A Bias Correction Method in Meta-analysis of Randomized Clinical Trials with no Adjustments for Zero-inflated Outcomes

Many clinical endpoint measures, such as the number of standard drinks consumed per week or the number of days that patients stayed in the hospital, are count data with excessive zeros. However, the zero-inflated nature of such outcomes is often ignored in analyses, which leads to biased estimates and, consequently, a biased estimate of the overall intervention effect in a meta-analysis. The current study proposes a novel statistical approach, the Zero-inflation Bias Correction (ZIBC) method, that can account for the bias introduced when using the Poisson regression model despite a high rate of zeros in the outcome distribution for randomized clinical trials. This correction method utilizes summary information from individual studies to correct intervention effect estimates as if they were appropriately estimated in zero-inflated Poisson regression models. Simulation studies and real data analyses show that the ZIBC method has good performance in correcting zero-inflation bias in many situations. This method provides a methodological solution in improving the accuracy of meta-analysis results, which is important to evidence-based medicine

A Simulation Study of the Performance of Statistical Models for Count Outcomes with Excessive Zeros

Background: Outcome measures that are count variables with excessive zeros are common in health behaviors research. There is a lack of empirical data about the relative performance of prevailing statistical models when outcomes are zero-inflated, particularly compared with recently developed approaches. Methods: The current simulation study examined five commonly used analytical approaches for count outcomes, including two linear models (with outcomes on raw and log-transformed scales, respectively) and three count distribution-based models (i.e., Poisson, negative binomial, and zero-inflated Poisson (ZIP) models). We also considered the marginalized zero-inflated Poisson (MZIP) model, a novel alternative that estimates the effects on overall mean while adjusting for zero-inflation. Extensive simulations were conducted to evaluate their the statistical power and Type I error rate across various data conditions. Results: Under zero-inflation, the Poisson model failed to control the Type I error rate, resulting in higher than expected false positive results. When the intervention effects on the zero (vs. non-zero) and count parts were in the same direction, the MZIP model had the highest statistical power, followed by the linear model with outcomes on raw scale, negative binomial model, and ZIP model. The performance of a linear model with a log-transformed outcome variable was unsatisfactory. When only one of the effects on the zero (vs. non-zero) part and the count part existed, the ZIP model had the highest statistical power. Conclusions: The MZIP model demonstrated better statistical properties in detecting true intervention effects and controlling false positive results for zero-inflated count outcomes. This MZIP model may serve as an appealing analytical approach to evaluating overall intervention effects in studies with count outcomes marked by excessive zeros

The relationship of examinees’ individual characteristics and perceived acceptability of smart device-based testing to test scores on the practice test of the Korea Emergency Medicine Technician Licensing Examination

Purpose Smart device-based testing (SBT) is being introduced into the Republic of Korea’s high-stakes examination system, starting with the Korean Emergency Medicine Technician Licensing Examination (KEMTLE) in December 2017. In order to minimize the effects of variation in examinees’ environment on test scores, this study aimed to identify any associations of variables related to examinees’ individual characteristics and their perceived acceptability of SBT with their SBT practice test scores. Methods Of the 569 candidate students who took the KEMTLE on September 12, 2015, 560 responded to a survey questionnaire on the acceptability of SBT after the examination. The questionnaire addressed 8 individual characteristics and contained 2 satisfaction, 9 convenience, and 9 preference items. A comparative analysis according to individual variables was performed. Furthermore, a generalized linear model (GLM) analysis was conducted to identify the effects of individual characteristics and perceived acceptability of SBT on test scores. Results Among those who preferred SBT over paper-and-pencil testing, test scores were higher for male participants (mean± standard deviation [SD], 4.36± 0.72) than for female participants (mean± SD, 4.21± 0.73). According to the GLM, no variables evaluated— including gender and experience with computer-based testing, SBT, or using a tablet PC—showed a statistically significant relationship with the total score, scores on multimedia items, or scores on text items. Conclusion Individual characteristics and perceived acceptability of SBT did not affect the SBT practice test scores of emergency medicine technician students in Korea. It should be possible to adopt SBT for the KEMTLE without interference from the variables examined in this study

Histidine 454 plays an important role in polymerization of human glutamate dehydrogenase

AbstractAlthough previous chemical modification studies have suggested several residues to be involved in the maintenance of the quaternary structure of glutamate dehydrogenase (GDH), there are conflicting views for the polymerization process and no clear evidence has been reported yet. In the present study, cassette mutagenesis at seven putative positions (Lys333, Lys337, Lys344, Lys346, Ser445, Gly446, and His454) was performed using a synthetic human GDH gene to examine the polymerization process. Of the mutations at the seven different sites, only the mutagenesis at His454 results in depolymerization of the hexameric GDH into active trimers as determined by HPLC gel filtration analysis and native gradient polyacrylamide gel electrophoresis. The mutagenesis at His454 has no effects on expression or stability of the protein. The KM values for NADH and 2-oxoglutarate were 1.5-fold and 2.5-fold greater, respectively, for the mutant GDH than for wild-type GDH, indicating that substitution at position 454 had appreciable effects on the affinity of the enzyme for both NADH and 2-oxoglutarate. The Vmax values were similar for wild-type and mutant GDH. The kcat/KM value of the mutant GDH was reduced up to 2.8-fold. The decreased efficiency of the mutant, therefore, results from the increase in KM values for NADH and 2-oxoglutarate. The results with cassette mutagenesis and HPLC gel filtration analysis suggest that His454 is involved in the polymerization process of human GDH

