Bayesian consensus clustering for multivariate longitudinal data

In clinical and epidemiological studies, there is a growing interest in studying the heterogeneity among patients based on longitudinal characteristics to identify subtypes of the study population. Compared to clustering a single longitudinal marker, simultaneously clustering multiple longitudinal markers allow additional information to be incorporated into the clustering process, which reveals co-existing longitudinal patterns and generates deeper biological insight. In the current study, we propose a Bayesian consensus clustering (BCC) model for multivariate longitudinal data. Instead of arriving at a single overall clustering, the proposed model allows each marker to follow marker-specific local clustering and these local clusterings are aggregated to find a global (consensus) clustering. To estimate the posterior distribution of model parameters, a Gibbs sampling algorithm is proposed. We apply our proposed model to the primary biliary cirrhosis study to identify patient subtypes that may be associated with their prognosis. We also perform simulation studies to compare the clustering performance between the proposed model and existing models under several scenarios. The results demonstrate that the proposed BCC model serves as a useful tool for clustering multivariate longitudinal data.     

大鼠骨髓间充质干细胞培养鉴定及复方扶芳藤合剂含药血清对细胞增殖的影响

目的:建立SD大鼠骨髓间充质干细胞(BMSCs)的分离培养方法,观察不同浓度的复方扶芳藤合剂大鼠含药血清对大鼠BMSCs增殖的影响。方法:通过全骨髓贴壁法体外分离、培养、纯化BMSCs,对其进行细胞形态学观察,将BMSCs进行成骨、成脂定向诱导分化,采用流式细胞仪检测其表面标志物,分析其细胞周期,进行BMSCs鉴定;采用不同浓度(20%、10%和5%)的复方扶芳藤合剂含药血清和空白血清连续7 d对大鼠BM SCs进行干预,以CCK-8法检测其吸光度值,对比各组细胞生长情况。结果:BMSCs具有典型的成纤维样细胞形态,集落生长呈漩涡状。BMSCs成脂、成骨诱导后,油红O染色和茜素红染色均呈阳性。第3代BMSCs表型CD29、CD44、CD34、CD44表达分别为99.645%、99.677%、0.016%、0.133%;不同浓度的复方扶芳藤合剂含药血清和空白血清连续干预7 d后,CCK-8法检测显示:20%浓度的复方扶芳藤合剂含药血清组,其1~7 d的吸光度均值均高于20%浓度的空白血清组(P<0.05);10%的含药血清组的吸光度均值在3~7 d,高于10%的空白血清组(P<0.05);5%的含药血清组与5%的空白血清组比较无明显差异(P>0.05)。结论:全骨髓贴壁法分离、培养BM SCs,操作简单,方法稳定,可大量扩增BMSCs。扩增后的BMSCs具有间充质干细胞的生物学特性,具有多向分化潜能。复方扶芳藤合剂含药血清干预后的BMSCs增殖能力增强,其中20%浓度的复方扶芳藤合剂含药血清在本实验中为最佳干预浓度。     

肠炎清合剂治疗慢性复发型溃疡性结肠炎大肠湿热证的临床观察

目的:观察肠炎清合剂对慢性复发型溃疡性结肠炎(UC)大肠湿热证患者诱导缓解效果及维持治疗对复发的影响,并从神经-内分泌-免疫炎症网络方面探讨了其作用机制。方法:将112例符合要求的患者随机分成对照组55例和观察组57例。对照组内服美沙拉嗪肠溶片,1.0 g/次,4次/d;Mayo评分系统≥7分者,加服醋酸泼尼松片,0.75 mg·kg^-1·d^-1;加用双歧杆菌活菌散剂,1包/次,2次/d,餐后温水冲服。观察组在对照组治疗的基础上服用肠炎清合剂,1包/次,分早晚2次服用。两组疗程均为连续治疗6周,再每周门诊复诊1次。进入缓解期后,两组患者均给予美沙拉嗪肠溶片,0.5 g/次,3次/d,维持治疗;观察组仍内服肠炎清合剂内服,至大肠湿热证评分减少≥90%以上。记录进入6周内缓解期的人数和缓解时间;进行治疗前后结肠镜检查,并进行Geboes指数和Baron法评价;进行治疗前后大肠湿热证评分和Mayo评分;检测治疗前后外周血白细胞介素-6(IL-6),IL-8,IL^-10,IL^-17,血管活性肠肽(VIP),胃动素(MTL)和神经肽Y(NPY);随访24周,记录复发情况。结果:经6周治疗后,观察组临床有效率为100%,黏膜愈合率为96.4%,均分别高于对照组的89.09%和81.82%(P<0.05),两组患者内镜应答率均为100%;经6周治疗后,观察组临床缓解率为91.23%,高于对照组的76.36%(χ2=4.581,P<0.05),观察组平均缓解时间短于对照组(P<0.01);治疗后观察组结肠黏膜评分,Geboes指数、大肠湿热证评分和Mayo评分均低于对照组(P<0.01);观察组患者外周血IL-6,IL-8和IL^-17水平均低于对照组(P<0.01),IL^-10水平高于对照组(P<0.01);观察组患者外周血VIP,MTL水平均低对照组(P<0.01),NPY水平高于对照组(P<0.01);观察组复发率为17.54%,低于对照组的38.18%(χ2=5.955,P<0.05);观察组平均复发时间长于对照组(P<0.01)。结论:在常规西医治疗的基础上,肠炎清合剂用于慢性复发型UC大肠湿热证的治疗,可诱导病情缓解,缩短病程,并能降低复发率,推迟复发时间,并对神经-内分泌-免疫炎症网络具有调节作用,从而可改善病情。     

