MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

A single-nucleotide polymorphism (SNP) in the promoter region of MDM2, SNP 309, is associated with hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus infection. The effect of p53 codon 72 polymorphism Arg72Pro on HCC risk remains inconsistent. This study evaluated the association of MDM2 and p53 polymorphisms with the presence and early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection. In total, 583 consecutive patients with chronic HBV infection were classified according to the presence (n = 287) or absence (n = 296) of HCC. The MDM2 SNP 309 and p53 Arg72Pro were genotyped using restriction fragment length polymorphism method. The MDM2 G/G and p53 Pro/Pro genotypes were more frequent in HCC group than in non-HCC group (P < 0.001 and P = 0.004, respectively). Multivariate analysis for the presence of HCC revealed that the odds ratio (OR) for MDM2 G/G over T/T was 4.89 (P < 0.001) and that of p53 Pro/Pro over Arg/Arg was 3.03 (P = 0.006). Combined MDM2 G/G and p53 Pro/Pro had a synergistic effect on HCC risk, with an OR of 20.78 (P < 0.001). The mean age of tumor onset in patients with MDM2 G/G genotype was 50.9 years compared with 55.1 with T/T genotype (P = 0.018) and that with p53 Pro/Pro was 49.7 years compared with 52.9 with Arg/Arg (P = 0.040). Thus, MDM2 SNP 309 and p53 Arg72Pro are associated with the early development of HCC in Korean patients with chronic HBV infection.ope

Non-invasive assessment of liver fibrosis by measuring the liver stiffness and biochemical markers in chronic hepatitis B patients

Background: Transient elastography (FibroScan(R)) is a rapid and non-invasive method to measure liver stiffness and this allow the assessment of liver fibrosis. The aim of this study was to assess the diagnostic accuracy of measuring the liver stiffness in addition to measuring the other biochemical markers such as the aspartate transaminase to platelet ratio index [APRI] and the AST/ALT ratio. Methods: We enrolled 228 HBsAg positive patients whose liver stiffness was measured by FibroScan(R) between March 2005 and September 2005. Liver biopsy examinations were performed in 34 patients. The fibrosis (F) was staged on a 0-4 scale according to the Ludwig classification. Results: According to the clinical diagnosis, the median values of liver stiffness were 7.0±2.7 kPa for inactive carriers (n=29), 8.3±5.3 kPa for chronic hepatitis patients (n=106), 15.9±8.3 kPa for compensated cirrhosis patients (n=63), 31.8±20.3 kPa for decompensated cirrhosis patients (n=26), and 45.1±34.5 kPa for HCC patients (n=4). The degree of liver stiffness was significantly different between the different disease groups (p<0.001). Liver stiffness was well correlated with the fibrosis stages (r=0.726; p< 0.001). The AUROC of FibroScan(R), the APRI and the AST/ALT ratio values were of the same order; 0.72, 0.61 and 0.58, respectively, for F≥2; 0.92, 0.73, and 0.56, respectively, for F≥3; and 0.97, 0.79, and 0.55, respectively, for F=4. FibroScan(R) offered the best diagnostic performance both for significant fibrosis (F≥2) and severe fibrosis-cirrhosis (F3-F4). Conclusions: FibroScan(R) is a reliable, rapid non-invasive method to diagnose the severity of chronic liver disease and to predict fibrosis in patients with chronic hepatitis B, in addition to using the APRI and AST/ALT ratio.ope

Efficacy of Individual Prediction Model for the Early Diagnosis of Hepatocellular Carcinoma

Background: Screening tests for hepatocellular carcinoma (HCC) in the high risk population can detect tumors at an earlier stage and thus confer a higher chance of receiving treatment. However, the usefulness, frequency and cost-effectiveness of screening for HCC may differ in different areas, possibly reflecting differences in risk factors. Last decade, we have identified risk factors for HCC in 4339 Korean patients. The aim of this study was to investigate the efficacy and usefulness of individual prediction model for the early diagnosis of HCC. Methods: We studied a total of 833 patients who visited Yonsei University Medical Center for regular check-up including ultrasonography and alpha-fetoprotein from January 1999 to December 2000. The patients were classified into a low risk group ( 15%) by the probability of HCC development according to individual prediction model (IPM). The patients who developed HCC during the follow-up periods were analyzed using IPM. All the detailed data of clinical parameters were obtained by our self-exploited data base system prospectively and analyzed by SAS program. Results: 44 (5.3%) out of 833 patients developed HCC during mean follow-up periods of 36 months. According to IPM, 2 (0.62%) of 324 patients in the low risk group, 20 (4.84%) of 413 patients in the intermediate risk group, and 22 (22.9%) of 96 patients in the high risk group were diagnosed as HCC. In 29 of 44 HCC patients (65.9%), initial presentation of tumor size was less than 3 cm in diameter. Conclusion: We confirmed the reliability of established IPM for screening of HCC and this model may help screening program to be done effectively by focusing high risk groups for HCCope

