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BMC Medical Research Methodology

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Open Access 01-12-2010 | Research article

Effectiveness of strategies to increase the validity of findings from association studies: size vs. replication

Authors: Rolf Weitkunat, Etienne Kaelin, Grégory Vuillaume, Gerd Kallischnigg

Published in: BMC Medical Research Methodology | Issue 1/2010

Abstract

Background

The capacity of multiple comparisons to produce false positive findings in genetic association studies is abundantly clear. To address this issue, the concept of false positive report probability (FPRP) measures "the probability of no true association between a genetic variant and disease given a statistically significant finding". This concept involves the notion of prior probability of an association between a genetic variant and a disease, making it difficult to achieve acceptable levels for the FPRP when the prior probability is low. Increasing the sample size is of limited efficiency to improve the situation.

Methods

To further clarify this problem, the concept of true report probability (TRP) is introduced by analogy to the positive predictive value (PPV) of diagnostic testing. The approach is extended to consider the effects of replication studies. The formula for the TRP after k replication studies is mathematically derived and shown to be only dependent on prior probability, alpha, power, and number of replication studies.

Results

Case-control association studies are used to illustrate the TRP concept for replication strategies. Based on power considerations, a relationship is derived between TRP after k replication studies and sample size of each individual study. That relationship enables study designers optimization of study plans. Further, it is demonstrated that replication is efficient in increasing the TRP even in the case of low prior probability of an association and without requiring very large sample sizes for each individual study.

Conclusions

True report probability is a comprehensive and straightforward concept for assessing the validity of positive statistical testing results in association studies. By its extension to replication strategies it can be demonstrated in a transparent manner that replication is highly effective in distinguishing spurious from true associations. Based on the generalized TRP method for replication designs, optimal research strategy and sample size planning become possible.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/10/47/prepub

Title: Effectiveness of strategies to increase the validity of findings from association studies: size vs. replication
Authors: Rolf Weitkunat
Etienne Kaelin
Grégory Vuillaume
Gerd Kallischnigg
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: BMC Medical Research Methodology / Issue 1/2010
Electronic ISSN: 1471-2288
DOI: https://doi.org/10.1186/1471-2288-10-47

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Effectiveness of strategies to increase the validity of findings from association studies: size vs. replication

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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