Improving analysis of cognitive outcomes in cardiovascular trials using different statistical approaches.

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) questionnaires are commonly used to measure global cognition in clinical trials. Because these scales are discrete and bounded with ceiling and floor effects and highly skewed, their analysis as continuous outcomes presents challenges. Normality assumptions of linear regression models are usually violated, which may result in failure to detect associations with variables of interest. METHODS: Alternative approaches to analyzing the results of these cognitive batteries include transformations (standardization, square root, or log transformation) of the scores in the multivariate linear regression (MLR) model, the use of nonlinear beta-binomial regression (which is not dependent on the assumption of normality), or Tobit regression, which adds a latent variable to account for bounded data. We aim to empirically compare the model performance of all proposed approaches using four large randomized controlled trials (ORIGIN, TRANSCEND, COMPASS, and NAVIGATE-ESUS), and using as metrics the Akaike information criterion (AIC). We also compared the treatment effects for the methods that have the same unit of measure (i.e., untransformed MLR, beta-binomial, and Tobit). RESULTS: The beta-binomial consistently demonstrated superior model performance, with the lowest AIC values among nearly all the approaches considered, followed by the MLR with square root and log transformations across all four studies. Notably, in ORIGIN, a substantial AIC reduction was observed when comparing the untransformed MLR to the beta-binomial, whereas other studies had relatively small AIC reductions. The beta-binomial model also resulted in a significant treatment effect in ORIGIN, while the untransformed MLR and Tobit regression showed no significance. The other three studies had similar and insignificant treatment effects among the three approaches. CONCLUSION: When analyzing discrete and bounded outcomes, such as cognitive scores, as continuous variables, a beta-binomial regression model improves model performance, avoids spurious significance, and allows for a direct interpretation of the actual cognitive measure. TRIALS REGISTRATION: ORIGIN (NCT00069784). Registered on October 1, 2003; TRANSCEND (NCT00153101). Registered on September 9, 2005; COMPASS (NCT01776424). Registered on January 24, 2013; NAVIGATE-ESUS (NCT02313909). Registered on December 8, 2014.

Diagnostic classification systems for disorders of gut-brain interaction should include psychological symptoms.

BACKGROUND AND AIMS: The group of disorders known as Disorders of Gut Brain Interaction (DGBI) were originally labeled functional GI disorders and were thought to be disorders of the gastrointestinal tract that had several psychological conditions as comorbidities. Despite mounting evidence that psychological morbidity plays an innate role in the etiology and maintenance of DGBI, none of the Rome IV criteria include any measure of psychological symptoms. This study tested the hypothesis that individuals would cluster differently if GI symptoms alone were considered versus GI symptoms combined with measures of psychological symptoms. METHODS: Data were obtained from the Rome Foundation Global Epidemiology Study measuring Rome IV GI symptoms, psychological measures and demographic characteristics. Latent profile models were used to cluster individuals based on (i) GI symptoms only (GI only) and then (ii) GI and psychological measures (GI + Psych). KEY RESULTS: Individuals clustering into the same group of individuals whether formed via GI only or GI + Psych, ranged from 96% for a 2-class solution (the most simplistic) to 76% with 6 classes (the parsimonious system) and 59% with twenty-two classes (mimicking Rome IV). The generalisability of this finding between six geographic regions was confirmed with agreement varying between 95%-97% for 2 clusters and 71-79% for 6 classes and 51%-63% for 22 classes. These findings were also consistent between DGBI (range 94% with 2 classes to 50% with 22 classes) and non-DGBI (range 97% with 2 clusters to 65% with 22 classes) groups. CONCLUSIONS & INFERENCES: Our data suggest that considering psychological as well as gastrointestinal symptoms would lead to a different clustering of individuals in more complex, and accurate, classification systems. For this reason, future work on DGBI classification should consider inclusion of psychological traits.

Exposure to air pollutants and subclinical carotid atherosclerosis measured by magnetic resonance imaging: A cross-sectional analysis.

OBJECTIVES: Long-term exposure to air pollution has been associated with higher risk of cardiovascular mortality. Less is known about the association of air pollution with initial development of cardiovascular disease. Herein, the association between low-level exposure to air pollutants and subclinical carotid atherosclerosis in adults without known clinical cardiovascular disease was investigated. DESIGN: Cross-sectional analysis within a prospective cohort study. SETTING: The Canadian Alliance for Healthy Hearts and Minds Cohort Study; a pan-Canadian cohort of cohorts. PARTICIPANTS: Canadian adults (n = 6645) recruited between 2014-2018 from the provinces of British Columbia, Alberta, Ontario, Quebec, and Nova Scotia, were studied, for whom averages of exposures to nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) were estimated for the years 2008-2012. MAIN OUTCOME MEASURE: Carotid vessel wall volume (CWV) measured by magnetic resonance imaging (MRI). RESULTS: In adjusted linear mixed models, PM2.5 was not consistently associated with CWV (per 5 µg/m3 PM2.5; adjusted estimate = -8.4 mm3; 95% Confidence Intervals (CI) -23.3 to 6.48; p = 0.27). A 5 ppb higher NO2 concentration was associated with 11.8 mm3 lower CWV (95% CI -16.2 to -7.31; p<0.0001). A 3 ppb increase in O3 was associated with 9.34 mm3 higher CWV (95% CI 4.75 to 13.92; p<0.0001). However, the coarse/insufficient O3 resolution (10 km) is a limitation. CONCLUSIONS: In a cohort of healthy Canadian adults there was no consistent association between PM2.5 or NO2 and increased CWV as a measure of subclinical atherosclerosis by MRI. The reasons for these inconsistent associations warrant further study.

Effectiveness and risk of ARB and ACEi among different ethnic groups in England: A reference trial (ONTARGET) emulation analysis using UK Clinical Practice Research Datalink Aurum-linked data.

BACKGROUND: Guidelines by the National Institute for Health and Care Excellence recommend an angiotensin receptor blocker (ARB) rather than an angiotensin-converting enzyme inhibitor (ACEi) for the treatment of hypertension for people of African and Caribbean descent, due to an increased risk of angioedema associated with ACEi use observed in US trials. However, the effectiveness and risk of these drugs in Black populations in UK routine care is unknown. METHODS AND FINDINGS: We applied a reference trial emulation approach to UK Clinical Practice Research Datalink Aurum data (linked with data from Hospital Episode Statistics and Office for National Statistics) to study the comparative effectiveness of ARB and ACEi in ethnic minority groups in England, after benchmarking results against the ONTARGET trial. Approximately 17,593 Black, 30,805 South Asian, and 524,623 White patients receiving a prescription for ARB/ACEi between 1 January 2001 and 31 July 2019 were included with a median follow-up of 5.2 years. The primary composite outcome was cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using an inverse-probability-weighted Cox proportional hazards model for ARB versus ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. For the primary outcome, 27,327 (18.0%) events were recorded in the ARB group (event rate: 25% per 5.5 person-years) and 80,624 (19.1%) events (event rate: 26% per 5.5 person-years) in the ACEi group. We benchmarked results against ONTARGET and observed hazard ratio (HR) 0.96 (95% CI: 0.95, 0.98) for the primary outcome, with an absolute incidence rate difference (IRD)% of -1.01 (95% CI: -1.42, -0.60) per 5.5 person-years. We found no evidence of treatment effect heterogeneity by ethnicity for the primary outcome on the multiplicative (Pint = 0.422) or additive scale (Pint = 0.287). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, which occurred in 37,554 (6.6%) people, there was strong evidence of heterogeneity on the multiplicative (Pint = 0.002) and additive scale (Pint < 0.001). Compared to ACEi, ARB were associated with more events in Black individuals (HR 1.20 (95% CI: 1.02, 1.40); IRD% 1.07 (95% CI: 0.10, 2.04); number-needed-to-harm (NNH): 93) and associated with fewer events in White individuals (HR 0.91 (95% CI: 0.88, 0.93); IRD% -0.87 (95% CI: -1.10, -0.63); number-needed-to-treat (NNT): 115), and no differences in South Asian individuals (HR 0.97 (95% CI: 0.86, 1.09); IRD% -0.17 (95% CI: -0.87, 0.53)). For angioedema, HR 0.56 (95% CI: 0.46, 0.67) with no heterogeneity for ARB versus ACEi on the multiplicative scale (Pint = 0.306). However, there was heterogeneity on the additive scale (Pint = 0.023). Absolute risks were higher in Black individuals (IRD% -0.49 (95% CI: -0.79, -0.18); NNT: 204) compared with White individuals (IRD% -0.06 (95% CI: -0.09, -0.03); NNT: 1667) and no difference among South Asian individuals (IRD% -0.05 (95% CI: -0.15, 0.05) for ARB versus ACEi. CONCLUSIONS: These results demonstrate variation in drug effects of ACEi and ARB for some outcomes by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals.

