Statistical Guidelines for Handling Missing Data in Traumatic Brain Injury Clinical Research

Abstract

Missing data is a persistent and unavoidable problem in even the most carefully designed traumatic brain injury (TBI) clinical research. Missing data patterns may result from participant dropout, non-compliance, technical issues, or even death. This review describes the types of missing data that are common in TBI research, and assesses the strengths and weaknesses of the statistical approaches used to draw conclusions and make clinical decisions from these data. We review recent innovations in missing values analysis (MVA), a relatively new branch of statistics, as applied to clinical TBI data. Our discussion focuses on studies from the International Traumatic Brain Injury Research (InTBIR) initiative project: Transforming Research and Clinical Knowledge in TBI (TRACK-TBI), Collaborative Research on Acute TBI in Intensive Care Medicine in Europe (CREACTIVE), and Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT). In addition, using data from the TRACK-TBI pilot study (n = 586) and the completed clinical trial assessing valproate (VPA) for the treatment of post-traumatic epilepsy (n = 379) we present real-world examples of typical missing data patterns and the application of statistical techniques to mitigate the impact of missing data in order to draw sound conclusions from ongoing clinical studies.

Keywords: TBI; assessment tools; missing data; statistical guidelines.

FIG. 1.

Monte Carlo simulations for number of imputations needed to maximize effect sizes based on percentages of missing data (adapted from Graham and coworkers). Color image is available online.

FIG. 2.

Recovery curves for cognitive function as measured by verbal learning tasks grouped by first reported measure of Glasgow Outcome Scale (GOS). (A–C) Top row are data from Study 1 (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] pilot) assessing neuropsychological testing measured by the California Verbal Learning Task (CVLT) normative data, blocked by their first GOS-Extended (GOS-E) rating at 3 months post-TBI, looking at either complete case analysis (A), or with missing data filled in by either expectation maximization (EM) (B), or multiple imputation (MI) (C). The bottom row are data from Study 2 (valproate [VPA]) using similar outcomes, in which the verbal learning was assessed using a Selective Reminding task and an older version of the GOS in which functional deficits were previously grouped into single categories for mild (green), moderate (blue), and severe (red) disability, with similar comparisons across complete case analysis (D), or EM-filled (E) or MI-filled (F) data sets. Color image is available online.

FIG. 3.

Missing data patterns for verbal learning tasks blocked by Glasgow Outcome Scale (Extended) (GOS[E]) score at each of the three time points for each study. (A–C) Percent of missing data for the California Verbal Learning Task (CVLT) in study 1 (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI) Pilot) between 6 and 12 months based on GOS-E scores at either 3 months (A), 6 months (B), or 12 months (C) post-TBI. (D–F) Percent of missing data for Selective Reminding in study 2 (valproate [VPA]) among 1, 6, and 12-months post-TBI based on GOS scores at those same time points. Patients with less disability (green lines) show a marked increase in missing data at the final time point when blocked by their GOS(E) at 1, 3, or 6 months, with a flat line at the 12-month mark indicating that the higher functioning patients did not have data for the final time point. Also of note are the black and gray lines that represent patients who either died (GOS[E] 1) or were in a vegetative state (GOS[E] 2) before the first time point and therefore show no change in missing data over time, with the exception of more data being collected over time for patients starting out at a GOS score of 2 at 1 month, and presumably improving and therefore being able to have Selective Reminding assessed. +GOS scores 3, 4, and 5 are an older version of the GOS-E, where 3/4, 5/6, and 7/8 have since been extended, respectively. Color image is available online.

FIG. 4.

Study 2 (valproate [VPA]) had codes for the reason for the missing data measured at 1 month (A), 6 months (B), and 12 months (C) to confirm hypotheses about why outcome data were missing for different groups of patients in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot, blocked by Glasgow Outcome Scale (GOS) severity. As expected, patients from the VPA study who were higher functioning (green) were less likely to participate in follow-up care, potentially a as a result of a lack of interest in staying in the study because they did not have a measurable disability. Whereas patients with severe disability (red) were more likely to have missing data because of central nervous system (CNS) problems preventing them from performing the task. Patients who started in a vegetative state (white) at 1 month generally could not be assessed because of CNS complications, with, presumably, patients moving to either the red category (out of a vegetative state, severe disability), or into the black category (dead). Color image is available online.