Efficient Estimation for Semiparametric Structural Equation Models With Censored Data

<p>Structural equation modeling is commonly used to capture complex structures of relationships among multiple variables, both latent and observed. We propose a general class of structural equation models with a semiparametric component for potentially censored survival times. We consider nonparametric maximum likelihood estimation and devise a combined expectation-maximization and Newton-Raphson algorithm for its implementation. We establish conditions for model identifiability and prove the consistency, asymptotic normality, and semiparametric efficiency of the estimators. Finally, we demonstrate the satisfactory performance of the proposed methods through simulation studies and provide an application to a motivating cancer study that contains a variety of genomic variables. Supplementary materials for this article are available online.</p

Semiparametric Regression Analysis of Multiple Right- and Interval-Censored Events

<p>Health sciences research often involves both right- and interval-censored events because the occurrence of a symptomatic disease can only be observed up to the end of follow-up, while the occurrence of an asymptomatic disease can only be detected through periodic examinations. We formulate the effects of potentially time-dependent covariates on the joint distribution of multiple right- and interval-censored events through semiparametric proportional hazards models with random effects that capture the dependence both within and between the two types of events. We consider nonparametric maximum likelihood estimation and develop a simple and stable EM algorithm for computation. We show that the resulting estimators are consistent and the parametric components are asymptotically normal and efficient with a covariance matrix that can be consistently estimated by profile likelihood or nonparametric bootstrap. In addition, we leverage the joint modelling to provide dynamic prediction of disease incidence based on the evolving event history. Furthermore, we assess the performance of the proposed methods through extensive simulation studies. Finally, we provide an application to a major epidemiological cohort study. Supplementary materials for this article are available online.</p

Loss-of-function mutations in APOC3, triglycerides, and coronary disease

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)