Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03450525 |
| Other study ID # |
g-corfitzen-201802231455 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 15, 2018 |
| Est. completion date |
August 2024 |
Study information
| Verified date |
September 2021 |
| Source |
Karolinska Institutet |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study aims to assess whether time between injury and first Glasgow Coma Scale measurement
will affect its predictive value.
Description:
Background
Trauma is a critical global public health concern and the number of fatalities as a result of
trauma continues to increase globally. In 2016 more than 4,6 million deaths were the result
of trauma making it the 8th leading cause of death. In the Global Burden and Disease study
(GBD), traumatic injuries account for nearly one-tenth of all deaths, more than malaria,
tuberculosis, HIV/AIDS and maternal conditions combined.
TBI is defined as brain injury caused by trauma, trauma being defined as damage inflicted on
the body as the direct or indirect result of an external force, with or without disruption of
structural continuity. Traumatic brain injury (TBI) is a leading cause of morbidity and
mortality globally. It is the largest contributor to trauma deaths in the world, having three
times higher mortality rate than trauma without accompanied TBI. It is estimated that TBI
affects more than 10 million people annually.
To guide physicians in diagnostics and resuscitation regimes, prognostic models predicting
TBI severity and outcome are of great importance. The Glasgow Coma Scale (GCS) is one of the
most widely used prognostic model. It is a neurological scale developed to assess the
response to stimuli in patients with craniocerebral injuries by using three parameters; eye
opening, verbal response and motor response. It has been used to assess level of
consciousness in both clinical practice and neurotrauma research. The GCS Score, the sum of
the three parameters used in GCS is used to assess severity, ranging from mild, moderate to
severe.
Several studies have researched the prognostic value of GCS and the prognostic value of GCS
individual components, but little is known about how the relationship of time between injury
and first GCS affects the predictive value of GCS. Studies have shown that GCS measured on
admission to trauma care is more predictive than GCS measured at the trauma site, and that
the median GCS on admission is higher than the median GCS at trauma site but if and how time
affects GCS scores has not been studied.
Aim
The aim of this study is to assess how the timing of measuring GCS affects its predictive
value after traumatic brain injury (TBI) in adult patients. The first objective is to assess
if the predictive performance of GCS is improved if adjusted for time from injury to when it
was recorded. The second objective is to assess if the predictive performance of GCS varies
depending on when it was recorded.
Study Design
This is a retrospective analysis of the cohort study Towards Improved Trauma Care Outcomes in
India (TITCO).
Setting
The de-identified TITCO cohort will be used. This cohort includes 16,000 patients enrolled
between July 2013 and December 2015 from four university hospitals in India. Project
officers, holding a health science master degree, collected data prospectively on admission
at each site by direct observation of the emergency room and filling out a standardized form.
The project officers worked in rotating eight-hour shifts (morning, evening, night). Data was
also retrieved retrospectively from patient records for patients admitted outside the
observed shifts.
Source and method of participant selection
The one-site project officer included patients from participating hospitals, either by
prospective observation or by retrospective data retrieval from patient records.
Explanatory variables The two explanatory variables of interest will be GCS and time between
injury and GCS recording in hours, henceforth referred to as time to GCS. GCS was extracted
from patient records as was the date and time of first GCS recorded. If date and time of
first GCS recording are missing date then time of arrival to the participating centre will be
used instead. Date and time of injury were extracted from patient records or directly
reported by participants. Data and time of first GCS recording or arrival to participating
centre were extracted from patient records.
Covariates The variables age, sex, mechanism of injury, whether the patient was transferred
from another health facility, and anatomical injury severity quantified using the injury
severity score (ISS) will be reported to characterise the study sample. Age, sex, mechanism
of injury and transfer status were either extracted from patient records or reported by
participants. ISS was calculated by a single accredited coder based on injury text
descriptions.
Bias
To account for human errors in recording GCS, Aal data collector observers were holders of
health science master degrees and were continually trained and supervised throughout the data
collection period.
Quantitative variables
GCS will be treated both as a linear term and as an ordinal variable with 12 levels. The
non-testable levels of the verbal and eye components will be treated as 1. Time between
injury and recorded GCS will be treated both as a continuous variable and a categorical
variable. When treated as continuous time between injury and GCS will be allowed to have a
non-linear association with mortality by modelling it using restricted cubic splines with
three knots placed at equally spaced percentiles. When treated as categorical it will be
divided into blocks of two hours.
Statistical methods
All analyses will be conducted in the statistical language and programming environment R. The
sample will first be temporally split into training and validation samples as outlined in the
study size section below. Each sample will then be characterised using medians and
inter-quartile ranges (IQR) to present quantitative variables and counts and percentages to
present qualitative variables.
In the training sample four simple prediction models will be fit using logistic regression
with mortality as the outcome. The first model will include only GCS as a linear term, the
second GCS as a linear term and time to GCS modelled using restricted cubic splines, the
third only GCS as an ordinal variable, and the fourth model GCS as an ordinal variable and
time to GCS modelled using restricted cubic splines. To avoid overfitting a shrinkage factor
will be estimated using a bootstrapping procedure which will then be applied to the model
coefficients.
The four models will then be applied in the validation sample and their predictive
performance estimated and compared. Predictive performance of each model will be evaluated
using the area under the receiver operating characteristics curve (AUROCC), positive and
negative predictive values. Differences in predictive performance between models and
associated 95% confidence intervals will be estimated using bootstrapping.
Each of the training and validation samples will then be divided into subsamples based on
time to GCS, so that the first subsample includes patients with time to GCS < 2 hours and the
second subsample includes patients with time to GCS between two and four hours and so on in
blocks of two hours. In each of the training subsamples a simple logistic model will be fit
including GCS as a linear term as the only independent variable. The coefficient of GCS in
each model will be shrunk.
The model developed in the first training subsample will then be applied to the first
validation subsample and so on. Model performance in each validation subsamples will be
evaluated using AUROCC and root mean square error. The trend in these measures across
validation subsamples will then be quantified using a simple generalised linear model with
performance measure data as the outcome variable and a nonlinear transformation of block
index number using restricted cubic splines with three knots as the only independent
variable.
Strategy to handle missing data
If the required sample size is reached if only patients with complete data on the outcome,
explanatory variable, and covariates are included then a complete case analysis will be
conducted. If not then missing data will be handled with multiple imputation using chained
equations. The number of imputed datasets will be equal to the percentage of incomplete
observations. The analysis will be conducted separately in each imputed dataset and the main
results presented as medians with IQR across imputations. For confidence intervals the most
extreme values of pooled upper and lower bounds will be reported.
Study size
The most data intensive analysis is likely to be fitting the model with GCS as an ordinal
variable and time to GCS as restricted cubic splines and therefore the study size is
estimated to accommodate this analysis. Simulation studies indicate that logistic regression
models need at least ten events, or observations with the outcome, per included parameter to
generate reliable coefficient estimates. Modelling GCS as an ordinal variable will involve
estimating coefficients for eleven parameters and including time to GCS adds two additional
parameters. The total number of parameters is then 13, indicating a need for at least 130
events. Assuming an outcome prevalence of 20% based on previous research the training sample
needs to include at least 650 observations. If this number is less than half of the complete
sample then the training and validation samples will be generated by splitting the complete
sample in two parts of equal size. If the complete sample includes less than 1300
observations the first 650 observations will be included in the training sample and the
remaining observations will be included in the validation sample. Regardless, the samples
will be created in such a way that the relative contribution of each centre is approximately
the same in both samples.