The Study of Ralph Vaughan Williamss song cycle <Songs of Travel> op.7

학위논문 (석사)-- 서울대학교 대학원 : 음악과(성악전공), 2013. 2. 서혜연.랄프 본 윌리엄스(Ralph Vaughan Williams, 1872-1958)는 17세기 바로크 시대를 대표하며 영국음악을 꽃피운 작곡가 헨리 퍼셀(Henry Purcell, 1659-1695) 이후, 영국이 낳은 최고의 작곡가로서 민족주의를 대표하는 작곡가이기도 하다. 랄프 본 윌리엄스는 가장 영국적인 음악으로 20세기 영국음악의 명성을 부흥시킨 인물이다. 특별히 영국 민요는 그의 예술적 영감의 원천이자 지향점이었다. ... 본 논문의 주제에 대한 이해를 돕고자 영국 음악의 시대적인 특징과 랄프 본 윌리엄스의 생애와 작품에 대해 조망해보았다. 이를 통하여 랄프 본 윌리엄스의 업적과 그가 형성한 영국음악의 특징을 발견하였다....국문초록 목차 및 악보목차 Ⅰ. 서 론 - 1 Ⅱ. 본 론 - 3 1. 영국음악의 시대적 배경과 특징 - 3 2. Ralph Vaughan Williams의 생애와 배경 - 7 3. Ralph Vaughan Williams의 작품 및 평가 - 11 4. 연가곡 『Song of Travel』Op.7 의 분석 - 14 4.1. 작곡 배경 - 14 4.2. 가사 해석 및 작품 분석 - 16 1) The Vagabond : 방랑자 - 16 2) Let Beauty Awake : 미(美)여 깨어나라 - 25 3) The Roadside Fire : 길가의 모닥불 - 33 4) Youth and Love : 젊은이와 사랑 - 41 5) In Dreams : 꿈에서 - 49 6) The Infinite Shining Heaven : 한량없이, 빛나는 하늘 - 56 7) Whither must I Wander? : 어디로 갈까? - 63 8) Bright is the Ring of Words : 밝게 울리는 목소리는 - 71 9) I Have Trod the Upward and the Downward Slope : 나는 오르막 내리막을 다 겪었네 - 78 Ⅲ. 결 론 - 84 참고문헌 - 86 Abstract - 88Maste

Methods for estimating penetrance from the Genotyped-Proband Design.

의학전산통계학협동과정 의학통계학전공/석사[한글] 본 논문에서는 유전자에서 희귀한 변이(mutation)의 침투율(penetrance)을 추정하기 위하여 지원자(volunteer), 또는 시조(proband)를 이용하는 단면연구(cross-sectional study)의 다른 형태인 GPD(Genotyped-proband desig n)를 이용하고, 그 중에서 Moore 등(2001)이 제시한 유사우도함수(pseudo likelihood function) 와 Chatterjee 등(2001)에 의하여 제안된 주변우도함수(marginal likelihood function)를 이용한 침투율의 추정에 관한 내용을 중점적으로 다룬다. 통계프로그램(S-PLUS)을 이용한 모의실험기법에서는 유사우도를 이용한 추정기법에 대한 평가를 하기 위하여, GPD에 기초한 모의자료를 멘델리안 계산(Li, 1976)을 적용하여 생성하였고, 유사우도추정기법과 환자-대조군 연구(case-control)에 기초한 추정기법을 비교했을 때, 다음과 같은 결론을 얻을 수 있었다. 첫째, 유사우도추정기법은 기존의 연구에 비해서, 조사해야 할 시조의 수(number of proband)에 덜 민감하다. 둘째, 변이가 드문 경우, 즉, 가 작은 경우에도 침투율을 추정하는데 있어서 보다 정확하게 추정치를 구할 수 있다는 것이다. -------------------- 핵심되는 말 : Genotyped-Proband Design, 침투율, 킨-코호트, EM 알고리즘, 시조, 유사우도, 주변우도 [영문] In the thesis, we developed the Genotyped-Proband Design(GPD), an alternative cross-sectional study that used volunteer or probands, for estimating the penetrance of a rare mutation. Especially, pseudo-likelihood (Moore et al, 2001), marginal-likelihood(Chatterjee et al, 2001) were main parts of the thesis about estimating penetrance. For the analysis of simulated data using S-PLUS, we generate pedigree data with respect to GPD, using Mendelian calculation in order to evaluate estimating method of pseudo-likelihood. Comparing to estimating method based on pseudo-likelihood and case-control, we found two conclusions. First, Pseudo-likelihood estimating method is less sensitive number of probands than case-control estimating method. Second, Pseudo-likelihood estimating method is more consistent estimate of penetrance than based on case-control approach in a rare mutation, small allele frequency.ope

