Dataset Information

Controlling false discovery proportion in identification of drug-related adverse events from multiple system organ classes.

ABSTRACT: Analyzing safety data from clinical trials to detect safety signals worth further examination involves testing multiple hypotheses, one for each observed adverse event (AE) type. There exists certain hierarchical structure for these hypotheses due to the classification of the AEs into system organ classes, and these AEs are also likely correlated. Many approaches have been proposed to identify safety signals under the multiple testing framework and tried to achieve control of false discovery rate (FDR). The FDR control concerns the expectation of the false discovery proportion (FDP). In practice, the control of the actual random variable FDP could be more relevant and has recently drawn much attention. In this paper, we proposed a two-stage procedure for safety signal detection with direct control of FDP, through a permutation-based approach for screening groups of AEs and a permutation-based approach of constructing simultaneous upper bounds for false discovery proportion. Our simulation studies showed that this new approach has controlled FDP. We demonstrate our approach using data sets derived from a drug clinical trial.

SUBMITTER: Tan X

PROVIDER: S-EPMC6731544 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Controlling false discovery proportion in identification of drug-related adverse events from multiple system organ classes.

Tan Xianming X Liu Guanghan F GF Zeng Donglin D Wang William W Diao Guoqing G Heyse Joseph F JF Ibrahim Joseph G JG

Statistics in medicine 20190717 22

Analyzing safety data from clinical trials to detect safety signals worth further examination involves testing multiple hypotheses, one for each observed adverse event (AE) type. There exists certain hierarchical structure for these hypotheses due to the classification of the AEs into system organ classes, and these AEs are also likely correlated. Many approaches have been proposed to identify safety signals under the multiple testing framework and tried to achieve control of false discovery rat ...[more]

PMID: 31313376

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Project description:BackgroundIn the analysis of microarray data one generally produces a vector of p-values that for each gene give the likelihood of obtaining equally strong evidence of change by pure chance. The distribution of these p-values is a mixture of two components corresponding to the changed genes and the unchanged ones. The focus of this article is how to estimate the proportion unchanged and the false discovery rate (FDR) and how to make inferences based on these concepts. Six published methods for estimating the proportion unchanged genes are reviewed, two alternatives are presented, and all are tested on both simulated and real data. All estimates but one make do without any parametric assumptions concerning the distributions of the p-values. Furthermore, the estimation and use of the FDR and the closely related q-value is illustrated with examples. Five published estimates of the FDR and one new are presented and tested. Implementations in R code are available.ResultsA simulation model based on the distribution of real microarray data plus two real data sets were used to assess the methods. The proposed alternative methods for estimating the proportion unchanged fared very well, and gave evidence of low bias and very low variance. Different methods perform well depending upon whether there are few or many regulated genes. Furthermore, the methods for estimating FDR showed a varying performance, and were sometimes misleading. The new method had a very low error.ConclusionThe concept of the q-value or false discovery rate is useful in practical research, despite some theoretical and practical shortcomings. However, it seems possible to challenge the performance of the published methods, and there is likely scope for further developing the estimates of the FDR. The new methods provide the scientist with more options to choose a suitable method for any particular experiment. The article advocates the use of the conjoint information regarding false positive and negative rates as well as the proportion unchanged when identifying changed genes.

Dataset Information

Controlling false discovery proportion in identification of drug-related adverse events from multiple system organ classes.

Publications

Controlling false discovery proportion in identification of drug-related adverse events from multiple system organ classes.

Similar Datasets

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