Allowing for stratification in sample size planning of two-arm trials with continuous or binary outcome: Overview and tutorial

More often than not, clinical trials and even nonclinical medical experiments have to be run with observational units sampled from populations to be assumed heterogeneous with respect to covariates associated with the outcome. Relevant covariates which are known prior to randomization are usually categorical in type, and the corresponding subpopulations are called strata. In contrast to randomization which in most cases is performed in a way ensuring approximately constant sample size ratios across the strata, sample size planning is rarely done taking stratification into account. This holds true although the statistical literature provides a reasonably rich repertoire of testing procedures for stratified comparisons between two treatments in a parallel group design. For all of them, at least approximate methods of power calculation are available from which algorithms or even closed-form formulae for required sample sizes can be derived. The objective of this tutorial is to give a systematic review of the most frequently applicable of these methods and to compare them in terms of their efficiency under standard settings. Based on the results, recommendations for the sample size planning of stratified two-arm trials are given.

Association of Circulating miR-145-5p and miR-let7c and Atherosclerotic Plaques in Hypertensive Patients

Aim: Hypertension is a strong risk factor for atherosclerosis. Increased carotid intima-media thickness (cIMT) and carotid plaques are considered subclinical markers of atherosclerosis. This study aimed at evaluating the serum expression of miRNAs previously related to adverse vascular remodeling and correlating them with carotid plaques and cIMT in hypertensive patients. Methods: We cross-sectionally evaluated the clinical and carotid characteristics as well as serum expression of miR-145-5p, miR-let7c, miR-92a, miR-30a and miR-451 in 177 hypertensive patients. Carotid plaques and cIMT were evaluated by ultrasound, and the expression of selected miRNAs was evaluated by a quantitative polymerase chain reaction. Results: Among all participants (age = 60.6 ± 10.7 years, 43% males), there were 59% with carotid plaques. We observed an increased expression of miR-145-5p (Fold Change = 2.0, p = 0.035) and miR-let7c (Fold Change = 3.8, p = 0.045) in participants with atherosclerotic plaque when compared to those without plaque. In the logistic regression analysis adjusted for relevant covariates, these miRNAs showed a stronger association with carotid plaques (miR-145-5p: Beta ± SE = 0.050 ± 0.020, p = 0.016 and miR-let7c: Beta ± SE = 0.056 ± 0.019, p = 0.003). Conclusions: Hypertensive patients with carotid plaques have an increased expression of miR-145-5p and miR-let7c, suggesting a potential role of these miRNAs as a biomarker for subclinical atherosclerosis in hypertensive individuals.

Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?

Background For patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period. Methods and Results We conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post‐Norwood and pre‐Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post‐Norwood. There were no significant differences in baseline clinical characteristics or post‐Norwood echocardiographic RV indices (RV end‐diastolic volume indexed, RV end‐systolic volume indexed, ejection fraction) in the digoxin versus no‐digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end‐diastolic volume (11 versus 15 mL, P =0.026) and the ΔRV end‐systolic volume (6 versus 9 mL, P =0.009) with the indexed ΔRV end‐systolic volume (11 versus 20 mL/BSA 1.3 , P =0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (−2 versus −5, P =0.056); however, the trend continued to be favorable for the digoxin group. Conclusions Digoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin’s survival benefit during the interstage period.

Dehumanization of Older Family Members: Novel Determinants of Elder Abuse Proclivity by Caregivers

Elder abuse affects one in six older persons globally. Three limitations converge to impede progress in prevention: most research is victim- rather than perpetrator-based; the reliance on explicit, self-reported factors; and failure to account for psychological factors that motivate abuse in the first place. The current study will be the first to address these gaps by examining whether family caregivers’ dehumanization of older persons, or the denial of humanness to older persons as one of the most hateful age stereotypes, could explain elder abuse proclivity. Implicit dehumanization of older persons was measured by a novel implicit-association-test developed for this study. Explicit dehumanization was measured by a semantic differential question widely used in the literature. We used the reliable and validated 8-item Caregiver Abuse Screen to measure elder abuse proclivity. In the final survey of 585 caregivers, dehumanization was found to be prevalent with 51% of the caregivers implicitly and 31% explicitly dehumanizing older persons. As predicted, implicit and explicit dehumanization uniquely contributed to elder abuse proclivity (OR=1.23, 95% CI=1.02-1.50, p=.03) and (OR=1.26, 95% CI=1.05-1.51, p=.01), respectively, after adjusting for relevant covariates including caregiver burden, and caregivers’ and care-recipients' health. Also as predicted, implicit dehumanization improved the prediction of abuse proclivity above and beyond the explicit dehumanization of older persons and caregiver burden. Socio-etiological models of elder abuse perpetration and corresponding prevention design should consider the inclusion of dehumanization as a key risk factor for abuse proclivity in family caregivers.

