title: Weighing the results of differing 'low dose' studies of the mouse prostate by Nagel, Cagen, and Ashby: quantification of experimental power and statistical results.
abstract: Differing experimental findings with respect to "low dose" responses in the mouse prostate after in utero exposure have generated considerable controversy. An analysis of such controversies requires a broad strength and weight of the evidence approach. For example, a National Toxicology Program review panel acquired the raw data from nearly 50 studies and then statistically reanalyzed these data in a common and comparable approach. However, the statistical power of the various studies was not calculated and the quantitative p values were not reported in this reanalysis. Such calculations and values address vital strength- and weight-of-the-evidence questions: (1) how sensitive were the various studies to detect changes in prostate weight, particularly the negative replicate studies and (2) what were the p values; were negative studies robust or only marginal in their inability to find an effect? We first examined the statistical power of the studies to detect a positive effect on prostate weight. Preliminary calculations indicated that the two subsequent replicating studies were indeed more sensitive to changes in prostate weight in comparison to the original study, having reasonable power to detect an effect at only 50% of the response reported in the original study. Additional calculations were performed using the raw data available from one negative replicating study and the methods recommended by the statistics subpanel of the original review. This analysis used Dunnett's multiple comparison procedure for groups with p<0.05 to infer statistical significance, employed an analysis-of-covariance model with body weight as a covariate, and addressed litter as a nested random effect. The quantitated p values for this replicated study, comparing the two Bisphenol A treatment groups (2 and 20 microg/kg/day) to the control, were 0.821 and 0.972, respectively. This indicates this study was indeed robust in finding no treatment-related effect. Thus, the weight and strength of the evidence, based on sensitivity and quantitative p value, was that it is highly unlikely for this negative replicating study to have missed a true effect. In the future, we recommend a similar use of statistical power analysis for those designing experimental studies and for those conducting weight-of-the-evidence reviews, and we also recommend the clear quantitation and reporting of p values to support the review's interpretation and conclusions.
authors.affiliation: Central Product Safety, The Procter & Gamble Company, Cincinnati, OH 45061, USA. owens.jw@pg.com
authors.forename: J W
authors.initials: JW
authors.lastname: Owens
authors.forename: J G
authors.initials: JG
authors.lastname: Chaney
mesh_terms: D000465:Algorithms; D000818:Animals; D001559:Benzhydryl Compounds; D001835:Body Weight / Q000187:drug effects; D003627:Data Interpretation, Statistical; D052244:Endocrine Disruptors / Q000633:toxicity; D005260:Female; D008297:Male; D051379:Mice; D015233:Models, Statistical; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010636:Phenols / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011467:Prostate / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds