Predicting Conversion Time from Mild Cognitive Impairment to Dementia with Interval-Censored Models.

Background: Mild cognitive impairment (MCI) patients are at a high risk of developing Alzheimer's disease and related dementias (ADRD) at an estimated annual rate above 10%. It is clinically and practically important to accurately predict MCI-to-dementia conversion time. Objective: It is clinically and practically important to accurately predict MCI-to-dementia conversion time by using easily available clinical data. Methods: The dementia diagnosis often falls between two clinical visits, and such survival outcome is known as interval-censored data. We utilized the semi-parametric model and the random forest model for interval-censored data in conjunction with a variable selection approach to select important measures for predicting the conversion time from MCI to dementia. Two large AD cohort data sets were used to build, validate, and test the predictive model. Results: We found that the semi-parametric model can improve the prediction of the conversion time for patients with MCI-to-dementia conversion, and it also has good predictive performance for all patients. Conclusions: Interval-censored data should be analyzed by using the models that were developed for interval- censored data to improve the model performance.

Rationale and Design for the BLOCK-SAH Study (Pterygopalatine Fossa Block as an Opioid-Sparing Treatment for Acute Headache in Aneurysmal Subarachnoid Hemorrhage): A Phase II, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial with a Sequential Parallel Comparison Design.

BACKGROUND: Acute post-subarachnoid hemorrhage (SAH) headaches are common and severe. Management strategies for post-SAH headaches are limited, with heavy reliance on opioids, and pain control is overall poor. Pterygopalatine fossa (PPF) nerve blocks have shown promising results in treatment of acute headache, including our preliminary and published experience with PPF-blocks for refractory post-SAH headache during hospitalization. The BLOCK-SAH trial was designed to assess the efficacy and safety of bilateral PPF-blocks in awake patients with severe headaches from aneurysmal SAH who require opioids for pain control and are able to verbalize pain scores. METHODS: BLOCK-SAH is a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial using the sequential parallel comparison design (SPCD), followed by an open-label phase. RESULTS: Across 12 sites in the United States, 195 eligible study participants will be randomized into three groups to receive bilateral active or placebo PPF-injections for 2 consecutive days with periprocedural monitoring of intracranial arterial mean flow velocities with transcranial Doppler, according to SPCD (group 1: active block followed by placebo; group 2: placebo followed by active block; group 3: placebo followed by placebo). PPF-injections will be delivered under ultrasound guidance and will comprise 5-mL injectates of 20 mg of ropivacaine plus 4 mg of dexamethasone (active PPF-block) or saline solution (placebo PPF-injection). CONCLUSIONS: The trial has a primary efficacy end point (oral morphine equivalent/day use within 24 h after each PPF-injection), a primary safety end point (incidence of radiographic vasospasm at 48 h from first PPF-injection), and a primary tolerability end point (rate of acceptance of second PPF-injection following the first PPF-injection). BLOCK-SAH will inform the design of a phase III trial to establish the efficacy of PPF-block, accounting for different headache phenotypes.

Statistical considerations when estimating time-saving treatment effects in Alzheimer's disease clinical trials.

INTRODUCTION: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods. METHODS: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial. RESULTS: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm. DISCUSSION: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods. HIGHLIGHTS: We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved.

Prior football or rugby exposure and white matter signal abnormalities in professional male mixed martial arts fighters.

