Identification of Multivariate Responders/Non-Responders Using Bayesian Growth Curve Latent Class Models

In this paper, we propose a multivariate growth curve mixture model that groups subjects based on multiple symptoms measured repeatedly over time. Our model synthesizes features of two models. First, we follow Roy and Lin (2000) in relating the multiple symptoms at each time point to a single latent variable. Second, we use the growth mixture model of Muthén and Shedden (1999) to group subjects based on distinctive longitudinal profiles of this latent variable. The mean growth curve for the latent variable in each class defines that class's features. For example, a class of "responders" would have a decline in the latent symptom summary variable over time. A Bayesian approach to estimation is employed where the methods of Elliott et al (2005) are extended to simultaneously estimate the posterior distributions of the parameters from the latent variable and growth curve mixture portions of the model. We apply our model to data from a randomized clinical trial evaluating the efficacy of Bacillus Calmette-Guerin (BCG) in treating symptoms of Interstitial Cystitis. In contrast to conventional approaches using a single subjective Global Response Assessment, we use the multivariate symptom data to identify a class of subjects where treatment demonstrates effectiveness. Simulations are used to confirm identifiability results and evaluate the performance of our algorithm. The definitive version of this paper is available at onlinelibrary.wiley.com.     

A comparison of non-homogeneous Markov regression models with application to Alzheimer's disease progression

Markov regression models are useful tools for estimating the impact of risk factors on rates of transition between multiple disease states. Alzheimer's disease (AD) is an example of a multi-state disease process in which great interest lies in identifying risk factors for transition. In this context, non-homogeneous models are required because transition rates change as subjects age. In this report we propose a non-homogeneous Markov regression model that allows for reversible and recurrent disease states, transitions among multiple states between observations, and unequally spaced observation times. We conducted simulation studies to demonstrate performance of estimators for covariate effects from this model and compare performance with alternative models when the underlying non-homogeneous process was correctly specified and under model misspecification. In simulation studies, we found that covariate effects were biased if non-homogeneity of the disease process was not accounted for. However, estimates from non-homogeneous models were robust to misspecification of the form of the non-homogeneity. We used our model to estimate risk factors for transition to mild cognitive impairment (MCI) and AD in a longitudinal study of subjects included in the National Alzheimer's Coordinating Center's Uniform Data Set. Using our model, we found that subjects with MCI affecting multiple cognitive domains were significantly less likely to revert to normal cognition.     

Modeling Longitudinal Obesity Data with Intermittent Missingness Using a New Latent Variable Model

We propose a latent variable model for informative missingness in longitudinal studies which is an extension of latent dropout class model. In our model, the value of the latent variable is affected by the missingness pattern and it is also used as a covariate in modeling the longitudinal response. So the latent variable links the longitudinal response and the missingness process. In our model, the latent variable is continuous instead of categorical and we assume that it is from a normal distribution. The EM algorithm is used to obtain the estimates of the parameter we are interested in and Gauss–Hermite quadrature is used to approximate the integration of the latent variable. The standard errors of the parameter estimates can be obtained from the bootstrap method or from the inverse of the Fisher information matrix of the final marginal likelihood. Comparisons are made to the mixed model and complete-case analysis in terms of a clinical trial dataset, which is Weight Gain Prevention among Women (WGPW) study. We use the generalized Pearson residuals to assess the fit of the proposed latent variable model.     

Random change point models: investigating cognitive decline in the presence of missing data

With the aim of identifying the age of onset of change in the rate of cognitive decline while accounting for the missing observations, we considered a selection modelling framework. A random change point model was fitted to data from a population-based longitudinal study of ageing (the Cambridge City over 75 Cohort Study) to model the longitudinal process. A missing at random mechanism was modelled using logistic regression. Random effects such as initial cognitive status, rate of decline before and after the change point, and the age of onset of change in rate of decline were estimated after adjustment for risk factors for cognitive decline. Among other possible predictors, the last observed cognitive score was used to adjust the probability of death and dropout. Individuals who experienced less variability in their cognitive scores experienced a change in their rate of decline at older ages than individuals whose cognitive scores varied more.     

