Clinical Implications of the Gastroesophageal Reflux Disease Questionnaire and Reflux Symptom Index in Patients With Suspected Laryngopharyngeal Reflux Symptoms.

Background/Aims: To evaluate the usefulness of gastroesophageal reflux disease questionnaire (GerdQ) and reflux symptom index (RSI) for diagnosis of gastroesophageal reflux disease (GERD) in patients with suspected laryngopharyngeal reflux (LPR) symptoms (cough, hoarseness, globus, and throat pain). Methods: A total of 98 patients with LPR symptoms were incorporated from either gastroenterology or otorhinolaryngology clinic. Patient's laryngoscopic findings were graded by reflux finding score (RFS), and RFS ≥ 7 was considered as positive LPR. Erosive esophagitis on endoscopy or abnormal results on ambulatory impedance-pH monitoring were used as diagnostic criteria for GERD. Esophageal motor function was evaluated using high-resolution esophageal manometry. Results: Ninety-three (94.9%) of the 98 subjects were diagnosed as LPR by RFS, but only 15 (15.3%) had GERD. For GerdQ, the cutoff value of 9 showed the highest area under curve (AUC) to diagnose GERD by receiver operating curve analysis (AUC = 0.565); the sensitivity, specificity, positive predictive value, and negative predictive value were unsatisfactory (50.0%, 70.7%, 22.6%, and 89.2%, respectively.) RSI also showed poor performance in diagnosing GERD; the cutoff value of 25 showed the highest yield (AUC = 0.581); the sensitivity, specificity, positive predictive value, and negative predictive value were 42.9%, 79.3%, 26.1%, and 89.0%, respectively. Ineffective esophageal motility was frequently observed (69 of 98, 70.4%), but there was no difference in esophageal motility parameters between GERD and non-GERD patients. Conclusions: In patients with LPR symptoms, significant discrepancies are observed between laryngoscopic diagnosis and GERD. In this population, neither GerdQ nor RSI is useful in diagnosing GERD.

Joint model for bivariate zero-inflated recurrent event data with terminal events.

Bivariate recurrent event data are observed when subjects are at risk of experiencing two different type of recurrent events. In this paper, our interest is to suggest statistical model when there is a substantial portion of subjects not experiencing recurrent events but having a terminal event. In a context of recurrent event data, zero events can be related with either the risk free group or a terminal event. For simultaneously reflecting both a zero inflation and a terminal event in a context of bivariate recurrent event data, a joint model is implemented with bivariate frailty effects. Simulation studies are performed to evaluate the suggested models. Infection data from AML (acute myeloid leukemia) patients are analyzed as an application.

Standardization of the first Korean national reference standard for snake (Gloydius brevicaudus) antivenom.

In 2017, the second national reference standard (NRS) for Gloydius snake venom was established to replace the first NRS for Gloydius snake venom. In connection with the second venom NRS, a candidate for the first NRS for Gloydius snake antivenom was produced in 2017. In this study, the qualification of the candidate was estimated and the potency was determined by a collaborative study. The potency (anti-lethal titer and anti-hemorrhagic titer) of the candidate was determined by measuring the capability of the antivenom to neutralize the lethal and hemorrhagic effects of the second NRS for Gloydius snake venom, which was calibrated against the regional reference standard for Gloydius snake antivenom established in 2006. Two Korean facilities contributed data from 20 independent assays. Subsequently, one foreign national control research laboratories participated in this collaborative study. The general common potency of the anti-lethal and anti-hemorrhagic titers was obtained from the results of a total of 25 tests performed at three facilities. According to the results of the present study, the candidate preparation showed good quality and is judged to be suitable to serve as the first NRS for Gloydius snake antivenom with the following potency: an anti-lethal titer of 3100 unit (U) (95% confidence interval 2991-3276 U) and anti-hemorrhagic titer of 3000 U (95% confidence interval 2849-3159 U). In conclusion, the first NRS for Gloydius snake antivenom was established in this study. This reference standard will be used routinely for quality control of a snake antivenom product by manufacturer in Korea, which also can be used for national quality control, including a national lot-release test of the snake antivenom product.

Joint model for recurrent event data with a cured fraction and a terminal event.

