© 2004 American Thoracic Society
Linkage to Apnea–Hypopnea Index Across the Life-SpanIs this a Viable Strategy?From the Authors:Dr. Pack and colleagues have dug up what has become a rather hoary chestnut in genetic epidemiology—the question of at what point one shares scientific knowledge and the extent to which one lives and dies by an LOD score (or the associated p value). Although tests of statistical significance are important, epidemiologists increasingly recognize that the magnitude, consistency, and biological plausibility of associations are far more central in interpreting data than meeting any given statistical criterion. These issues are particularly true in genetic epidemiology, where the question of what constitutes "genome-wide significance" has been, and continues to be, rather controversial (1, 2). Unfortunately, "standard criteria for interpreting linkage results" (acceptable to the majority of genetic statisticians) that would conveniently dictate the correct trade-off between false negatives and false positives in whole genome scans do not exist. Like everything else in genetics, this too is likely to be very context-specific—specific to study, to disease, to population, and to analytic method. We do note that the preliminary nature of the findings was in fact thoroughly discussed in our article, as was a lengthy justification of our decision to publish this work at this time (3). If our study is underpowered, then that is all the more reason to pick out the most significant result as being of special interest and deserving of further study. Moreover, in addition to highlighting linkage results of interest, our report described the complex genetics that underlie obesity and apnea and their interactions. Pack and colleagues also disagree with the inclusion of younger subjects in our linkage analyses. It may indeed be more difficult to look at the genetics of "disease" in studies of individuals of different ages when affection is defined by a single threshold level (or as a binary trait). Our analyses, however, focused on two quantitative traits, body mass index and apnea–hypopnea index (AHI), that we and others have demonstrated to be strongly heritable when examined in families of children and adults (4). As has been shown for traits such as blood pressure (5), which also shows a strong age dependency, much information can be derived from a pedigree study design that includes subjects across the age range when analyzed with appropriate age adjustments. With regard to the issue of menopause, this is only one of multiple factors that modestly influences AHI levels (6). However, in most of our published work on the Cleveland Family Study, adjustment for age, age2, and sex (as well as age–sex interactions in some analyses) appears to adequately control for this effect.
a University of Western Australia Perth, Australia FOOTNOTES Conflict of Interest Statement: L.J.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.K.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.R.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.C.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.V.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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