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Bayesian Hierarchical Varying-sparsity Regression Models with Application to Cancer Proteogenomics.

ABSTRACT: Identifying patient-specific prognostic biomarkers is of critical importance in developing personalized treatment for clinically and molecularly heterogeneous diseases such as cancer. In this article, we propose a novel regression framework, Bayesian hierarchical varying-sparsity regression (BEHAVIOR) models to select clinically relevant disease markers by integrating proteogenomic (proteomic+genomic) and clinical data. Our methods allow flexible modeling of protein-gene relationships as well as induces sparsity in both protein-gene and protein-survival relationships, to select ge-nomically driven prognostic protein markers at the patient-level. Simulation studies demonstrate the superior performance of BEHAVIOR against competing method in terms of both protein marker selection and survival prediction. We apply BEHAV-IOR to The Cancer Genome Atlas (TCGA) proteogenomic pan-cancer data and find several interesting prognostic proteins and pathways that are shared across multiple cancers and some that exclusively pertain to specific cancers.

SUBMITTER: Ni Y

PROVIDER: S-EPMC6552682 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Bayesian Hierarchical Varying-sparsity Regression Models with Application to Cancer Proteogenomics.

Ni Yang Y Stingo Francesco C FC Ha Min Jin MJ Akbani Rehan R Baladandayuthapani Veerabhadran V

Journal of the American Statistical Association 20180815 525

Identifying patient-specific prognostic biomarkers is of critical importance in developing personalized treatment for clinically and molecularly heterogeneous diseases such as cancer. In this article, we propose a novel regression framework, <i>Bayesian hierarchical varying-sparsity regression</i> (BEHAVIOR) models to select clinically relevant disease markers by integrating proteogenomic (proteomic+genomic) and clinical data. Our methods allow flexible modeling of protein-gene relationships as ...[more]

PMID: 31178611

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Project description:Bayesian hierarchical piecewise regression (BHPR) modeling has not been previously formulated to detect and characterise the mechanism of trajectory divergence between groups of participants that have longitudinal responses with distinct developmental phases. These models are useful when participants in a prospective cohort study are grouped according to a distal dichotomous health outcome. Indeed, a refined understanding of how deleterious risk factor profiles develop across the life-course may help inform early-life interventions. Previous techniques to determine between-group differences in risk factors at each age may result in biased estimate of the age at divergence.We demonstrate the use of Bayesian hierarchical piecewise regression (BHPR) to generate a point estimate and credible interval for the age at which trajectories diverge between groups for continuous outcome measures that exhibit non-linear within-person response profiles over time. We illustrate our approach by modeling the divergence in childhood-to-adulthood body mass index (BMI) trajectories between two groups of adults with/without type 2 diabetes mellitus (T2DM) in the Cardiovascular Risk in Young Finns Study (YFS).Using the proposed BHPR approach, we estimated the BMI profiles of participants with T2DM diverged from healthy participants at age 16 years for males (95% credible interval (CI):13.5-18 years) and 21 years for females (95% CI: 19.5-23 years). These data suggest that a critical window for weight management intervention in preventing T2DM might exist before the age when BMI growth rate is naturally expected to decrease. Simulation showed that when using pairwise comparison of least-square means from categorical mixed models, smaller sample sizes tended to conclude a later age of divergence. In contrast, the point estimate of the divergence time is not biased by sample size when using the proposed BHPR method.BHPR is a powerful analytic tool to model long-term non-linear longitudinal outcomes, enabling the identification of the age at which risk factor trajectories diverge between groups of participants. The method is suitable for the analysis of unbalanced longitudinal data, with only a limited number of repeated measures per participants and where the time-related outcome is typically marked by transitional changes or by distinct phases of change over time.

Project description:BACKGROUND:Emerging resistance to anti-malarial drugs has led malaria researchers to investigate what covariates (parasite and host factors) are associated with resistance. In this regard, investigation of how covariates impact malaria parasites clearance is often performed using a two-stage approach in which the WWARN Parasite Clearance Estimator or PCE is used to estimate parasite clearance rates and then the estimated parasite clearance is regressed on the covariates. However, the recently developed Bayesian Clearance Estimator instead leads to more accurate results for hierarchial regression modelling which motivated the authors to implement the method as an R package, called "bhrcr". METHODS:Given malaria parasite clearance profiles of a set of patients, the "bhrcr" package performs Bayesian hierarchical regression to estimate malaria parasite clearance rates along with the effect of covariates on them in the presence of "lag" and "tail" phases. In particular, the model performs a linear regression of the log clearance rates on covariates to estimate the effects within a Bayesian hierarchical framework. All posterior inferences are obtained by a "Markov Chain Monte Carlo" based sampling scheme which forms the core of the package. RESULTS:The "bhrcr" package can be utilized to study malaria parasite clearance data, and specifically, how covariates affect parasite clearance rates. In addition to estimating the clearance rates and the impact of covariates on them, the "bhrcr" package provides tools to calculate the WWARN PCE estimates of the parasite clearance rates as well. The fitted Bayesian model to the clearance profile of each individual, as well as the WWARN PCE estimates, can also be plotted by this package. CONCLUSIONS:This paper explains the Bayesian Clearance Estimator for malaria researchers including describing the freely available software, thus making these methods accessible and practical for modelling covariates' effects on parasite clearance rates.

Dataset Information

Bayesian Hierarchical Varying-sparsity Regression Models with Application to Cancer Proteogenomics.

Publications

Bayesian Hierarchical Varying-sparsity Regression Models with Application to Cancer Proteogenomics.

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