Worldwide Prevalence and Description of Cyclic Vomiting Syndrome According to the Results of the Rome Foundation Global Epidemiology Study.

INTRODUCTION: Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction of unknown origin. The aim of this study was to evaluate the global prevalence of this disorder and its associated factors. METHODS: Data were collected from nationwide Internet surveys in 26 countries, with subjects evenly distributed by age, sex, and country. The survey included the Rome IV questionnaire and an extensive supplemental questionnaire to evaluate additional factors. RESULTS: A total of 54,127 participants completed the questionnaire (51% male, mean age 44.3 years). The pooled prevalence of CVS was 0.3% (95% confidence interval [CI] 0.3%-0.4%; n = 187), highest in Brazil (1%, 95% CI 0.6-1.5), and lowest in Japan and Germany (with no subject who fulfilled the criteria for CVS). The mean age of participants with CVS was 36.7 years (SD 13.5), and it was more common in women (56.7% vs 43.5%). Factors independently associated with this syndrome were female sex (odds ratio [OR] 1.52, 95% CI 1.13-2.03), young age (OR 2.57, 95% CI 1.34-4.94, for people between the ages of 18 and 39 years, compared with those older than 65 years), depression (OR 3.14, 95% CI 2.05-4.82, P < 0.001), and anxiety (OR 1.79, 95% CI 1.15-2.78, P < 0.001). Individuals with CVS had impaired quality of life (QoL) (Patient-Reported Outcomes Measurement and Information System 10-item score: physical QoL mean, 12.9 vs 15.5, P < 0.001; mental QoL mean 12.3 vs 14.4, P < 0.001) compared with others. DISCUSSION: CVS is a relatively common disorder that has a negative impact on QoL. It is important to raise awareness on this syndrome to avoid underdiagnosis and improve clinical practice.

DNA damage and its association with early-life exposome: Gene-environment analysis in Colombian children under five years old.

Environmental exposures and gene-exposure interactions are the major causes of some diseases. Early-life exposome studies are needed to elucidate the role of environmental exposures and their complex interactions with biological mechanisms involved in childhood health. This study aimed to determine the contribution of early-life exposome to DNA damage and the modifying effect of genetic polymorphisms involved in air pollutants metabolism, antioxidant defense, and DNA repair. We conducted a cohort study in 416 Colombian children under five years. Blood samples at baseline were collected to measure DNA damage by the Comet assay and to determine GSTT1, GSTM1, CYP1A1, H2AX, OGG1, and SOD2 genetic polymorphisms. The exposome was estimated using geographic information systems, remote sensing, LUR models, and questionnaires. The association exposome-DNA damage was estimated using the Elastic Net linear regression with log link. Our results suggest that exposure to PM2.5 one year before the blood draw (BBD) (0.83, 95 %CI: 0.76; 0.91), soft drinks consumption (0.94, 0.89; 0.98), and GSTM1 null genotype (0.05, 0.01; 0.36) diminished the DNA damage, whereas exposure to PM2.5 one-week BBD (1.18, 1.06; 1.32), NO2 lag-5 days BBD (1.27, 1.18; 1.36), in-house cockroaches (1.10, 1.00; 1.21) at the recruitment, crowding at home (1.34, 1.08; 1.67) at the recruitment, cereal consumption (1.11, 1.04; 1.19) and H2AX (AG/GG vs. AA) (1.44, 1.11; 1.88) increased the DNA damage. The interactions between H2AX (AG/GG vs. AA) genotypes with crowding and PM2.5 one week BBD, GSTM1 (null vs. present) with humidity at the first year of life, and OGG1 (SC/CC vs. SS) with walkability at the first year of life were significant. The early-life exposome contributes to elucidating the effect of environmental exposures on DNA damage in Colombian children under five years old. The exposome-DNA damage effect appears to be modulated by genetic variants in DNA repair and antioxidant defense enzymes.

