Additive time-dependent hazard model with doubly truncated data

Background:Survival rates for breast cancer (BC) are often based on the outcomes of this disease. The aim of this study was to compare the performance of three survival models, namely Cox regression, Aalen's, and Lin and Ying's additive hazards (AH) models for identifying the prognostic factors regarding the survival time of BC patients.Materials and Methods:This study was a historical cohort study which used 1025 females' medical records that underwent modified radical mastectomy or breast saving. These patients were admitted to Besat and Chamran Hospitals, Tehran, Iran, during 2010–2015 and followed until 2017. The Aalen's and Lin and Ying's AH models and also traditional Cox model were applied for analysis of time to death of BC patients using R 3.5.1 software.Results:In Aalen's and also Lin and Ying's AH models, age at diagnosis, history of disease, number of lymph nodes, metastasis, hormonal therapy, and evacuation lymph nodes were prognostic factors for the survival of BC patients (P < 0.05). In addition, in the Lin and Ying's AH model tumor size (P = 0.048) was also identified as a significant factor. According to Aalen's plot, metastasis, age at diagnosis, and number of lymph nodes had a time-varying effect on survival time. These variables had a different slope as the times go on.Conclusion:AH model may yield new insights in prognostic studies of survival time of patients with BC over time. Because of the positive slope of estimated cumulative regression function in Aalen's plot, metastasis, higher age at diagnosis, and high number of lymph nodes are important factors in reducing the survival BC, and then based on these factors, the therapists should consider a special therapeutic protocol for BC patients.

Goodness-of-fit tests for Cox's proportional hazards model and Aalen's additive risk model, in which each model is compared on an equal footing with the best fitting fully nonparametric model, are developed. The goodness-of-fit statistics are based on differences each model, with a fully nonparametric estimator of d recently introduced by the authors. Here A( , z) denotes the conditional hazard function of the survival time of an individual with covariate vector z. Comparison of the results of the tests makes it possible to decide whether Cox's proportional hazards or Aalen's additive risk model gives a better fit to the data. In addition, a goodness-of-fit test for Cox's model within the family of all proportional hazards models A(t, z) = AO(t)r(z), where AO is a baseline hazard function and r is a general relative risk function, is developed. Additive hazards and proportional hazards regression models used in the analysis of censored survival data can give substantially different results. For instance, in connection with a study of cancer mortality among Japanese atomic bomb survivors, Muirhead & Darby (1987) have noted that the two models give substantially different estimates of the age-spe- cific probability that an individual will develop radiation induced cancer. Muirhead & Darby (see also Aranda-Ordaz, 1983) introduced a generalized parametric model which contains parametric additive hazards and proportional hazards models as special cases. The goodness- of-fit of each model is then obtained by comparing with the best fitting model within the generalized family, allowing the two special models to be treated on an equal footing. Beyond the parametric setting, much effort has been devoted to the development of goodness-of-fit tests for Cox's (1972) proportional hazards model

Background:One substantial part of microarray studies is to predict patients’ survival based on their gene expression profile. Variable selection techniques are powerful tools to handle high dimensionality in analysis of microarray data. However, these techniques have not been investigated in competing risks setting. This study aimed to investigate the performance of four sparse variable selection methods in estimating the survival time.Methods:The data included 1381 gene expression measurements and clinical information from 301 patients with bladder cancer operated in the years 1987 to 2000 in hospitals in Denmark, Sweden, Spain, France, and England. Four methods of the least absolute shrinkage and selection operator, smoothly clipped absolute deviation, the smooth integration of counting and absolute deviation and elastic net were utilized for simultaneous variable selection and estimation under an additive hazards model. The criteria of area under ROC curve, Brier score and c-index were used to compare the methods.Results:The median follow-up time for all patients was 47 months. The elastic net approach was indicated to outperform other methods. The elastic net had the lowest integrated Brier score (0.137±0.07) and the greatest median of the over-time AUC and C-index (0.803±0.06 and 0.779±0.13, respectively). Five out of 19 selected genes by the elastic net were significant (P<0.05) under an additive hazards model. It was indicated that the expression of RTN4, SON, IGF1R and CDC20 decrease the survival time, while the expression of SMARCAD1 increase it.Conclusion:The elastic net had higher capability than the other methods for the prediction of survival time in patients with bladder cancer in the presence of competing risks base on additive hazards model.

