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Mixed-effects models for joint modeling of sequence data in longitudinal studies.

ABSTRACT: In this paper, we propose a novel mixed-effects model for longitudinal changes of systolic blood pressure (SBP) over time that can estimate the joint effect of multiple sequence variants on SBP after accounting for familial correlation and the time dependencies within individuals. First we carried out agenome-wide association study (GWAS) using chromosome 3 single-nucleotide polymorphisms(SNPs) to identify regions associated with SBP levels. In a second step, we examined the sequence data to fine-map additional variants in these regions. Four SNPs from two intergenic regions (PLXNA1-TPRA1, BPESC1-PISTR1) and one gene (NLGN1) were detected to be significantly associated with SBP after adjusting for multiple testing. These SNPs were used to capture the multilocus genotype diversity in the regions. The multilocus genotypes derived from these four variants were then treated as random effects in the mixed-effects model, and the corresponding confidence intervals (Cis) were built to assess the significance of the joint effect of the sequence variants on SBP. We found that multilocus genotypes (GG,TT,AG,GG), (GG,TT,GG,GG), and (GG,TT,AA,AG) are associated with higher SBPand (GG,CT,AA,AA), (AA,TT,AA,AA), and (AG,CT,AA,AG) are associated with lower SBP. The linear mixed-effects models provide a powerful tool for GWAS and the analysis of joint modeling of multilocus genotypes.

SUBMITTER: Wu YY

PROVIDER: S-EPMC4143749 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Mixed-effects models for joint modeling of sequence data in longitudinal studies.

Wu Yan Yan YY Briollais Laurent L

BMC proceedings 20140617 Suppl 1

In this paper, we propose a novel mixed-effects model for longitudinal changes of systolic blood pressure (SBP) over time that can estimate the joint effect of multiple sequence variants on SBP after accounting for familial correlation and the time dependencies within individuals. First we carried out agenome-wide association study (GWAS) using chromosome 3 single-nucleotide polymorphisms(SNPs) to identify regions associated with SBP levels. In a second step, we examined the sequence data to fin ...[more]

PMID: 25519347

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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.

Dataset Information

Mixed-effects models for joint modeling of sequence data in longitudinal studies.

Publications

Mixed-effects models for joint modeling of sequence data in longitudinal studies.

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