Adjustment For Covariates Research Articles

Epicardial adipose tissue and subclinical alterations in cardiac structure and function in early adulthood

Abstract Background Epicardial adipose tissue (EAT) is the visceral fat depot surrounding the heart and coronary arteries and shares the same microcirculation with myocardium. Under normal physiologic conditions EAT contains important cardioprotective properties such as cushioning the heart against mechanical stress, thermoregulation of the myocardium in hypothermia as well as balancing myocardial fatty acid homeostasis. Higher accumulation of EAT has been reported to independently associate with deleterious alterations in cardiac structure and function. However, majority of previously addressed study results are derived from older study population and in presence of cardiovascular diseases. Data on the associations of EAT and cardiac echocardiograpghically derived structural and functional parameters in a young and middle-aged population without prevalent cardiovascular disease is scarce. Purpose We aimed to address this knowledge gap by investigating the associations of echocardiographically measured EAT thickness and possible adverse subclinical alteration in cardiac structure and function in a population cohort of young and middle-aged adults. Methods This study participants were examined as part of the ongoing multi-centre longitudinal cohort, focusing on cardiovascular risk factors from childhood through adulthood. EAT thickness was measured by manual delineation from parasternal long-axis echocardiograms at end systole. Transthoracic and Doppler echocardiograpghy was performed and data on cardiac structural and functional parameters were derived comprehensively in accordance with EAE/ASE guidelines. Results In this study population (N=1677, men=770, women=897 ; age range 34-49 years) mean EAT thickness was 4.0 mm in whole population. In multivariable regression analysis models adjusted for age, sex, waist circumference and systolic blood pressure, significant independent associations of EAT and left atrial dimension (P<.0001) and various measures of left ventricular (LV) wall thickness such as LV mean wall thickness (P<.001), LV relative wall thickness (P<.001) as well as LV posterior wall thickness (P<.001) were observed. We found no significant associations between EAT thickness and cardiac functional and hemodynamic parameters after covariate adjustments in multivariable analysis models. Conclusion The findings of this study highlight that larger EAT thickness is associated with subclinical alteration in cardiac wall thicknesses in young and middle-aged adults. However, we found no associations between EAT thickness and cardiac functional parameters, which is perhaps due to the high cardiac adaptation properties in our relatively young study population. Therefore, further follow-ups is required to address long-term probable alterations in cardiac hemodynamics when the participants are older.

Association between autonomic dysfunction, 12-year mortality and 10-year incident cardiovascular disease

Abstract Background Standing from a supine position requires a co-ordinated response in peripheral and central haemodynamic signals to protect the brain and body from sudden drops in blood pressure (BP) and has previously been shown to be an important measure of neuro-cardiovascular health (1-3). Previous studies have found an association between BP and heart rate recovery (HRR) to standing with all-cause mortality, cardiovascular disease and other health outcomes (4-8). However, almost all of these studies have exclusively investigated the association of consensus-defined HR/BP phenotypes measured at specific timepoints during standing. Purpose We hypothesised that assessing information from the entire haemodynamic response to orthostasis - instead of discrete timepoints or consensus definitions - may uncover novel associations between BP/HR responses to active stand and neuro-cardiovascular health in older adults. This may afford better physiological understanding of the longitudinal relationships between the response to standing and both Cardiovascular Disease (CVD) and mortality. Methods We used functional Principal Components Analysis (FPCA) to examine the determinants of variability in the complete haemodynamic response to active stand and examine which components were related to mortality and incident CVD in >4500 community-dwelling adults aged 50+. Results Figure 1 shows the mean response curve according to mortality status and Figure 2 the mean curve for participants free of CVD at baseline who later have CVD vs those who remain CVD-free during 10 year follow-up. All-cause mortality was associated with functional principal components which discriminate higher baseline HR, blunted HR peak and impaired HRR up to ~25 seconds after standing. Components that discriminated high baseline and impaired recovery of SBP from the post-stand nadir to 60 seconds post stand were also associated with all-cause mortality. This association remained even after covariate adjustment. Interestingly, neither baseline SBP nor orthostatic hypotension (OH) were associated with mortality. Components which discriminate high baseline and blunted HR peak; elevated stroke volume index and impaired recovery of DBP from ~25 seconds post stand were associated with 10-year incident CVD. Conclusions To our knowledge this is the first study to incorporate data driven information over the entire trace of the haemodynamic response to standing to investigate associations with incident CVD and mortality. The fact that components which discriminated high BP and impaired recovery of BP were associated with 12-year mortality and 10-year incident CVD when traditional summary measures of OH and baseline BP were not; suggests that incorporating information across the entire response to standing allows for richer and more flexible associations with health outcomes to be uncovered and allows for a better understanding of the underlying physiology leading to such associations.Figure 1:Mean trace of Mortality StatusFigure 2:Mean Trace of CVD Status

Association of cardio-cerebrovascular death with isolated diastolic hypertension: a nationally representative survey of 85, 138 adults

