Compliance with Testosterone Replacement Therapy in Patients with Testosterone Deficiency Syndrome: A 10-Year Observational Study in Korea.

PURPOSE: To determine the compliance rate with testosterone replacement therapy (TRT) in patients with testosterone deficiency syndrome (TDS), we evaluated the treatment continuation rate and the reasons for discontinuation of initial treatment according to each formulations and patient characteristics. MATERIALS AND METHODS: Among men over 40 years of age who were diagnosed with TDS and then underwent TRT, their medical records were retrospectively analyzed for those who were followed up for more than 10 years. RESULTS: A total of 640 patients were included in the analysis. It was found that 75.9% of patients continued treatment for 1 year after starting. Patients treated with 1,000 mg of testosterone undecanoate injection had the highest treatment rate. Inconvenience of medication was the most common reason for discontinuing treatment, followed by cost, concern about side effects, lack of efficacy, and symptom recovery. The reasons for discontinuing treatment differed according to the type of formulations, and the longest continuous treatment period in all patients was 15.4±7.6 months on average. The treatment continuation rate tended to be high in patients with low serum total testosterone before starting treatment, in patients with severe erectile dysfunction, and in patients using phosphodiesterase-5 (PDE5) inhibitors. CONCLUSIONS: Among the various formulations of TDS, testosterone undecanoate injection (1,000 mg) had the highest compliance rate. In addition, it was found that the reasons for discontinuation of treatment varied according to the characteristics of each formulation.

Extended negative binomial hurdle models.

Poisson models are widely used for statistical inference on count data. However, zero-inflation or zero-deflation with either overdispersion or underdispersion could occur. Currently, there is no available model for count data, that allows excessive occurrence of zeros along with underdispersion in non-zero counts, even though there have been reported necessity of such models. Furthermore, given an excessive zero rate, we need a model that allows a larger degree of overdispersion than existing models. In this paper, we use a random-effect model to produce a general statistical model for accommodating such phenomenon occurring in real data analyses.

H-likelihood approach for joint modeling of longitudinal outcomes and time-to-event data.

In longitudinal studies, a subject may have different types of outcomes that could be correlated. For example, a response variable of interest would be measured repeatedly over time on the same subject and at the same time, an event time representing a single event or competing-risks event is also observed. In this paper, we propose a joint modeling framework that accounts for the inherent association between such multiple outcomes via frailties (unobserved random effects). Among outcomes, at least one outcome is an event time that has a type of a single event or competing-risks event. For inference we use the hierarchical likelihood (h-likelihood) that provides an unified efficient fitting procedure for the joint models. Numerical studies are provided to show the performance of the proposed method and two data examples are shown.

A Methodological Perspective on the Longitudinal Cognitive Change after Stroke.

BACKGROUND/AIMS: Most studies of poststroke cognitive impairment (PSCI) have analyzed cognitive levels at specific time points rather than their changes over time. Furthermore, they seldom consider correlations between cognitive domains. We aimed to investigate the effects of these methodological considerations on determining significant PSCI predictors in a longitudinal stroke cohort. METHODS: In patients who underwent neuropsychological tests at least twice after stroke, we adopted a multilevel hierarchical mixed-effects model with domain-specific cognitive changes and a multivariate model for multiple outcomes to reflect their correlations. RESULTS: We enrolled 375 patients (median follow-up of 34.1 months). Known predictors of PSCI were generally associated with cognitive levels; however, most of the statistical significances disappeared when cognitive changes were set as outcomes, except age for memory, prior stroke and baseline cognition for executive/attention domain, and baseline cognition for visuospatial function. The multivariate analysis which considered multiple outcomes simultaneously further altered these associations. CONCLUSIONS: This study shows that defining outcomes as changes over time and reflecting correlations between outcomes may affect the identification of predictors of PSCI.

Antiplatelet effect of ticagrelor compared to tirofiban in non-ST-segment elevation ACS patients undergoing PCI. The result of the TE-CLOT trial.

