A time-dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases

The paper presents an extension of the regressive logistic models proposed by Bonney [Biometrics 42:611-625, 1986], to address the problems of variable age-of-onset and time-dependent covariates in analysis of familial diseases. This goal is achieved by using failure time data analysis methods, and partitioning the time of follow up in K mutually exclusive intervals. The conditional probability of being affected within the kth interval (k = 1...K) given not affected before represents the hazard function in this discrete formulation. A logistic model is used to specify a regression relationship between this hazard function and a set of explanatory variables including genotype, phenotypes of ancestors, and other covariates which can be time dependent. The probability that a given person either becomes affected within the kth interval (i.e., interval k includes age of onset of the person) or remains unaffected by the end of the kth interval (i.e., interval k includes age at examination of the person) are derived from the general results of failure time data analysis and used for the likelihood formulation. This proposed approach can be used in any genetic segregation and linkage analysis in which a penetrance function needs to be defined. Application of the method to familial leprosy data leads to results consistent with our previous analysis performed using the unified mixed model [Abel and Demenais, Am J Hum Genet 42:256-266, 1988], i.e., the presence of a recessive major gene controlling susceptibility to leprosy. Furthermore, a simulation study shows the capability of the new model to detect major gene effects and to provide accurate parameter estimates in a situation of complete ascertainment.     

Time-Dependent Disposition of β-Naphthoflavone in the Rat

The pharmacokinetics of -naphthoflavone (BNF) have been investigated in rats following various modes of intravenous administration. From intravenous bolus studies it was established that BNF showed a high blood clearance (130 ml/min/kg) and no detectable excretion of unchanged compound in the urine. The volume of distribution for BNF was large (6 L/kg), and binding to plasma proteins extensive (96%). Intravenous infusion studies where the length of infusion was increased from 1 to 8 hr showed marked signs of time-dependent pharmacokinetics. During continuous infusions the plasma concentrations accrued for approximately 1 hr, after which plasma concentrations declined in an apparent exponential fashion to a plateau value. In the short infusion studies the postinfusion half-life (27 min) was significantly shorter than the terminal half-life after bolus administration (40 min). Time-dependent clearance of BNF resulting from enhancement/induction of P450IA enzymes is proposed as the mechanism for these unusual pharmacokinetic features. The use of antipyrine as an independent probe for P450 activity gave similar trends in antipyrine clearance for various modes of BNF administration. Computer simulations based on an autoinduction model for time-dependent clearance were consistent with the observations on BNF in the rat.     

带时变协变量多状态Cox回归模型分析影响2型糖尿病多状态进程的因素

目的探讨2型糖尿病不同发展阶段的影响因素，为2型糖尿病的防治提供科学依据。方法采用回顾性调查方法调查了367例2型糖尿病人，针对2型糖尿病具有多状态进程以及某些因素具有时依特点，采用带时变协变量多状态Cox回归模型进行分析。结果体重指数、家庭月人均收入以及甜食3个因素主要作用于第一阶段（IGT→DM2），体重指数越大，家庭月人均收入越高以及甜食吃得越多的患者，由IGT转化为DM2的风险越高。吸烟和血糖监测两个因素主要作用于第二个阶段（DM2→CDM2），经常吸烟和参与血糖监测频次较少的患者，由DM2转化CDM2的风险增大。主食、荤油、生活事件、健康教育和体力活动量5个因素对两个阶段的作用均有统计学意义。主食吃得越少，荤油吃得越多和经常经历剌激性生活事件的患者，由IGT转化为DM2和由DM2转化CDM2的风险越高；接受过糖尿病知识健康教育和经常参加体力活动的患者，由IGT转化为DM2和由DM2转化CDM2的风险均相应降低。结论对于IGT病人，控制体重、合理分配家庭收入、成甜食应作为重点防治措施；对于DM2病人，戒烟和经常参与血糖监测应作为重点防治措施。另外，无论是IGT病人还是DM2病人，为了延缓疾病的进程，适量增加谷类或面粉类主食，少吃荤油，保持乐观开朗的处世态度，经常参加一些糖尿病知识讲座，适当增加体力活动量，都是非常必要的。     

Extreme Gradient Boosting Model Has a Better Performance in Predicting the Risk of 90-Day Readmissions in Patients with Ischaemic Stroke

