Analysis of ordinal longitudinal data under nonignorable missingness and misreporting: An application to Alzheimer’s disease study

In survival analyses that include a time-dependent covariate, the standard partial likelihood approach is often complicated by the fact that the necessary observations of the time-dependent covariate are not always available for the subjects in each risk set. In this article, we consider the situation of a binary time-dependent covariate. We specify a longitudinal model for the binary covariate with missing observations and a proportional hazards model for survival time conditional on fixed covariates and the completed time-dependent covariate history. The joint posterior distribution of the missing covariates and the parameters in the covariate and hazard models is simulated using Gibbs sampling. The joint modeling approach allows the missing covariates to be generated using all of the observed covariates as well as the disease outcome and failure time information. Simulation studies show that this approach often leads to lower bias of relative risk estimates associated with the time-dependent covariate and superior coverage of interval estimates as compared to variations of approaches based on imputing missing covariate values using previous values and then performing partial likelihood analysis. Our research is motivated by a study of survival of lung cancer patients after surgery in which current smoking status is a binary time-dependent covariate. We apply the methods to data from this study and explore the advantages of the joint modeling approach. The application demonstrates that the joint modeling approach can have improved efficiency in estimating the coefficients of both the fixed and the time-dependent covariates. Moreover, it can facilitate analyses using more complicated functions of the time-dependent covariate, such as cumulative smoking, that are difficult or inappropriate to use with the comparison methods.

The analysis of longitudinal data with non-ignorable missingness remains an active area in biostatistics research. This article discusses various random effects and latent process models which have been proposed for analyzing longitudinal binary data subject to both non-ignorable intermittent missing data and dropout. These models account for non-ignorable missingness by introducing random effects or a latent process which is shared between the response model and the model for the missing-data mechanism. We discuss various random effects and latent processes approaches and compare these approaches with analyses from an opiate clinical trial data set, which had high proportion of intermittent missingness and dropout. We also compare these random effect and latent process approaches with other methods for accounting for non-ignorable missingness using this data set.

Valid inference can be drawn from a random-effects model for repeated measures that are incomplete if whether the data are missing or not, known as missingness, is independent of the missing data. Data that are missing completely at random or missing at random are two data types for which missingness is ignorable. Given ignorable missingness, statistical inference can proceed without addressing the source of the missing data in the model. If the missingness is not ignorable, however, recommendations are to fit multiple models that represent different plausible explanations of the missing data. A popular choice in methods for evaluating nonignorable missingness is a random-effects pattern-mixture model that extends a random-effects model to include one or more between-subjects variables that represent fixed patterns of missing data. Generally straightforward to implement, a fixed pattern-mixture model is one among several options for assessing nonignorable missingness, and when it is used as the sole model to address nonignorable missingness, understanding the impact of missingness is greatly limited. This paper considers alternatives to a fixed pattern-mixture model for nonignorable missingness that are generally straightforward to fit and encourage researchers to give greater attention to the possible impact of nonignorable missingness in longitudinal data analysis. Patterns of both monotonic and non-monotonic (intermittently) missing data are addressed. Empirical longitudinal psychiatric data are used to illustrate the models. A small Monte Carlo data simulation study is presented to help illustrate the utility of such methods.Supplementary InformationThe online version contains supplementary material available at 10.3758/s13428-023-02128-y.

Missing data in longitudinal studies , Missing data in longitudinal studies , کتابخانه دیجیتال جندی شاپور اهواز

Relating time-varying biomarkers of Alzheimer's disease to time-to-event using a Cox model is complicated by the fact that Alzheimer's disease biomarkers are sparsely collected, typically only at study entry; this is problematic since Cox regression with time-varying covariates requires observation of the covariate process at all failure times. The analysis might be simplified by using study entry as the time origin and treating the time-varying covariate measured at study entry as a fixed baseline covariate. In this paper, we first derive conditions under which using an incorrect time origin of study entry results in consistent estimation of regression parameters when the time-varying covariate is continuous and fully observed. We then derive conditions under which treating the time-varying covariate as fixed at study entry results in consistent estimation. We provide methods for estimating the regression parameter when a functional form can be assumed for the time-varying biomarker, which is measured only at study entry. We demonstrate our analytical results in a simulation study and apply our methods to data from the Rush Religious Orders Study and Memory and Aging Project and data from the Alzheimer's Disease Neuroimaging Initiative.

Progression of disease within 36 months (POD36) of starting first-line targeted therapy independently predicts poor overall survival in patients with chronic lymphocytic leukemia (CLL)

BackgroundThe preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD.MethodWe access 257 CU older individuals that had available Aβ‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers.ResultWe demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aβ(CL20‐40), rather than merely Aβ positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aβ positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aβ levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy.ConclusionOur results suggest that to monitor large scale large‐scale population interventions in CU Aβ positive individuals’ plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aβ is more cost‐effective than trials using Aβ‐positive individuals in clinical.

Timing of Disease Progression and Impact on Survival in Mantle Cell Lymphoma: A Novel Illness-Death Model Study from the Swedish Mclcomplete Project

This thesis presents a comprehensive exploration of linear mixed models that incorporate measurement errors in specific covariates for longitudinal data with non-ignorable and non-monotone missing responses. The primary objective is to estimate mean response parameters and variance components utilizing a combined methodology of Regression Calibration (RC) and Monte Carlo EM. The investigation begins with an in-depth examination of the RC method applied to linear mixed models, particularly its adaptation to longitudinal data with covariates affected by measurement errors. A thorough simulation study is conducted, involving various mean response functions, revealing that the RC method produces unbiased and efficient estimators in scenarios where the true underlying model includes covariates with measurement errors. Subsequently, linear mixed models are introduced for longitudinal data with non-ignorable missing responses. The thesis proposes a semi-parametric Monte Carlo EM algorithm for the simultaneous estimation of regression parameters and variance components in linear mixed models with non-ignorable and non-monotone missing responses, combining the Monte Carlo EM algorithm of Ibrahim et al. and the RC method. The simulation study demonstrates the effectiveness of the proposed method, even in the presence of a substantial proportion of non-ignorable missing responses. The thesis concludes with an application of the proposed RC-MCEM method to actual longitudinal data from the Canadian Community Health Survey (CCHS), focusing on individuals with alcoholism and exploring how measurement errors in certain covariates can introduce biases in parameter estimation. The complexity of the problem is further elucidated when missingness occurs in the response variable.