Addition of a potent P2Y12 inhibitor to aspirin is the standard therapy for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa inhibitor, together with antiplatelet therapy, may be considered as part of initial therapy in NSTE-ACS patients with high-risk features. This study investigated the antiplatelet effect of ticagrelor loading dose (LD) versus tirofiban bolus injection with a post-bolus infusion on top of aspirin among NSTE-ACS patients planned to PCI. NSTE-ACS patients were randomised to receive either ticagrelor (n = 47) or tirofiban (n = 48). Platelet reactivity was assessed by light transmittance aggregometry at 0, 2, 8, and 24 hours (h) after treatment initiation. Primary endpoint was inhibition of platelet aggregation (IPA, 20 µM ADP, final extent) at 2 h after LD therapy, with a non-inferiority margin of 10%. The prevalence of high on-treatment platelet reactivity (HPR) was also compared at 0, 2, 8, and 24 h. The mean difference in IPA between ticagrelor and tirofiban was -9.9% (95% confidence interval: -25.7% to 5.9%) at 2 h, -1.6% (-8.0% to 4.8%) at 8 h, and -3.3% (-18.4% to 12.0%) at 24 h. The prevalence of HPR did not differ between the two groups at any time point (all p values ≥ 0.059), which was almost abolished by 8 h post-LD (< 5%). In conclusion, the antiplatelet effect during the early phase (~2 h) after ticagrelor LD appeared to be relatively strong, but it did not reach that of tirofiban in NSTE-ACS patients.

Spatial modeling of data with excessive zeros applied to reindeer pellet-group counts.

We analyze a real data set pertaining to reindeer fecal pellet-group counts obtained from a survey conducted in a forest area in northern Sweden. In the data set, over 70% of counts are zeros, and there is high spatial correlation. We use conditionally autoregressive random effects for modeling of spatial correlation in a Poisson generalized linear mixed model (GLMM), quasi-Poisson hierarchical generalized linear model (HGLM), zero-inflated Poisson (ZIP), and hurdle models. The quasi-Poisson HGLM allows for both under- and overdispersion with excessive zeros, while the ZIP and hurdle models allow only for overdispersion. In analyzing the real data set, we see that the quasi-Poisson HGLMs can perform better than the other commonly used models, for example, ordinary Poisson HGLMs, spatial ZIP, and spatial hurdle models, and that the underdispersed Poisson HGLMs with spatial correlation fit the reindeer data best. We develop R codes for fitting these models using a unified algorithm for the HGLMs. Spatial count response with an extremely high proportion of zeros, and underdispersion can be successfully modeled using the quasi-Poisson HGLM with spatial random effects.

Deprivation and suicide mortality across 424 neighborhoods in Seoul, South Korea: a Bayesian spatial analysis.

OBJECTIVES: A neighborhood-level analysis of mortality from suicide would be informative in developing targeted approaches to reducing suicide. This study aims to examine the association of community characteristics with suicide in the 424 neighborhoods of Seoul, South Korea. METHODS: Neighborhood-level mortality and population data (2005-2011) were obtained to calculate age-standardized suicide rates. Eight community characteristics and their associated deprivation index were employed as determinants of suicide rates. The Bayesian hierarchical model with mixed effects for neighborhoods was used to fit age-standardized suicide rates and other covariates with consideration of spatial correlations. RESULTS: Suicide rates for 424 neighborhoods were between 7.32 and 71.09 per 100,000. Ninety-nine percent of 424 neighborhoods recorded greater suicide rates than the Organization for Economic Cooperation and Development member countries' average. A stepwise relationship between area deprivation and suicide was found. Neighborhood-level indicators for lack of social support (residents living alone and the divorced or separated) and socioeconomic disadvantages (low educational attainment) were positively associated with suicide mortality after controlling for other covariates. CONCLUSIONS: Finding from this study could be used to identify priority areas and to develop community-based programs for preventing suicide in Seoul, South Korea.