COVID-19 vaccine effectiveness among South Asians in Canada.

We evaluated the effectiveness of COVID-19 vaccines among South Asians living in Ontario, Canada compared to non-South Asians and compared the odds of symptomatic COVID-19 infection and related hospitalizations and deaths among non-vaccinated South Asians and non-South Asians. This was a test negative design study conducted in Ontario, Canada between December 14, 2020 and November 15, 2021. All eligible individuals >18 years with symptoms of COVID-19 were subdivided by ethnicity (South Asian vs other) and vaccination status (vaccinated versus not). The primary outcome was vaccine effectiveness as defined by COVID-19 infections, hospitalizations, and deaths, and secondary outcome was the odds of COVID-19 infections, hospitalizations, and death comparing non-vaccinated South Asians to non-vaccinated non-South Asians. 883,155 individuals were included. Among South Asians, two doses of COVID-19 vaccine prevented 93.8% (95% CI 93.2, 94.4) of COVID-19 infections and 97.5% (95% CI 95.2, 98.6) of hospitalizations and deaths. Among non-South Asians, vaccines prevented 86.6% (CI 86.3, 86.9) of COVID-19 infections and 93.1% (CI 92.2, 93.8) of hospitalizations and deaths. Non-vaccinated South Asians had higher odds of symptomatic SARS-CoV-2 infection compared to non-vaccinated non-South Asians (OR 2.35, 95% CI 2.3, 2.4), regardless of their immigration status. COVID-19 vaccines are effective in preventing infections, hospitalizations and deaths among South Asians living in Canada. The observation that non-vaccinated South Asians have higher odds of symptomatic COVID-19 infection warrants further investigation.

Symptom profiles compatible with disorders of gut-brain interaction (DGBI) in organic gastrointestinal diseases: A global population-based study.

BACKGROUND: Patients with organic gastrointestinal (GI) diseases and diabetes mellitus (DM) can have concomitant disorders of gut-brain interaction (DGBI). OBJECTIVE: This study aimed to compare the global prevalence of DGBI-compatible symptom profiles in adults with and without self-reported organic GI diseases or DM. METHODS: Data were collected in a population-based internet survey in 26 countries, the Rome Foundation Global Epidemiology Study (n = 54,127). Individuals were asked if they had been diagnosed by a doctor with gastroesophageal reflux disease, peptic ulcer, coeliac disease, inflammatory bowel disease (IBD), diverticulitis, GI cancer or DM. Individuals not reporting the organic diagnosis of interest were included in the reference group. DGBI-compatible symptom profiles were based on Rome IV diagnostic questions. Odds ratios (ORs [95% confidence interval]) were calculated using mixed logistic regression models. RESULTS: Having one of the investigated organic GI diseases was linked to having any DGBI-compatible symptom profile ranging from OR 1.64 [1.33, 2.02] in GI cancer to OR 3.22 [2.80, 3.69] in IBD. Those associations were stronger than for DM, OR 1.26 [1.18, 1.35]. Strong links between organic GI diseases and DGBI-compatible symptom profiles were seen for corresponding (e.g., IBD and bowel DGBI) and non-corresponding (e.g., IBD and esophageal DGBI) anatomical regions. The strongest link was seen between fecal incontinence and coeliac disease, OR 6.94 [4.95, 9.73]. After adjusting for confounding factors, associations diminished, but persisted. CONCLUSION: DGBI-compatible symptom profiles are more common in individuals with self-reported organic GI diseases and DM compared to the general population. The presence of these concomitant DGBIs should be considered in the management of organic (GI) diseases.

