Trial Sequential Analysis

Trial Sequential Analysis (TSA) is a user-friendly software application which makes it easy for authors of systematic reviews and meta-analysis to apply a number of advanced sequential hypothesis testing techniques to their meta-analyses.

TSA is a methodology that combines an information size calculation (cumulated sample sizes of all included trials) for a meta-analysis with the threshold of statistical significance. TSA is a tool for quantifying the statistical reliability of data in the cumulative meta-analysis adjusting significance levels for sparse data and repetitive testing on accumulating data.

Meta-analysis may result in type I errors due to systematic errors (bias) or random errors (play of chance) due to sparse data and repeated significance testing when updating meta-analysis with new trials. Bias from trials with low methodological quality, outcome measure bias, publication bias, early stopping for benefit, and small trial bias may result in spurious P-values.

In a single trial, interim analyses increase the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries are applied to decide whether a trial could be terminated early because of a sufficiently small P-value, that is if the cumulative Z-curve crosses the monitoring boundaries (1). Sequential monitoring boundaries can be applied to meta-analysis as well, called trial sequential monitoring boundaries. In TSA the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and TSA controls the risks for type I and type II errors and helps to clarify whether additional trials are needed. Additionally, TSA provides us with important information regarding the required sample size for such trials.

The TSA software is free of charge and can be downloaded here. It is a Java-based software application which means that it runs on all operating systems that support Java (Windows, Mac OS, Linux and more), and it comes with a comprehensive manual suitable for systematic review authors with various levels of statistical background knowledge. For more detailed information, please refer to the TSA manual in EnglishChinese and Spanish.

You are welcome to use it in your analyses and publications of cumulative meta-analyses with proper reference to the software and some of our articles describing the methodology. Below are some publications where the use of the TSA software is illustrated.

In case you need assistance with the TSA software, please contact us via email: tsa@ctu.dk.

TSA and RM5 Converter are distributed by the Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark.

  1. Lan KKG. and DeMets G. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70(3): 659-663. View.
Example of a TSA plot