Chanjuan Li

Optimal Caliper Width for Propensity Score Matching of Three Treatment Groups: A Monte Carlo Study

Propensity score matching is a method to reduce bias in non-randomized and observational studies. Propensity score matching is mainly applied to two treatment groups rather than multiple treatment groups, because some key issues affecting its application to multiple treatment groups remain unsolved, such as the matching distance, the assessment of balance in baseline variables, and the choice of optimal caliper width. The primary objective of this study was to compare propensity score matching methods using different calipers and to choose the optimal caliper width for use with three treatment groups. The authors used caliper widths from 0.1 to 0.8 of the pooled standard deviation of the logit of the propensity score, in increments of 0.1. The balance in baseline variables was assessed by standardized difference. The matching ratio, relative bias, and mean squared error (MSE) of the estimate between groups in different propensity score-matched samples were also reported. The results of Monte Carlo simulations indicate that matching using a caliper width of 0.2 of the pooled standard deviation of the logit of the propensity score affords superior performance in the estimation of treatment effects. This study provides practical solutions for the application of propensity score matching of three treatment groups.

Immunogenicity and safety of a 23-valent pneumococcal polysaccharide vaccine in Chinese healthy population aged >2 years: A randomized, double-blinded, active control, phase III trial

Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. Vaccines have become the most effective way to prevent pneumococcal infections. This phase III trial was designed to evaluate the immunogenicity and safety of a 23-valent pneumococcal polysaccharide vaccine in Chinese healthy population aged >2 years. We conducted a randomized, double-blinded, active-controlled, multicenter trial in which 1660 healthy population (>2 years of age) were randomly assigned in a 1 : 1 ratio to receive 2 intramuscular doses of either the treatment vaccine or the active control vaccine, PNEUMOVAX 23. The surveillance period was 30 days. The primary end point was the 2-fold increase rate of anti-pneumococcal antibody for all 23 included serotypes in each group. In the intention-to-treat cohort, the 2-fold increase rate of anti-pneumococcal antibody for 23 included serotypes varied from 62.47% to 97.01% in the treatment group, and from 51.49% to 95.77% in the control group. According to −10% non-inferiority margin and 95% confidence intervals of rate difference, almost all included serotypes of the treatment group reached non-inferiority to control group except for serotype 6B, the lower limit of rate difference of which was −10.00%, equal to the non-inferiority margin. The 2-fold increase rates of anti-pneumococcal antibody were significantly higher in the treatment group for serotype 2, 3, 4, 10A, 11A and 20. Furthermore, for all 23 serotypes, IgG geometric mean concentrations (GMCs) at day 30 were significantly higher in treatment group for serotype 2, 3, 4, 9V, 10A, 11A, 15B, 18C, 19A, 22F and 33F. Higher geometric mean fold increase (GMFI) were also observed in the treatment group correspondingly. Serious adverse events occurred in 3 of 830 participants in the treatment group (0.36%) and 2 of 830 participants in the control group (0.24%). No death occurred during the trial. The frequencies of both solicited and unsolicited adverse events (AEs) were small lower in the treatment group (34.34% vs 35.66% for solicited AEs, 4.34% vs 5.42% for unsolicited AEs). Both vaccines were well tolerated and most AEs were mild or moderate in intensity. The newly vaccine was well tolerated and immunologically non-inferior to the active control vaccine PNEUMOVAX 23 for all 23 vaccine serotypes in the Chinese population (>2 years of age).