Autisme binnen de opvoeding

This study investigates the relationship between the perceived stress of parents with a child with (characteristics of) an autism spectrum disorder (ASD) and the degree of ASD characteristics within parents. Data from 222 children (mean age 7.8 years) and their primary caregivers, previously collected as part of the Social Spectrum Study, were analyzed. Linear regression analyses were used to investigate the association between experienced parenting stress and the influence of parents’ own ASD characteristics, taking into account relevant covariates. This study shows that the experienced parenting stress does not show a significant relationship with the ASD characteristics of parents when relevant covariates (such as own psychiatric problems, ASD characteristics of the child and the partner relationship) are added. This study finds indications that parenting stress in parents of children with ASD appears to be more strongly related to their general perceived psychopathology than to their specific ASD characteristics. Further replication is warranted, and we advise research into interventions for parents that possibly prevent (further) stress associated with raising a child with ASD (characteristics).

Abstract 1122‐000083: Endovascular Therapy Delay for Acute LVO is Associated with Worse Functional Outcome and Increased Mortality

Introduction : The importance of early mechanical thrombectomy (MT) has shown to improve functional outcomes for patients with acute large vessel occlusion (LVO). As well, prior studies have shown that earlier MT resulted in reduced hospital stay, more home‐time, and more desirable living situation in the 90 days after stroke. We hypothesized that delay in MT in patients with LVO would result in worse clinical outcome and increased mortality. Methods : We performed a retrospective analysis of consecutive patients who underwent MT for LVO in a large academic comprehensive stroke center between 01/2018 and 05/2021. We compared outcomes including in‐hospital mortality and 90‐day modified Rankin Scale (mRS) based on time from door‐to‐puncture and door‐to‐reperfusion, adjusting for relevant covariates using logistic regression. Results : Patients that had shorter door‐to‐puncture time were found to have higher probability of a lower modified Rankin Scale (mRS 0–2) at discharge (p = 0.03). Patients with door‐to‐puncture less than 60 minutes had a probability of 50% of achieving a good outcome. Longer door‐to‐puncture times were associated with lower probability of achieving mRS 0–2 at discharge. A similar finding was seen in patients that had shorter times to reperfusion (p = 0.05). Adjusting for age, baseline NIHSS score, and final TICI score, delayed door‐to‐reperfusion time in minutes was an independent predictor of increased mortality at 90 days of 9% for every 10 minutes delay (OR 1.009, 95% CI 1.003‐1.016, p = 0.006). Every 10 minutes delay in door‐to‐reperfusion time had 7% higher chance of poor functional outcome at 90 days (OR 1.007, 95% CI 1.004‐1.019, p = 0.015). Conclusions : Shorter times to MT and reperfusion impact functional outcome and mortality in LVO stroke patients. This indicates that an adequate hospital protocol and continuous education may lead to faster and more efficient stroke activations leading to a shorter time to MT and eventual reperfusion. Goals of door‐to‐puncture must be established in order to achieve better outcomes.

