Leveraging Methylation Alterations to Discover Potential Causal Genes Associated With the Survival Risk of Cervical Cancer in TCGA Through a Two-Stage Inference Approach.

BACKGROUND: Multiple genes were previously identified to be associated with cervical cancer; however, the genetic architecture of cervical cancer remains unknown and many potential causal genes are yet to be discovered. METHODS: To explore potential causal genes related to cervical cancer, a two-stage causal inference approach was proposed within the framework of Mendelian randomization, where the gene expression was treated as exposure, with methylations located within the promoter regions of genes serving as instrumental variables. Five prediction models were first utilized to characterize the relationship between the expression and methylations for each gene; then, the methylation-regulated gene expression (MReX) was obtained and the association was evaluated via Cox mixed-effect model based on MReX. We further implemented the aggregated Cauchy association test (ACAT) combination to take advantage of respective strengths of these prediction models while accounting for dependency among the p-values. RESULTS: A total of 14 potential causal genes were discovered to be associated with the survival risk of cervical cancer in TCGA when the five prediction models were separately employed. The total number of potential causal genes was brought to 23 when conducting ACAT. Some of the newly discovered genes may be novel (e.g., YJEFN3, SPATA5L1, IMMP1L, C5orf55, PPIP5K2, ZNF330, CRYZL1, PPM1A, ESCO2, ZNF605, ZNF225, ZNF266, FICD, and OSTC). Functional analyses showed that these genes were enriched in tumor-associated pathways. Additionally, four genes (i.e., COL6A1, SYDE1, ESCO2, and GIPC1) were differentially expressed between tumor and normal tissues. CONCLUSION: Our study discovered promising candidate genes that were causally associated with the survival risk of cervical cancer and thus provided new insights into the genetic etiology of cervical cancer.

Measuring effects of medication adherence on time-varying health outcomes using Bayesian dynamic linear models.

One of the most significant barriers to medication treatment is patients' non-adherence to a prescribed medication regimen. The extent of the impact of poor adherence on resulting health measures is often unknown, and typical analyses ignore the time-varying nature of adherence. This article develops a modeling framework for longitudinally recorded health measures modeled as a function of time-varying medication adherence. Our framework, which relies on normal Bayesian dynamic linear models (DLMs), accounts for time-varying covariates such as adherence and non-dynamic covariates such as baseline health characteristics. Standard inferential procedures for DLMs are inefficient when faced with infrequent and irregularly recorded response data. We develop an approach that relies on factoring the posterior density into a product of two terms: a marginal posterior density for the non-dynamic parameters, and a multivariate normal posterior density of the dynamic parameters conditional on the non-dynamic ones. This factorization leads to a two-stage process for inference in which the non-dynamic parameters can be inferred separately from the time-varying parameters. We demonstrate the application of this model to the time-varying effect of antihypertensive medication on blood pressure levels for a cohort of patients diagnosed with hypertension. Our model results are compared to ones in which adherence is incorporated through non-dynamic summaries.