Complete Remission of Unresectable Colon Cancer after Preoperative Chemotherapy Selected by Adenosine Triphosphate-Based Chemotherapy Response Assay

The adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is a chemosensitivity test that offers the potential of selecting cancer treatments based on the responsiveness of individual tumors. We report a case of 47-yr-old male, presented with sigmoid colon cancer with multiple liver and peritoneal metastases, in which there was a complete response for the primary colon cancer after administration of preoperative chemotherapy selected by ATP-CRA. Oxaliplatin was the most sensitive drug based on the ATP-CRA where the specimen obtained by ultrasound-guided percutaneous liver biopsy was used. After twelve cycles of oxaliplatin-capecitabine chemotherapy, abdominopelvic computed tomography revealed marked shrinkage of the liver metastases and positron emission tomography showed no uptake of 18F-fluoro-deoxy-glucose (FDG) either in the liver or peritoneum except localized uptake in the sigmoid colon. The patient underwent an anterior resection and radiofrequency ablation of the liver metastases, which resulted in a macroscopic curative resection of the cancer cells. Histological examination revealed no residual cancer cells in the resected specimen of the sigmoid colon. This result suggested that preoperative chemotherapy chosen by ATP-CRA may be useful for treating advanced colon cancer with unresectable liver and peritoneal metastases

Conventional reversal of rocuronium-induced neuromuscular blockade by sugammadex in Korean children: pharmacokinetics, efficacy, and safety analyses

Background: Sugammadex is known to reverse neuromuscular blockade induced by non-depolarizing agents. In children, the recommended dose for reversal of moderate neuromuscular blockade is 2 mg/kg. We investigated the pharmacokinetics and pharmacodynamics of sugammadex in Korean children.Methods: Children (2–17 years of age) undergoing brain or spine surgery were enrolled and randomly assigned to control (neostigmine) and 2, 4, or 8 mg/kg sugammadex groups. Following induction of anesthesia and monitoring of the response to train-of-four stimulation, 1 mg/kg rocuronium was intravenously administered. Upon reappearance of the second twitch to train-of-four stimulation, the study drug was administered according to group allocation. The plasma concentrations of rocuronium and sugammadex were serially measured at nine predefined time points following study drug administration. To determine efficacy, we measured the time elapsed from drug administration to recovery of T4/T1 ≥ 0.9. For pharmacokinetics, non-compartmental analysis was performed and we monitored adverse event occurrence from the time of study drug administration until 24 h post-surgery.Results: Among the 29 enrolled participants, the sugammadex (2 mg/kg) and control groups showed recovery times [median (interquartile range)] of 1.3 (1.0–1.9) and 7.7 (5.3–21.0) min, respectively (p = 0.002). There were no significant differences in recovery time among the participants in sugammadex groups. The pharmacokinetics of sugammadex were comparable to those of literature findings. Although two hypotensive events related to sugammadex were observed, no intervention was necessary.Conclusion: The findings of this pharmacokinetic analysis and efficacy study of sugammadex in Korean children indicated that sugammadex (2 mg/kg) may be safely administered for reversing moderate neuromuscular blockade. Some differences in pharmacokinetics of sugammadex were observed according to age.Clinical Trial Registration:http://clinicaltrials.gov (NCT04347486

Brief motivational interventions for college student drinking may not be as powerful as we think: An individual participant-level data meta-analysis

Background For over two decades, brief motivational interventions (BMIs) have been implemented on college campuses to reduce heavy drinking and related negative consequences. Such interventions include in-person motivational interviews (MIs), often incorporating personalized feedback (PF), and stand-alone PF interventions delivered via mail, computer, or the Web. Both narrative and meta-analytic reviews using aggregate data from published studies suggest at least short-term efficacy of BMIs, although overall effect sizes have been small. Method The present study was an individual participant-level data (IPD) meta-analysis of 17 randomized clinical trials evaluating BMIs. Unlike typical meta-analysis based on summary data, IPD meta-analysis allows for an analysis that correctly accommodates the sampling, sample characteristics, and distributions of the pooled data. In particular, highly skewed distributions with many zeroes are typical for drinking outcomes, but have not been adequately accounted for in existing studies. Data are from Project INTEGRATE, one of the largest IPD meta-analysis projects to date in alcohol intervention research, representing 6,713 individuals each with two to five repeated measures up to 12 months post-baseline. Results We used Bayesian multilevel over-dispersed Poisson hurdle models to estimate intervention effects on drinks per week and peak drinking, and Gaussian models for alcohol problems. Estimates of overall intervention effects were very small and not statistically significant for any of the outcomes. We further conducted post hoc comparisons of three intervention types (Individual MI with PF, PF only, and Group MI) vs. control. There was a small, statistically significant reduction in alcohol problems among participants who received an individual MI with PF. Short-term and long-term results were similar. Conclusions The present study questions the efficacy and magnitude of effects of BMIs for college drinking prevention and intervention and suggests a need for the development of more effective intervention strategies