Design and Analysis of Randomized Controlled Trials in Traumatic Brain Injury

Randomized controlled trials in traumatic brain injury (TBI) are challenging due to the inherent heterogeneity of the patient population, the lack of early mechanistic end points, and relative insensitivity of outcome measures. Approaches to deal with the heterogeneity of the patient population are presented in this thesis. The use of strict enrollment criteria is not recommended, as this is inefficient. Rather, broad enrollment criteria may be preferred combined with covariate adjustment in the analysis phase. Dichotomization of the Glasgow Outcome Scale as the primary outcome measure in most trials is not recommended. Ordinal approaches to analysis of tr

Pitfalls of single-study external validation illustrated with a model predicting functional outcome after aneurysmal subarachnoid hemorrhage

Background: Prediction models are often externally validated with data from a single study or cohort. However, the interpretation of performance estimates obtained with single-study external validation is not as straightforward as assumed. We aimed to illustrate this by conducting a large number of external validations of a prediction model for functional outcome in subarachnoid hemorrhage (SAH) patients.Methods: We used data from the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository (n = 11,931, 14 studies) to refit the SAHIT model for predicting a dichotomous functional outcome (favorable versus unfavorable), with the (extended) Glasgow Outcome Scale or modified Rankin Scale score, at a minimum of three months after discharge. We performed leave-one-cluster-out cross-validation to mimic the process of multiple single-study external validations. Each study represented one cluster. In each of these validations, we assessed discrimination with Harrell’s c-statistic and calibration with calibration plots, the intercepts, and the slopes. We used random effects meta-analysis to obtain the (reference) mean performance estimates and between-study heterogeneity (I2-statistic). The influence of case-mix variation on discriminative performance was assessed with the model-based c-statistic and we fitted a “membership model” to obtain a gross estimate of transportability. Results: Across 14 single-study external validations, model performance was highly variable. The mean c-statistic was 0.74 (95%CI 0.70–0.78, range 0.52–0.84, I2 = 0.92), the mean intercept was -0.06 (95%CI -0.37–0.24, range -1.40–0.75, I2 = 0.97), and the mean slope was 0.96 (95%CI 0.78–1.13, range 0.53–1.31, I2 = 0.90). The decrease in discriminative performance was attributable to case-mix variation, between-study heterogeneity, or a combination of both. Incidentally, we observed poor generalizability or transportability of the model. Conclusions: We demonstrate two potential pitfalls in the interpretation of model performance with single-study external validation. With single-study external validation. (1) model performance is highly variable and depends on the choice of validation data and (2) no insight is provided into generalizability or transportability of the model that is needed to guide local implementation. As such, a single single-study external validation can easily be misinterpreted and lead to a false appreciation of the clinical prediction model. Cross-validation is better equipped to address these pitfalls.</p

Performance of a Diagnostic Model for the Presence of Unruptured Intracranial Aneurysms in the General Population

Introduction: The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage can be prevented by screening for UIAs followed by monitoring and, if needed, preventive neurosurgical or endovascular treatment of identified UIAs. Therefore, we developed a diagnostic model for the presence of UIAs in the general population to help identify persons at high risk of having UIAs. Methods: Between 2005 and 2015, participants from the populationbased Rotterdam Study underwent brain magnetic resonance imaging at 1.5 T, on which the presence of incidental UIAs was evaluated. We developed a multivariable logistic regression model using candidate diagnostic markers that were selected based on the literature, including sex, age, hypertension, smoking, hypercholesterolemia, diabetes, alcohol, and their interactions. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: 5,835 persons were included (55.0% women, mean age 64.9 ± 10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI]: 0.60 0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cutoff value of 4%. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95% CI: 0.62 0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95% CI: 0.52 0.63) with smoking as the only diagnostic marker. Conclusion: Our diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.</p

Determinants of the Presence and Size of Intracranial Aneurysms in the General Population The Rotterdam Study