In a longitudinal study where the recurrence of an event and a terminal event such as death are observed, a certain portion of the subjects may experience no event during a long follow-up period; this often denoted as the cure group which is assumed to be the risk-free from both recurrent events and death. However, this assumption ignores the possibility of death, which subjects in the cure group may experience. In the present study, such misspecification is investigated with the addition of a death hazard model to the cure group. We propose a joint model using a frailty effect, which reflects the association between a recurrent event and death. For the estimation, an expectation-maximization (EM) algorithm was developed and PROC NLMIXED in SAS was incorporated under a piecewise constant baseline. Simulation studies were performed to check the performance of the suggested method. The proposed method was applied to leukemia patients experiencing both infection and death after bone marrow transplant.

[Development of Koreans Gut Quotient Measurement Scales].

BACKGROUND/AIMS: The aim of this study was to develop 'Koreans Gut Quotient Measurement Scales (GQ)', in which Koreans respond to questionnaires about the subjective feelings and symptoms of their intestinal health status. METHODS: Among 66 items pooled from previous studies and 4 items that were added following a focus group interview, 15 items were chosen using the Delphi survey. The content validity was evaluated using the content validity ratio. Data collected from 1,120 people from the general public in Korea were analyzed to verify the reliability and validity of GQ. RESULTS: The finalized GQ consisted of 17 items (including two exploratory measurement items) that were classified into three independent factors based on exploratory factor analysis (EFA): 'perceived intestine discomfort', 'bowel movement discomfort', and 'bowel movement control discomfort'. The discriminant and convergent validity of GQ were identified using EFA, reliability test, and confirmatory factor analysis. In addition, the criterion-related validity of GQ was identified using correlation and multiple regression analysis. CONCLUSIONS: The GQ, which is a simplified intestinal health index developed based on an easy questionnaire for the public to understand, can be used as a tool for the public to evaluate their own intestinal health and determine when to visit clinics.

A Collaborative Study to Establish the Second Korean National Reference Standard for Snake Venom.

In 2015, a candidate for the second national reference standard (NRS) of Gloydius snake venom was produced to replace the first NRS of Gloydius snake venom. In the present study, the potencies of the candidate were determined by a collaborative study, and the qualification of the candidate was estimated. The potencies of the candidate were determined by measuring the murine lethal titers and lapine hemorrhagic titers of venom against the regional working reference standard (RWRS) for antivenom using the methods described in the previous report for the first NRS of Gloydius snake venom. Three Korean facilities contributed data from a total of 30 independent assays. Subsequently, two foreign national control research laboratories contributed to this collaborative study. The results were calculated using the Reed-Muench method for lethality and determined using a mixed-effects model for hemorrhage. The general common potencies of the lethal and hemorrhagic titers were obtained from the results of the 30 tests performed at three Korean facilities. The results are expressed in micrograms for 1 test dose (TD) with a 95% confidence interval as follows: a lethal titer of 90.13 µg/TD (95% confidence interval = 87.39~92.86 µg) and a hemorrhagic titer of 10.80 µg/TD (95% confidence interval = 10.46~11.14 µg). In addition, the candidate preparation showed good quality evaluation according to the results of the quality estimation of the candidate and is judged to be suitable to serve as the Korean NRS for snake venom. In conclusion, the second NRS of Gloydius snake venom was established in this study and will be used for national quality control, including a national lot release test of Korean antivenom products.

[A case of colonic collision tumor (adenocarcinoma and neuroendocrine carcinoma)].

Collision tumors of the colon are rare. A 54-year-old man was referred to our hospital for the evaluation of hematochezia. Colonoscopy demonstrated the presence of about 3 cm sized mass in the rectosigmoid junction. After surgical resection, the colonic lesion was histologically composed of two discrete lesions: adenocarcinoma in the superficial layer and poorly differentiated neuroendocrine carcinoma in the deeper layer. We report this case of colonic collision tumor (adenocarcinoma and neuroendocrine carcinoma) with a review of the literature.

Regression analysis of clustered interval-censored data with informative cluster size.