Evidence that the ratio of donor kidney weight to recipient body weight, donor age, and episodes of acute rejection correlate independently with live donor graft function

BACKGROUND: We demonstrated that higher donor kidney weight-to-recipient body weight (KW/BW) ratio showed better graft function in acute rejection-free renal recipients. METHODS: We investigated the impacts of KW/BW ratios on the graft function including acute rejection and donor's age in 259 live-donor renal recipients. Renal parameters were measured yearly. Correlations between the variables and each parameter were assessed by mixed regression and analysis of variance. RESULTS: Renal function showed a positive correlation with the KW/BW ratio, but an inverse correlation with the rejection episodes and donor's age. The regression slope for serum creatinine or creatinine clearance by these covariants was consistent each year. On comparing the lower KW/BW ratios ( or =4.5), the higher was associated with better graft function. Increased donor's age was associated with worse graft function. CONCLUSIONS: KW/BW ratio, donor's age, and the number of acute rejections are independent covariants for graft function.ope

A study of HME model in time-course microarray data

의학전산통계학협동과정 의학통계학전공/박사[한글] DNA microarray 자료에 대한 통계적 분석방법 중 군집분석(clustering analysis)기법은 수많은 유전자들과 생물학적 네트워크의 복잡성을 가지는 유전자 발현자료의 분석에 대하여 유용하게 설명할 수 있는 방법이다. 그러나 이러한 군집분석방법은 시간에 따라 반복되는 자료에 대해서는 이러한 시간에 따른 정보를 이용할 수 없다는 제약을 가지고 있다. 그러므로 시간에 따른 유전자 발현자료에 대하여 각 유전자들에 대한 군집(cluster) 및 각 군집에 대한 특성을 파악하는 통계학적 방법이 요구되고 있다. 본 논문에서는 시간에 따른 반복측정 microarray 자료에 대하여 HME모형을 이용한 군집(clustering) 및 각 군집에 따른 특성을 선형혼합모형(linear mixed effect model)을 이용하여 추정하는 방법에 대하여 제안하였다. 제안된 모형의 방법론적 타당성을 확인하기 위하여, 모의자료를 이용하여 기존의 군집분석방법과 비교해 보았을 때 시간에 대한 영향력을 고려한 군집(clustering) 및 이에 대한 선형추세(linear trend)를 확인할 수 있었다. 아울러 본 연구의 방법에 대하여 실제 기존에 발표된자료들에도 적용시켰을 때, 기존에 보고된 결과와 유사함을 알 수 있었다. [영문]For statistical microarray data analysis, clustering analysis is a useful exploratory technique and offer the promise of studying the variation of many genes simutaneously. But most of the proposed clustering method are not rigorously solved for time-course microarray data cluster and for fitting time covariate, so statistical method is needed by forming cluster and representing linear trend of each cluster for each genes. In this thesis, we developed modified HME model to suggest clustering data and characterizing each cluster using linear mixed model. For validity of suggested HME model, we could make certain that each cluster and linear trend are existed against other proposed method in simulated data. Also, we applied our method to the published data in time-course microarray data and found that it was similar with reported result.ope

Haplotype combination of Calpain-10 gene polymorphism is associated with metabolic syndrome in type 2 diabetes