Evaluation of an acetated Ringer-based contrast material mixture for postmortem computed tomography angiography

PurposeThe purpose of this study was to compare an established postmortem contrast medium mixture based on polyethylene glycol (PEG) to an isotonic crystalloid with acetated Ringer solution (AR) as the base, both mixed with water-soluble iodinated contrast medium for postmortem computed tomography angiography (PMCTA) with the aim to avoid alterations of the corpse during autopsy.Materials and methodsThe study included 20 cadavers; 10 had PMCTA with AR and 10 with PEG. PMCTA images were analyzed with respect to image quality, vascular contrast patterns and artifacts. Autopsy was evaluated for visual, organ, vessel and haptic alterations. The Wilcoxon rank sum test was used to search for differences in image quality between the two groups. Statistical significance was set at P < 0.05.ResultsAR provided excellent contrast within the right coronary artery (P < 0.001) but a lack of contrast within the left coronary artery (P = 0.008) whereas PEG showed the opposite. A better image quality was observed in the PEG group by comparison with the AR group for right common carotid artery (P = 0.03), left common carotid artery (P = 0.01) and left coronary artery (P = 0.008). No differences were found for ascending aorta (P = 0.65), aortic arch (P = 0.09), right circle of Willis (P = 0.17), left circle of Willis (P = 0.08), inferior vena cava (P = 0.07) and abdominal aorta (P = 0.08). Severe extravasation occurred in all (10/10; 100%) cadavers in the AR group but in none (0/10; 0%) in the PEG group (P < 0.001). At autopsy, visual alteration with lilac discoloration of the face was observed in 4/10 cadavers (40%) in the AR group and in 9/10 cadavers (90%) in the PEG group (P = 0.057). Haptic alterations were observed in 3/10 cadavers (30%) in the AR group and 10/10 cadavers (100%) in the PEG group (P = 0.003).ConclusionAR results in contrast medium mixture extravasation in all cadavers, but PEG altered the autopsy more severely. Both carrier substances result in specific substance-related artifacts and dependent opacification of the coronary arteries, but PEG is recommended for PMCTA exclusively with regard to diagnostic imaging.     

Bayesian bent‐cable growth mixture tobit models for longitudinal data with skewness and detection limit: application to AIDS studies

This paper presents a new Bayesian methodology for identifying a transition period for the development of drug resistance to antiretroviral drug or therapy in HIV/AIDS studies or other related fields. Estimation of such a transition period requires an availability of longitudinal data where growth trajectories of a response variable tend to exhibit a gradual change from a declining trend to an increasing trend rather than an abrupt change. We assess this clinically important feature of the longitudinal HIV/AIDS data using the bent‐cable framework within a growth mixture Tobit model. To account for heterogeneity of drug resistance among subjects, the parameters of the bent‐cable growth mixture Tobit model are also allowed to differ by subgroups (subpopulations) of patients classified into latent classes on the basis of trajectories of observed viral load data with skewness and left‐censoring. The proposed methods are illustrated using real data from an AIDS clinical study. Copyright © 2016 John Wiley & Sons, Ltd.     

益气养阴合剂中10种有效成分的含量测定

目的：建立同时测定益气养阴合剂中丹参酮ⅡA、丹酚酸A、丹酚酸B、毛蕊异黄酮、毛蕊异黄酮葡萄糖苷、五味子醇甲、五味子醇乙、五味子甲素、五味子乙素、丹皮酚含量的方法。方法：采用Hedera C₁₈ ODS-2色谱柱（4.6 mm×250 mm，5 μm），以乙腈-0.1%磷酸水溶液梯度为流动相，柱温30℃，流速1.0 mL·min^-1，检测波长215nm。结果：毛蕊异黄酮、毛蕊异黄酮葡萄糖苷、丹皮酚、五味子醇甲、五味子醇乙、五味子甲素、五味子乙素、丹参酮ⅡA、丹酚酸A、丹酚酸B浓度分别在2.93~62.76（r=0.999 6）、2.53~54.06（r=0.999 9）、2.78~59.64（r=0.999 9）、2.72~58.38（r=0.999 2）、2.79~59.76（r=0.999 6）、2.87~61.44（r=0.999 7）、2.61~63.66（r=0.999 2）、2.28~48.78（r=0.999 6）、2.99~64.08（r=0.999 5）、2.69~57.66（r=0.999 1）范围内与峰面积呈良好的线性关系，平均回收率在93.23%~100.68%之间。结论：3批样品测定结果表明，建立的方法可以用于同时测定益气养阴合剂中10种成分的含量。     

