Conditional score approaches to errors-in-variables competing risks data in discrete time.

Analysis of competing risks data has been an important topic in survival analysis due to the need to account for the dependence among the competing events. Also, event times are often recorded on discrete time scales, rendering the models tailored for discrete-time nature useful in the practice of survival analysis. In this work, we focus on regression analysis with discrete-time competing risks data, and consider the errors-in-variables issue where the covariates are prone to measurement errors.

The angiogenesis-modulating effects of coumarin-derivatives.

Coumarin is a natural compound that is rich in plants. Coumarin and its derivates were reported to have many biological activities, such as anti-bacterial, anti-tumor, and anti-coagulation. In this study, we examined the angiogenic modulating activities of six previously synthesized coumarin derivatives (Compound #1-#6) in zebrafish embryos and further confirmed them in a chick model.

Analyzing recurrent and nonrecurrent terminal events data in discrete time.

Joint analysis of recurrent and nonrecurrent terminal events has attracted substantial attention in literature. However, there lacks formal methodology for such analysis when the event time data are on discrete scales, even though some modeling and inference strategies have been developed for discrete-time survival analysis. We propose a discrete-time joint modeling approach for the analysis of recurrent and terminal events where the two types of events may be correlated with each other.

Discrete-time survival data with longitudinal covariates.

Survival analysis has been conventionally performed on a continuous time scale. In practice, the survival time is often recorded or handled on a discrete scale; when this is the case, the discrete-time survival analysis would provide analysis results more relevant to the actual data scale. Besides, data on time-dependent covariates in the survival analysis are usually collected through intermittent follow-ups, resulting in the missing and mismeasured covariate data.

Joint analysis of panel count and interval-censored data using distribution-free frailty analysis.

We propose a joint analysis of recurrent and nonrecurrent event data subject to general types of interval censoring. The proposed analysis allows for general semiparametric models, including the Box-Cox transformation and inverse Box-Cox transformation models for the recurrent and nonrecurrent events, respectively. A frailty variable is used to account for the potential dependence between the recurrent and nonrecurrent event processes, while leaving the distribution of the frailty unspecified.

Embryonic exposure to 4-methylimidazole leads to zebrafish myofibril misalignment.

4-methylimidazole (4-MI) is an imidazole-derived organic chemical compound that can be used as a raw material in the manufacture of diverse chemicals and has been identified as an ingredient of caramel color in soybean sauce, beers, and other soft drinks. The aim of the present study was to investigate the teratogenic effects of 4-MI during zebrafish embryogenesis. Zebrafish embryos were treated with different dosages of 4-MI (0-120 mM) for different exposure durations (12-60 hours).

Pseudo and conditional score approach to joint analysis of current count and current status data.

We develop a joint analysis approach for recurrent and nonrecurrent event processes subject to case I interval censorship, which are also known in literature as current count and current status data, respectively. We use a shared frailty to link the recurrent and nonrecurrent event processes, while leaving the distribution of the frailty fully unspecified. Conditional on the frailty, the recurrent event is assumed to follow a nonhomogeneous Poisson process, and the mean function of the recurrent event and the survival function of the nonrecurrent event are assumed to follow some general form of semiparametric transformation models.

Sample size determination for semiparametric analysis of current status data.

Semiparametric transformation models, which include the Cox proportional hazards and proportional odds models as special cases, are popular in current practice of survival analysis owing to that, in contrast to parametric models, no assumption on the baseline distribution is required. Although sample size calculations for semiparametric survival analysis with right-censored data are available, no such calculation exits in literature for semiparametric analysis with current status data, where only an examination time and whether the event occurs prior to the examination are observable. We develop sample size calculation for semiparametric two-group comparison or regression analysis with current status data.

Evaluation of the teratogenic effects of three traditional Chinese medicines, Si Jun Zi Tang, Liu Jun Zi Tang and Shenling Baizhu San, during zebrafish pronephros development.

The aim of this study was to evaluate the teratogenic effects of three common Chinese medical prescriptions, Si Jun Zi Tang (SJZT), Liu Jun Zi Tang (LJZT) and Shenling Baizhu San (SLBS), during zebrafish pronephros development. We used the transgenic zebrafish line Tg(wt1b:EGFP) to assess the teratogenic effects using 12 different protocols, which comprised combinations of 4 doses (0, 25, 250, 1,250 ng/mL) and 3 exposure methods [methods I, 12-36 hours post fertilization (hpf), II, 24-48 hpf, and III, 24-36 hpf]. As a result, few defects in the kidneys were observed in the embryos exposed to 25 ng/mL of each medical prescription.

