In Reply: Understanding and uncovering bias concealed within scientific studies are critical to the scientific process, and especially pertinent in the context of metaanalysis whereby unrecognized bias may be amplified. Dr Ioannidis' comments underscore the need to question the results of individual trials, or a series of individual trials, that seem to be statistically or clinically too good to be true, or that prompt one to question the validity of the presented effect estimates. In the context of acute volume resuscitation, considerable between-trial heterogeneity would have been expected in the small trials conducted by Boldt et al due to random sampling error. Even though the evolution and contribution of trials conducted by Boldt et al may have obfuscated signals of harm associated with the use of hydroxyethyl starch for acute volume resuscitation, it is important to recognize that the findings of our meta-analysis, and thus our conclusions, are not predicated on issues of bias, statistical homogeneity, or potential academic misconduct. Even with the inclusion of the data by Boldt et al, hydroxyethyl starch is clearly associated with clinically important harm reflected by increased mortality and increased use of renal replacement therapy.
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