Pain is a cardinal symptom cutting across Rome IV anatomical categories in disorders of gut-brain interaction: A network-based approach.

INTRODUCTION: Disorders of gut-brain interaction (DGBI) are symptom-based disorders categorized by anatomic location but have high overlap and heterogeneity. Viewing DGBI symptoms on a spectrum (i.e. dimensionally) rather than categorically may better inform interventions to accommodate complex clinical presentations. We aimed to evaluate symptom networks to identify how DGBI symptoms interact. METHODS: We used the Rome IV Diagnostic Questionnaire continuously/ordinally scored items collected from the Rome Foundation Global Epidemiology Study. We excluded participants who reported ≥1 organic/structural gastrointestinal disorder(s). We sought to (1) identify core symptoms in the DGBI symptom networks, (2) identify bridge pathways between Rome IV diagnostic categories (esophageal, bowel, gastroduodenal, anorectal), and (3) explore how symptoms group together into communities. RESULTS: Of 54,127 adults, 20,229 met criteria for at least one DGBI (age mean = 42.2 ± 15.5; 57% female). General abdominal pain and epigastric pain were the core symptoms in the DGBI symptom network (i.e., had the strongest connections to other symptoms). Pain symptoms emerged as bridge pathways across existing DGBI diagnostic anatomic location (i.e., abdominal pain connected to chest pain, epigastric pain, rectal pain). Without a priori category definitions, exploratory network community analysis showed that symptoms grouped together into "pain," "gastroduodenal," and "constipation," rather than into groups by anatomic location. CONCLUSION: Our findings suggest pain symptoms are central and serve as a key connection to other symptoms, crosscutting anatomic location. Future longitudinal research is needed to test symptom network relations longitudinally and investigate whether targeting pain symptoms (rather than anatomic- or disorder-specific symptoms) has clinical impact.

Corrigendum: Bleeding Risk Prediction in Patients Treated with Antithrombotic Drugs According to the Anatomic Site of Bleeding, Indication for Treatment, and Time Since Treatment Initiation.

[This corrects the article DOI: 10.1055/a-2259-1134.].

Results of the COMPASS Trial Analyzed Using Win Ratio Compared With Conventional Analytic Approaches.

BACKGROUND: Win ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches. METHODS: We used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points. We compared the WR results with those obtained using the Cox proportional hazards regression model for first events and Anderson-Gill method for total events. We calculated the win difference to estimate absolute treatment effects. RESULTS: The WR approach produced results consistent with those obtained using conventional statistical methods for the primary composite end point (first event: WR, 1.32 [95% confidence interval (CI), 1.14-1.52]; 1/Cox hazard ratio, 1.32 [95% CI, 1.16-1.52]; total [first plus recurrent] events: WR, 1.32 [95% CI, 1.14-1.52]; 1/Anderson-Gill hazard ratio, 1.32 [95% CI, 1.16-1.54]) as well as for main safety and net clinical benefit end points. The absolute benefits of the combination of rivaroxaban and aspirin compared with aspirin alone calculated using the win difference were greatest in those with multiple high-risk features. CONCLUSIONS: Reanalysis of the COMPASS trial results using WR produced results that were consistent with those obtained using conventional statistical approaches. CLINICAL TRIAL REGISTRATION: NCT01776424.

The aging gastrointestinal tract: Epidemiology and clinical significance of disorders of gut-brain interaction in the older general population.