BACKGROUND: White matter signal abnormalities have been associated with traumatic brain injury (TBI) and repetitive head impacts (RHI) in contact sports (e.g. American football, rugby). However, previous studies of mixed martial arts (MMA) fighters from the Professional Fighters Brain Health Study have not found greater white matter signal abnormalities in fighters versus controls. OBJECTIVE: This study aims to explore the varying white matter effects of football/rugby and MMA by analyzing how football/rugby history in mixed martial arts fighters may relate to white matter signal abnormalities, helping to further our understanding of sport-specific brain health risks. METHODS: Baseline visits for 90 active, professional, male mixed martial arts fighters and 27 unexposed male controls were cross-sectionally analyzed. Wilcoxon and Kruskal-Wallis tests compared demographics and white matter signal abnormalities, and multivariable regression models examined the associations between football/rugby history and white matter signal abnormality burden in fighters, adjusting for age, education, race, fights, MRI scanner, and supratentorial volume. RESULTS: 37/90 fighters had football/rugby history (mean: 4 years; range: 1-12 years). White matter signal abnormalities were significantly greater in fighters with football/rugby history compared to fighters without football/rugby history (Wilcoxon, p = 0.0190). Football/rugby history was significantly associated with white matter signal abnormality burden >75th percentile (OR: 12, CI: 3.3-61, p < 0.001) and >50th percentile (OR: 3.2, CI: 1.2-9.4, p = 0.024) in fighters. Years of football/rugby were also significantly associated with white matter signal abnormalities. CONCLUSION: Our findings expand on previous literature by demonstrating a significant relationship between white matter signal abnormalities (WMSAs) and football/rugby history but not MMA. Furthermore, our study suggests an added risk for WMSAs in MMA fighters with a history of football/rugby. Future research should further evaluate WMSAs in contact sports, helping to inform athletes, regulatory bodies, and healthcare providers of the potential brain health risks of contact sports.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. Objective: To develop a new composite score to improve the prediction of outcome change. Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. Results: The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

Validation of the Keele STarT MSK Tool for Patients With Musculoskeletal Pain in United States-based Outpatient Physical Therapy Settings.

The STarT MSK tool was developed to enable risk stratification of patients with common musculoskeletal (MSK) pain conditions and help identify individuals who may require more targeted interventions or closer monitoring in primary care settings, however, its validity in U.S.-based outpatient physical therapy settings has not been investigated. The 10-item Keele STarT MSK risk stratification tool was tested for construct (convergent and discriminant) and predictive validity using a multicenter, prospective cohort study design. Participants (n = 141) receiving physical therapy for MSK pain of the back, neck, shoulder, hip, knee, or multisite regions completed intake questionnaires including the Keele STarT MSK tool, Functional Comorbidity Index (FCI), Optimal Screening for Prediction of Referral and Outcome Review-of-Systems and Optimal Screening for Prediction of Referral and Outcome Yellow Flag tools. Pain intensity, pain interference, and health-related quality of life (Medical Outcomes Study 8-item Short-Form Health Survey (SF-8) physical [PCS] and mental [MCS] component summary scores) were measured at 2- and 6-month follow-up. Participants were classified as STarT MSK tool low (44%), medium (39%), and high (17%) risk. Follow-up rates were 70.2% (2 months) and 49.6% (6 months). For convergent validity, fair relationships were observed between the STarT MSK tool and FCI and SF-8 MCS (r = .35-.37) while moderate-to-good relationships (r = .51-.72) were observed for 7 other clinical measures. For discriminant validity, STarT MSK tool risk-dependent relationships were observed for Optimal Screening for Prediction of Referral and Outcome Review-of-Systems, Optimal Screening for Prediction of Referral and Outcome Yellow Flag, pain interference, and SF-8 PCS (low < medium < high; P < .01) and FCI, pain intensity, and SF-8 MCS (low < medium-or-high; P < .01). For predictive validity, intake STarT MSK tool scores explained additional variability in pain intensity (11.2%, 20.0%), pain interference (7.5%, 14.1%), and SF-8 PCS (8.2%, 12.8%) scores at 2 and 6 months, respectively. This study contributes to the existing literature by providing additional evidence of STarT MSK tool cross-sectional construct validity and longitudinal predictive validity. PERSPECTIVE: This study presents STarT MSK risk stratification tool validity findings from a U.S. outpatient physical therapy sample. The STarT MSK tool has the potential to help physical therapists identify individuals presenting with the most common MSK pain conditions who may require more targeted interventions or closer monitoring.

Comparison of Pocock and Simon's covariate-adaptive randomization procedures in clinical trials.

