Estimating effects of rare haplotypes on failure time using a penalized Cox proportional hazards regression model
Estimating effects of rare haplotypes on failure time using a penalized Cox proportional hazards regression model
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DOI：
10.1186/1471-2156-9-9
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发表时间：
2008-01-25
期刊：
影响因子：
2.9
通讯作者：
Tanck, Michael W. T.
中科院分区：
文献类型：
--
作者：
Souverein, Olga W.;Zwinderman, Aeilko H.;Tanck, Michael W. T.
背景：本文描述了一种似然方法，用于在单倍型阶段未知的无关个体的研究中对失败时间与单倍型之间的关系进行建模，同时通过考虑惩罚对数似然来处理由于罕见单倍型而导致的估计不稳定的问题。结果：此处提出的 Cox 模型将与多个杂合个体的未知阶段相关的不确定性纳入作为权重。使用 EM 算法进行估计。在E步中估计权重，在M步中通过最大化联合对数似然的期望来估计参数估计，并计算基线危险函数和单倍型频率。迭代这些步骤直到参数估计收敛。考虑了两种惩罚函数，即岭惩罚和差异惩罚，这是基于相似单倍型表现出相似效果的假设。通过模拟来研究该方法的特性，并在 GENDER 研究的 2653 名患者中调查了 IL10 单倍型与目标血管血运重建风险之间的关联。结论：模拟和实际数据的结果表明，惩罚对数似然方法产生了有效的结果，表明该方法在研究时值得关注稀有单倍型与无关个体研究中的失败时间之间的关联。
Background: This paper describes a likelihood approach to model the relation between failure time and haplotypes in studies with unrelated individuals where haplotype phase is unknown, while dealing with the problem of unstable estimates due to rare haplotypes by considering a penalized log-likelihood.Results: The Cox model presented here incorporates the uncertainty related to the unknown phase of multiple heterozygous individuals as weights. Estimation is performed with an EM algorithm. In the E-step the weights are estimated, and in the M-step the parameter estimates are estimated by maximizing the expectation of the joint log-likelihood, and the baseline hazard function and haplotype frequencies are calculated. These steps are iterated until the parameter estimates converge. Two penalty functions are considered, namely the ridge penalty and a difference penalty, which is based on the assumption that similar haplotypes show similar effects.Simulations were conducted to investigate properties of the method, and the association between IL10 haplotypes and risk of target vessel revascularization was investigated in 2653 patients from the GENDER study.Conclusion: Results from simulations and real data show that the penalized log-likelihood approach produces valid results, indicating that this method is of interest when studying the association between rare haplotypes and failure time in studies of unrelated individuals.