Does a geographical context of deprivation affect differences in injury mortality? A multilevel analysis in South Korean adults residing in metropolitan cities.

BACKGROUND: This study aimed to examine whether the socioeconomic context of urban areas affects differences in adult mortality from injuries in the districts of all seven South Korean metropolitan cities, after adjusting for individual demographic and socioeconomic indicators. METHODS: Two different sets of data were used in this study: (1) the National Death Registration data from 2003 to 2008; and (2) the National Census in 2005. Variables for individual characteristics were gender, age, residential area and educational level. A geographic deprivation index was calculated based on the Carstairs Index. Multilevel Poisson regression models were used to analyse the relationship between area deprivation levels and injury mortality. RESULTS: Greater mortality risks of traffic accidents, falls, suicide and all injuries were found in the elderly, the less educated and men, compared with their counterparts. The most deprived districts were at greater risks of death due to traffic accidents (risk ratio (RR)=1.34; 95% CI 1.05 to 1.73), falls (RR=1.63; 95% CI 1.20 to 2.20), suicide (RR=1.09; 95% CI 1.01 to 1.17) and all injuries (RR=1.14; 95% CI 1.07 to 1.22) compared with the least deprived districts, even after individual level socioeconomic variables were controlled for. However, area level deprivation did not show cross level interactions with the individual level education in estimating fatal injury risks. CONCLUSIONS: Both contextual and compositional effects of socioeconomic status on injury mortality among urban areas in South Korea should be considered in allocating resources for injury prevention.

Are there spatial and temporal correlations in the incidence distribution of scrub typhus in Korea?

OBJECTIVES: A hierarchical generalized linear model (HGLM) was applied to estimate the transmission pattern of scrub typhus from 2001 to 2011 in the Republic of Korea, based on spatial and temporal correlation. METHODS: Based on the descriptive statistics of scrub typhus incidence from 2001 to 2011 reported to the Korean Centers for Disease Control and Prevention, the spatial and temporal correlations were estimated by HGLM. Incidences according to age, sex, and year were also estimated by the best-fit model out of nine HGLMs. A disease map was drawn to view the annual regional spread of the disease. RESULTS: The total number of scrub typhus cases reported from 2001 to 2011 was 51,136: male, 18,628 (36.4%); female, 32,508 (63.6%). The best-fit model selected was a combination of the spatial model (Markov random-field model) and temporal model (first order autoregressive model) of scrub typhus transmission. The peak incidence was 28.80 per 100,000 persons in early October and the peak incidence was 40.17 per 100,000 persons in those aged 63.3 years old by the best-fit HGLM. The disease map showed the spread of disease from the southern central area to a nationwide area, excepting Gangwon-do (province), Gyeongsangbuk-do (province), and Seoul. CONCLUSION: In the transmission of scrub typhus in Korea, there was a correlation to the incidence of adjacent areas, as well as that of the previous year. According to the disease map, we are unlikely to see any decrease in the incidence in the near future, unless ongoing aggressive measures to prevent the exposure to the vector, chigger mites, in rural areas, are put into place.

Spatial and Temporal Distribution of Plasmodium vivax Malaria in Korea Estimated with a Hierarchical Generalized Linear Model.

OBJECTIVES: The spatial and temporal correlations were estimated to determine Plasmodium vivax malarial transmission pattern in Korea from 2001-2011 with the hierarchical generalized linear model. METHODS: Malaria cases reported to the Korea Centers for Disease Control and Prevention from 2001 to 2011 were analyzed with descriptive statistics and the incidence was estimated according to age, sex, and year by the hierarchical generalized linear model. Spatial and temporal correlation was estimated and the best model was selected from nine models. Results were presented as diseases map according to age and sex. RESULTS: The incidence according to age was highest in the 20-25-year-old group (244.52 infections/100,000). Mean ages of infected males and females were 31.0 years and 45.3 years with incidences 7.8 infections/100,000 and 7.1 infections/100,000 after estimation. The mean month for infection was mid-July with incidence 10.4 infections/100,000. The best-fit model showed that there was a spatial and temporal correlation in the malarial transmission. Incidence was very low or negligible in areas distant from the demilitarized zone between Republic of Korea and Democratic People's Republic of Korea (North Korea) if the 20-29-year-old male group was omitted in the diseases map. CONCLUSION: Malarial transmission in a region in Korea was influenced by the incidence in adjacent regions in recent years. Since malaria in Korea mainly originates from mosquitoes from North Korea, there will be continuous decrease if there is no further outbreak in North Korea.