BACKGROUND AND PURPOSE: The prevalence of unruptured intracranial aneurysms (UIAs) in the adult population is ≈3%. Rupture of an intracranial aneurysm can have devastating consequences, which emphasizes the importance of identification of potentially modifiable determinants for the presence and size of UIAs. Our aim was to study the association of a broad spectrum of potential determinants with the presence and size of UIAs in a general adult population. METHODS: Between 2005 and 2015, 5841 participants from the population-based Rotterdam Study (mean age, 64.4 years, 45.0% male) underwent brain magnetic resonance imaging (1.5T). These scans were evaluated for the presence of incidental UIAs. We determined number and volume of the UIAs. Using logistic and linear regression models, we assessed the association of cardiovascular, lifestyle and emerging inflammatory and hormonal determinants with the presence and volume of UIAs. RESULTS: In 134 (2.3%) participants, ≥1 UIAs were detected (149 UIAs in total), with a median volume of 61.1 mm3 (interquartile range, 33.2–134.0). In multivariable models, female sex (odds ratio, 1.92 [95% CI, 1.33–2.84]), hypertension (odds ratio, 1.73 [95% CI, 1.13–2.68]), and current smoking (odds ratio, 3.75 [95% CI, 2.27–6.33]) were associated with the presence of UIAs. We found no association of alcohol use, physical activity, or diet quality with UIA presence. Finally, we found white blood cell count to relate to larger aneurysm volume (difference in volume of 33.6 mm3 per 109/L increase in white blood cell [95% CI, 3.92–63.5]). CONCLUSIONS: In this population-based study, female sex, hypertension, and smoking, but no other lifestyle determinants, were associated with the presence of UIAs. White blood cell count is associated with size of UIAs. Preventive strategies should focus on treating hypertension and promoting cessation of smoking

Personalized decision‑making for aneurysm treatment of aneurysmal subarachnoid hemorrhage:development and validation of a clinical prediction tool

Background: In patients with aneurysmal subarachnoid hemorrhage suitable for endovascular coiling and neurosurgical clip-reconstruction, the aneurysm treatment decision-making process could be improved by considering heterogeneity of treatment effect and durability of treatment. We aimed to develop and validate a tool to predict individualized treatment benefit of endovascular coiling compared to neurosurgical clip-reconstruction. Methods: We used randomized data (International Subarachnoid Aneurysm Trial, n = 2143) to develop models to predict 2-month functional outcome and to predict time-to-rebleed-or-retreatment. We modeled for heterogeneity of treatment effect by adding interaction terms of treatment with prespecified predictors and with baseline risk of the outcome. We predicted outcome with both treatments and calculated absolute treatment benefit. We described the patient characteristics of patients with ≥ 5% point difference in the predicted probability of favorable functional outcome (modified Rankin Score 0–2) and of no rebleed or retreatment within 10 years. Model performance was expressed with the c-statistic and calibration plots. We performed bootstrapping and leave-one-cluster-out cross-validation and pooled cluster-specific c-statistics with random effects meta-analysis. Results: The pooled c-statistics were 0.72 (95% CI: 0.69–0.75) for the prediction of 2-month favorable functional outcome and 0.67 (95% CI: 0.63–0.71) for prediction of no rebleed or retreatment within 10 years. We found no significant interaction between predictors and treatment. The average predicted benefit in favorable functional outcome was 6% (95% CI: 3–10%) in favor of coiling, but 11% (95% CI: 9–13%) for no rebleed or retreatment in favor of clip-reconstruction. 134 patients (6%), young and in favorable clinical condition, had negligible functional outcome benefit of coiling but had a ≥ 5% point benefit of clip-reconstruction in terms of durability of treatment. Conclusions: We show that young patients in favorable clinical condition and without extensive vasospasm have a negligible benefit in functional outcome of endovascular coiling – compared to neurosurgical clip-reconstruction – while at the same time having a substantially lower probability of retreatment or rebleeding from neurosurgical clip-reconstruction – compared to endovascular coiling. The SHARP prediction tool (https://sharpmodels.shinyapps.io/sharpmodels/) could support and incentivize a multidisciplinary discussion about aneurysm treatment decision-making by providing individualized treatment benefit estimates.</p

Personalized decision‑making for aneurysm treatment of aneurysmal subarachnoid hemorrhage:development and validation of a clinical prediction tool

