Hyunsoon Cho

INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis.

Background Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16INK4a, p15INK4b, ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs. Methodology/Principal Findings We analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15INK4b, p16INK4a, ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs. Conclusions/Significance Genotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.

Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging

Expression of the p16INK4a tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age‐induced functional decline of certain self‐renewing compartments. These observations have suggested that p16INK4a expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16INK4a expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T‐lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16INK4a, but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16INK4a expression did not independently correlate with gender or body‐mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16INK4a expression was associated with plasma interleukin‐6 concentration, a marker of human frailty. These data suggest that p16INK4a expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.

Bayesian Case Influence Diagnostics for Survival Models

We propose Bayesian case influence diagnostics for complex survival models. We develop case deletion influence diagnostics for both the joint and marginal posterior distributions based on the Kullback-Leibler divergence (K-L divergence). We present a simplified expression for computing the K-L divergence between the posterior with the full data and the posterior based on single case deletion, as well as investigate its relationships to the conditional predictive ordinate. All the computations for the proposed diagnostic measures can be easily done using Markov chain Monte Carlo samples from the full data posterior distribution. We consider the Cox model with a gamma process prior on the cumulative baseline hazard. We also present a theoretical relationship between our case-deletion diagnostics and diagnostics based on Coxs partial likelihood. A simulated data example and two real data examples are given to demonstrate the methodology.

Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study

Objective To investigate whether screening for thyroid cancer led to the current “epidemic” in South Korea. Design Review of the medical records of nationally representative samples of patients with a diagnosis of thyroid cancer in 1999, 2005, and 2008. Setting Sample cases were randomly selected from South Korea’s nationwide cancer registry, using a systematic sampling method after stratification by region. Participants 5796 patients with thyroid cancer were included (891 in 1999, 2355 in 2005, and 2550 in 2008). Main outcome measures The primary outcome was age standardised incidence of thyroid cancer and the changes in incidence between 1999 and 2008 according to the methods used to detect tumours (screen detection versus clinical detection versus unspecified). Results Between 1999 and 2008, the incidence of thyroid cancer increased 6.4-fold (95% confidence interval 4.9-fold to 8.4-fold), from 6.4 (95% confidence interval 6.2 to 6.6) per 100 000 population to 40.7 (40.2 to 41.2) per 100 000 population. Of the increase, 94.4% (34.4 per 100 000 population) were for tumours less than 20 mm, which were detected mainly by screening. 97.1% of the total increase was localised and regional tumours according to the Surveillance, Epidemiology, and End Results (SEER) summary stage. Where cases were clinically detected, 99.9% of the increased incidences (6.4 per 100 000 population) over the same period were tumours less than 20 mm. Conclusion The current “epidemic” of thyroid cancer in South Korea is due to an increase in the detection of small tumours, most likely as a result of overdetection. Concerted efforts are needed at a national level to reduce unnecessary thyroid ultrasound examinations in the asymptomatic general population.

PERTURBATION AND SCALED COOK'S DISTANCE

Cooks (Cook, 1977) distance is one of the most important diagnostic tools for detecting influential individual or subsets of observations in linear regression for cross-sectional data. However, for many complex data structures (e.g., longitudinal data), no rigorous approach has been developed to address a fundamental issue: deleting subsets with different numbers of observations introduces different degrees of perturbation to the current model fitted to the data and the magnitude of Cooks distance is associated with the degree of the perturbation. The aim of this paper is to address this issue in general parametric models with complex data structures. We propose a new quantity for measuring the degree of the perturbation introduced by deleting a subset. We use stochastic ordering to quantify the stochastic relationship between the degree of the perturbation and the magnitude of Cooks distance. We develop several scaled Cooks distances to resolve the comparison of Cooks distance for different subset deletions. Theoretical and numerical examples are examined to highlight the broad spectrum of applications of these scaled Cooks distances in a formal influence analysis.

Risk of Second Primary Cancer among Prostate Cancer Patients in Korea: A Population-Based Cohort Study

As patients with prostate cancer have a long life expectancy, there is increasing interest in predicting the risk of development of a second primary cancer (SPC), and we therefore designed this study to estimate the overall risk of developing SPCs among Korean prostate cancer patients. We used a population-based cohort from the Korean Central Cancer Registry composed of 55,378 men diagnosed with a first primary prostate cancer between 1993 and 2011. Standardized incidence ratios (SIRs) of SPCs were analyzed by age at diagnosis, latency period, period of diagnosis, and type of initial treatment. Survival analysis was stratified by development of SPC. Men with primary prostate cancer had an overall lower risk of developing an SPC [SIR = 0.75; 95% CI, 0.72−0.78], which was significant for SPCs of the esophagus, stomach, rectum, liver, gallbladder, bile duct, pancreas, larynx, lung, and bronchus. In contrast, there were significant increases in the risk of bladder and thyroid cancers, which tended to decrease after longer follow-up. Patients who received initial radiation therapy had an increased risk of subsequent rectal cancer, although this was still lower than that of the general male population. Other urinary tract cancers including those of the kidney, renal pelvis, and ureter tended to be associated with a higher risk of developing an SPC, but this difference did not reach statistical significance. The patients with prostate cancer and SPC had lower overall survival rates than those with one primary prostate cancer. Our findings suggest that men with prostate cancer have a 25% lower risk of developing an SPC in Korea, but a higher risk of developing subsequent bladder and thyroid cancers, which suggests the need for continued cancer surveillance among prostate cancer survivors.

