A Semiparametric Additive-multiplicative Rates Model for the Weighted Composite Endpoint of Recurrent and Terminal Events

Recurrent event data are commonly encountered in many scientific fields,including biomedical studies,clinical trials and epidemiological surveys,and many statistical methods have been proposed for their analysis.In this paper,we consider to use a weighted composite endpoint of recurrent and terminal events,which is weighted by the severity of each event,to assess the overall effects of covariates on the two types of events.A flexible additive-multiplicative model incorporating both multiplicative and additive effects on the rate function is proposed to analyze such weighted composite event process,and more importantly,the dependence structure among the recurrent and terminal events is left unspecified.For the estimation,we construct the unbiased estimating equations by virtue of the inverse probability weighting technique,and the resulting estimators are shown to be consistent and asymptotically normal under some mild regularity conditions.We evaluate the finite-sample performance of the proposed method via simulation studies and apply the proposed method to a set of real data arising from a bladder cancer study.

Dietary copper improves intestinal structural integrity in juvenile grass carp(Ctenopharyngodon idella)probably related to its increased intestinal antioxidant capacity and apical junction complex

This research evaluated the effects of copper(Cu)on intestinal antioxidant capacity and apical junctional complex(AJC)in juvenile grass carp.A total of 1080 healthy juvenile grass carp(11.16±0.01 g)were fed six diets including different dosages of Cu,namely 0,2,4,6,8 mg/kg(Cu citrate[CuCit]as Cu source)and 3 mg/kg(CuSO_(4)·5H_(2)O as Cu source).The trial lasted for 9 weeks.The findings revealed that dietary optimal Cu supplementation(2.2 to 4.1 mg/kg)promoted intestinal growth,including intestinal length,intestinal length index,intestinal weight,and intestinal somatic index(P>0.05).On the other hand,optimal Cu increased intestinal tight junction(TJ)proteins(except for claudin 15b)and adherens junction(AJ)proteins(E-cadherin,α-catenin,β-catenin,nectin and afadin)mRNA levels(P<0.05),which could be connected to the signaling pathway formed by the Ras homolog gene family,member A(RhoA),Rho-associated kinase(ROCK),and myosin light chain kinase(MLCK).Finally,based on serum indicator D-lactate and intestinal oxidative damage index(ROS),Cu requirement(CuCit as Cu source)for juvenile grass carp from initial weight to final weight(from 11 to 173 g)was determined to be 4.14 and 4.12 mg/kg diet,respectively.This work may provide a theoretical foundation for identifying putative Cu regulation pathways on fish intestinal health.

Aflatoxin B1 decreased flesh flavor and inhibited muscle development in grass carp(Ctenopharyngodon idella)

In nature,aflatoxins,especially aflatoxin B1(AFB1),are the common mycotoxins,which cause serious health problems for humans and animals.This paper aimed to study the effects of AFB1 on flesh flavor and muscle development of grass carp(Ctenopharyngodon idella)and its mechanism.There were 1440 individual fish in total,with 6 treatments and each treatment replicated 3 times.The 6 treatments were fed a control diet with different doses of AFB1(0.04,29.48,58.66,85.94,110.43 and 146.92μg/kg diet)for 60 d.AFB1 increased myofiber diameter,as well as decreased myofiber density of grass carp muscle(P<0.05).The contents of free amino acid decreased gradually(P<0.05)as dietary AFB1 increased in the muscle of grass carp.The levels of reactive oxygen species,malonaldehyde and protein carbonyl(PC)were increased(P<0.05)with the dietary AFB1 increased.The levels of antioxidant enzyme(glutathione peroxidase,glutathione,glutathione reductase,total antioxidant capacity,anti-superoxide anion,and anti-hydroxyl radical)were decreased(P<0.05)with the dietary AFB1 increased.In addition,dietary AFB1 decreased the content of collagen,and downregulated the mRNA and protein levels of transforming growth factor-β(TGF-β)/Smads signaling pathway in grass carp muscle(P<0.05).The mRNA and protein levels of myogenic regulatory factors were downregulated in grass carp muscle(P<0.05).Furthermore,the activities of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)were increased(P<0.05),and the protein levels of phosphorylate-38 mitogen-activated protein kinase(p-p38MAPK),phosphorylate-c-Jun N-terminal kinase,urokinase-type plasminogen activator(uPA),MMP-2 and MMP-9 were upregulated(P<0.05),but collagenⅠ,lamininβ1 and fibronectin were downregulated(P<0.05)with the dietary AFB1 increased in the muscle of grass carp.Based on the results of this study,we can draw the following conclusion:dietary AFB1 might damage flesh flavor and inhibit the muscle development through MAPK/uPA/MMP/extracellular matrix(ECM)signaling pathway in grass carp.Moreover,the recommended safe limit of AFB1 in feed is no more than 26.77μg/kg diet according to the PC levels in grass carp muscle.

Regression Analysis of Doubly Censored Data with a Cured Subgroup under a Class of Promotion Time Cure Models

In some situations,the failure time of interest is defined as the gap time between two related events and the observations on both event times can suffer either right or interval censoring.Such data are usually referred to as doubly censored data and frequently encountered in many clinical and observational studies.Additionally,there may also exist a cured subgroup in the whole population,which means that not every individual under study will experience the failure time of interest eventually.In this paper,we consider regression analysis of doubly censored data with a cured subgroup under a wide class of flexible transformation cure models.Specifically,we consider marginal likelihood estimation and develop a two-step approach by combining the multiple imputation and a new expectation-maximization(EM)algorithm for its implementation.The resulting estimators are shown to be consistent and asymptotically normal.The finite sample performance of the proposed method is investigated through simulation studies.The proposed method is also applied to a real dataset arising from an AIDS cohort study for illustration.