Dataset Information

Kernel machine testing for risk prediction with stratified case cohort studies.

ABSTRACT: Large assembled cohorts with banked biospecimens offer valuable opportunities to identify novel markers for risk prediction. When the outcome of interest is rare, an effective strategy to conserve limited biological resources while maintaining reasonable statistical power is the case cohort (CCH) sampling design, in which expensive markers are measured on a subset of cases and controls. However, the CCH design introduces significant analytical complexity due to outcome-dependent, finite-population sampling. Current methods for analyzing CCH studies focus primarily on the estimation of simple survival models with linear effects; testing and estimation procedures that can efficiently capture complex non-linear marker effects for CCH data remain elusive. In this article, we propose inverse probability weighted (IPW) variance component type tests for identifying important marker sets through a Cox proportional hazards kernel machine (CoxKM) regression framework previously considered for full cohort studies (Cai et al., 2011). The optimal choice of kernel, while vitally important to attain high power, is typically unknown for a given dataset. Thus, we also develop robust testing procedures that adaptively combine information from multiple kernels. The proposed IPW test statistics have complex null distributions that cannot easily be approximated explicitly. Furthermore, due to the correlation induced by CCH sampling, standard resampling methods such as the bootstrap fail to approximate the distribution correctly. We, therefore, propose a novel perturbation resampling scheme that can effectively recover the induced correlation structure. Results from extensive simulation studies suggest that the proposed IPW CoxKM testing procedures work well in finite samples. The proposed methods are further illustrated by application to a Danish CCH study of Apolipoprotein C-III markers on the risk of coronary heart disease.

SUBMITTER: Payne R

PROVIDER: S-EPMC4899160 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Kernel machine testing for risk prediction with stratified case cohort studies.

Payne Rebecca R Neykov Matey M Jensen Majken Karoline MK Cai Tianxi T

Biometrics 20151221 2

Large assembled cohorts with banked biospecimens offer valuable opportunities to identify novel markers for risk prediction. When the outcome of interest is rare, an effective strategy to conserve limited biological resources while maintaining reasonable statistical power is the case cohort (CCH) sampling design, in which expensive markers are measured on a subset of cases and controls. However, the CCH design introduces significant analytical complexity due to outcome-dependent, finite-populati ...[more]

PMID: 26692376

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Project description:Identification of novel biomarkers for risk prediction is important for disease prevention and optimal treatment selection. However, studies aiming to discover which biomarkers are useful for risk prediction often require the use of stored biological samples from large assembled cohorts, and thus the depletion of a finite and precious resource. To make efficient use of such stored samples, two-phase sampling designs are often adopted as resource-efficient sampling strategies, especially when the outcome of interest is rare. Existing methods for analyzing data from two-phase studies focus primarily on single marker analysis or fitting the Cox regression model to combine information from multiple markers. However, the Cox model may not fit the data well. Under model misspecification, the composite score derived from the Cox model may not perform well in predicting the outcome. Under a general two-phase stratified cohort sampling design, we present a novel approach to combining multiple markers to optimize prediction by fitting a flexible nonparametric transformation model. Using inverse probability weighting to account for the outcome-dependent sampling, we propose to estimate the model parameters by maximizing an objective function which can be interpreted as a weighted C-statistic for survival outcomes. Regardless of model adequacy, the proposed procedure yields a sensible composite risk score for prediction. A major obstacle for making inference under two phase studies is due to the correlation induced by the finite population sampling, which prevents standard inference procedures such as the bootstrap from being used for variance estimation. We propose a resampling procedure to derive valid confidence intervals for the model parameters and the C-statistic accuracy measure. We illustrate the new methods with simulation studies and an analysis of a two-phase study of high-density lipoprotein cholesterol (HDL-C) subtypes for predicting the risk of coronary heart disease.

Dataset Information

Kernel machine testing for risk prediction with stratified case cohort studies.

Publications

Kernel machine testing for risk prediction with stratified case cohort studies.

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