ObjectIschemic stroke readmission within 90 days of hospital discharge is an important quality of care metric. The readmission rates of ischemic stroke patients are usually higher than those of patients with other chronic diseases. Our aim was to identify the ischemic stroke readmission risk factors and establish a 90-day readmission prediction model for first-time ischemic stroke patients.MethodsThe readmission prediction model was developed using the extreme gradient boosting (XGboost) model, which can generate an ensemble of classification trees and assign a predictive risk score to each feature. The patient data were split into a training set (5159) and a validation set (911). The prediction results were evaluated with the receiver operating characteristic (ROC) curve and time-dependent ROC curve, which were compared with the outputs from the logistic regression (LR) model.ResultsA total of 6070 adult patients (39.6% female, median age 67 years) without any ischemic attack (IS) history were included, and 520 (8.6%) were readmitted within 90 days. The XGboost-based prediction model achieved a standard area under the curve (AUC) value of .782 (.729-.834), and the best time-dependent AUC value was .808 in 54 days for the validation set. In contrast, the LR model yielded a standard AUC value of .771 (.714-.828) and best time-dependent AUC value of .797.ConclusionsThe XGboost model obtained a better risk prediction for 90-day readmission for first-time ischemic stroke patients than the LR model. This model can also reveal the high risk factors for stroke readmission in first-time ischemic stroke patients.     

重组人骨形态发生蛋白2调节人脂肪间充质干细胞表达血管内皮生长因子

背景：重组人骨形态发生蛋白2可以促进组织工程骨血管化,但是对于其作用于人体细胞时的生物学规律不明确。目前对于重组人骨形态发生蛋白2调节人体细胞血管内皮生长因子表达的规律国内还未见相关报道。 目的：从基因和蛋白水平观察比较不同时间点重组人骨形态发生蛋白2诱导下人脂肪间充质干细胞血管内皮生长因子的表达。 方法：从成人脂肪组织中分离培养脂肪间充质干细胞,取第3代细胞用于实验,分为诱导组和对照组。诱导组采用终浓度为100 μg/L重组人骨形态发生蛋白2诱导人脂肪间充质干细胞,分别诱导3,6,12,18,24,36,48 h后收集样本,用RT-PCR和ELISA分别从基因水平和蛋白水平检测血管内皮生长因子的表达,并与空白对照组比较。 结果与结论：重组人骨形态发生蛋白2调节人脂肪间充质干细胞表达血管内皮生长因子具有时间依赖性,在不同时间点血管内皮生长因子表达量不同。与空白对照组相比,3-6 h时间段重组人骨形态发生蛋白2抑制血管内皮生长因子表达(P < 0.05),18-24 h时间段重组人骨形态发生蛋白2促进血管内皮生长因子表达(P < 0.05),当利用重组人骨形态发生蛋白2促进组织工程骨血管化时这两个时间段应当引起特别关注。     

Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats

The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of time-dependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg(-1) and 0.40 mg kg(-1)), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg(-1)), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h(-1) kg(-1) of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg(-1)) was approximately 8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.     

Prognostic significance of peripheral blood S + G2/M phase size in adult acute non-lymphoblastic leukaemia

Flow cytometric analysis of peripheral blood (PB) S + G2/M phase size was performed in 73 adult patients with untreated acute non-lymphoblastic leukaemia, to assess whether the results may correlate to response rate and patient prognosis. All patients were treated with the same induction chemotherapy regimen: ARA-C alone or in combination with an anthracycline antibiotic. Pretreatment PB S + G2/M phase size is significantly correlated to induction response rate (p less than 0.02), duration of response (p less than 0.02) and duration of survival. Patients with low PB S + G2/M phase size experience a longer survival, in patients over and below 50 yr (p less than 0.001). Lastly, early deaths tend to be more frequent in the high median age and high PB S + G2/M phase size group. Our study suggests that PB S + G2/M phase size has prognostic significance in obtaining response and duration of survival.     

Two types of diencephalically driven RSA (theta) as a means of studying memory formation in mice

In mice, electrical stimulation of the medial forebrain bundle (MFB) drove hippocampal RSA with a frequency range of 7–9 Hz, whereas stimulation of the dorsomedial hypothalamus (DMH) drove RSA at 9–12 Hz. The post-trial effects of both stimulations on operant conditioning were tested. Improved retention was observed, but MFB stimulation had a short gradient of effectiveness (5 min), whereas DMH stimulation had a long gradient (up to 1 h post-training).