Background: In patients with aneurysmal subarachnoid hemorrhage suitable for endovascular coiling and neurosurgical clip-reconstruction, the aneurysm treatment decision-making process could be improved by considering heterogeneity of treatment effect and durability of treatment. We aimed to develop and validate a tool to predict individualized treatment benefit of endovascular coiling compared to neurosurgical clip-reconstruction. Methods: We used randomized data (International Subarachnoid Aneurysm Trial, n = 2143) to develop models to predict 2-month functional outcome and to predict time-to-rebleed-or-retreatment. We modeled for heterogeneity of treatment effect by adding interaction terms of treatment with prespecified predictors and with baseline risk of the outcome. We predicted outcome with both treatments and calculated absolute treatment benefit. We described the patient characteristics of patients with ≥ 5% point difference in the predicted probability of favorable functional outcome (modified Rankin Score 0–2) and of no rebleed or retreatment within 10 years. Model performance was expressed with the c-statistic and calibration plots. We performed bootstrapping and leave-one-cluster-out cross-validation and pooled cluster-specific c-statistics with random effects meta-analysis. Results: The pooled c-statistics were 0.72 (95% CI: 0.69–0.75) for the prediction of 2-month favorable functional outcome and 0.67 (95% CI: 0.63–0.71) for prediction of no rebleed or retreatment within 10 years. We found no significant interaction between predictors and treatment. The average predicted benefit in favorable functional outcome was 6% (95% CI: 3–10%) in favor of coiling, but 11% (95% CI: 9–13%) for no rebleed or retreatment in favor of clip-reconstruction. 134 patients (6%), young and in favorable clinical condition, had negligible functional outcome benefit of coiling but had a ≥ 5% point benefit of clip-reconstruction in terms of durability of treatment. Conclusions: We show that young patients in favorable clinical condition and without extensive vasospasm have a negligible benefit in functional outcome of endovascular coiling – compared to neurosurgical clip-reconstruction – while at the same time having a substantially lower probability of retreatment or rebleeding from neurosurgical clip-reconstruction – compared to endovascular coiling. The SHARP prediction tool (https://sharpmodels.shinyapps.io/sharpmodels/) could support and incentivize a multidisciplinary discussion about aneurysm treatment decision-making by providing individualized treatment benefit estimates.</p

Patients’ Perspectives Regarding Digital Health Technology to Support Self-management and Improve Integrated Stroke Care:Qualitative Interview Study

Background: Digital technologies such as mobile apps and robotics have the potential to involve stroke patients better in the care process and to promote self-management. However, barriers exist that constrain the adoption and acceptance of technology in clinical practice. Examples of barriers are privacy concerns, challenges regarding usability, and the perception that there is no need for health-related technology. To address these barriers, co-design can be used to enable patients to reflect on their experiences of a service and to tailor digital technologies to the needs and preferences of end users regarding content and usability. Objective: This study aims to explore the perspectives of stroke patients toward how digital health technology could support self-management regarding health and well-being, as well as integrated stroke care. Methods: A qualitative study was conducted to understand patient perspectives. Data were collected in co-design sessions during the ValueCare study. Patients from a Dutch hospital who experienced an ischemic stroke (n=36) within the past 18 months were invited to participate. Data collection took place between December 2020 and April 2021 via one-to-one telephone interviews. A short self-report questionnaire was used to collect data on sociodemographics, disease-specific information, and technology use. All interviews were audio-taped and transcribed verbatim. The interview data were analyzed using a thematic approach. Results: Patients held mixed attitudes toward digital health technologies. Some patients viewed digital technology as a convenient product or service, while others expressed no desire or need to use technology for self-management or care. Digital features suggested by stroke patients included (1) information about the causes of stroke, medication, prognosis, and follow-up care; (2) an online library with information regarding stroke-related health and care issues; (3) a personal health record by which patients can retrieve and manage their own health information; and (4) online rehabilitation support to empower patients to exercise at home. Regarding the user interface of future digital health technology, patients emphasized the need for easy-to-use and simple designs. Conclusions: Stroke patients mentioned credible health information, an online library with stroke-related health and care information, a personal health record, and online rehabilitation support as the main features to include in future digital health technologies. We recommend that developers and designers of digital health for stroke care listen to the “voice of the stroke patients” regarding both functionality and the characteristics of the interface.</p

Prevalence and risk factors of symptomatic carotid stenosis in patients with recent transient ischaemic attack or ischaemic stroke in the Netherlands

Introduction: Literature on prevalence of symptomatic internal carotid artery stenosis is scarce and heterogeneous. Prevalence may have decreased in recent years due to improved management of cardiovascular risk factors. We aim to estimate current prevalence and identify risk factors of ipsilateral internal carotid artery stenosis in patients with recent hemispheric transient ischaemic attack or isch