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In cancer genomics, it is of great importance to distinguish driver mutations, which contribute to cancer progression, from causally neutral passenger mutations. We propose a random-effect regression approach to estimate the effects of mutations on the expressions of genes in tumor samples, where the estimation is assisted by a prespecified gene network. The model allows the mutation effects to vary across subjects. We develop a subject-specific mutation score to quantify the effect of a mutation on the expressions of its downstream genes, so mutations with large scores can be prioritized as drivers. We demonstrate the usefulness of the proposed methods by simulation studies and provide an application to a breast cancer genomics study., Comment: 23 pages; 9 figures

Interval-censored multi-state data arise in many studies of chronic diseases, where the health status of a subject can be characterized by a finite number of disease states and the transition between any two states is only known to occur over a broad time interval. We formulate the effects of potentially time-dependent covariates on multi-state processes through semiparametric proportional intensity models with random effects. We adopt nonparametric maximum likelihood estimation (NPMLE) under general interval censoring and develop a stable expectation-maximization (EM) algorithm. We show that the resulting parameter estimators are consistent and that the finite-dimensional components are asymptotically normal with a covariance matrix that attains the semiparametric efficiency bound and can be consistently estimated through profile likelihood. In addition, we demonstrate through extensive simulation studies that the proposed numerical and inferential procedures perform well in realistic settings. Finally, we provide an application to a major epidemiologic cohort study., Comment: 49 pages

Interval censoring arises frequently in clinical, epidemiological, financial, and sociological studies, where the event or failure of interest is known only to occur within an interval induced by periodic monitoring. We formulate the effects of potentially time-dependent covariates on the interval-censored failure time through a broad class of semiparametric transformation models that encompasses proportional hazards and proportional odds models. We consider nonparametric maximum likelihood estimation for this class of models with an arbitrary number of monitoring times for each subject. We devise an EM-type algorithm that converges stably, even in the presence of time-dependent covariates, and show that the estimators for the regression parameters are consistent, asymptotically normal, and asymptotically efficient with an easily estimated covariance matrix. Finally, we demonstrate the performance of our procedures through extensive simulation studies and application to an HIV/AIDS study conducted in Thailand., Comment: This paper has been withdrawn by the author due to some errors in the proofs

Interval-censored competing risks data arise when each study subject may experience an event or failure from one of several causes and the failure time is not observed exactly but rather known to lie in an interval between two successive examinations. We formulate the effects of possibly time-varying covariates on the cumulative incidence or sub-distribution function (i.e., the marginal probability of failure from a particular cause) of competing risks through a broad class of semiparametric regression models that captures both proportional and non-proportional hazards structures for the sub-distribution. We allow each subject to have an arbitrary number of examinations and accommodate missing information on the cause of failure. We consider nonparametric maximum likelihood estimation and devise a fast and stable EM-type algorithm for its computation. We then establish the consistency, asymptotic normality, and semiparametric efficiency of the resulting estimators by appealing to modern empirical process theory. In addition, we show through extensive simulation studies that the proposed methods perform well in realistic situations. Finally, we provide an application to a study on HIV-1 infection with different viral subtypes., Comment: This paper has been withdrawn by the author due to some errors in the proofs

The cumulative incidence is the probability of failure from the cause of interest over a certain time period in the presence of other risks. A semiparametric regression model proposed by Fine and Gray (1999) has become the method of choice for formulating the effects of covariates on the cumulative incidence. Its estimation, however, requires modeling of the censoring distribution and is not statistically efficient. In this paper, we present a broad class of semiparametric transformation models which extends the Fine and Gray model, and we allow for unknown causes of failure. We derive the nonparametric maximum likelihood estimators (NPMLEs) and develop simple and fast numerical algorithms using the profile likelihood. We establish the consistency, asymptotic normality, and semiparametric efficiency of the NPMLEs. In addition, we construct graphical and numerical procedures to evaluate and select models. Finally, we demonstrate the advantages of the proposed methods over the existing ones through extensive simulation studies and an application to a major study on bone marrow transplantation., Comment: This paper has been withdrawn by the author due to some errors in the proofs