In an attempt to prevent the dismissal of a technique that does, when used appropriately, give useful information, but also not to mislead, Heart
has now formulated instructions to authors that indicate what this journal feels may be expected of genetic case–control association studies (http://heart.bmjjournals.com/misc/ifora.shtml
). Within these guidelines is an acceptance that the demands for the level of correction for multiple comparisons and statistical certainty suggested by some (p values often to 10−5
are likely to kill off this type of research and, in any case, are not always statistically appropriate. It is also recognised that repeated findings of the same association add to confidence that the association is real but it is noted that initial studies which have since been replicated have had p values less than 10−3
Thus, initial studies which are seen as “hypothesis generating” and requiring subsequent replication, can be of value.
It is also clear that where there are associations between genetic variation and an intermediate marker (phenotype) that is closely or immediately related to the gene product, the size of the study can more reliably fit with conventional levels of significance and assessment of power. Absolute requirements on size of study have not been set as it is clear that the power to detect, or exclude, a given genetic effect depends on many parameters other than the number of informative events/cases. Thus, stringent selection of cases to enrich for genetic load, analysis of functional variants or of previously implicated haplotypes of variants, and analysis of heritable intermediate phenotypes all increase the prior likelihood that an observed association will be real. In contrast, it is important for this journal that it does not encourage the publication of articles reporting associations that cannot be confidently made and that are not transparent in the accurate assessment and description of the phenotype, as well as making an honest assessment of the number of comparisons that have been made with a dataset.
It is recognised that there is room for a matter of opinion in this area, and indeed the consultation exercise that was undertaken suggests that opinion is quite widely spread. The new guidelines to authors, however, contain some flexibility, but set clear lines for what this journal feels may be acceptable for publication and the style in which it wishes to receive the submissions. It is hoped that this will not only facilitate the review process and lead to more consistency in what is accepted for publication, but that it may help investigators design better studies from the outset.