When describing the influence of equipment state to failure rate, traditional additive hazard model (AHM) has certain defects. Therefore, an improved AHM with equipment age and health index (HI) as variables is established, in which HI is used to describe the equipment state. In order to fit out the model's five parameters, a nonlinear constrained optimization problem was posed. A sampling algorithm based on Monte Carlo method was also proposed to obtain parameter ranges and initial values. When the sample data are complete, the parameters can be fitted out by Trust Region algorithm. Historical data of most equipment lack HI time series at present, so non-sequential Monte Carlo method is applied in the section of example analysis to obtain approximate solution of parameters. Fitting results of the example show that an AHM with practical significance can be acquired through the parameter fitting method. Compared with the results of two models with age as the only variable, sum of squares due to error (SSE) of the AHM decreases by at least 10%.

The Cox regression model is widely used for survival data analysis. The Cox model requires a proportional hazard. If the proportional hazard assumption is doubtful, then the additive hazard model can be used, where the covariates act in an additively to the baseline hazard function. If the observed survival time is more than once for one individual during the observation, it is called a recurrent event. The additive hazard model measures risk difference to the effect of a covariate in absolutely, while the proportional hazards model measure hazard ratio in relatively. The risk coefficients estimation in the additive hazard model mimics the multiplicative hazard model, using partial likelihood methods. The derivation of these estimators, outlined in the technical notes, is based on the counting process approach. The counting process approach was first developed by Aalen on 1975 which combines elements of stochastic integration, martingale theory and counting process theory. The method is applied to study about the effect of supplementation on infant growth and development. Based on the processing results, the factors that affect the growth and development of the infant are gender, treatment and mother's education.

In the disciplines of medicine, biology and social science, causal mediation analysis is widely used to examine the effect of an exposure on an outcome through different causal pathways. Recently, there is rapid development of mediation analysis with survival data. An early work of Lange and Hansen proposed to identify the direct and indirect causal effects under the additive hazards model with a single mediator. However, inaccurate measurements of mediators and confounders may lead to biased causal effect estimation. We propose a measurement error correction approach to tackle measurement error in the mediators and confounders under the additive hazards model where multiple mediators are present. We apply the proposed corrected method to the ACTG175 Study data set, and uncover interesting findings.

Additive hazards model with random effects is proposed for modelling the correlated failure time data when focus is on comparing the failure times within clusters and on estimating the correlation between failure times from the same cluster, as well as the marginal regression parameters. Our model features that, when marginalized over the random effect variable, it still enjoys the structure of the additive hazards model. We develop the estimating equations for inferring the regression parameters. The proposed estimators are shown to be consistent and asymptotically normal under appropriate regularity conditions. Furthermore, the estimator of the baseline hazards function is proposed and its asymptotic properties are also established. We propose a class of diagnostic methods to assess the overall fitting adequacy of the additive hazards model with random effects. We conduct simulation studies to evaluate the finite sample behaviors of the proposed estimators in various scenarios. Analysis of the Diabetic Retinopathy Study is provided as an illustration for the proposed method.

SUMMARY When there are covariate effects to be considered, multi-state survival analysis is dominated either by parametric Markov regression models or by semiparametric Markov regression models using Cox's (1972) proportional hazards models for transition intensities between the states. The purpose of this research work is to study alternatives to Cox's model in a general finite-state Markov process setting. We shall look at two alternative models, Aalen's (1989) nonparametric additive hazards model and Lin & Ying's (1994) semiparametric additive hazards model. The former allows the effects of covariates to vary freely over time, while the latter assumes that the regression coefficients are constant over time. With the basic tools of the product integral and the functional delta-method, we present an estimator of the transition probability matrix and develop the large-sample theory for the estimator under each of these two models. Data on 1459 HLA identical sibling transplants for acute leukaemia from the International Bone Marrow Transplant Registry serve as illustration.

Mediation analysis plays an increasingly crucial role in identifying potential causal pathways between exposures and outcomes. However, there is currently a lack of developed mediation approaches for high-dimensional survival data, particularly when considering additive hazard models. The present study introduces two novel approaches for identifying statistically significant mediators in high-dimensional additive hazard models, including the multiple testing-based mediator selection method and knockoff filter procedure. The simulation results demonstrate the outstanding performance of these two proposed methods. Finally, we employ the proposed methodology to analyze the Cancer Genome Atlas (TCGA) cohort in order to identify DNA methylation markers that mediate the association between smoking and survival time among lung cancer patients.