Interval-censored data are commonly found in studies of diseases that progress without symptoms, which require clinical evaluation for detection. Several techniques have been suggested with independent assumption. However, the assumption will not be valid if observations come from clusters. Furthermore, when the cluster size relates to response variables, commonly used methods can bring biased results. For example, in a study on lymphatic filariasis, a parasitic disease where worms make several nests in the infected person's lymphatic vessels and reside until adulthood, the response variable of interest is the nest-extinction times. As the extinction times of nests are checked by repeated ultrasound examinations, exact extinction times are not observed. Instead, data are composed of two examination points: the last examination time with living worms and the first examination time with dead worms. Furthermore, as Williamson et al. (Statistics in Medicine 2008; 27:543-555) pointed out, larger nests show a tendency for low clearance rates. This association has been denoted as an informative cluster size. To analyze the relationship between the numbers of nests and interval-censored nest-extinction times, this study proposes a joint model for the relationship between cluster size and clustered interval-censored failure data. A proportional hazard model with random effect and a mixed ordinal regression model are applied to failure times and cluster size, respectively. The joint model approach addresses both the association among failure times from the same cluster and the dependency of failure times on cluster size. Simulation studies are performed to assess the finite sample properties of the estimators and lymphatic filariasis data are analyzed as an illustration.

Huang-Lian-Jie-Du-Tang supplemented with Schisandra chinensis Baill. and Polygonatum odoratum Druce improved glucose tolerance by potentiating insulinotropic actions in islets in 90% pancreatectomized diabetic rats.

We investigated to determine what effects, if any, the respective water extracts of Radix scutellariae (RS), Fructus schisandrae chinensis (FSC), Huang-Lian-Jie-Du-Tang (HLJDT), and HLJDT supplemented with FSC, and Rhizoma Polygonati odorati (HLJDT-M) would have on glucose tolerance by modulating glucose-stimulated insulin secretion, beta-cell mass, and morphometry in 90% pancreatectomized (Px) diabetic rats fed high-fat diets. Through the elevation of intracellular cAMP levels, FSC RS, HLJDT, and HLJDT-M increased insulin secretion in Min6 cells and GLP-1 secretion in NCI-H716 cells. After an 8-week period of treatment, it was found that HLJDT-M improved glucose tolerance in an oral glucose tolerance test in Px rats. HLJDT-M also potentiated first- and second-phase insulin secretion, but RS and HLJDT elevated only the second phase at hyperglycemic clamp. RS and HLJDT increased beta-cell mass by hyperplasia and hypertrophy, while HLJDT-M increased it only by hyperplasia. The rise in hyperplasia was associated with elevated IRS2 and PDX-1 expression in the islets. In conclusion, HLJDT-M worked as an anti-diabetic prescription by enhancing insulinotropic actions in diabetic rats.

A generalized log-rank-type test for comparing survivals with doubly interval-censored data.

In doubly interval-censored data, the survival time of interest is defined as the elapsed time between an initial event and a subsequent event, but the occurrences of both events cannot be observed exactly. Instead, only right- or interval-censored observations on the occurrence times are available. Our purpose is to develop a generalized log-rank-type test for comparing survival functions of several groups. For the same problem, Sun (The Statistical Analysis of Interval-censored Failure Time Data, Springer, New York) suggested a nonparametric test based on the estimated marginal survival functions of the two related events. We consider a new method using uniform weights, which depend only on the size of the risk set at each observed time. The proposed method does not require the estimation of marginal survival functions and furthermore can reduce to the log-rank test for right-censored data. Results from a simulation study show that our test performs well in terms of size and power. We analyze the AIDS cohort study data taken from Kim et al. (Biometrics 49, 13-22).

Treatment response and duration of maintenance treatment with adjunctive antidepressants in bipolar depression: A retrospective chart review.

Objective. The aim of this study was to investigate the treatment response and optimal maintenance period of antidepressants to minimize the risk of switching in bipolar depression in clinical practice. Methods. In a retrospective chart review, 78 bipolar patients, treated for a depressive episode by adding antidepressant to ongoing mood-stabilizing medications and had been followed for at least 6 months were identified. We determined recovery to euthymia and/or switching into mania during the 6-month follow-up period and estimated the time from antidepressant initiation to mood change. Results. Antidepressants treatment responses were classified into four groups. In one group, depression was sustained for 6 months despite continuous antidepressant treatment (poor-response group, 10.3%). In the second, abrupt switch into mania occurred during antidepressant treatment (acute-switch group, 19.2%). In the third, the depression improved to euthymia without manic switching (good-response group, 50%). In the fourth, the depression improved to euthymia but manic switching occurred during maintenance with antidepressants (delayed-switch group, 20.5%), and the mean duration of antidepressants maintenance was 54.6±38.9 days. Conclusions. Bipolar depression has heterogeneous treatment responses to adjunctive antidepressant. Antidepressants should be discontinued within 8 weeks after improvement to euthymia to minimize the risk of manic switching.