A latent process model for dementia and psychometric tests

We jointly model longitudinal values of a psychometric test and diagnosis of dementia. The model is based on a continuous-time latent process representing cognitive ability. The link between the latent process and the observations is modeled in two phases. Intermediate variables are noisy observations of the latent process; scores of the psychometric test and diagnosis of dementia are obtained by categorizing these intermediate variables. We propose maximum likelihood inference for this model and we propose algorithms for performing this task. We estimated the parameters of such a model using the data of the 5 year follow-up of the PAQUID study. In particular this analysis yielded interesting results about the effect of educational level on both latent cognitive ability and specific performance in the mini mental test examination. The predictive ability of the model is illustrated by predicting diagnosis of dementia at the 8 year follow-up of the PAQUID study based on the information from the first 5 years.     

Investigating impacts of complex sampling on latent growth curve modelling

We investigate the impacts of complex sampling on point and standard error estimates in latent growth curve modelling of survey data. Methodological issues are illustrated with empirical evidence from the analysis of longitudinal data on life satisfaction trajectories using data from the British Household Panel Survey, a national representative survey in Great Britain. A multi-process second-order latent growth curve model with conditional linear growth is used to study variation in the two perceived life satisfaction latent factors considered. The benefits of accounting for the complex survey design are considered, including obtaining unbiased both point and standard error estimates, and therefore correctly specified confidence intervals and statistical tests. We conclude that, even for the rather elaborated longitudinal data models that were considered, estimation procedures are affected by variance-inflating impacts of complex sampling.     

Latent class piecewise linear trajectory modelling for short-term cognition responses after chemotherapy for breast cancer patients

This paper investigates the impact of chemotherapy on cognitive function of breast cancer patients and whether this response is homogeneous for all patients. Latent class piecewise linear trajectory (growth) models were employed to describe changes and identify subgroups in three Auditory Verbal Learning Test measures (learning, immediate retention and delayed recall) in 130 breast cancer patients taken at three time periods: before chemotherapy and 1 and 6 months post-chemotherapy. Two distinct subgroups of women exhibiting different patterns of response were identified for learning and delayed recall and three for immediate retention. The groups differed in level (intercept) at 1 month post-chemotherapy and patterns of decline and recovery. Binomial and multinomial logistic regressions on the latent classes found that age, initial National Adult Reading Test (NART)-predicted IQ, stage of cancer and the initial Functional Assessment of Cancer Therapy-Breast subscale (or subsets thereof) to be significant predictors of classes.     

A Latent Process Model for Joint Modeling of Events and Marker

The paper formulates joint modeling of a counting process and a sequence of longitudinal measurements, governed by a common latent stochastic process. The latent process is modeled as a function of explanatory variables and a Brownian motion process. The conditional likelihood given values of the latent process at the measurement times, has been drawn using Brownian bridge properties; then integrating over all possible values of the latent process at the measurement times leads to the desired joint likelihood. An estimation procedure using joint likelihood and a numerical optimization is described. The method is applied to the study of cognitive decline and Alzheimer's disease.     

Latent class models for longitudinal studies of the elderly with data missing at random

The elderly population in the USA is expected to double in size by the year 2025, making longitudinal health studies of this population of increasing importance. The degree of loss to follow-up in studies of the elderly, which is often because elderly people cannot remain in the study, enter a nursing home or die, make longitudinal studies of this population problematic. We propose a latent class model for analysing multiple longitudinal binary health outcomes with multiple-cause non-response when the data are missing at random and a non-likelihood-based analysis is performed. We extend the estimating equations approach of Robins and co-workers to latent class models by reweighting the multiple binary longitudinal outcomes by the inverse probability of being observed. This results in consistent parameter estimates when the probability of non-response depends on observed outcomes and covariates (missing at random) assuming that the model for non-response is correctly specified. We extend the non-response model so that institutionalization, death and missingness due to failure to locate, refusal or incomplete data each have their own set of non-response probabilities. Robust variance estimates are derived which account for the use of a possibly misspecified covariance matrix, estimation of missing data weights and estimation of latent class measurement parameters. This approach is then applied to a study of lower body function among a subsample of the elderly participating in the 6-year Longitudinal Study of Aging.     

A statistical algorithm for detecting cognitive plateaus in Alzheimer’s disease

Repeated neuropsychological measurements, such as mini-mental state examination (MMSE) scores, are frequently used in Alzheimer’s disease (AD) research to study change in cognitive function of AD patients. A question of interest among dementia researchers is whether some AD patients exhibit transient “plateaus” of cognitive function in the course of the disease. We consider a statistical approach to this question, based on irregularly spaced repeated MMSE scores. We propose an algorithm that formalizes the measurement of an apparent cognitive plateau, and a procedure to evaluate the evidence of plateaus in AD using this algorithm based on applying the algorithm to the observed data and to data sets simulated from a linear mixed model. We apply these methods to repeated MMSE data from the Michigan Alzheimer’s Disease Research Center, finding a high rate of apparent plateaus and also a high rate of false discovery. Simulation studies are also conducted to assess the performance of the algorithm. In general, the false discovery rate of the algorithm is high unless the rate of decline is high compared with the measurement error of the cognitive test. It is argued that the results are not a problem of the specific algorithm chosen, but reflect a lack of information concerning the presence of plateaus in the data.     