Incidence of Adult-Onset Epilepsy and the Contributory Role of Neurocysticercosis in a Five-Year, Population-Based, Prospective Study in Rural Ecuador

This prospective cohort study aimed to assess incidence and etiology of adult-onset epilepsy in previously seizure-free Atahualpa residents aged ≥ 20 years. Persons with adult-onset epilepsy occurring over 5 years were identified from annual door-to-door surveys and other overlapping sources. Those who emigrated or declined consent were excluded at the administrative censoring date of the last survey when these subjects were interviewed. Persons who died and those who developed incident epilepsy were censored at the time of these outcomes. Poisson regression models adjusted for demographics, education, alcohol intake, and the length of observation time, were used to estimate annual adult-onset epilepsy incidence rate ratio and cumulative incidence. Systematic neuroimaging screening was offered to participants to get insights on the etiology of epilepsy. Individuals enrolled in this cohort (N = 1,480) contributed to 6,811.6 years of follow-up. Seventeen developed incident adult-onset epilepsy, for an annual incident rate of 249.2 per 100,000 persons-year (95% CI: 130.7–367.7). Cumulative incidence was 1,245.9 per 100,000 persons (95% CI: 653.7–1,838.3) after a mean of 4.6 (SE: 0.06) years of follow-up. Six persons with incident epilepsy had neurocysticercosis (35%). Individuals with neurocysticercosis were six times more likely to develop adult-onset epilepsy than those without this disease (IRR: 6.01; 95% CI: 2.16–16.7), after adjusting for relevant covariates. The attributable fraction of incident adult-onset epilepsy due to neurocysticercosis was 30.9% (95% CI: 25.6–46.2%). This rural Ecuadorian population has a high incidence of adult-onset epilepsy, with neurocysticercosis being an important contributory cause.

Confederate monuments and the history of lynching in the American South: An empirical examination

The present work interrogates the history of Confederate memorializations by examining the relationship between these memorializations and lynching, an explicitly racist act of violence. We obtained and merged data on Confederate memorializations at the county level and lynching victims, also at the county level. We find that the number of lynching victims in a county is a positive and significant predictor of the number of Confederate memorializations in that county, even after controlling for relevant covariates. This finding provides concrete, quantitative, and historically and geographically situated evidence consistent with the position that Confederate memorializations reflect a racist history, one marred by intentions to terrorize and intimidate Black Americans in response to Black progress.

Associations between Longitudinal Patterns of Substance Use and Anxiety and Depression Symptoms among a Sample of Canadian Secondary School Students

The objective of this study is to examine the longitudinal associations between latent classes of substance use and anxiety and depression scores among youth who use substances. This study uses data from three waves (Wave 1: 2017/18, Wave 2: 2018/19, and Wave 3: 2019/20) of the COMPASS study. Students in grades 9 and 10 who reported substance use at baseline (n = 738) report their substance use (alcohol, cannabis, cigarettes, and e-cigarettes) and anxiety and depression symptoms at each wave. A Repeated Measures Latent Class Analysis (RMLCA) is used to determine substance use classes, and mixed models are used to examine the associations between substance use classes and anxiety and depression. We identify three classes of substance use: (1) occasional alcohol and e-cigarette use, (2) escalating poly-substance use, and (3) consistent poly-substance use. After controlling for relevant covariates, consistent poly-substance use is associated with depression (Female OR: 1.24 [95%CI: 0.46, 2.02]; Male OR 1.13 [95%CI: 0.38, 1.87]) but not anxiety. Escalating poly-substance use is associated with depression among males (OR 0.72 [95%CI: 0.10, 1.33]). These findings should be taken into consideration when creating prevention programming and treatment strategies for adolescents. Substance use programming should be comprehensive, consider multiple substances, and be cognizant of symptoms of mental illness, particularly depression.

Functional data analysis characterizes the shapes of the first COVID-19 epidemic wave in Italy

We investigate patterns of COVID-19 mortality across 20 Italian regions and their association with mobility, positivity, and socio-demographic, infrastructural and environmental covariates. Notwithstanding limitations in accuracy and resolution of the data available from public sources, we pinpoint significant trends exploiting information in curves and shapes with Functional Data Analysis techniques. These depict two starkly different epidemics; an “exponential” one unfolding in Lombardia and the worst hit areas of the north, and a milder, “flat(tened)” one in the rest of the country—including Veneto, where cases appeared concurrently with Lombardia but aggressive testing was implemented early on. We find that mobility and positivity can predict COVID-19 mortality, also when controlling for relevant covariates. Among the latter, primary care appears to mitigate mortality, and contacts in hospitals, schools and workplaces to aggravate it. The techniques we describe could capture additional and potentially sharper signals if applied to richer data.