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Kernel machine score test for pathway analysis in the presence of semi-competing risks.

ABSTRACT: In cancer studies, patients often experience two different types of events: a non-terminal event such as recurrence or metastasis, and a terminal event such as cancer-specific death. Identifying pathways and networks of genes associated with one or both of these events is an important step in understanding disease development and targeting new biological processes for potential intervention. These correlated outcomes are commonly dealt with by modeling progression-free survival, where the event time is the minimum between the times of recurrence and death. However, identifying pathways only associated with progression-free survival may miss out on pathways that affect time to recurrence but not death, or vice versa. We propose a combined testing procedure for a pathway's association with both the cause-specific hazard of recurrence and the marginal hazard of death. The dependency between the two outcomes is accounted for through perturbation resampling to approximate the test's null distribution, without any further assumption on the nature of the dependency. Even complex non-linear relationships between pathways and disease progression or death can be uncovered thanks to a flexible kernel machine framework. The superior statistical power of our approach is demonstrated in numerical studies and in a gene expression study of breast cancer.

SUBMITTER: Neykov M

PROVIDER: S-EPMC5446310 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Kernel machine score test for pathway analysis in the presence of semi-competing risks.

Neykov Matey M Hejblum Boris P BP Sinnott Jennifer A JA

Statistical methods in medical research 20160602 4

In cancer studies, patients often experience two different types of events: a non-terminal event such as recurrence or metastasis, and a terminal event such as cancer-specific death. Identifying pathways and networks of genes associated with one or both of these events is an important step in understanding disease development and targeting new biological processes for potential intervention. These correlated outcomes are commonly dealt with by modeling progression-free survival, where the event ...[more]

PMID: 27255336

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Project description:In the analysis of semi-competing risks data interest lies in estimation and inference with respect to a so-called non-terminal event, the observation of which is subject to a terminal event. Multi-state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non-terminal and terminal events specified, in part, by a unit-specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ2. When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi-competing risks analysis that permit the non-parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi-parametric efficient score under the complete data setting and propose a non-parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small-sample operating characteristics evaluated via simulation. Although the proposed semi-parametric transformation model and non-parametric score imputation method are motivated by the analysis of semi-competing risks data, they are broadly applicable to any analysis of multivariate time-to-event outcomes in which a unit-specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.

Dataset Information

Kernel machine score test for pathway analysis in the presence of semi-competing risks.

Publications

Kernel machine score test for pathway analysis in the presence of semi-competing risks.

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