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 randomized 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 hypothesized 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 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-randomization covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥10 units of red blood cells within 24 hours of admission. Despite favorable 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.

Hypertonic Saline Primes Activation of the p53–p21 Signaling Axis in Human Small Airway Epithelial Cells That Prevents Inflammation Induced by Pro-inflammatory Cytokines

“…14 Despite discouraging results from clinical trials on traumatic brain injury patients, 15,16 it has been proposed that a single early small dose of HTS could influence the long-term survival of this population. 16 …”

Recurrent event frailty models reduced time-varying and other biases in evaluating transfusion protocols for traumatic hemorrhage

“…However, in addition to introducing collider bias [10], this approach misclassifies and effectively excludes bleeding patients who do not survive long enough to receive a 10 th unit of RBCs. Instead, we considered all 919 PROMMTT study patients who had survived long enough to receive at least 3 blood product units and had complete observations for the following baseline variables: systolic blood pressure (SBP), heart rate (HR), hemoglobin concentration (Hgb) and pH.…”

“…While early transfusion of plasma and platelets has been associated with improved outcomes [2,4–6], findings among observational studies seeking to identify optimum trauma transfusion protocols have been conflicting and difficult to interpret [7,8]. In earlier works [9,10], our group has identified major challenges in the design and statistical analysis of trauma transfusion studies.…”

Mortality and Ratio of Blood Products Used in Patients With Severe Trauma—Reply

“…3 We did not use any definition of massive transfusion as an outcome or to define a subgroup; doing so would have introduced survival or collider bias, or both. 4 Because approximately 50% of patients in the PROPPR trial experienced a penetrating injury, we will be exploring the issue of mechanism in the future. The platelet-first strategy in the 1:1:1 group was based on data from the Prospective, Observational, Multicenter Major Trauma Transfusion study, in which platelets were often administered late or not at all.…”

“…4 Multiple secondary analyses are under way, exploring subsets of patients with traumatic brain injury, those with massive bleeding, and those with available thrombelastography data.…”