Trends and Age-Period-Cohort Effects on the Incidence and Mortality Rate of Cervical Cancer in Korea

Purpose This study was conducted to describe the trends and age-period-cohort effects on the incidence and mortality rate of cervical cancer in Korea. Materials and Methods The incidence and mortality rate of cervical cancer among ≥ 20-year-old women from 1993 to 2012 were obtained from the Korea Central Cancer Registry and the Korean Statistical Information Service. Age-standardized rates were calculated and Joinpoint regression was used to evaluate the trends in the incidence and mortality rate. Age-period-cohort analysis was performed to investigate the independent effects of age, period and cohort. Results The incidence of cervical cancer decreased from 32.8 per 100,000 in 1993 to 15.9 per 100,000 in 2012 (annual percent change [APC], –3.9%; 95% confidence interval [CI], –4.2% to –3.6%). The mortality rate decreased from 5.2 per 100,000 in 1993 to 2.1 per 100,000 in 2012 (APC, –4.8%; 95% CI, –5.1% to –4.4%); however, the incidence and mortality rates among young women (< 30 years old) increased. An age-period-cohort model of the incidence and mortality rate showed decreasing period effects between 1993 and 2008 and decreasing cohort effects between 1928 and 1973, while birth cohorts after 1973 exhibited slight increases in the incidence and mortality rate of cervical cancer. Conclusion Recent decreases in the incidence and mortality rate of cervical cancer were due to decreases in the period and cohort effects, which reflect the implementation of a cancer screening program and changes in lifestyle. However, our findings also highlighted an increase in cohort effects on the incidence and mortality rate among young women born after 1973.

Bayesian Case Influence Measures for Statistical Models With Missing Data

We examine three Bayesian case influence measures including the φ-divergence, Cook’s posterior mode distance, and Cook’s posterior mean distance for identifying a set of influential observations for a variety of statistical models with missing data including models for longitudinal data and latent variable models in the absence/presence of missing data. Since it can be computationally prohibitive to compute these Bayesian case influence measures in models with missing data, we derive simple first-order approximations to the three Bayesian case influence measures by using the Laplace approximation formula and examine the applications of these approximations to the identification of influential sets. All of the computations for the first-order approximations can be easily done using Markov chain Monte Carlo samples from the posterior distribution based on the full data. Simulated data and an AIDS dataset are analyzed to illustrate the methodology. Supplemental materials for the article are available online.

Current Trends in the Incidence and Survival Rate of Urological Cancers in Korea.

Purpose This descriptive study assessed the current trends in the incidence of urological cancers and patient survival in Korea. Materials and Methods In this nationwide retrospective observational study based on the data from the Korea National Cancer Incidence Database (KNCIDB), this study analyzed the age-standardized incidence rates (ASRs) and annual percentage changes (APCs) of kidney, bladder, prostate, testicular, and penile cancers as well as cancer of the renal pelvis and ureter between 1999 and 2012. The relative survival rates (RSRs) were calculated for urological cancer patients diagnosed between 1993 and 2012 from the KNCIDB data. Results Prostate cancer was diagnosed in 66,812 individuals followed by bladder (41,549) and kidney (36,836) cancers. The overall ASR (18.26 per 100,000) increased with age because of the higher ASRs of bladder and prostate cancers in the elderly. The ASR for kidney cancer was highest in the 40-59-year-old group, whereas testicular cancer occurred most frequently before the age of 40. The incidence of most urological cancers increased (overall APC, 6.39%; p < 0.001), except for penile (APC, –2.01%; p=0.05) and bladder (APC, –0.40%; p=0.25) cancers. The overall survival increased steadily (5-year RSR, 66.4% in 1993-1995 vs. 84.2% in 2008-2012; p < 0.001), particularly for prostate (by 34.10%) and kidney (by 16.30%) cancers, but not for renal pelvis and ureter cancers (–7.20%). Conclusion The most common urological cancer in Korea was prostate cancer followed by bladder and kidney cancers. The incidence of most urological cancers, except for penile and bladder cancers, increased. Survival also increased, particularly for prostate and kidney cancers.

Socioeconomic Inequalities in Stomach Cancer Screening in Korea, 2005–2015: After the Introduction of the National Cancer Screening Program

Purpose This study aimed to investigate socioeconomic inequalities in stomach cancer screening in Korea and trends therein across income and education groups. Materials and Methods Data from the Korean National Cancer Screening Survey, a nationwide cross-sectional survey, were utilized. A total of 28913 men and women aged 40 to 74 years were included for analysis. Prior experience with stomach cancer screening was defined as having undergone either an endoscopy or gastrointestinal series within the past two years. The slope index of inequality (SII) and relative index of inequality (RII) were evaluated to check inequalities. Results Stomach cancer screening rates increased from 40.0% in 2005 to 74.8% in 2015, with an annual percent change of 5.8% [95% confidence interval (CI) 4.2 to 7.5]. Increases in stomach cancer screening rates were observed for all age, education, and household income groups. Inequalities in stomach cancer screening were noted among individuals of differing levels of education, with a pooled SII estimate of 6.14% (95% CI, 3.94 to 8.34) and RII of 1.26 (95% CI, 1.12 to 1.40). Also, income-related inequalities were observed with an SII of 6.93% (95% CI, 4.89 to 8.97) and RII of 1.30 (95% CI, 1.17 to 1.43). The magnitude of inequality was larger for income than for education. Conclusion Both education and income-related inequalities were found in stomach cancer screening, despite a continuous increase in screening rate over the study period. Income-related inequality was greater than education-related inequality, and this was more apparent in women than in men.