Dataset Information

Efficient Estimation of Nonparametric Genetic Risk Function with Censored Data.

ABSTRACT: With an increasing number of causal genes discovered for complex human disorders, it is crucial to assess the genetic risk of disease onset for individuals who are carriers of these causal mutations and compare the distribution of age-at-onset with that in non-carriers. In many genetic epidemiological studies aiming at estimating causal gene effect on disease, the age-at-onset of disease is subject to censoring. In addition, some individuals' mutation carrier or non-carrier status can be unknown due to the high cost of in-person ascertainment to collect DNA samples or death in older individuals. Instead, the probability of these individuals' mutation status can be obtained from various sources. When mutation status is missing, the available data take the form of censored mixture data. Recently, various methods have been proposed for risk estimation from such data, but none is efficient for estimating a nonparametric distribution. We propose a fully efficient sieve maximum likelihood estimation method, in which we estimate the logarithm of the hazard ratio between genetic mutation groups using B-splines, while applying nonparametric maximum likelihood estimation for the reference baseline hazard function. Our estimator can be calculated via an expectation-maximization algorithm which is much faster than existing methods. We show that our estimator is consistent and semiparametrically efficient and establish its asymptotic distribution. Simulation studies demonstrate superior performance of the proposed method, which is applied to the estimation of the distribution of the age-at-onset of Parkinson's disease for carriers of mutations in the leucine-rich repeat kinase 2 gene.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4581539 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Efficient Estimation of Nonparametric Genetic Risk Function with Censored Data.

Wang Yuanjia Y Liang Baosheng B Tong Xingwei X Marder Karen K Bressman Susan S Orr-Urtreger Avi A Giladi Nir N Zeng Donglin D

Biometrika 20150901 3

With an increasing number of causal genes discovered for complex human disorders, it is crucial to assess the genetic risk of disease onset for individuals who are carriers of these causal mutations and compare the distribution of age-at-onset with that in non-carriers. In many genetic epidemiological studies aiming at estimating causal gene effect on disease, the age-at-onset of disease is subject to censoring. In addition, some individuals' mutation carrier or non-carrier status can be unknown ...[more]

PMID: 26412864

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Project description:This work presents methods for estimating genotype-specific distributions from genetic epidemiology studies where the event times are subject to right censoring, the genotypes are not directly observed, and the data arise from a mixture of scientifically meaningful subpopulations. Examples of such studies include kin-cohort studies and quantitative trait locus (QTL) studies. Current methods for analyzing censored mixture data include two types of nonparametric maximum likelihood estimators (NPMLEs) which do not make parametric assumptions on the genotype-specific density functions. Although both NPMLEs are commonly used, we show that one is inefficient and the other inconsistent. To overcome these deficiencies, we propose three classes of consistent nonparametric estimators which do not assume parametric density models and are easy to implement. They are based on the inverse probability weighting (IPW), augmented IPW (AIPW), and nonparametric imputation (IMP). The AIPW achieves the efficiency bound without additional modeling assumptions. Extensive simulation experiments demonstrate satisfactory performance of these estimators even when the data are heavily censored. We apply these estimators to the Cooperative Huntington's Observational Research Trial (COHORT), and provide age-specific estimates of the effect of mutation in the Huntington gene on mortality using a sample of family members. The close approximation of the estimated non-carrier survival rates to that of the U.S. population indicates small ascertainment bias in the COHORT family sample. Our analyses underscore an elevated risk of death in Huntington gene mutation carriers compared to non-carriers for a wide age range, and suggest that the mutation equally affects survival rates in both genders. The estimated survival rates are useful in genetic counseling for providing guidelines on interpreting the risk of death associated with a positive genetic testing, and in facilitating future subjects at risk to make informed decisions on whether to undergo genetic mutation testings.

Dataset Information

Efficient Estimation of Nonparametric Genetic Risk Function with Censored Data.

Publications

Efficient Estimation of Nonparametric Genetic Risk Function with Censored Data.

Similar Datasets

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