A biomedical application of latent class models with random effects

Traditional latent class modelling has been used in many biomedical settings. Unfortunately, many of these applications assume that the diagnostic tests are independent given the true disease status, an assumption that is often violated in practice. Qu, Tan and Kutner developed general latent class models with random effects to model the conditional dependence among multiple diagnostic tests. In this paper latent class modelling with random effects is used to estimate the sensitivity and specificity of six screening tests for detecting Chlamydia trachomatis in endocervical specimens from women attending family planning clinics.     

On the performance of MixTVEM: a simulation study

Abstract

The mixture of time-varying effect model (MixTVEM) was proposed to handle both nonlinearity and heterogeneity in describing the complex patterns of change over time in the analysis of intensive longitudinal data (ILD). We conducted simulation studies to assess the performance of the MixTVEM. We found that in most cases, the MixTVEM could identify correctly the number of latent classes, as well as reveal accurately the coefficient functions. However, the estimation accuracy and feasibility of the computation could be affected by the sample size. Moreover, the MixTVEM is highly intensive computationally, compared with the original TVEM.     

Joint modeling of multivariate longitudinal mixed measurements and time to event data using a Bayesian approach

In many longitudinal studies multiple characteristics of each individual, along with time to occurrence of an event of interest, are often collected. In such data set, some of the correlated characteristics may be discrete and some of them may be continuous. In this paper, a joint model for analysing multivariate longitudinal data comprising mixed continuous and ordinal responses and a time to event variable is proposed. We model the association structure between longitudinal mixed data and time to event data using a multivariate zero-mean Gaussian process. For modeling discrete ordinal data we assume a continuous latent variable follows the logistic distribution and for continuous data a Gaussian mixed effects model is used. For the event time variable, an accelerated failure time model is considered under different distributional assumptions. For parameter estimation, a Bayesian approach using Markov Chain Monte Carlo is adopted. The performance of the proposed methods is illustrated using some simulation studies. A real data set is also analyzed, where different model structures are used. Model comparison is performed using a variety of statistical criteria.     

Testing for qualitative interaction of multiple sources of informative dropout in longitudinal data

Longitudinal studies suffer from patient dropout. The dropout process may be informative if there exists an association between dropout patterns and the rate of change in the response over time. Multiple patterns are plausible in that different causes of dropout might contribute to different patterns. These multiple patterns can be dichotomized into two groups: quantitative and qualitative interaction. Quantitative interaction indicates that each of the multiple sources is biasing the estimate of the rate of change in the same direction, although with differing magnitudes. Alternatively, qualitative interaction results in the multiple sources biasing the estimate of the rate of change in opposing directions. Qualitative interaction is of special concern, since it is less likely to be detected by conventional methods and can lead to highly misleading slope estimates. We explore a test for qualitative interaction based on simultaneous confidence intervals. The test accommodates the realistic situation where reasons for dropout are not fully understood, or even entirely unknown. It allows for an additional level of clustering among participating subjects. We apply these methods to a study exploring tumor growth rates in mice as well as a longitudinal study exploring rates of change in cognitive functioning for Alzheimer's patients.     

Measures of discrimination for latent group-based trajectory models

In clinical research, patient care decisions are often easier to make if patients are classified into a manageable number of groups based on homogeneous risk patterns. Investigators can use latent group-based trajectory modeling to estimate the posterior probabilities that an individual will be classified into a particular group of risk patterns. Although this method is increasingly used in clinical research, there is currently no measure that can be used to determine whether an individual's group assignment has a high level of discrimination. In this study, we propose a discrimination index and provide confidence intervals of the probability of the assigned group for each individual. We also propose a modified form of entropy to measure discrimination. The two proposed measures were applied to assess the group assignments of the longitudinal patterns of conduct disorders among young adolescent girls.     