When multiple influential covariates need to be balanced during a clinical trial, stratified blocked randomization and covariate-adaptive randomization procedures are frequently used in trials to prevent bias and enhance the validity of data analysis results. The latter approach is increasingly used in practice for a study with multiple covariates and limited sample sizes. Among a group of these approaches, the covariate-adaptive procedures proposed by Pocock and Simon are straightforward to be utilized in practice. We aim to investigate the optimal design parameters for the patient treatment assignment probability of their developed three methods. In addition, we seek to answer the question related to the randomization performance when additional covariates are added to the existing randomization procedure. We conducted extensive simulation studies to address these practically important questions.

Continuity corrected score confidence interval for the difference in proportions in paired data.

For paired binary data, the hybrid method and the score method are often recommended for use to calculate the confidence interval for risk difference. These asymptotic intervals do not control the coverage probability. We propose to develop a new score interval with continuity correction to further improve the performance of the existing intervals. The traditional correction value may be too large which leads to a wide interval. For that reason, we propose three different correction values to identify the optimal correction interval with balanced coverage probability and interval width. From simulation studies, we find that a small correction value for the score interval has good performance. In addition, we derive the non-iterative solutions for the developed continuity correction score intervals.

Association of Win-Loss Record With Neuropsychiatric Symptoms and Brain Health Among Professional Fighters.

OBJECTIVE: Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes. METHODS: The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data. RESULTS: Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume. CONCLUSIONS: These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.

Continuity corrected Wilson interval for the difference of two independent proportions.

Confidence interval for the difference of two proportions has been studied for decades. Many methods were developed to improve the approximation of the limiting distribution of test statistics, such as the profile likelihood method, the score method, and the Wilson method. For the Wilson interval developed by Beal (1987), the approximation of the Z test statistic to the standard normal distribution may be further improved by utilizing the continuity correction, in the observation of anti-conservative intervals from the Wilson interval. We theoretically prove that the Wilson interval is nested in the continuity corrected Wilson interval under mild conditions. We compare the continuity corrected Wilson interval with the commonly used methods with regards to coverage probability, interval width, and mean squared error of coverage probability. The proposed interval has good performance in many configurations. An example from a Phase II cancer trial is used to illustrate the application of these methods.

A Research Protocol to Study the Priming Effects of Breathing Low Oxygen on Enhancing Training-Related Gains in Walking Function for Persons With Spinal Cord Injury: The BO2ST Trial.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three interventions: tAIH + WALKtSTIM; Placebo + WALKtSTIM; and tAIH + WALKtSHAM. Participants receive daily tAIH (fifteen 90-sec episodes at 10% O2 with 60-sec intervals at 21% O2) or daily placebo (fifteen 90-sec episodes at 21% O2 with 60-sec intervals at 21% O2) before a 45-min session of WALKtSTIM or WALKtSHAM. Our primary outcome measures assess walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up and Go Test). For safety, we also measure pain levels, spasticity, sleep behavior, cognition, and rates of systemic hypertension and autonomic dysreflexia. Assessments occur before, during, and after sessions, as well as at 1, 4, and 8 weeks post-intervention. Results from this study extend our understanding of the functional benefits of tAIH priming by investigating its capacity to boost the neuromodulatory effects of transcutaneous spinal stimulation on restoring walking after SCI. Given that there is no known cure for SCI and no single treatment is sufficient to overcome walking deficits, there is a critical need for combinatorial treatments that accelerate and anchor walking gains in persons with lifelong SCI. Trial Registration: ClinicalTrials.gov, NCT05563103.

Blood biomarkers and neurodegeneration in individuals exposed to repetitive head impacts.