A web-based quantitative signal detection system on adverse drug reaction in China

ObjectiveTo establish a web-based quantitative signal detection system for adverse drug reactions (ADRs) based on spontaneous reporting to the Guangdong province drug-monitoring database in China.MethodsUsing Microsoft Visual Basic and Active Server Pages programming languages and SQL Server 2000, a web-based system with three software modules was programmed to perform data preparation and association detection, and to generate reports. Information component (IC), the internationally recognized measure of disproportionality for quantitative signal detection, was integrated into the system, and its capacity for signal detection was tested with ADR reports collected from 1 January 2002 to 30 June 2007 in Guangdong.ResultsA total of 2,496 associations including known signals were mined from the test database. Signals (e.g., cefradine-induced hematuria) were found early by using the IC analysis. In addition, 291 drug-ADR associations were alerted for the first time in the second quarter of 2007.ConclusionsThe system can be used for the detection of significant associations from the Guangdong drug-monitoring database and could be an extremely useful adjunct to the expert assessment of very large numbers of spontaneously reported ADRs for the first time in China.

A Practical Simulation Method to Calculate Sample Size of Group Sequential Trials for Time-to-Event Data under Exponential and Weibull Distribution

Group sequential design has been widely applied in clinical trials in the past few decades. The sample size estimation is a vital concern of sponsors and investigators. Especially in the survival group sequential trials, it is a thorny question because of its ambiguous distributional form, censored data and different definition of information time. A practical and easy-to-use simulation-based method is proposed for multi-stage two-arm survival group sequential design in the article and its SAS program is available. Besides the exponential distribution, which is usually assumed for survival data, the Weibull distribution is considered here. The incorporation of the probability of discontinuation in the simulation leads to the more accurate estimate. The assessment indexes calculated in the simulation are helpful to the determination of number and timing of the interim analysis. The use of the method in the survival group sequential trials is illustrated and the effects of the varied shape parameter on the sample size under the Weibull distribution are explored by employing an example. According to the simulation results, a method to estimate the shape parameter of the Weibull distribution is proposed based on the median survival time of the test drug and the hazard ratio, which are prespecified by the investigators and other participants. 10+ simulations are recommended to achieve the robust estimate of the sample size. Furthermore, the method is still applicable in adaptive design if the strategy of sample size scheme determination is adopted when designing or the minor modifications on the program are made.

Design of adaptive two-stage double-arm clinical trials for dichotomous variables

It is well known that flexibility is one of the major advantages of an adaptive two-stage design, and the intended adaptation should be as preplanned as possible to maintain the integrity of the clinical trial. The design of adaptive two-stage double-arm clinical trials for dichotomous variables was proposed by simulation and forecasting procedure at the planning stage. To further ensure the integrity of the clinical trial, the sample size scheme for each scenario, which was supposed to be based on the first stage, was provided in the protocol by Monte Carlo simulation. In addition, the study parameters were determined by comparing the assessment indexes such as total sample size, expected sample size and the test power at the first stage. Furthermore, Fishers combination test and pooled data analysis were considered and compared through the simulation. The latter, which has the larger overall power and the better overall type I error control, with the same sample size was adopted for further simulation and statistical analysis in the clinical trial.

Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

abstract Human enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). In a previous phase III trial in children, a human diploid cell-based inactivated EV71 vaccine elicited EV71 specific immune responses and protection against EV71 associated HFMD. This study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. This was a randomized, double-blinded, placebo-controlled, phase III clinical trial of a human diploid vaccine carried out in 12,000 children in Guangxi Zhuang Autonomous Region, China (ClinicalTrials.gov: NCT01569581). Solicited events were recorded for 7 days and unsolicited events were reported for 28 days after each injection. Age trend analysis of adverse reaction was conducted in each treatment group. Multiple logistic regression models were built to identify factors influencing the severity of adverse reactions. Fewer solicited adverse reactions were observed in older participants within the first 7 days after vaccination (P < 0.0001), except local pain and pruritus. More severe adverse reactions were observed after the initial injection than after the booster injection. Serious cold or respiratory tract infections (RTI) were observed more often in children aged 6–36 months than in older children. Only the severity of local swelling was associated with body mass index. Children with throat discomfort before injection had a higher risk of serious cold or RTI. These results indicated that the human diploid cell-based vaccine achieved a satisfactory safety profile.

