Dataset Information

Negative Binomial mixed models estimated with the maximum likelihood method can be used for longitudinal RNAseq data.

ABSTRACT: Time-course RNAseq experiments, where tissues are repeatedly collected from the same subjects, e.g. humans or animals over time or under several different experimental conditions, are becoming more popular due to the reducing sequencing costs. Such designs offer the great potential to identify genes that change over time or progress differently in time across experimental groups. Modelling of the longitudinal gene expression in such time-course RNAseq data is complicated by the serial correlations, missing values due to subject dropout or sequencing errors, long follow up with potentially non-linear progression in time and low number of subjects. Negative Binomial mixed models can address all these issues. However, such models under the maximum likelihood (ML) approach are less popular for RNAseq data due to convergence issues (see, e.g. [1]). We argue in this paper that it is the use of an inaccurate numerical integration method in combination with the typically small sample sizes which causes such mixed models to fail for a great portion of tested genes. We show that when we use the accurate adaptive Gaussian quadrature approach to approximate the integrals over the random-effects terms, we can successfully estimate the model parameters with the maximum likelihood method. Moreover, we show that the boostrap method can be used to preserve the type I error rate in small sample settings. We evaluate empirically the small sample properties of the test statistics and compare with state-of-the-art approaches. The method is applied on a longitudinal mice experiment to study the dynamics in Duchenne Muscular Dystrophy. Contact:s.tsonaka@lumc.nl Roula Tsonaka is an assistant professor at the Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center. Her research focuses on statistical methods for longitudinal omics data. Pietro Spitali is an assistant professor at the Department of Human Genetics, Leiden University Medical Center. His research focuses on the identification of biomarkers for neuromuscular disorders.

SUBMITTER: Tsonaka R

PROVIDER: S-EPMC8293834 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Longitudinal targeted maximum likelihood estimation (LTMLE) has very rarely been used to estimate dynamic treatment effects in the context of time-dependent confounding affected by prior treatment when faced with long follow-up times, multiple time-varying confounders, and complex associational relationships simultaneously. Reasons for this include the potential computational burden, technical challenges, restricted modeling options for long follow-up times, and limited practical guidance in the literature. However, LTMLE has desirable asymptotic properties, ie, it is doubly robust, and can yield valid inference when used in conjunction with machine learning. It also has the advantage of easy-to-calculate analytic standard errors in contrast to the g-formula, which requires bootstrapping. We use a topical and sophisticated question from HIV treatment research to show that LTMLE can be used successfully in complex realistic settings, and we compare results to competing estimators. Our example illustrates the following practical challenges common to many epidemiological studies: (1) long follow-up time (30 months); (2) gradually declining sample size; (3) limited support for some intervention rules of interest; (4) a high-dimensional set of potential adjustment variables, increasing both the need and the challenge of integrating appropriate machine learning methods; and (5) consideration of collider bias. Our analyses, as well as simulations, shed new light on the application of LTMLE in complex and realistic settings: We show that (1) LTMLE can yield stable and good estimates, even when confronted with small samples and limited modeling options; (2) machine learning utilized with a small set of simple learners (if more complex ones cannot be fitted) can outperform a single, complex model, which is tailored to incorporate prior clinical knowledge; and (3) performance can vary considerably depending on interventions and their support in the data, and therefore critical quality checks should accompany every LTMLE analysis. We provide guidance for the practical application of LTMLE.

Project description:This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins (2000, 2002) and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of inverse probability weighted (IPW) estimators using simulations. Concepts are illustrated using an example in which the aim is to estimate the causal effect of delayed switch following immunological failure of first line antiretroviral therapy among HIV-infected patients. Data from the International Epidemiological Databases to Evaluate AIDS, Southern Africa are analyzed to investigate this question using both TML and IPW estimators. Our results demonstrate practical advantages of the pooled TMLE over an IPW estimator for working marginal structural models for survival, as well as cases in which the pooled TMLE is superior to its stratified counterpart.

Dataset Information

Negative Binomial mixed models estimated with the maximum likelihood method can be used for longitudinal RNAseq data.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets