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In Reply: We note that all writers indicated broad agreement with our conclusion of the need for robust validation of genetic risk factors to provide convincing evidence that a true genetic risk factor has been identified. We agree with the comments of Dr Feero and colleagues that unbiased studies of whole genome association are likely to lead to important discoveries. Recent findings have illustrated the power of this approach and underscore the frequent need for large sample sizes and replication cohorts to achieve meaningful and convincing results.^1-5 Of interest is that the variants identified in these studies show consistent replication of the identical alleles in diverse cohorts.

Dr Bochud and colleagues point out pitfalls in case-control studies. Our study's aim was to investigate whether previously reported genetic risk factors could be replicated in a large cohort of patients similar to those encountered in clinical practice. Our null results provide little . . . [Full Text of this Article]

Thomas M. Morgan, MD
morgan_t@kids.wustl.edu
Washington University School of Medicine
St Louis, Missouri

Harlan M. Krumholz, MD, MS; Richard P. Lifton, MD, PhD
Yale University School of Medicine
New Haven, Connecticut

John A. Spertus, MD, MPH
Mid America Heart Institute
Kansas City, Missouri