Braden Scale: evaluation of clinical usefulness in an intensive care unit.

AIM: This paper is a report of a study conducted to determine the usability and utility of the Braden in intensive care units. BACKGROUND: An understanding of the clinical usage of the Braden Scale is valuable when considering the incidence of pressure ulcers in a critical-care setting. METHODS: A retrospective analysis of 21,115 hospital-days of 715 inpatients in an intensive-care unit in 2006 in South Korea was applied to data extracted electronically from an electronic medical record system in October 2007. RESULTS: Of the 715 patients, 42 (5.9%) developed a pressure ulcer, corresponding to an incidence density of 198 ulcers per 1000 hospital-days. The usage rate of the Braden Scale was 11.26%, and an analysis of its utility, based on a receiver operating characteristic analysis with the cutoff set at 13, gave sensitivity, specificity, positive predictive values and negative predictive values of 75.9%, 47.3%, 18.1% and 92.8% respectively. There were weak correlations between the scores and nursing interventions except for the category of position changes. The variety of nursing interventions was also limited. CONCLUSION: Our data suggest that the Braden Scale has a very low usage rate and a low-to-moderate positive predictive performance. Our quantification of the relationship between Braden Scale score and nursing interventions indicates the need for a more comprehensive and fundamental approach to the use of this scale.

Mitochondrial DNA analysis of ancient human bones excavated from Nukdo island, S.Korea.

We have performed analyses using ancient DNA extracted from 25 excavated human bones, estimating around the 1(st) century B.C. Ancient human bones were obtained from Nukdo Island, which is located off of the Korean peninsula of East Asia. We made concerted efforts to extract ancient DNA of high quality and to obtain reproducible PCR products, as this was a primary consideration for this extensive kind of undertaking. We performed PCR amplifications for several regions of the mitochondrial DNA, and could determine mitochondrial haplogroups for 21 ancient DNA samples. Genetic information from mitochondrial DNA belonged to super-haplogroup M, haplogroup D or its sub-haplogroups (D4 or D4b), which are distinctively found in East Asians, including Koreans or Japanese. The dendrogram and principal component analysis based on haplogroup frequencies revealed that the Nukdo population was close to those of the East Asians and clearly distinguished from populations shown in the other regions. Considering that Nukdo is geologically isolated in the southern part of them Korean peninsula and is a site of commercial importance with neighboring countries, these results may reflect genetic continuity for the habitation and migration of ethnic groups who had lived in a particular area in the past. Therefore, we suggest that phylogenetic analyses of ancient DNA have significant advantages for clarifying the origins and migrations of ethnic groups, or human races.

Acute kidney injury after transarterial chemoembolization for hepatocellular carcinoma: a retrospective analysis.

BACKGROUND: Transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) may result in acute kidney injury (AKI) like other angiographic interventions. METHODS: To investigate the incidence, risk factor and outcomes of AKI after TACE, defined by Acute Kidney Injury Network (AKIN) criteria, we retrospectively analyzed 442 TACE treatment sessions in 236 HCC patients. RESULTS: The incidence of AKI in the first 48 h after TACE was 9.8% (23 of 236 patients at risk). Presence of hypertension (OR 3.24, 95% CI 1.21-8.72, p = 0.02), lower baseline serum albumin (OR 0.29, 95% CI 0.15-0.56, p < 0.01) and higher creatinine level (OR 12.02, 95% CI 3.49-41.39, p < 0.01) were independent risk factors of AKI. Prolonged renal insufficiency after 1 month was observed in 24.1% of AKI episodes. CONCLUSION: AKI is a common complication after TACE and we have to pay attention to the prevention and early recognition of AKI occurrence in high-risk patients.