BACKGROUND: Most previous reports on the prevalence of disorders of gut-brain interaction (DGBI) show higher rates in younger individuals. Exceptions are faecal incontinence and functional constipation. AIM: To compare prevalence rates for 22 DGBI and 24 primary symptoms, by age, using the Rome Foundation Global Epidemiology (RFGES) study dataset. METHODS: The RFGES dataset enables diagnosis of 22 DGBI among 54,127 participants (≥18 years) in 26 countries. Older age was defined as ≥65 years. We assessed differences between age groups by sex, geographic region, somatisation, abnormal anxiety and depression scores, quality of life (QoL), individual gastrointestinal symptoms and disease severity for irritable bowel syndrome (IBS). RESULTS: Rates for any DGBI were 41.9% and 31.9% in the <65 and ≥65 age groups, respectively. For all Rome IV diagnoses except faecal incontinence, rates were higher in the younger group. The older group had lower scores for any DGBI by geographic region, non-gastrointestinal somatic symptoms, abnormal anxiety and depression scores, and IBS severity, and better scores for QoL. The mean number of endorsed symptoms and their frequency were higher in the younger group. CONCLUSIONS: In this large general population study, the prevalence and impact of DGBI, apart from faecal incontinence, were higher in the younger group. Despite this, DGBI rates are still high in absolute terms in the ≥65 age group and necessitate clinical awareness and, perhaps, an age-specific treatment approach.

Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.

BACKGROUND & AIMS: Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the health care system, and examining reproducibility. METHODS: We applied our model to 2195 individuals in the RFGES with Rome IV-defined IBS. As described previously, we identified 7 clusters, based on gastrointestinal symptom severity and psychological burden. We assessed demographics, health care-seeking, symptom severity, and quality of life in each. We also used the RFGES to derive a new model, examining whether the broader concepts of our original model were replicated, in terms of breakdown and characteristics of identified clusters. RESULTS: All 7 clusters were identified. Those in clusters with highest psychological burden, and particularly cluster 6 with high overall gastrointestinal symptom severity, were more often female, exhibited higher levels of health care-seeking, were more likely to have undergone previous abdominal surgeries, and had higher symptom severity and lower quality of life (P < .001 for trend for all). When deriving a new model, the best solution consisted of 10 clusters, although at least 2 seemed to be duplicates, and almost all mapped on to the previous clusters. CONCLUSIONS: Even in the community, our original clusters derived from patients with physician-confirmed IBS identified groups of individuals with significantly higher rates of health care-seeking and abdominal surgery, more severe symptoms, and impairments in quality of life.

Cardiorenal effects of Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers in people underrepresented in trials: analysis of routinely collected data with emulation of a reference trial (ONTARGET).

Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups.

Accounting for center-level effects in multicenter randomized controlled trials.

Investigators often conduct randomized controlled trials (RCTs) at multiple centers/sites when determining the effect of a treatment or an intervention. Diversifying recruitment across multiple institutions allows investigators to make recruitment go faster within a shorter timeframe and allows generalizing the study results across diverse populations. Despite having a common study protocol across multiple centers, the eligible participants may be heterogeneous, site policies and practices may vary, and the investigators' experience, training, and expertise may also vary across sites. These factors may contribute to the heterogeneity in effect estimates across centers. As a result, we usually observe some degree of heterogeneity in effect estimates across centers, despite all centers following the same study protocol. During the analysis of such a trial, investigators typically ignore center effects, but some have suggested considering centers as fixed or random effects in the model. It is not clear how considering the effects of centers, either as fixed or random effects, impacts the test of the primary hypothesis. In this article, we first review the practice of accounting for center effects in the analyses of published RCTs and illustrate the extent of heterogeneity observed in a few preexisting multicenter RCTs. To determine the impact of heterogeneity on the test of a primary hypothesis of an RCT, we considered continuous and binary outcomes and the corresponding appropriate model, namely, a simple linear regression model for a continuous outcome and a logistic regression model for the binary outcome. For each model type, we considered three methods: (a) ignore the center effect, (b) account for centers as fixed effects, or (c) account for centers as random effects. Based on simulation studies of these models, we then examine whether considering the center as a fixed or random effect in the model helps to preserve or reduce the type I and type II error rates during the analysis phase of an RCT. Finally, we outline the threshold at which center-level effects are negligible and thus negligible and provide recommendations on when it may be necessary to account for center effects during the analyses of multicenter randomized controlled trials.