Instrumental variable (IV) methods are popular in non-experimental studies to estimate the causal effects of medical interventions. These approaches allow for the consistent estimation of treatment effects even if important confounding factors are unobserved. Despite the increasing use of these methods, there have been few extensions of IV methods to censored data problems. In this article, we discuss challenges in applying IV techniques to the proportional hazards model and demonstrate the utility of the additive hazards formulation for IV analyses with censored data. Assuming linear structural equation models for the hazard function, we develop a closed-form, two-stage estimator for the causal effect in the additive hazard model. The methods permit both continuous and discrete exposures, and enable the estimation of causal relative survival measures. The asymptotic properties of the estimators are derived and the resulting inferences are shown to perform well in simulation studies and in an application to a data set on the effectiveness of a novel chemotherapeutic agent for colon cancer.

Background/Aims: Our goal is to look at the relationship between long-term exposure to multiple air pollutants and mortality among Medicare participants in the United States on an additive hazard scale using a doubly robust model. Methods: We used a doubly robust additive hazard model (DRAHM) to assess the effect of long-term exposure to PM2.5, NO2, and ozone on mortality among Medicare participants across the contiguous United States from 2000 to 2016. This effect estimates from this model are unbiased if either the inverse probability weight (IPW) model for exposure or the outcome regression model are correctly specified. Furthermore, unlike the Cox proportional hazards model, it does not require a proportional hazards assumption. PM2.5, NO2, and ozone levels were obtained from a previously validated high-resolution prediction models which utilized machine learning algorithms. These predictions were averaged spatio-temporally to obtain annual exposure on a zip code level. Mortality information was derived from the Medicare denominator file. Covariates included demographic and socioeconomic variables. Effect measure modification was assessed for sex, age, race, and Medicaid eligibility. We then repeated the analyses among observations that were less than the international annual standard of 10 mcg/m3 for PM2.5 and 20 ppb for NO2. For the ozone subgroup analysis, we looked at individuals in whom all years of observation had levels below 50 ppb. Results: Our preliminary results indicate that exposure to PM2.5 led to a 0.00248% (95% CI: -0.000252% to 0.00521%) per 1 µg/m3 increase in the hazard of death among the study population after adjustment for individual demographic factors and zip code-level socioeconomic and air pollution factors. Further results are pending. Conclusions: Long-term exposure to fine particulate matter does not significantly increase the hazard of mortality in the elderly Medicare population on an additive scale.

ABSTRACTThis paper discusses the regression analysis of current status failure time data arising from the additive hazards model with auxiliary covariates. As often occurs in practice, it is impossible or impractical to measure the exact magnitude of covariates for all subjects in a study. To compensate the missing information, some auxiliary covariates are utilized instead. We propose two easy-to-implement procedures for estimation of regression parameters by making use of auxiliary information. The asymptotic properties of the resulting estimators are established and extensive numerical studies indicate that both procedures work well in practice.

ABSTRACTMany methods have been developed in the literature for regression analysis of current status data with noninformative censoring and also some approaches have been proposed for semiparametric regression analysis of current status data with informative censoring. However, the existing approaches for the latter situation are mainly on specific models such as the proportional hazards model and the additive hazard model. Corresponding to this, in this paper, we consider a general class of semiparametric linear transformation models and develop a sieve maximum likelihood estimation approach for the inference. In the method, the copula model is employed to describe the informative censoring or relationship between the failure time of interest and the censoring time, and Bernstein polynomials are used to approximate the nonparametric functions involved. The asymptotic consistency and normality of the proposed estimators are established, and an extensive simulation study is conducted and indicates that the proposed approach works well for practical situations. In addition, an illustrative example is provided.

Gap times between recurrent events are often of primary interest in medical and observational studies. The additive hazards model, focusing on risk differences rather than risk ratios, has been widely used in practice. However, the marginal additive hazards model does not take the dependence among gap times into account. In this paper, we propose an additive mixed effect model to analyze gap time data, and the proposed model includes a subject-specific random effect to account for the dependence among the gap times. Estimating equation approaches are developed for parameter estimation, and the asymptotic properties of the resulting estimators are established. In addition, some graphical and numerical procedures are presented for model checking. The finite sample behavior of the proposed methods is evaluated through simulation studies, and an application to a data set from a clinic study on chronic granulomatous disease is provided.

For multivariate survival data, we study the generalized method of moments (GMM) approach to estimation and inference based on the marginal additive hazards model. We propose an efficient iterative algorithm using closed‐form solutions, which dramatically reduces the computational burden. Asymptotic normality of the proposed estimators is established, and the corresponding variance–covariance matrix can be consistently estimated. Inference procedures are derived based on the asymptotic chi‐squared distribution of the GMM objective function. Simulation studies are conducted to empirically examine the finite sample performance of the proposed method, and a real data example from a dental study is used for illustration.