictive distribution formula to Bayesian computation for incomplete data models

We consider exact and approximate Bayesian computation in the presence of latent variables or missing data. Specifically we explore the application of a posterior predictive distribution formula derived in Sweeting And Kharroubi (2003), which is a particular form of Laplace approximation, both as an importance function and a proposal distribution. We show that this formula provides a stable importance function for use within poor man’s data augmentation schemes and that it can also be used as a proposal distribution within a Metropolis-Hastings algorithm for models that are not analytically tractable. We illustrate both uses in the case of a censored regression model and a normal hierarchical model, with both normal and Student t distributed random effects. Although the predictive distribution formula is motivated by regular asymptotic theory, it is not necessary that the likelihood has a closed form or that it possesses a local maximum.     

Impact of selection bias on the evaluation of clusters of chemical compounds in the drug discovery process

Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess the potential of each cluster, and with appropriate statistical methods, these qualitative assessments can be quantified into a success probability for each of them. However, one crucial element often overlooked is the procedure by which the clusters are assigned to/selected by the experts for evaluation. In the present work, the impact such a procedure may have on the statistical analysis and the entire evaluation process is studied. It has been shown that some implementations of the selection procedure may seriously compromise the validity of the evaluation even when the rating and selection processes are independent. Consequently, the fully random allocation of the clusters to the experts is strongly advocated. Copyright © 2014 John Wiley & Sons, Ltd.