Nephroprotective role of resveratrol and ursolic Acid in aristolochic Acid intoxicated zebrafish.

The nephrotoxicity of aristolochic acid (AA) is well known, but information regarding the attenuation of AA-induced toxicity is limited. The aim of the present study was to study the nephroprotective effects of resveratrol (Resv) and ursolic acid (UA) in a zebrafish model. We used two transgenic lines, Tg(wt1b:EGFP) and Tg(gata1:DsRed), to evaluate the nephroprotective effects of Resv and UA by recording subtle changes in the kidney and red blood cell circulation.

Protective Role of Comfrey Leave Extracts on UV-induced Zebrafish Fin Damage.

In zebrafish, UV exposure leads to fin malformation phenotypes including fin reduction or absence. The present study evaluated UV-protective activities of comfrey leaves extracts in a zebrafish model by recording fin morphological changes. Chemopreventive effects of comfrey leave extracts were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression.

Perturbation of cytosolic calcium by 2-aminoethoxydiphenyl borate and caffeine affects zebrafish myofibril alignment.

The objective of the current study was to investigate the effects of Ca(2+) levels on myofibril alignment during zebrafish embryogenesis. To investigate how altered cytoplasmic Ca(2+) levels affect myofibril alignment, we exposed zebrafish embryos to 2-aminothoxyldiphenyl borate (2-APB; an inositol 1,4,5-trisphosphate receptor inhibitor that reduces cytosolic Ca(2+) levels) and caffeine (a ryanodine receptor activator that enhances cytosolic Ca(2+) levels). The results demonstrated that the most evident changes in zebrafish embryos treated with 2-APB were shorter body length, curved trunk and malformed somite boundary.

Modeling pegylated liposomal doxorubicin-induced hand-foot syndrome and intestinal mucositis in zebrafish.

Pegylated liposomal doxorubicin (PLD) has been widely used to treat cancer. The adverse effects of PLD noted in clinical practice, especially hand-foot syndrome (HFS), are regarded as unique, and the management methods for them remain limited. This study was aimed at developing a feasible experimental model for translational medicine to solve this clinical issue by using skin fluorescent transgenic zebrafish.

A functional inference for multivariate current status data with mismeasured covariate.

Covariate measurement error problems have been recently studied for current status failure time data but not yet for multivariate current status data. Motivated by the three-hypers dataset from a health survey study, where the failure times for three-hypers (hyperglycemia, hypertension, hyperlipidemia) are subject to current status censoring and the covariate self-reported body mass index may be subject to measurement error, we propose a functional inference method under the proportional odds model for multivariate current status data with mismeasured covariates. The new proposal utilizes the working independence strategy to handle correlated current status observations from the same subject, as well as the conditional score approach to handle mismeasured covariate without specifying the covariate distribution.

Overdose of D-serine Induces Movement Disorder and Neuromuscular Changes of Zebrafish Larvae.

D-serine is a well-known activator of N-methyl-D-aspartate receptors; however, little is known about the teratogenic effects of D-serine overdose during early embryonic development. Here, we used zebrafish as a model to test toxicity and teratogenicity, since they have transparent eggs, making the organogenesis of zebrafish embryos easier to be observed. After D-serine injection (100-1000 ppm), the most evident defective phenotypes were bent trunk phenotypes, including malformed somite boundary, twisted body axis and shorter body length.

Semiparametric analysis of incomplete current status outcome data under transformation models.

This work, motivated by an osteoporosis survey study, considers regression analysis with incompletely observed current status data. Here the current status data, including an examination time and an indicator for whether or not the event of interest has occurred by the examination time, is not observed for all subjects. Instead, a surrogate outcome subject to misclassification of the current status is available for all subjects.

Evaluation of the anti-inflammatory effect of chalcone and chalcone analogues in a zebrafish model.