BACKGROUND: It is unknown if fluid biomarkers reflective of brain pathologies are useful in detecting and following a neurodegenerative process in individuals exposed to repetitive head impacts. This study explores the relationship between blood biomarkers and longitudinal change in cognitive function and regional brain volumes in a cohort of professional fighters. METHODS: Participants are drawn from a convenience sample of active and retired professional boxers and Mixed Martial Arts fighters and a control group with no prior exposure to head impacts. 3 T MRI brain imaging, plasma samples, and computerized cognitive testing were obtained at baseline and, for a subset, annually. MRI regional volumes were extracted, along with plasma levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), p-tau231, and N-terminal tau (NTA). Statistical analyses were performed to assess the relationship between plasma levels and regional brain volumes and cognitive performance at baseline and longitudinally. RESULTS: One hundred forty active boxers (mean age: 31 with standard deviation (SD) of 8), 211 active MMA (mean age of 30 with SD of 5), 69 retired boxers (mean age 49 with SD of 9), and 52 control participants (mean age 36 with SD of 12) were included in the analyses. Baseline GFAP levels were highest in the retired boxers (retired boxers v. active MMA: p = 0.0191), whereas active boxers had higher levels of NfL (active boxers v. MMA: p = 0.047). GFAP showed an increase longitudinally in retired boxers that was associated with decreasing volumes of multiple cortical and subcortical structures (e.g., hippocampus: B = - 1.25, 95% CI, - 1.65 to - 0.85) and increase in lateral ventricle size (B = 1.75, 95% CI, 1.46 to 2.04). Furthermore, performance on cognitive domains including memory, processing speed, psychomotor speed, and reaction time declined over time with increasing GFAP (e.g., processing speed: B = - 0.04, 95% CI, - 0.07 to - 0.02; reaction time: B = 0.52, 95% CI, 0.28 to 0.76). Among active fighters, increasing levels of GFAP were correlated with lower thalamic (B = - 1.42, 95% CI, - 2.34 to -0.49) and corpus callosum volumes, along with worsening scores on psychomotor speed (B = 0.14, 95% CI, 0.01 to 0.27). CONCLUSION: Longitudinal plasma GFAP levels may have a role in identifying individuals exposed to repetitive head impacts who are at risk of showing progressive regional atrophy and cognitive decline.

Two-stage response adaptive randomization designs for multi-arm trials with binary outcome.

In recent years, adaptive randomization methods have gained significant popularity in clinical research and trial design due to their ability to provide both efficiency and flexibility in adjusting the statistical procedures of ongoing clinical trials. For a study to compare multiple treatments, a multi-arm two-stage design could be utilized to select the best treatment from the first stage and further compare that treatment with control in the second stage. The traditional design used equal randomization in both stages. To better utilize the interim results from the first stage, we propose to develop response adaptive randomization two-stage designs for a multi-arm clinical trial with binary outcome. Two allocation methods are considered: (1) an optimal allocation based on a sequential design; (2) the play-the-winner rule. Optimal multi-arm two-stage designs are obtained under three criteria: minimizing the expected number of failures, minimizing the average expected sample size, and minimizing the expected sample size under the null hypothesis. Simulation studies show that the proposed adaptive design based on the play-the-winner rule has good performance. A phase II trial for patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation was used to illustrate the application of the proposed response adaptive randomization designs.

Promising zone two-stage design for a single-arm study with binary outcome.

Adaptive designs are increasingly used in clinical trials to assess the effectiveness of new drugs. For a single-arm study with a binary outcome, several adaptive designs were developed by using numerical search algorithms and the conditional power approach. The design based on numerical search algorithms is able to identify the global optimal design, but the computational intensity limits the usage of these designs. The conditional power approach searches for the optimal design without expensive computing time. In addition, promising zone strategy was proposed to move on drug development to the follow-up stages when the interim results are promising. We propose to develop two adaptive designs: One based on the conditional power approach, and the other based on the promising zone strategy. These two designs preserve types I and II error rates. It is preferable to satisfy the monotonic property for adaptive designs: The second stage sample size decreases as the first stage responses go up. We theoretically prove this important property for the two proposed designs. The proposed designs can be easily applied to real trials with limited computing resources.

