Effectiveness of strategies to increase the validity of findings from association studies: size vs. replication.
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.
Department of Biostatistics & Epidemiology, R&D, Philip Morris International, Neuchâtel, Switzerland. rolf.weitkunat@pmintl.com
Rolf
R
Weitkunat
Etienne
E
Kaelin
Grégory
G
Vuillaume
Gerd
G
Kallischnigg
D016022:Case-Control Studies; D005189:False Positive Reactions; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques / Q000706:statistics & numerical data*; D006801:Humans; D015203:Reproducibility of Results; D018401:Sample Size