title: Collider bias in trauma comparative effectiveness research: the stratification blues for systematic reviews.
abstract: BACKGROUND
  Collider bias, or stratifying data by a covariate consequence rather than cause (confounder) of treatment and outcome, plagues randomised and observational trauma research. Of the seven trials of prehospital hypertonic saline in dextran (HSD) that have been evaluated in systematic reviews, none found an overall between-group difference in survival, but four reported significant subgroup effects. We hypothesised that an avoidable type of collider bias often introduced inadvertently into trauma comparative effectiveness research could explain the incongruous findings.
  
  
  METHODS
  The two most recent HSD trials, a single-site pilot and a multi-site pivotal study, provided data for a secondary analysis to more closely examine the potential for collider bias. The two trials had followed the a priori statistical analysis plan to subgroup patients by a post-randomisation covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥ 10 unit of red blood cells within 24h of admission. Despite favourable HSD effects in the MT subgroup, opposite effects in the non-transfused subgroup halted the pivotal trial early. In addition to analyzing the data from the two trials, we constructed causal diagrams and performed a meta-analysis of the results from all seven trials to assess the extent to which collider bias could explain null overall effects with subgroup heterogeneity.
  
  
  RESULTS
  As in previous trials, HSD induced significantly greater increases in systolic blood pressure (SBP) from prehospital to admission than control crystalloid (p=0.003). Proportionately more HSD than control decedents accrued in the non-transfused subgroup, but with paradoxically longer survival. Despite different study populations and a span of over 20 years across the seven trials, the reported mortality effects were consistently null, summary RR=0.99 (p=0.864, homogeneity p=0.709).
  
  
  CONCLUSIONS
  HSD delayed blood transfusion by modifying standard triggers like SBP with no detectable effect on survival. The reported heterogeneous HSD effects in subgroups can be explained by collider bias that trauma researchers can avoid by improved covariate selection and data capture strategies.
authors.affiliation: University of Texas Health Science Center, Department of Surgery, Houston, TX, United States. Electronic address: deborah.j.deljunco@uth.tmc.edu.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Del Junco
authors.affiliation: University of Washington, Department of Surgery, Seattle, WA, United States.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bulger
authors.affiliation: University of Texas Health Science Center, Department of Surgery, Houston, TX, United States.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Fox
authors.affiliation: University of Texas Health Science Center, Department of Surgery, Houston, TX, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: Holcomb
authors.affiliation: Oregon Health & Science University, Department of Surgery, Portland, OR, United States.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Brasel
authors.affiliation: American College of Surgeons, Chicago, IL, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Hoyt
authors.affiliation: University of Connecticut Health Center, Institute for Clinical and Translational Science, Farmington, CT, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Grady
authors.affiliation: University of Texas Health Science Center, Department of Surgery, Houston, TX, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Duran
authors.affiliation: University of Washington, Department of Surgery, Seattle, WA, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Klotz
authors.affiliation: U.S. Army Institute of Surgical Research, San Antonio, TX, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dubick
authors.affiliation: University of Texas Health Science Center, Department of Surgery, Houston, TX, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wade
mesh_terms: D015982:Bias; D001803:Blood Transfusion / Q000401:mortality / Q000706:statistics & numerical data*; D057186:Comparative Effectiveness Research; D006801:Humans; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012196:Review Literature as Topic; D016019:Survival Analysis; D014193:Trauma Centers / Q000706:statistics & numerical data*; D014947:Wounds and Injuries / Q000401:mortality* / Q000628:therapy
keywords: Bias; Comparative effectiveness research; Massive transfusion; Observational; Randomised clinical trial; Resuscitation; Subgroup; Survival; Trauma