Patients with metabolic syndrome are at increased risk of developing cardiovascular disease. The combinations of the haplotype created by the alleles of three single nucleotide polymorphisms (SNPs): SNP-43, -19, and -63 of the Calpain-10 gene (CAPN10), have been reported to be associated with the risk of type 2 diabetes in many populations. The aim of this study was to examine the association of the CAPN10 polymorphism with metabolic syndrome in patients with type 2 diabetes in Korea. Overall, 382 patients with type 2 diabetes were enrolled in this study. All the subjects were genotyped according to CAPN10 SNP-43, -19, and -63. The restriction fragment length polymorphism method was used for the three SNPs. The baseline presence of components of metabolic syndrome was determined. Two hundred and sixty-five (69.4%) patients had metabolic syndrome. Patients with the 111/121 haplotype combination showed a higher risk of hypertension than the other haplotype combinations (odd ratio (OR) = 2.334, P = 0.010). Patients with the 111/121 haplotype combination had a significantly high risk of metabolic syndrome (OR = 1.927, P = 0.042). The results of this study suggest that a novel 111/121 haplotype combination created by the CAPN10 SNP-43, -19, and -63 increases the susceptibility to the metabolic syndrome in patients with type 2 diabetes.ope

Regression Methods for Overdispersed Dichotomous Response Data

In neuropsychiatrical research, many problems of statistical inference concern the relationship between the PTSD and traumatic experiences. The logistic model is widely used for modeling a relationship between the covariate and the magnitude of the PTSD. A common complication in the logistic model for dichotomous response data is overdispersion. In this study, two different methods for analyzing dichotomous response data are illustrated and compared. One method is the logistic regression approach, where the numbers of dichotomous responses are predicted by the logistic function of covariates. The other one is the overdispersed logistic regression approach, where the overdispersion is measured by a scale parameter in the variance function of the dichotomous response. In dichotomous response model, when reponses are overdispersed, the overdispersed logistic regression produces more appropriate standard errors of the regression coefficients and the 95% confidence intervals of odds ratios. Therefore, in neuropsychiatrical research, it is recommended to examine the overdispersion problems for their data set before applying the logistic regression model.ope

Time-dependent Effect of Non-immunologic Factors on the Graft Survival and Graft Function in Haplotype Matched Living Donor Renal Transplant Recipients

Purpose: In the analysis of risk factors affecting the renal graft survival and graft function, time-dependent effect of each risk factor should be differentiated from net effect of risk factor. We attempted to analyze the impact of immunologic and/or non-immunologic risk factors on the graft function and survival after renal transplantation among the recipients having same immunologic risks at the time of transplantation. Methods: Three hundred ninety recipients who underwent haplotype matched living related donor kidney transplantation and have been regularly followed-up were retrospectively evaluated in a single center. All recipients were treated with cyclosporine-based double or triple regimens. The graft function was evaluated by serum creatinine (Scr) level and 24 hours urinary excretion of protein every year until 5 years after transplantation. The donor kidney weight/ recipient body weight ratio (KW/BW), donor age/ recipient age ratio (DA/RA), donor-recipient sex (D-R sex) relationship, and episodes of acute rejection (AR) within 1 year were regarded as the potential risk factors affecting the graft survival and function in this study. Kaplan-Meier method and Cox proportional-hazard model were used for survival analysis. ANOVA to evaluate time-point difference of graft function, and repeated measures ANOVA to evaluate the yearly difference of graft function were used. Results: Only the episode of AR was a significant risk factor affecting the graft survival. However, each non-immunologic risk factors (KW/BW, DA/RA, D-R sex) and AR episode persistently showed statistically significant impact on Scr level until 5 years after transplantation. Recipients having lowest KW/BW (1st Q KW/BW) and highest DA/RA (4th Q DA/RA) had experienced accelerated increment of Scr level from 4th year after transplantation. From 3rd year after transplantation, there is a significant correlation between the numbers of non-immunologic risk factor the recipients having had and yearly increment of Scr level. However, episode of AR didn’t influence the annual slope of Scr level even 4th year after transplantation. Conclusion: Non-immunologic risk factors had an detrimental effect on renal graft function, especially from 3rd year after transplantation. To have a better long-term graft function, non-immunologic risk factors should be considered from the time of live donor evaluation for transplantation. From the early period of transplantation, the recipients should be aware of the negative impact of overweight in terms of graft function and other metabolic derangement.ope