Technical note: improved ancient DNA purification for PCR using ion-exchange columns.

A novel method of ancient DNA (aDNA) purification was developed using ion-exchange columns to improve PCR-amplifiable DNA extraction from ancient bone samples. Thirteen PCR-resistant ancient bone samples aged 500-3,300 years were tested to extract aDNA using a recently reported, silica-based aDNA extraction method and an ion-exchange column method for the further purification. The PCR success rates of the aDNA extracts were evaluated for the amplification ability of the fragments of mitochondrial DNA, a high-copy DNA, and amelogenin, a low-copy DNA. The results demonstrate that the further purification of silica-based aDNA extracts using ion-exchange columns considerably improved PCR amplification. We suggest that the ion-exchange column-based method will be useful for the improvement of PCR-amplifiable aDNA extraction, particularly from the poorly preserved, PCR-resistant, ancient samples.

Determinants of hospital closure in South Korea: use of a hierarchical generalized linear model.

Understanding causes of hospital closure is important if hospitals are to survive and continue to fulfill their missions as the center for health care in their neighborhoods. Knowing which hospitals are most susceptible to closure can be of great use for hospital administrators and others interested in hospital performance. Although prior studies have identified a range of factors associated with increased risk of hospital closure, most are US-based and do not directly relate to health care systems in other countries. We examined determinants of hospital closure in a nationally representative sample: 805 hospitals established in South Korea before 1996 were examined-hospitals established in 1996 or after were excluded. Major organizational changes (survival vs. closure) were followed for all South Korean hospitals from 1996 through 2002. With the use of a hierarchical generalized linear model, a frailty model was used to control correlation among repeated measurements for risk factors for hospital closure. Results showed that ownership and hospital size were significantly associated with hospital closure. Urban hospitals were less likely to close than rural hospitals. However, the urban location of a hospital was not associated with hospital closure after adjustment for the proportion of elderly. Two measures for hospital competition (competitive beds and 1-Hirshman--Herfindalh index) were positively associated with risk of hospital closure before and after adjustment for confounders. In addition, annual 10% change in competitive beds was significantly predictive of hospital closure. In conclusion, yearly trends in hospital competition as well as the level of hospital competition each year affected hospital survival. Future studies need to examine the contribution of internal factors such as management strategies and financial status to hospital closure in South Korea.

Dispersion frailty models and HGLMs.

In medical research recurrent event times can be analysed using a frailty model in which the frailties for different individuals are independent and identically distributed. However, such a homogeneous assumption about frailties could sometimes be suspect. For modelling heterogeneity in frailties we describe dispersion frailty models arising from a new class of models, namely hierarchical generalized linear models. Using the kidney infection data we illustrate how to detect and model heterogeneity among frailties. Stratification of frailty models is also investigated.

Robust ascertainment-adjusted parameter estimation.

Nonrandom ascertainment is commonly used in genetic studies of rare diseases, since this design is often more convenient than the random-sampling design. When there is an underlying latent heterogeneity, Epstein et al. ([2002] Am. J. Hum. Genet. 70:886-895) showed that it is possible to get unbiased or consistent estimation of population parameters under ascertainment adjustment, but Glidden and Liang ([2002] Genet. Epidemiol. 23:201-208) showed in a simulation study that the resulting estimates are highly sensitive to misspecification of the latent components. To overcome this difficulty, we consider a heavy-tailed model for latent variables that allows a robust estimation of the parameters. We describe a hierarchical-likelihood approach that avoids the integration used in the standard marginal likelihood approach. We revisit and extend the previous simulation, and show that the resulting estimator is efficient and robust against misspecification of the distribution of latent variables.