Sparring and the Brain: The Associations between Sparring and Regional Brain Volumes in Professional Mixed Martial Arts Fighters.

BACKGROUND: Mixed martial arts (MMA) fighters, due to exposure to repetitive head impacts, are at risk for brain atrophy and neurodegenerative sequelae. Simultaneously, motor skills training and cognition-rich activities have been linked with larger regional brain volumes. The majority of an MMA fighter's sporting activity occurs during practice (e.g., sparring) rather than formal competition. This study, therefore, aims to be the first to explore regional brain volumes associated with sparring in MMA fighters. METHODS: Ninety-four active, professional MMA fighters from the Professional Fighters Brain Health Study met inclusion criteria for this cross-sectional analysis. Adjusted multivariable regression analyses were utilized to examine the relationship between the number of sparring practice rounds per week during typical training and a select number of regional brain volumes (i.e., caudate, thalamus, putamen, hippocampus, amygdala). RESULTS: A higher number of weekly sparring rounds during training was significantly associated with larger left (beta = 13.5 µL/round, 95% CI 2.26-24.8) and right (beta = 14.9 µL/round, 95% CI 3.64-26.2) caudate volumes. Sparring was not significantly associated with left or right thalamus, putamen, hippocampus, or amygdala volumes. CONCLUSIONS: More weekly rounds of sparring was not significantly associated with smaller volumes in any of the brain regions studied in active, professional MMA fighters. Sparring's significant association with larger caudate volume raises questions about whether fighters who spar more experience attenuated trauma-related decreases in caudate volume relative to fighters who spar less, whether fighters who spar more experience minimal or even positive changes to caudate volume, whether baseline differences in caudate size may have mediated results, or whether some other mechanism may be at play. Given limitations inherent to the cross-sectional study design, more research is needed to further explore the brain effects of sparring in MMA.

Response adaptive randomization design for a two-stage study with binary response.

Response adaptive randomization has the potential to treat more participants in better treatments in a trial to benefit participants. We propose optimal response adaptive randomization designs for a two-stage study with binary response, having the smallest expected sample size or the fewest expected number of failures. Equal randomization is used in the first stage, and data from the first stage is used to determine the adaptive sample size ratio in the second stage. In the proposed optimal designs, the type I error rate and the statistical power are calculated from the asymptotic normal distributions. The new designs that minimize the expected number of failures have the advantage over the existing optimal randomized designs to substantially reduce the number of failures.

New Confidence Intervals for Relative Risk of Two Correlated Proportions.

Biomedical studies, such as clinical trials, often require the comparison of measurements from two correlated tests in which each unit of observation is associated with a binary outcome of interest via relative risk. The associated confidence interval is crucial because it provides an appreciation of the spectrum of possible values, allowing for a more robust interpretation of relative risk. Of the available confidence interval methods for relative risk, the asymptotic score interval is the most widely recommended for practical use. We propose a modified score interval for relative risk and we also extend an existing nonparametric U-statistic-based confidence interval to relative risk. In addition, we theoretically prove that the original asymptotic score interval is equivalent to the constrained maximum likelihood-based interval proposed by Nam and Blackwelder. Two clinically relevant oncology trials are used to demonstrate the real-world performance of our methods. The finite sample properties of the new approaches, the current standard of practice, and other alternatives are studied via extensive simulation studies. We show that, as the strength of correlation increases, when the sample size is not too large the new score-based intervals outperform the existing intervals in terms of coverage probability. Moreover, our results indicate that the new nonparametric interval provides the coverage that most consistently meets or exceeds the nominal coverage probability.

Traumatic encephalopathy syndrome: application of new criteria to a cohort exposed to repetitive head impacts.

