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Repeated measures ASCA+ for analysis of longitudinal intervention studies with multivariate outcome data

ABSTRACT: Longitudinal intervention studies with repeated measurements over time are an important type of experimental design in biomedical research. Due to the advent of “omics”-sciences (genomics, transcriptomics, proteomics, metabolomics), longitudinal studies generate increasingly multivariate outcome data. Analysis of such data must take both the longitudinal intervention structure and multivariate nature of the data into account. The ASCA+-framework combines general linear models with principal component analysis and can be used to separate and visualize the multivariate effect of different experimental factors. However, this methodology has not yet been developed for the more complex designs often found in longitudinal intervention studies, which may be unbalanced, involve randomized interventions, and have substantial missing data. Here we describe a new methodology, repeated measures ASCA+ (RM-ASCA+), and show how it can be used to model metabolic changes over time, and compare metabolic changes between groups, in both randomized and non-randomized intervention studies. Tools for both visualization and model validation are discussed. This approach can facilitate easier interpretation of data from longitudinal clinical trials with multivariate outcomes. Author summary Clinical trials are increasingly generating large amounts of complex biological data. Examples can include measuring metabolism or gene expression in tissue or blood sampled repeatedly over the course of a treatment. In such cases, one might wish to compare changes in not one, but hundreds, or thousands of variables simultaneously. In order to effectively analyze such data, both the study design and the multivariate nature of the data should be considered during data analysis. ANOVA simultaneous component analysis+ (ASCA+) is a statistical method which combines general linear models with principal component analysis, and provides a way to separate and visualize the effects of different factors on complex biological data. In this work, we describe how repeated measures linear mixed models, a class of models commonly used when analyzing changes over time and treatment effects in longitudinal studies, can be used together with ASCA+ for analyzing clinical trials in a novel method called repeated measures-ASCA+ (RM-ASCA+).

SUBMITTER: Madssen T

PROVIDER: S-EPMC8604364 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Joint modeling is appropriate when one wants to predict the time to an event with covariates that are measured longitudinally and are related to the event. An underlying random effects structure links the survival and longitudinal submodels and allows for individual-specific predictions. Multiple time-varying and time-invariant covariates can be included to potentially increase prediction accuracy. The goal of this study was to estimate a multivariate joint model on several longitudinal observational studies of Huntington's disease, examine external validity performance, and compute individual-specific predictions for characterizing disease progression. Emphasis was on the survival submodel for predicting the hazard of motor diagnosis. METHODS:Data from four observational studies was analyzed: Enroll-HD, PREDICT-HD, REGISTRY, and Track-HD. A Bayesian approach to estimation was adopted, and external validation was performed using a time-varying AUC measure. Individual-specific cumulative hazard predictions were computed based on a simulation approach. The cumulative hazard was used for computing predicted age of motor onset and also for a deviance residual indicating the discrepancy between observed diagnosis status and model-based status. RESULTS:The joint model trained in a single study had very good performance in discriminating among diagnosed and pre-diagnosed participants in the remaining test studies, with the 5-year mean AUC?=?.83 (range .77-.90), and the 10-year mean AUC?=?.86 (range .82-.92). Graphical analysis of the predicted age of motor diagnosis showed an expected strong relationship with the trinucleotide expansion that causes Huntington's disease. Graphical analysis of the deviance-type residual revealed there were individuals who converted to a diagnosis despite having relatively low model-based risk, others who had not yet converted despite having relatively high risk, and the majority falling between the two extremes. CONCLUSIONS:Joint modeling is an improvement over traditional survival modeling because it considers all the longitudinal observations of covariates that are predictive of an event. Predictions from joint models can have greater accuracy because they are tailored to account for individual variability. These predictions can provide relatively accurate characterizations of individual disease progression, which might be important in the timing of interventions, determining the qualification for appropriate clinical trials, and general genotypic analysis.

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Repeated measures ASCA+ for analysis of longitudinal intervention studies with multivariate outcome data

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