Panel count data occur in many fields including clinical, demographical and industrial studies and an extensive literature has been established for their regression analysis. However, most of the existing methods apply only to the situations where both covariates and their effects are constant or one of them may be time-dependent. In the first part of this dissertation, we consider a situation where both covariates and their effects may be time-dependent and an estimating equation-based approach is developed for estimating those time-varying effects. In the method, B-spline functions are employed to approximate time-dependent coefficients and the asymptotic properties of the proposed estimators are established. To assess the performance of the proposed approach, an extensive simulation study is conducted and suggests that it works well in practical situations. An application to the China Health and Nutrition Survey (CHNS) study is provided. In practice, there could exist more than one type of event of interest, such as two types of tumor recurrence, leading to multivariate panel count data. The second part of this dissertation considers marginal mean model for multivariate panel count data with time-dependent coefficient and covariate effects, which has limited previous research. Based on the conditional estimating equation method developed for time-dependent covariates, we approximate the coefficients by B-splines, hence allow both coefficients and covariates to be time-dependent. Simulation studies show that the proposed estimation procedures work well for practical situations. The methodology is again applied to the China Health and Nutrition Survey (CHNS) study. When we consider time-varying covariates and coefficients effects, most of the previous study focused on the proportional mean model because the likelihood function under the rate model involves intractable integration. However, the rate model is more realistic and efficient. Hence, in the third part of this dissertation, we propose a semi-parametric MLE method under the rate model for panel count data with time-dependent covariates and time-varying effects. B-spline functions are employed again to approximate time-dependent coefficients and an efficient Expectation-Maximization-type algorithm is developed to overcome the computational difficulty. The resulting estimators are shown to be consistent and asymptotically efficient. Monte Carlo simulation studies demonstrate that the proposed method enjoys desirable finite-sample properties. An application to The Young Women's Project (YWP) is provided.

In the Lung Health Study (LHS), compliance with the use of inhaled medication was assessed at each follow-up visit both by self-report and by weighing the used medication canisters. One or both of these assessments were missing if the participant failed to attend the visit or to return all canisters. Approximately 30% of canister-weight data and 5% to 15% of self-report data were missing at different visits. We use Gibbs sampling with data augmentation and a multivariate Hastings update step to implement a Bayesian hierarchical model for LHS inhaler compliance. Incorporating individual-level random effects to account for correlations among repeated measures on the same participant, our model is a longitudinal extension of the Tobit models used in econometrics to deal with partially unobservable data. It enables (a) assessment of the relationships among visit attendance, canister return, self-reported compliance level, and canister weight compliance, and (b) determination of demographic, physiological, and behavioral predictors of compliance. In addition to addressing the estimation and prediction questions of substantive interest, we use sampling-based methods for covariate screening and model selection and investigate a range of informative priors on missing data.

This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.

SummaryWe develop a new approach to using estimating equations to estimate marginal regression models for longitudinal data with time-dependent covariates. Our approach classifies time-dependent covariates into three types—types I, II and III. The type of covariate determines what estimating equations can be used involving the covariate. We use the generalized method of moments to make optimal use of the estimating equations that are made available by the covariates. Previous literature has suggested the use of generalized estimating equations with the independent working correlation when there are time-dependent covariates. We conduct a simulation study that shows that our approach can provide substantial gains in efficiency over generalized estimating equations with the independent working correlation when a time-dependent covariate is of types I or II, and our approach remains consistent and comparable in efficiency with generalized estimating equations with the independent working correlation when a time-dependent covariate is of type III. We apply our approach to analyse the relationship between the body mass index and future morbidity among children in the Philippines.

BackgroundLongitudinal ordinal data are commonly analyzed using a marginal proportional odds model for relating ordinal outcomes to covariates in the biomedical and health sciences. The generalized estimating equation (GEE) consistently estimates the regression parameters of marginal models even if the working covariance structure is misspecified. For small-sample longitudinal binary data, recent studies have shown that the bias of regression parameters may result from the GEE and have addressed the issue by applying Firth’s adjustment for the likelihood score equation to the GEE as if generalized estimating functions were likelihood score functions. In this manuscript, for the proportional odds model for longitudinal ordinal data, the small-sample properties of the GEE were investigated, and a bias-reduced GEE (BR-GEE) was derived.MethodsBy applying the adjusted function originally derived for the likelihood score function of the proportional odds model to the GEE, we produced the BR-GEE. We investigated the small-sample properties of both GEE and BR-GEE through simulation and applied them to a clinical study dataset.ResultsIn simulation studies, the BR-GEE had a bias closer to zero, smaller root mean square error than the GEE with coverage probability of confidence interval near or above the nominal level. The simulation also showed that BR-GEE maintained a type I error rate near or below the nominal level.ConclusionsFor the analysis of longitudinal ordinal data involving a small number of subjects, the BR-GEE is advantageous for obtaining estimates of the regression parameters of marginal proportional odds models.

Improving power with repeated measures: diet and serum lipids