OBJECTIVE: To examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they show differences in MRI-based regional brain volumes, cognitive domains, and certain plasma biomarkers. METHODS: Professional fighters 35 years of age or older and/or retired were included. Participants were categorised as either having TES (TES+) or not (non-TES). TES+ participants were further subtyped by their cognitive profile. Multiple linear regression models were used to compare MRI-based regional brain volumes, cognitive performance, plasma tau and neurofilament light levels between TES- and TES+ groups. RESULTS: 176 participants (110 boxers and 66 MMA) were included in the analysis. 72 (41%)/176 were categorised as having TES, the likelihood of TES increasing with age. TES+ participants tended to be boxers, started fighting at a younger age, had more professional fights and knocked out more frequently. The TES+ group had lower regional brain volumes including both grey and white matter structures. TES+ also had lower scores on simple and choice reaction time, psychomotor speed and Trails A . CONCLUSION: The new TES criteria does distinguish a group of fighters with differences in regional brain volumes and reduced cognitive function. Our findings support the use of the NINDS criteria for TES in further research of the long-term effects of repetitive head impacts.

Acute Headache Management for Patients with Subarachnoid Hemorrhage: An International Survey of Health Care Providers.

BACKGROUND: Severe headaches are common after subarachnoid hemorrhage. Guidelines recommend treatment with acetaminophen and opioids, but patient data show that headaches often persist despite multimodal treatment approaches. Considering an overall slim body of data for a common complaint affecting patients with SAH during their intensive care stay, we set out to assess practice patterns in headache management among clinicians who treat patients with SAH. METHODS: We conducted an international cross-sectional study through a 37-question Web-based survey distributed to members of five professional societies relevant to intensive and neurocritical care from November 2021 to January 2022. Responses were characterized through descriptive analyses. Fisher's exact test was used to test associations. RESULTS: Of 516 respondents, 329 of 497 (66%) were from North America and 121 of 497 (24%) from Europe. Of 435 respondents, 379 (87%) reported headache as a major management concern for patients with SAH. Intensive care teams were primarily responsible for analgesia during hospitalization (249 of 435, 57%), whereas responsibility shifted to neurosurgery at discharge (233 of 501, 47%). Most used medications were acetaminophen (90%), opioids (66%), corticosteroids (28%), and antiseizure medications (28%). Opioids or medication combinations including opioids were most frequently perceived as most effective by 169 of 433 respondents (39%, predominantly intensivists), followed by corticosteroids or combinations with corticosteroids (96 of 433, 22%, predominantly neurologists). Of medications prescribed at discharge, acetaminophen was most common (303 of 381, 80%), followed by opioids (175 of 381, 46%) and antiseizure medications (173 of 381, 45%). Opioids during hospitalization were significantly more prescribed by intensivists, by providers managing higher numbers of patients with SAH, and in Europe. At discharge, opioids were more frequently prescribed in North America. Of 435 respondents, 299 (69%) indicated no change in prescription practice of opioids with the opioid crisis. Additional differences in prescription patterns between continents and providers and while inpatient versus at discharge were found. CONCLUSIONS: Post-SAH headache in the intensive care setting is a major clinical concern. Analgesia heavily relies on opioids both in use and in perception of efficacy, with no reported change in prescription patterns for opioids for most providers despite the significant drawbacks of opioids. Responsibility for analgesia shifts between hospitalization and discharge. International and provider-related differences are evident. Novel treatment strategies and alignment of prescription between providers are urgently needed.

Monte Carlo cross-validation for a study with binary outcome and limited sample size.

Cross-validation (CV) is a resampling approach to evaluate machine learning models when sample size is limited. The number of all possible combinations of folds for the training data, known as CV rounds, are often very small in leave-one-out CV. Alternatively, Monte Carlo cross-validation (MCCV) can be performed with a flexible number of simulations when computational resources are feasible for a study with limited sample size. We conduct extensive simulation studies to compare accuracy between MCCV and CV with the same number of simulations for a study with binary outcome (e.g., disease progression or not). Accuracy of MCCV is generally higher than CV although the gain is small. They have similar performance when sample size is large. Meanwhile, MCCV is going to provide reliable performance metrics as the number of simulations increases. Two real examples are used to illustrate the comparison between MCCV and CV.