Prediction and Outcome Analyses in Acute Neurological Diseases

Most treatments and interventions in health care are aimed at optimizing clinical outcomes. Ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH) and traumatic brain injury (TBI) are acute neurological diseases with a heterogeneous disease course that are often associated with poor functional outcomes and reduced quality of life. This stimulates measurement of clinical outcomes in terms of prognosis, variation across settings and new assessment methods. The overall aim of this thesis is to identify patients at high risk for poor outcome after acute neurological diseases (Part II) and to enhance knowledge on outcome variation and statistical efficiency of new outcome measures (Part III). Specific research questions are: 1. What characteristics are associated with poor outcome after acute neurological diseases? 2. What is the methodological quality of existing prognostic models in acute neurological diseases? 3. Do these models provide reliable predictions for patients in specific clinical settings? 4. What are the differences in clinical outcomes between patients with aSAH in a range of international hospitals, and can these differences be explained by variation in case-mix? 5. What is the statistical efficiency of new outcome measures for acute neurological diseases

Validation of prognostic models: challenges and opportunities

Multivariable prognostic models combine several characteristics to provide predictions for individual patients. Prognostic models can be applied in research and clinical practice, for instance to assist clinicians with decisions regarding treatment choices or informing patients and family members on prognosis (1). Before application in clinical practice, prognostic models should be validated to judge their generalizability. Although guidelines have been proposed to improve development and reporting of prognostic models, a majority of the published models is not thoroughly validated (1,2). In this viewpoint, we focus on design and analysis of validation

Development of prognostic models for Health-Related Quality of Life following traumatic brain injury

Background Traumatic brain injury (TBI) is a leading cause of impairments affecting Health-Related Quality of Life (HRQoL). We aimed to identify predictors of and develop prognostic models for HRQoL following TBI. Methods We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Core study, including patients with a clinical diagnosis of TBI and an indication for computed tomography presenting within 24 h of injury. The primary outcome measures were the SF-36v2 physical (PCS) and mental (MCS) health component summary scores and the Quality of Life after Traumatic Brain Injury (QOLIBRI) total score 6 months post injury. We considered 16 patient and injury characteristics in linear regression analyses. Model performance was expressed as proportion of variance explained (R-2) and corrected for optimism with bootstrap procedures. Results 2666 Adult patients completed the HRQoL questionnaires. Most were mild TBI patients (74%). The strongest predictors for PCS were Glasgow Coma Scale, major extracranial injury, and pre-injury health status, while MCS and QOLIBRI were mainly related to pre-injury mental health problems, level of education, and type of employment. R-2 of the full models was 19% for PCS, 9% for MCS, and 13% for the QOLIBRI. In a subset of patients following predominantly mild TBI (N = 436), including 2 week HRQoL assessment improved model performance substantially (R-2 PCS 15% to 37%, MCS 12% to 36%, and QOLIBRI 10% to 48%). Conclusion Medical and injury-related characteristics are of greatest importance for the prediction of PCS, whereas patient-related characteristics are more important for the prediction of MCS and the QOLIBRI following TBI.Development and application of statistical models for medical scientific researchAnalysis and support of clinical decision makin

National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424

Letter by Dijkland et al Regarding Article, "Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation: The Maugeri Model"

_To the Editor:_ With great interest, we read the study by Scrutinio et al, which describes the development and validation of the Maugeri model that predicts functional outcome after inpatient stroke rehabilitation based on easily obtainable clinical characteristics. We agree with the authors that prediction of functional outcome after stroke rehabilitation is important to inform patients and relatives on prognosis and to identify rehabilitation goals. The authors performed external validation of the model, which is crucial to evaluate generalizability. However, we noted opportunities for methodological improvement in the development and validation of the Maugeri

Prognosis in Moderate and Severe Traumatic Brain Injury: A Systematic Review of Contemporary Models and Validation Studies

Analysis and support of clinical decision makin

Outcome Prediction after Moderate and Severe Traumatic Brain Injury: External Validation of Two Established Prognostic Models in 1742 European Patients

The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict functional outcome after moderate and severe traumatic brain injury (TBI). We aimed to assess their performance in a contemporary cohort of patients across Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective, observational cohort study in patients presenting with TBI and an indication for brain computed tomography. The CENTER-TBI core cohort consists of 4509 TBI patients available for analyses from 59 centers in 18 countries across Europe and Israel. The IMPACT validation cohort included 1173 patients with GCS = 14, and 6-month Glasgow Outcome Scale-Extended (GOSE) available. The CRASH validation cohort contained 1742 patients with GCS = 16, and 14-day mortality or 6-month GOSE available. Performance of the three IMPACT and two CRASH model variants was assessed with discrimination (area under the receiver operating characteristic curve; AUC) and calibration (comparison of observed vs. predicted outcome rates). For IMPACT, model discrimination was good, with AUCs ranging between 0.77 and 0.85 in 1173 patients and between 0.80 and 0.88 in the broader CRASH selection (n = 1742). For CRASH, AUCs ranged between 0.82 and 0.88 in 1742 patients and between 0.66 and 0.80 in the stricter IMPACT selection (n = 1173). Calibration of the IMPACT and CRASH models was generally moderate, with calibration-in-the-large and calibration slopes ranging between -2.02 and 0.61 and between 0.48 and 1.39, respectively. The IMPACT and CRASH models adequately identify patients at high risk for mortality or unfavorable outcome, which supports their use in research settings and for benchmarking in the context of quality-of-care assessment.Development and application of statistical models for medical scientific researc

Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository

OBJECTIVE Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH).METHODS The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1-3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4-6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country.RESULTS The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16-1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11-1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00-1.40).CONCLUSIONS Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.Analysis and support of clinical decision makin

Risk of Intracranial Complications in Minor Head Injury: The Role of Loss of Consciousness and Post-Traumatic Amnesia in a Multi-Center Observational Study

Analysis and support of clinical decision makin

National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke

Contains fulltext : 219673.pdf (Publisher’s version ) (Open Access)Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424