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1.  Medical records based post-marketing safety evaluation of rare events with uncertain status 
We develop a simple statistic for comparing rates of rare adverse events between treatment groups in post-marketing safety studies where the events have uncertain status. In this setting, the statistic is asymptotically equivalent to the logrank statistic, but the limiting distribution has Poisson and binomial components instead of being Guassian. We develop two new procedures for computing critical values, a Gaussian approximation and a parametric bootstrap. Both numerical and asymptotic properties of the procedures are studied. The test procedures are demonstrated on a post-marketing safety study of the RotaTeq vaccine. This vaccine was developed to reduce the incidence of severe diarrhea in infants.
doi:10.1080/10543406.2013.735783
PMCID: PMC3557815  PMID: 23331231
Logrank statistic; Post-marketing safety; Poisson process; Rare events
2.  cSSMD: assessing collective activity for addressing off-target effects in genome-scale RNA interference screens 
Bioinformatics  2011;27(20):2775-2781.
Motivation: Off-target activity commonly exists in RNA interference (RNAi) screens and often generates false positives. Existing analytic methods for addressing the off-target effects are demonstrably inadequate in RNAi confirmatory screens.
Results: Here, we present an analytic method assessing the collective activity of multiple short interfering RNAs (siRNAs) targeting a gene. Using this method, we can not only reduce the impact of off-target activities, but also evaluate the specific effect of an siRNA, thus providing information about potential off-target effects. Using in-house RNAi screens, we demonstrate that our method obtains more reasonable and sensible results than current methods such as the redundant siRNA activity (RSA) method, the RNAi gene enrichment ranking (RIGER) method, the frequency approach and the t-test.
Contact: xiaohua_zhang@merck.com
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr474
PMCID: PMC3202303  PMID: 21846737
3.  Evaluating the safety of a rotavirus vaccine: the REST of the story 
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq® with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events.
doi:10.1177/1740774508090507
PMCID: PMC2602609  PMID: 18375651
4.  Sequential Generalized Likelihood Ratio Tests for Vaccine Safety Evaluation 
Statistics in medicine  2010;29(26):2698-2708.
SUMMARY
The evaluation of vaccine safety involves pre-clinical animal studies, pre-licensure randomized clinical trials and post-licensure safety studies. Sequential design and analysis are of particular interest because they allow early termination of the trial or quick detection that the vaccine exceeds a prescribed bound on the adverse event rate. After a review of recent developments in this area, we propose a new class of sequential generalized likelihood ratio tests for evaluating adverse event rates in two-armed pre-licensure clinical trials and single-armed post-licensure studies. The proposed approach is illustrated using data from the Rotavirus Efficacy and Safety Trial (REST). Simulation studies of the performance of the proposed approach and other methods are also given.
doi:10.1002/sim.4036
PMCID: PMC2975406  PMID: 20799244
Generalized likelihood ratio tests; rotavirus; sequential probability ratio test; vaccine safety
5.  Hit selection with false discovery rate control in genome-scale RNAi screens 
Nucleic Acids Research  2008;36(14):4667-4679.
RNA interference (RNAi) is a modality in which small double-stranded RNA molecules (siRNAs) designed to lead to the degradation of specific mRNAs are introduced into cells or organisms. siRNA libraries have been developed in which siRNAs targeting virtually every gene in the human genome are designed, synthesized and are presented for introduction into cells by transfection in a microtiter plate array. These siRNAs can then be transfected into cells using high-throughput screening (HTS) methodologies. The goal of RNAi HTS is to identify a set of siRNAs that inhibit or activate defined cellular phenotypes. The commonly used analysis methods including median ± kMAD have issues about error rates in multiple hypothesis testing and plate-wise versus experiment-wise analysis. We propose a methodology based on a Bayesian framework to address these issues. Our approach allows for sharing of information across plates in a plate-wise analysis, which obviates the need for choosing either a plate-wise or experimental-wise analysis. The proposed approach incorporates information from reliable controls to achieve a higher power and a balance between the contribution from the samples and control wells. Our approach provides false discovery rate (FDR) control to address multiple testing issues and it is robust to outliers.
doi:10.1093/nar/gkn435
PMCID: PMC2504311  PMID: 18628291

Results 1-5 (5)