title: Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials.
abstract: BACKGROUND
  Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies.
  
  
  OBJECTIVE
  We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status.
  
  
  METHODS
  We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers.
  
  
  RESULTS
  Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm.
  
  
  CONCLUSIONS
  Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions.
authors.affiliation: Division of Gerontology, Geriatrics, and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kennedy
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cutter
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Guoqiao
authors.initials: G
authors.lastname: Wang
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D002986:Clinical Trials as Topic / Q000379:methods; D060825:Cognitive Dysfunction / Q000235:genetics*; D003627:Data Interpretation, Statistical; D006801:Humans; D012107:Research Design
chemical_list: D053327:Apolipoprotein E4
keywords: Alzheimer’s disease; clinical trials; mild cognitive impairment; statistical analysis; trial design