Construction of an Early Warning Model for Ischemic Stroke Recurrence Based on Generalized Estimating Equation

Objective:To explore the appropriate modeling method of the early warning model of ischemic stroke recurrence in TCM.Methods:This was a prospective,multi-center and registered study conducted in 7 clinical subcenters from 8 provinces and 10 cities in China between 3rd November 2016 and 27th April,2019.1,741 patients with first-ever ischemic stroke were recruited.Univariate analysis was carried out using distance correlation coefficient,mutual information entropy,and statistical correlation test.Multivariate analysis adopted multi-factor Cox regression model and combined with expert opinions in the field of stroke to determine modeling variables.The generalized estimating equation of longitudinal data and the Cox proportional hazard regression model of cross-sectional data were used to construct and compare in the early warning model of ischemic stroke recalls.The area under the ROC curve(AUC value)was used to evaluate the early warning capability of the model.Results:The follow-up time was 1-3 years,and the median follow-up time was 1.42 years(95%CI:1.37-1.47).Recurrence events occurred in 175 cases,and the cumulative recurrence rate was 10.05%(95%CI:8.64%-11.47%).The AUC values of the TCM syndrome and TCM constitution model were 0.71809 and 0.72668 based on the generalized estimating equation and the AUC values.Conclusion:The generalized estimating equation may be more suitable for the construction of early warning models of stroke recurrence with TCM characteristics,which provides a certain reference for the evaluation of secondary prevention of ischemic stroke.

Empirical Likelihood Based Longitudinal Data Analysis

In longitudinal data analysis, our primary interest is in the estimation of regression parameters for the marginal expectations of the longitudinal responses, and the longitudinal correlation parameters are of secondary interest. The joint likelihood function for longitudinal data is challenging, particularly due to correlated responses. Marginal models, such as generalized estimating equations (GEEs), have received much attention based on the assumption of the first two moments of the data and a working correlation structure. The confidence regions and hypothesis tests are constructed based on the asymptotic normality. This approach is sensitive to the misspecification of the variance function and the working correlation structure which may yield inefficient and inconsistent estimates leading to wrong conclusions. To overcome this problem, we propose an empirical likelihood (EL) procedure based on a set of estimating equations for the parameter of interest and discuss its characteristics and asymptotic properties. We also provide an algorithm based on EL principles for the estimation of the regression parameters and the construction of its confidence region. We have applied the proposed method in two case examples.

Modeling Individual Patient Count/Rate Data over Time with Applications to Cancer Pain Flares and Cancer Pain Medication Usage

The purpose of this article is to investigate approaches for modeling individual patient count/rate data over time accounting for temporal correlation and non-constant dispersions while requiring reasonable amounts of time to search over alternative models for those data. This research addresses formulations for two approaches for extending generalized estimating equations (GEE) modeling. These approaches use a likelihood-like function based on the multivariate normal density. The first approach augments standard GEE equations to include equations for estimation of dispersion parameters. The second approach is based on estimating equations determined by partial derivatives of the likelihood-like function with respect to all model parameters and so extends linear mixed modeling. Three correlation structures are considered including independent, exchangeable, and spatial autoregressive of order 1 correlations. The likelihood-like function is used to formulate a likelihood-like cross-validation (LCV) score for use in evaluating models. Example analyses are presented using these two modeling approaches applied to three data sets of counts/rates over time for individual cancer patients including pain flares per day, as needed pain medications taken per day, and around the clock pain medications taken per day per dose. Means and dispersions are modeled as possibly nonlinear functions of time using adaptive regression modeling methods to search through alternative models compared using LCV scores. The results of these analyses demonstrate that extended linear mixed modeling is preferable for modeling individual patient count/rate data over time, because in example analyses, it either generates better LCV scores or more parsimonious models and requires substantially less time.

Usefulness of fecal lactoferrin in predicting and monitoring the clinical severity of infectious diarrhea

AIM:To explore the value of fecal lactoferrin in predicting and monitoring the clinical severity of infectious diarrhea.METHODS:Patients with acute infectious diarrhea ranging from 3 mo to 10 years in age were enrolled,and one to three stool samples from each subject were collected.Certain parameters,including white blood cells /differential count,C-reactive protein,fecal mucus,fecal pus cells,duration of fever,vomiting,diarrhea and severity(indicated by Clark and Vesikari scores),were recorded and analyzed.Fecal lactoferrin was determined by enzyme-linked immunosorbent assay and compared in different pathogen and disease activity.Generalized estimating equations(GEE) were also used for analysis.RESULTS:Data included 226 evaluations for 117 individuals across three different time points.Fecal lactoferrin was higher in patients with Salmonella(11.17 μg/g ± 2.73 μg/g) or Campylobacter(10.32 μg/g ± 2.94 μg/g) infections and lower in patients with rotavirus(2.82 μg/g ± 1.27 μg/g) or norovirus(3.16 μg/g ± 1.18 μg/g) infections.Concentrations of fecal lactoferrin were significantly elevated in patients with severe(11.32 μg/g ± 3.29 μg/g) or moderate(3.77 μg/g ± 2.08 μg/g) disease activity compared with subjects with mild(1.51 μg/g ± 1.36 μg/g) disease activity(P < 0.05).GEE analysis suggests that this marker could be used to monitor the severity and course of gastrointestinal infections and may provide information for disease management.CONCLUSION:Fecal lactoferrin increased during bacterial infection and with greater disease severity and may be a good marker for predicting and monitoring intestinal inflammation in children with infectious diarrhea.

Longitudinal Changes in Liver Aminotransferases Predict Metabolic Syndrome in Chinese Patients with Nonviral Hepatitis

Objective This study explored the correlation of longitudinal changes in serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） levels with the incidence of metabolic syndrome （Mets） based on a dynamic health examination cohort. Methods A Mets-free dynamic cohort involving 4541 participants who underwent at least three health examinations from 2006 to 2011 was included in the study. Mets was defined according to the Chinese Medical Association Diabetes Branch definition that included hypertension, obesity, hyperlipidemia, and hyperglycemia. Generalized estimating equation （GEE） model was used to analyze multivariate relative risk （RR） of repeated observations of ALT and AST in quartiles for Mets or its components according to gender. Results In all, 826 Mets cases were reported. Adjustment of relevant parameters indicated that time-varying changes in ALT and AST levels were positively associated with the incidence of Mets in a dose-response manner. Positive association between high ALT levels and fatty liver was much stronger than that between high AST levels and fatty liver, particularly in male participants. These associations were consistently observed in the following subgroups： participants with ALT and AST levels of 〈40 U/L, participants with of 〈25 kg/m2, and participants with non-fatty liver. Furthermore, participants with 2 Mets components at baseline showed lower multivariate adjusted RRs of ALT and AST for Mets than participants with 0-1 Mets component. Conclusion These results suggested that elevated serum ALT and AST levels were early biomarkers of Mets or its components.

Hepatitis B virus persistent infection-related single nucleotide polymorphisms in HLA regions are associated with viral load in hepatoma families

BACKGROUND Genome-wide association studies from Asia indicate that HLA-DP and HLA-DQ loci are important in persistent hepatitis B virus(HBV)infections.One of the key elements for HBV-related carcinogenesis is persistent viral replication and inflammation.AIM To examine genetic and nongenetic factors with persistent HBV infection and viral load in families with hepatocellular carcinoma(HCC).METHODS The HCC families included 301 hepatitis B surface antigen(HBsAg)carriers and 424 noncarriers born before the nationwide vaccination program was initiated in 1984.Five HBV-related single nucleotide polymorphisms(SNPs)—rs477515,rs9272105,rs9276370,rs7756516,and rs9277535—were genotyped.Factors associated with persistent HBV infection and viral load were analyzed by a generalized estimating equation.RESULTS In the first-stage persistent HBV study,all SNPs except rs9272105 were associated with persistent infection.A significantly higher area under the reciprocal operating characteristic curve for nongenetic factors vs genetic factors(P<0.001)suggests that the former play a major role in persistent HBV infection.In the second-stage viral load study,we added 8 HBsAg carriers born after 1984.The 309 HBsAg carriers were divided into low(n=162)and high viral load(n=147)groups with an HBV DNA cutoff of 105 cps/mL.Sex,relationship to the index case,rs477515,rs9272105,and rs7756516 were associated with viral load.Based on the receiver operating characteristic curve analysis,genetic and nongenetic factors affected viral load equally in the HCC family cohort(P=0.3117).CONCLUSION In these east Asian adults,the mechanism of persistent HBV infection-related SNPs was a prolonged viral replication phase.

ROBUST ESTIMATION IN PARTIAL LINEAR MIXED MODEL FOR LONGITUDINAL DATA

In this article, robust generalized estimating equation for the analysis of partial linear mixed model for longitudinal data is used. The authors approximate the nonparametric function by a regression spline. Under some regular conditions, the asymptotic properties of the estimators are obtained. To avoid the computation of high-dimensional integral, a robust Monte Carlo Newton-Raphson algorithm is used. Some simulations are carried out to study the performance of the proposed robust estimators. In addition, the authors also study the robustness and the efficiency of the proposed estimators by simulation. Finally, two real longitudinal data sets are analyzed.