The aim of this study was to investigate novel chalcones with potent anti-inflammatory activities in vivo. Chalcone and two chalcone analogues (compound 5 and 9) were evaluated using a caudal fin-wounded transgenic zebrafish line "Tg(mpx:gfp)" to visualize the effect of neutrophil recruitment dynamically. Results showed that treatment with compound 9 not only affected wound-induced neutrophil recruitment, but also affected Mpx enzymatic activity.

Evaluation of the structure-activity relationship of flavonoids as antioxidants and toxicants of zebrafish larvae.

The antioxidant ability of an array of commercially available flavonoids was evaluated on the larvae of the zebrafish model organism, in order to find flavonoids with lower toxicities and higher radical oxygen-scavenging properties than flavone. Among the flavonoids tested, chrysin and morin possessed higher reactive oxygen species (ROS)-scavenging rates (-99% and -101%, respectively) and lower toxicity (LD(50)>100 ppm). Zebrafish fins in the UVB+chrysin group were 6.

Assessing age-at-onset risk factors with incomplete covariate current status data under proportional odds models.

Motivated by an epidemiological survey of fracture in elderly women, we develop a semiparametric regression analysis of current status data with incompletely observed covariate under the proportional odds model. To accommodate both the interval-censored nature of current status failure time data and the incompletely observed covariate data, we propose an analysis based on the validation likelihood (VL), which is derived from likelihood pertaining to the validation sample, namely the subset of the sample where the data are completely observed. The missing data mechanism is assumed to be missing at random and is explicitly modeled and estimated in the VL approach.

Cox regression for mixed case interval-censored data with covariate errors.

Covariate measurement error problems have been extensively studied in the context of right-censored data but less so for interval-censored data. Motivated by the AIDS Clinical Trial Group 175 study, where the occurrence time of AIDS was examined only at intermittent clinic visits and the baseline covariate CD4 count was measured with error, we describe a semiparametric maximum likelihood method for analyzing mixed case interval-censored data with mismeasured covariates under the proportional hazards model. We show that the estimator of the regression coefficient is asymptotically normal and efficient and provide a very stable and efficient algorithm for computing the estimators.

Caffeine treatment disturbs the angiogenesis of zebrafish embryos.

Caffeine is a widely consumed substance that occurs in numerous dietary sources, but teratogenic effects of caffeine intake during embryonic development are still not clear. In the present study, we used the zebrafish as a model to assess caffeine-induced toxicity on embryonic vascular development. A green fluorescent vascular endothelium transgenic line, Tg(fli1:egfp), was utilized for the sensitive detection of vascular development, including vasculo- and angiogenesis.

Flavone is efficient to protect zebrafish fins from UV-induced damage.

We used ultraviolet (UV)-induced fin damage in zebrafish as a system for evaluating the chemopreventive potential of flavonoids. Chemopreventive effects of each compound, including flavone, flavanone, and chalcone, on fin development were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression. Results showed that 1) flavone has the highest capacity to protect zebrafish fins from UV-induced damages among other groups; 2) zebrafish fins in the UV+1 ppm flavone group are 1.

Fin reduction is a novel and unexpected teratogenic effect of amikacin-treated zebrafish embryos.

We used zebrafish as a model to assess amikacin-induced embryotoxicity. We exposed zebrafish embryos to amikacin, using different amikacin doses (0-10 ppm), durations (12-48 h), and onsets (0, 24, 48 hpf). Amikacin-induced embryonic toxicity and reduced survival rate were found dependent on the exposure dose, duration and onset.

Embryonic exposure to diclofenac disturbs actin organization and leads to myofibril misalignment.

The objective of this study was to investigate the embryotoxicity of diclofenac. Zebrafish (Danio rerio) embryos at 12 hpf were treated with different dosages of diclofenac (0-2,000 ppm) for different time courses (12-72 hr). Results showed no evident differences in survival rates or morphological changes between the mock-treated control (0 ppm) zebrafish embryos and those with 1-ppm diclofenac-exposure (12-24, 12-36 hpf).

Analysis of current status data with missing covariates.

Statistical inference based on right-censored data for the proportional hazards (PH) model with missing covariates has received considerable attention, but interval-censored or current status data with missing covariates has not yet been investigated. Our study is partly motivated by the analysis of fracture data from the 2005 National Health Interview Survey Original Database in Taiwan, where the occurrence of fractures was interval censored and the covariate osteoporosis was not reported for all residents. We assume that the data are realized from a PH model.