title: The treatment of missing data in a large cardiovascular clinical outcomes study.
abstract: The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data.
  
  
  
  A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed.
  
  
  
  Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions.
  
  
  
  Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern.
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA rlittle@umich.edu.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Little
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Suh
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: Clinical Research, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Sarich
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Oppenheimer
authors.affiliation: Clinical Research, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Plotnikov
authors.affiliation: Statistics Collaborative, Inc., Washington, DC, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.affiliation: Bayer Healthcare, Wuppertal, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Cook-Bruns
authors.affiliation: Clinical Research, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Burton
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.affiliation: Department of Biostatistics, Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Surya
authors.initials: S
authors.lastname: Mohanty
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000401:mortality; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors / Q000627:therapeutic use*; D006801:Humans; D059012:Lost to Follow-Up; D015337:Multicenter Studies as Topic; D009203:Myocardial Infarction / Q000453:epidemiology; D010352:Patient Dropouts; D016032:Randomized Controlled Trials as Topic; D000069552:Rivaroxaban / Q000627:therapeutic use*; D020521:Stroke / Q000453:epidemiology; D016019:Survival Analysis
chemical_list: D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban
keywords: Clinical trials; follow-up studies; fraction of missing information; missing data; multiple imputation; sensitivity analysis; survival analysis; tipping-point analysis