Weighted estimating equation： modified GEE in longitudinal data analysis

The method of generalized estimating equations （GEE） introduced by K. Y. Liang and S. L. Zeger has been widely used to analyze longitudinal data. Recently, this method has been criticized for a failure to protect against misspecification of working correlation models, which in some cases leads to loss of efficiency or infeasibility of solutions. In this paper, we present a new method named as ＇weighted estimating equations （WEE）＇ for estimating the correlation parameters. The new estimates of correlation parameters are obtained as the solutions of these weighted estimating equations. For some commonly assumed correlation structures, we show that there exists a unique feasible solution to these weighted estimating equations regardless the correlation structure is correctly specified or not. The new feasible estimates of correlation parameters are consistent when the working correlation structure is correctly specified. Simulation results suggest that the new method works well in finite samples.

A general additive-multiplicative rates model for recurrent event data

In this article, we propose a general additive-multiplicative rates model for recurrent event data. The proposed model includes the additive rates and multiplicative rates models as special cases. For the inference on the model parameters, estimating equation approaches are developed, and asymptotic properties of the proposed estimators are established through modern empirical process theory. In addition, an illustration with multiple-infection data from a clinic study on chronic granulomatous disease is provided.

A moving average Cholesky factor model in joint mean-covariance modeling for longitudinal data

Modeling the mean and covariance simultaneously is a common strategy to efficiently estimate the mean parameters when applying generalized estimating equation techniques to longitudinal data. In this article, using generalized estimation equation techniques, we propose a new kind of regression models for parameterizing covariance structures. Using a novel Cholesky factor, the entries in this decomposition have moving average and log innovation interpretation and are modeled as the regression coefficients in both the mean and the linear functions of covariates. The resulting estimators for eovarianee are shown to be consistent and asymptotically normally distributed. Simulation studies and a real data analysis show that the proposed approach yields highly efficient estimators for the parameters in the mean, and provides parsimonious estimation for the covariance structure.

Joint semiparametric mean-covariance model in longitudinal study

Semiparametric regression models and estimating covariance functions are very useful for longitudinal study. To heed the positive-definiteness constraint, we adopt the modified Cholesky decomposition approach to decompose the covariance structure. Then the covariance structure is fitted by a semiparametric model by imposing parametric within-subject correlation while allowing the nonparametric variation function. We estimate regression functions by using the local linear technique and propose generalized estimating equations for the mean and correlation parameter. Kernel estimators are developed for the estimation of the nonparametric variation function. Asymptotic normality of the the resulting estimators is established. Finally, the simulation study and the real data analysis are used to illustrate the proposed approach.

Local asymptotic behavior of regression splines for marginal semiparametric models with longitudinal data

In this paper, we study the local asymptotic behavior of the regression spline estimator in the framework of marginal semiparametric model. Similarly to Zhu, Fung and He (2008), we give explicit expression for the asymptotic bias of regression spline estimator for nonparametric function f. Our results also show that the asymptotic bias of the regression spline estimator does not depend on the working covariance matrix, which distinguishes the regression splines from the smoothing splines and the seemingly unrelated kernel. To understand the local bias result of the regression spline estimator, we show that the regression spline estimator can be obtained iteratively by applying the standard weighted least squares regression spline estimator to pseudo-observations. At each iteration, the bias of the estimator is unchanged and only the variance is updated.

Marginal Accelerated Hazard Model with Multivariate Failure Time Data

Multivariate failure time data are frequently encountered in biomedical research.In this article,we model marginal hazards with accelerated hazards model to analyze multivariate failure time data.Estimating equations are derived analogous to generalized estimating equation method.Under certain regular conditions,the resultant estimators for the regression parameters are shown to be asymptotically normal.Furthermore,we also establish the weak convergence of estimators for the baseline cumulative hazard functions.

Parsimonious Mean-Covariance Modeling for Longitudinal Data with ARMA Errors

Based on the generalized estimating equation approach,the authors propose a parsimonious mean-covariance model for longitudinal data with autoregressive and moving average error process,which not only unites the existing autoregressive Cholesky factor model and moving average Cholesky factor model but also provides a wide variety of structures of covariance matrix.The resulting estimators for the regression coefficients in both the mean and the covariance are shown to be consistent and asymptotically normally distributed under mild conditions.The authors demonstrate the effectiveness,parsimoniousness and desirable performance of the proposed approach by analyzing the CD4-I-cell counts data set and conducting extensive simulations.