Sociodemographic factors associated with vaccine hesitancy in the South Asian community in Canada.

OBJECTIVE: South Asians represent the largest non-white ethnic group in Canada and were disproportionately impacted by the COVID-19 pandemic. We sought to determine the factors associated with vaccine hesitancy in South Asian Canadians. METHODS: We conducted a cross-sectional analysis of vaccine hesitancy using data collected at the baseline assessment of a prospective cohort study, COVID CommUNITY South Asian. Participants (18 + years) were recruited from the Greater Toronto and Hamilton Area in Ontario (ON) and the Greater Vancouver Area in British Columbia (BC) between April and November 2021. Demographic characteristics and vaccine attitudes measured by the Vaccine Attitudes Examination (VAX) scale were collected. Each item is scored on a 6-point Likert scale, and higher scores reflect greater hesitancy. A multivariable linear mixed effects model was used to identify sociodemographic factors associated with vaccine hesitancy, adjusting for multiple covariates. RESULTS: A total of 1496 self-identified South Asians (52% female) were analyzed (mean age = 38.5 years; standard deviation (SD): 15.3). The mean VAX score was 3.2, SD: 0.8 [range: 1.0‒6.0]. Factors associated with vaccine hesitancy included: time since immigration (p = 0.04), previous COVID-19 infection (p < 0.001), marital status (p < 0.001), living in a multigenerational household (p = 0.03), age (p = 0.02), education (p < 0.001), and employment status (p = 0.001). CONCLUSION: Among South Asians living in ON and BC, time since immigration, prior COVID-19 infection, marital status, living in a multigenerational household, age, education, and employment status were associated with vaccine hesitancy. This information can be used to address vaccine hesitancy in the South Asian population in future COVID-19 waves or pandemics.

RéSUMé: OBJECTIF: Les Asiatiques du Sud, qui représentent le plus grand groupe ethnique non-blanc au Canada, ont été démesurément touchés par la pandémie de COVID-19. Nous avons cherché à déterminer les facteurs associés à l'hésitation vaccinale chez les Canadiennes et les Canadiens asiatiques du Sud. MéTHODE: Nous avons mené une analyse transversale de l'hésitation vaccinale à l'aide des données collectées durant l'évaluation préliminaire d'une étude de cohorte prospective du nom de COVID CommUNITY South Asian. Les personnes participantes (18 ans et plus) ont été recrutées dans la région du grand Toronto et de Hamilton, en Ontario, et dans la région du Grand Vancouver, en Colombie-Britannique, entre avril et novembre 2021. Le profil démographique et les attitudes face aux vaccins, mesurées selon l'échelle Vaccine Attitudes Examination (VAX), ont été obtenus. Chaque élément a été noté selon une échelle de Likert en 6 points (plus la note est élevée, plus l'hésitation vaccinale est importante). Un modèle linéaire multivarié à effets mixtes a servi à identifier les facteurs sociodémographiques associés à l'hésitation vaccinale, en rajustant les données pour tenir compte de plusieurs covariables. RéSULTATS: En tout, 1 496 personnes s'identifiant comme étant Asiatiques du Sud (dont 52 % de femmes) ont été analysées (âge moyen = 38,5 ans; écart-type [S] : 15,3). La note VAX moyenne était de 3,2, S : 0,8 [intervalle : 1,0‒6,0]. Les facteurs associés à l'hésitation vaccinale étaient : le temps écoulé depuis l'immigration (p = 0,04), une infection antérieure par la COVID-19 (p < 0,001), l'état matrimonial (p < 0,001), le fait de vivre dans un ménage multigénérationnel (p = 0,03), l'âge (p = 0,02), l'instruction (p < 0,001) et la situation d'emploi (p = 0,001). CONCLUSION: Chez les Asiatiques du Sud vivant en Ontario et en Colombie-Britannique, le temps écoulé depuis l'immigration, une infection antérieure par la COVID-19, l'état matrimonial, le fait de vivre dans un ménage multigénérationnel, l'âge, l'instruction et la situation d'emploi étaient associés à l'hésitation vaccinale. Ces informations peuvent être utilisées pour aborder l'hésitation vaccinale dans la population asiatique du Sud lors de vagues de COVID-19 ou de pandémies futures.