A likelihood-based approach for multivariate one-sided tests with missing data

Inequality-restricted hypotheses testing methods containing multivariate one-sided testing methods are useful in practice, especially in multiple comparison problems. In practice, multivariate and longitudinal data often contain missing values since it may be difficult to observe all values for each variable. However, although missing values are common for multivariate data, statistical methods for multivariate one-sided tests with missing values are quite limited. In this article, motivated by a dataset in a recent collaborative project, we develop two likelihood-based methods for multivariate one-sided tests with missing values, where the missing data patterns can be arbitrary and the missing data mechanisms may be non-ignorable. Although non-ignorable missing data are not testable based on observed data, statistical methods addressing this issue can be used for sensitivity analysis and might lead to more reliable results, since ignoring informative missingness may lead to biased analysis. We analyse the real dataset in details under various possible missing data mechanisms and report interesting findings which are previously unavailable. We also derive some asymptotic results and evaluate our new tests using simulations.     

Modeling population and subject-specific growth in a latent trait measured by multiple instruments over time using a hierarchical Bayesian framework

Psychometric growth curve modeling techniques are used to describe a person’s latent ability and how that ability changes over time based on a specific measurement instrument. However, the same instrument cannot always be used over a period of time to measure that latent ability. This is often the case when measuring traits longitudinally in children. Reasons may be that over time some measurement tools that were difficult for young children become too easy as they age resulting in floor effects or ceiling effects or both. We propose a Bayesian hierarchical model for such a scenario. Within the Bayesian model we combine information from multiple instruments used at different age ranges and having different scoring schemes to examine growth in latent ability over time. The model includes between-subject variance and within-subject variance and does not require linking item specific difficulty between the measurement tools. The model’s utility is demonstrated on a study of language ability in children from ages one to ten who are hard of hearing where measurement tool specific growth and subject-specific growth are shown in addition to a group level latent growth curve comparing the hard of hearing children to children with normal hearing.KEYWORDS: Bayesian hierarchical models, psychometric modeling, language ability, growth curve modeling, longitudinal analysis     

A Two-Latent-Class Model for Smoking Cessation Data with Informative Dropouts

Non ignorable missing data is a common problem in longitudinal studies. Latent class models are attractive for simplifying the modeling of missing data when the data are subject to either a monotone or intermittent missing data pattern. In our study, we propose a new two-latent-class model for categorical data with informative dropouts, dividing the observed data into two latent classes; one class in which the outcomes are deterministic and a second one in which the outcomes can be modeled using logistic regression. In the model, the latent classes connect the longitudinal responses and the missingness process under the assumption of conditional independence. Parameters are estimated by the method of maximum likelihood estimation based on the above assumptions and the tetrachoric correlation between responses within the same subject. We compare the proposed method with the shared parameter model and the weighted GEE model using the areas under the ROC curves in the simulations and the application to the smoking cessation data set. The simulation results indicate that the proposed two-latent-class model performs well under different missing procedures. The application results show that our proposed method is better than the shared parameter model and the weighted GEE model.     

Evaluation of long-term health care services through a latent Markov model with covariates

We focus on the evaluation of the long-term health care services provided to elderly patients by nursing homes of four different health districts in the Umbria region (Italy). To this end, we analyze data coming from a longitudinal survey aimed at assessing several aspects of patient health conditions and develop an extended version of the latent Markov model with covariates, which allows us to deal with dropout and intermittent missing data patterns that are common in longitudinal studies. Maximum likelihood estimates are obtained by a two-step approach that allows for fast estimation of model parameters and prevents some drawbacks of the standard maximum likelihood method encountered in the presence of many response variables and covariates. In the application to the observed data, we show how to obtain indicators of the effectiveness of the health care services delivered by each health district, by means of a resampling procedure.     

A Bayesian latent spatial model for mapping the cortical signature of progression to Alzheimer's disease

Prior studies have shown that atrophy in vulnerable cortical regions is associated with an increased risk of progression to clinical dementia. In this work, we utilize the longitudinal structural magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to investigate the relationship between the temporally changing spatial topography of cortical thickness and conversion from mild cognitive impairment to Alzheimer's disease (AD). We develop a novel Bayesian latent spatial model that employs the spatial information underlying the thickness effects across the cortical surface. The proposed method facilitates the development of imaging markers by reliably quantifying and mapping the regional vulnerability to AD progression across the cortical surface. Simulation results showed substantial gains in statistical power and estimation performance by accounting for the spatial structure of the association. Using MRI data from ADNI, we examined the topographic patterns of anatomic regions where cortical thinning is associated with an increased risk of developing AD.