OutlierD: an R package for outlier detection using quantile regression on mass spectrometry data.

UNLABELLED: It is important to preprocess high-throughput data generated from mass spectrometry experiments in order to obtain a successful proteomics analysis. Outlier detection is an important preprocessing step. A naive outlier detection approach may miss many true outliers and instead select many non-outliers because of the heterogeneity of the variability observed commonly in high-throughput data. Because of this issue, we developed a outlier detection software program accounting for the heterogeneous variability by utilizing linear, non-linear and non-parametric quantile regression techniques. Our program was developed using the R computer language. As a consequence, it can be used interactively and conveniently in the R environment. AVAILABILITY: An R package, OutlierD, is available at the Bioconductor project at http://www.bioconductor.org

Analysis of recurrent event data with incomplete observation gaps.

In analysis of recurrent event data, recurrent events are not completely experienced when the terminating event occurs before the end of a study. To make valid inference of recurrent events, several methods have been suggested for accommodating the terminating event (Statist. Med. 1997; 16:911-924; Biometrics 2000; 56:554-562). In this paper, our interest is to consider a particular situation, where intermittent dropouts result in observation gaps during which no recurrent events are observed. In this situation, risk status varies over time and the usual definition of risk variable is not applicable. In particular, we consider the case when information on the observation gap is incomplete, that is, the starting time of intermittent dropout is known but the terminating time is not available. This incomplete information is modeled in terms of an interval-censored mechanism. Our proposed method is applied to the study of the Young Traffic Offenders Program on conviction rates, wherein a certain proportion of subjects experienced suspensions with intermittent dropouts during the study.

Cure rate model with interval censored data.

In cancer trials, a significant fraction of patients can be cured, that is, the disease is completely eliminated, so that it never recurs. In general, treatments are developed to both increase the patients' chances of being cured and prolong the survival time among non-cured patients. A cure rate model represents a combination of cure fraction and survival model, and can be applied to many clinical studies over several types of cancer. In this article, the cure rate model is considered in the interval censored data composed of two time points, which include the event time of interest. Interval censored data commonly occur in the studies of diseases that often progress without symptoms, requiring clinical evaluation for detection (Encyclopedia of Biostatistics. Wiley: New York, 1998; 2090-2095). In our study, an approximate likelihood approach suggested by Goetghebeur and Ryan (Biometrics 2000; 56:1139-1144) is used to derive the likelihood in interval censored data. In addition, a frailty model is introduced to characterize the association between the cure fraction and survival model. In particular, the positive association between the cure fraction and the survival time is incorporated by imposing a common normal frailty effect. The EM algorithm is used to estimate parameters and a multiple imputation based on the profile likelihood is adopted for variance estimation. The approach is applied to the smoking cessation study in which the event of interest is a smoking relapse and several covariates including an intensive care treatment are evaluated to be effective for both the occurrence of relapse and the non-smoking duration.

Regression analysis of doubly censored failure time data with frailty.

In doubly censored failure time data, the survival time of interest is defined as the elapsed time between an initial event and a subsequent event, and the occurrences of both events cannot be observed exactly. Instead, only right- or interval-censored observations on the occurrence times are available. For the analysis of such data, a number of methods have been proposed under the assumption that the survival time of interest is independent of the occurrence time of the initial event. This article investigates a different situation where the independence may not be true with the focus on regression analysis of doubly censored data. Cox frailty models are applied to describe the effects of covariates and an EM algorithm is developed for estimation. Simulation studies are performed to investigate finite sample properties of the proposed method and an illustrative example from an acquired immune deficiency syndrome (AIDS) cohort study is provided.

Regression analysis of doubly censored failure time data using the additive hazards model.

Doubly censored failure time data arise when the survival time of interest is the elapsed time between two related events and observations on occurrences of both events could be censored. Regression analysis of doubly censored data has recently attracted considerable attention and for this a few methods have been proposed (Kim et al., 1993, Biometrics 49, 13-22; Sun et al., 1999, Biometrics 55, 909-914; Pan, 2001, Biometrics 57, 1245-1250). However, all of the methods are based on the proportional hazards model and it is well known that the proportional hazards model may not fit failure time data well sometimes. This article investigates regression analysis of such data using the additive hazards model and an estimating equation approach is proposed for inference about regression parameters of interest. The proposed method can be easily implemented and the properties of the proposed estimates of regression parameters are established. The method is applied to a set of doubly censored data from an AIDS cohort study.