The association of red and processed meat with gestational diabetes mellitus: Results from 2 Canadian birth cohort studies.

OBJECTIVE: Red and processed meat is considered risk factors of gestational diabetes mellitus (GDM), but the evidence is inconclusive. We aimed to examine the association between red and processed meat intake and odds of GDM among South Asian and White European women living in Canada. METHODS: This is a cross-sectional analysis of pregnant women from two birth cohorts: SouTh Asian biRth cohorT (START; n = 976) and Family Atherosclerosis Monitoring In earLY life (FAMILY; n = 581). Dietary intake was assessed using a validated 169-item semi-quantitative food-frequency questionnaire (FFQ). Multivariate logistic regression models were used to examine the associations between gestational diabetes and: 1) total red and processed meat; 2) unprocessed red meat; 3) processed meat and GDM after adjustment for potential confounders. RESULTS: There were 241 GDM cases in START and 91 in FAMILY. The median total red and processed meat intake were 1.5 g/d (START) and 52.8 g/d (FAMILY). In START, the multivariable-adjusted odds ratio (OR) showed neither lower nor higher intakes of unprocessed red meat (p-trend = 0.68), processed meat (p-trend = 0.90), or total red and processed meat (p-trend = 0.44), were associated with increased odds of GDM, when compared with medium intake. Similar results were observed in FAMILY except for processed meat intake [OR = 0.94 (95% CI 0.47-1.91), for medium versus low and OR = 1.51 (95% CI 0.77-2.29) for medium versus high; p-trend = 0.18] after adjusting for additional dietary factors such as the diet quality score, total fiber, saturated fat and glycemic load. CONCLUSION: Medium compared with low or high red and processed meat intake is not associated with GDM in White Europeans and South Asians living in Canada.

Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial.

BACKGROUND: Although intravenous tranexamic acid is used in cardiac surgery to reduce bleeding and transfusion, topical tranexamic acid results in lower plasma concentrations compared with intravenous tranexamic acid, which may lower the risk of seizures. We aimed to determine whether topical tranexamic acid reduces the risk of in-hospital seizure without increasing the risk of transfusion among cardiac surgery patients. METHODS: We conducted a multicenter, double dummy, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. Between September 17, 2019, and November 28, 2023, a total of 3242 patients from 16 hospitals in 6 countries were randomly assigned (1:1 ratio) to receive either intravenous tranexamic acid (control) through surgery or topical tranexamic acid (treatment) at the end of surgery. The primary outcome was seizure, and the secondary outcome was red blood cell transfusion. After the last planned interim analysis, when 75% of anticipated participants had completed follow up, the data and safety monitoring board recommended to terminate the trial, and upon unblinding, the operations committee stopped the trial for safety. RESULTS: Among 3242 randomized patients (mean age, 66.0 years; 77.7% male), in-hospital seizure occurred in 4 of 1624 patients (0.2%) in the topical group, and 11 of 1628 patients (0.7%) in the intravenous group (absolute risk difference, -0.5% [95% CI, -0.9 to 0.03]; P=0.07). Red blood cell transfusion occurred in 570 patients (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3% [95% CI, 5.2-11.5]; P=0.007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared with the intravenous group was 8.2% (95% CI, 3.4-12.9). CONCLUSIONS: Among patients undergoing cardiac surgery, topical administration of tranexamic acid resulted in an 8.3% absolute increase in transfusion without reducing the incidence of seizure, compared with intravenous tranexamic acid. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03954314.