Comparison of Immunogenicity and Persistence between Inactivated Hepatitis A Vaccine Healive® and Havrix® among Children: A 5-Year Follow-up Study.

ABSTRACT Background: Inactivated vaccines for hepatitis A virus (HAV) infection are widely used in China. Mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection. Methods: A prospective, randomized, open-label clinical trial was conducted to compare geometric mean concentrations (GMCs) and seroconversion rates (SRs) of anti-HAV antibody elicited by the inactivated vaccines Healive and Havrix for 5 y post immunization, in which 400 healthy children were randomly assigned in a 3:1 ratio to receive 2 doses of Healive or Havrix at 0 and 6 month. Anti-HAV antibody concentration was detected by microparticle enzyme immunoassay (MEIA) during the study. Furthermore, an attempt was made to predict persistence of protective immunogenicity by using a suitable statistical model. Results: The GMCs were significantly higher after vaccination with Healive than after Havrix as comparator vaccine at 1, 6, 7, 18, 30, 42, 54 and 66 month (P < 0.01) with the peak point at 7 month (3427.2 mIU/ml for Healive and 1441.9 mIU/ml for Comparator). Similarly significant differences of SRs were found between the 2 groups at 1 and 6 month (P < 0.01). Afterwards, the SRs of both groups reached 100% at 7 month and did not decline until 66 month(99.1% for Healive and 97.5% for Comparator). A linear mixed model with a change point at 18 month(Model 3) was found to be suitable to predict persistence of protective immunogenicity induced by vaccines. It was estimated that the duration of protection for Healive was at least 20 y with a lower limit of GMC 95% confidence interval (CI) no less than 20 mIU/mL. Conclusions: Compared with Havrix, the new preservative-free inactivated hepatitis A vaccine (Healive) in 2 doses showed better persistence of antibody concentrations for 5 y after full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 y.

The Continual Reassessment Method for Multiple Toxicity Grades: A Bayesian Model Selection Approach

Grade information has been considered in Yuan et al. (2007) wherein they proposed a Quasi-CRM method to incorporate the grade toxicity information in phase I trials. A potential problem with the Quasi-CRM model is that the choice of skeleton may dramatically vary the performance of the CRM model, which results in similar consequences for the Quasi-CRM model. In this paper, we propose a new model by utilizing bayesian model selection approach – Robust Quasi-CRM model – to tackle the above-mentioned pitfall with the Quasi-CRM model. The Robust Quasi-CRM model literally inherits the BMA-CRM model proposed by Yin and Yuan (2009) to consider a parallel of skeletons for Quasi-CRM. The superior performance of Robust Quasi-CRM model was demonstrated by extensive simulation studies. We conclude that the proposed method can be freely used in real practice.

A Novel Bayesian Seamless Phase I/II Design

This paper proposes a novel bayesian phase I/II design featuring using a hybrid mTPI method in phase I for targeting the MTD level and a randomization allocation schema for adaptively assigning patients to desirable doses in phase II. The mechanism of simultaneously escalating dose in phase I and expanding promising doses to phase II is inherited from a design proposed in literature. Extensive simulation studies indicate that our proposed design can vastly save sample size and efficiently assign more patients to optimal dose when compared to two competing designs.

A SAS macro for target dose estimation by reinforced urn processes in phase I clinical trials

The reinforced urn processes (RUPs) approach can estimate the target dose on the basis of the prior distribution function precisely and conveniently without the requirements about the explicit-estimated dose-response curve and the posterior complicated inference. The application of the RUPs approach was not discussed from the perspective of phase I clinical trial in the previous studies which just focused on the theory and methodology. And the modification of the traditional RUPs design should be considered for the purposes of ethnics and efficiency. A SAS macro was designed to explore the appropriate parameter settings according to the simulation outcomes in different situations and apply the RUPs approach for two state processes in phase I clinical trail with the modified RUPs design. The posterior estimation can be obtained precisely and efficiently with application of SAS program following the appropriate workflow and determination rule which were described in the example.