Exploring the DNA mixture deconvolution through simulation

ABSTRACT

If an unambiguous single-source DNA profile is obtained from a crime scene, then a potential person of interest can either match or not match the crime scene profile and the likelihood ratio for the single matching genotype can be easily computed. Mixed DNA profiles on the other hand are typically ambiguous and a vast number of different likelihood ratios can be obtained depending on the genotype of a potential person of interest that is compared with the mixture later. In the absence of a person of interest it can be unclear how suitable the profile is for discriminating between donors and non-donors. We introduce a simulation method to explore the range of likelihood ratios that is expected to be obtained when a non-donor or a true donor is compared with the mixed DNA profile. Sampling is conditional on the mixture deconvolution obtained using probabilistic genotyping. These simulations help to decide whether or not a (mixed) profile is suitable for comparison to a person of interest. Moreover, the methods can be used to determine whether a profile is suitable for upload to a database and whether or not potential rework could be advised.     

升髓合剂防治化疗后骨髓抑制的临床研究

目的:观察患者临床症状、客观检测指标及用药期间是否出现不良反应等,评价升髓合剂对多西他赛联合顺铂方案(Docetaxel Combined with Cis-platinum,DP)化疗所致骨髓抑制的有效性及安全性。方法:将50例符合标准的恶性肿瘤患者随机分为两组,治疗组和对照组各25例。对照组:DP方案化疗同时加服地榆升白片,治疗组:在DP方案化疗基础上加用升髓合剂。2个周期后观察患者化疗后第3、7、14 d外周血细胞变化及骨髓抑制情况,化疗后中医临床症状评分及疗效以及体力状况评分(Karnofsky,KPS)、体质量变化及其不良反应。结果:①两组化疗完成率观察组明显高于对照组(P<0.05);②观察组血常规中白细胞、中性粒细胞、血小板计数治疗后1周与治疗前比较无统计学意义,(P>0.05),而对照组白细胞、中性粒细胞、血小板计数下降显著,与治疗前差异有统计学意义,(P<0.05);两组相比,化疗后1周观察组血常规白细胞、中性粒细胞、血小板水平明显高于对照组,差距有统计学意义(P<0.05);③化疗后2周观察组白细胞计数升高明显高于对照组,两组差异有显著性(P<0.05);④化疗后中医证候改善方面,观察组症状改善显著(P<0.05)。对照组症状上改善不明显(P>0.05),两组在总体症状改善率方面相比较有显著性差异,治疗组明显优于对照组(P<0.05);⑤治疗组KPS评分明显优于对照组(P<0.05);⑥治疗组不良反应的发生率明显低于对照组(P<0.05)。结论:升髓合剂对于多西他赛联合顺铂化疗方案引起的骨髓抑制等不良反应具有防治作用。     

Evaluation of the MHSeqTyper47 kit for forensically challenging DNA samples

Microhaplotypes have been highly regarded for forensic mixture DNA deconvolution because they do not experience interference from stutters in the same way as short tandem repeat markers, and they tend to be more polymorphic than single nucleotide polymorphism markers. However, forensic microhaplotype kits have not been reported. The MHSeqTyper47 kit genotypes 47 microhaplotype loci. In this study, MiSeq FGx sequencing metrics for MHSeqTyper47 were presented, and the genotyping accuracy of this kit was examined. The sensitivity of MHSeqTyper47 reached 62.5 pg, and full genotyping results were obtained from degraded DNA samples with degradation indexes ≤ 3.00. Full genotypes were obtained in the presence of 100 ng/μL tannin, 50 μM heme, 25 ng/μL humic acid, and 1.25 μg/μL indigo dye. In DNA mixture studies, a minimum of 31 loci of the minor contributor were correctly genotyped at 1:99 or 99:1 mixing ratios, with the cumulative random matching probability of these loci reaching 4.54 × 10⁻²⁵. Mixing ratios could be reliably predicted from two-donor DNA mixtures based on the loci with four called alleles. Taken together, these data showed that the MHSeqTyper47 kit was effective for forensically challenging DNA analysis.