Abstract Background Recently, the 2023 European Society of Hypertension (ESH) guideline for hypertension management include isolated diastolic hypertension (IDH) as a distinct classification. But, studies have yielded inconsistent associations between IDH and cardiovascular disease (CVD) events. Method We obtained data from 85138 participants without CVD and antihypertensive medication use who included in the China Chronic Disease and Risk Factors Surveillance (CCDRFS) project 2010. We extracted data on deaths from any cause, cardiovascular diseases, and stroke during follow up. The hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality, cardiovascular mortality, and stroke mortality associated with each blood pressure (BP) group were calculated using Cox proportional hazards models, with the normotension group as the reference. Our analyses were performed with sequential adjustment. In the first step, we carried out unadjusted analyses (model 1). In model 2, we added age, sex, ethnic, location, educational attainment, smoking status, alcohol drinking status, exercise, BMI, high-density-lipoprotein cholesterol, low-density-lipoprotein cholesterol, fasting glucose level as adjustment covariates. Results Overall, 57144 (67.1%) participants had normotension, 3826 (4.5%) participants had IDH, 11013 (12.9%) participants had isolated systolic hypertension (ISH), 13155 (15.5%) participants had systolic and diastolic hypertension (SDH). Compared with normotension, IDH was not statistically associated with a significantly increased risk of all-cause mortality (HR, 1.09 [95% CI, 0.86–1.39], model 2), or cardiovascular mortality (HR, 1.21 [95% CI, 0.74–1.96], model 2). On the contrary, IDH was significantly associated with a modestly higher risk of stroke mortality (HR, 1.84 [95% CI, 1.13–3.00], model 2). IDH was significantly associated with a modestly higher risk of stroke mortality in middle aged and older adults, but not young adults (age <45years). Similar results were obtained for men, while for women the associations between the prevalence of IDH and a higher incidence of stroke mortality were not significant. Stage 1 to stage 3 ISH or SDH were associated with a higher risk for all-cause mortality, cardiovascular mortality, and stroke mortality. Conclusion IDH was associated with an increased risk of stroke mortality among the large nationally representative Chinese population. Intervention for IDH may be effective in reducing the burden of stroke in China.

Red-cell omega-3 fatty acids associate with increased hippocampal volume and superior longitudinal cognition in atrial fibrillation

Abstract Background Atrial fibrillation (AF) is associated with cognitive impairment and dementia. Omega-3 Fatty Acids (n-3 FAs) have anti-thrombotic, anti-inflammatory and anti-oxidative properties; however, their neuroprotective effects remain controversial. Here, we report the association of n-3 FAs with both structural (hippocampal volume) and functional (cognition) readouts in a large cohort of AF pts. Purpose a) To determine the association of n-3 FAs and left and right hippocampal volume at baseline in AF pts. b) To assess the predictive value of HV and n-3 FAs for the risk of cognitive impairment after a 7-year follow-up period. Methods This prospective ongoing multicenter Swiss Atrial Fibrillation study (Swiss-AF) included 2,359 pts with documented AF and baseline red-cell n-3 FAs levels, measured by gas chromatography and mass spectrometry. Hippocampal volume (HV) and segmentation based intracranial volume (ICV) were analyzed by FreeSurfer's (v 7.4.0) subregion segmentation module and Sequence Adaptive Multimodal SEGmentation from brain MRI in 1,736 pts. Detailed neurocognitive assessments in pts at baseline and follow up periods were performed. We used mixed-effect linear regression models to determine the association of n-3 FAs and HV. For conversion to cognitive impairment (defined as MoCA score < 26), we performed cox-proportional hazards regression model. Two adjustment models were applied as described in the figures. Results Patients with AF (mean age, 73 years old [±8.5 SD]; 157 women [27%]) with 9569 cognitive evaluations (mean follow-up, 3.6 years [±2.3 SD]) were assessed. At baseline, we observed statistically significant associations between total n-3 FAs levels (EPA + DHA + ALA + DPA) and individual n-3 FAs (EPA, DHA, DPA) with increased HV after adjustment for ICV and other covariates (Fig1A, 1B). After all adjustments, EPA remained associated with both bilateral HV and right HV. Furthermore, we observed a significant association between HV and neurocognitive assessments, as measured both in global (MoCA, CoCo) and specific tests (TMT-A, TMT-B, DSST, SF) (Fig1C). Over time, quartile 4 (Q4, highest n-3) compared to quartile 1 (Q1, lowest), had a 16% lower risk of cognitive impairment (HR, 0.84 [CI 0.75-0.93]; P=0.001) for total n-3 FAs and even 30% lower specifically for EPA (HR, 0.7 [CI 0.63-0.78]; P<0.001). The risk of cognitive impairment was 47% lower (HR, 0.53 [CI 0.45-0.63]; P<0.001) when the highest HV Q4 was compared to lowest HV Q1 (Fig2A). In combination, the highest quartile of bilateral HV and EPA demonstrated an increased probability of being cognitive impairment-free and they had a 72% lower (HR, 0.28 [0.18-0.43]; P<0.001) risk of cognitive impairment (Fig2B). Conclusions 1. Red cell n-3 FAs levels are associated with higher HV in AF pts. 2. Higher baseline levels of n-3 FAs, particularly of EPA, are associated with both an increased HV and a decreased risk of cognitive impairment after 7 years follow up.

Socioeconomic disparity in utilization of transcatheter aortic valve replacement

Abstract Introduction Transcatheter aortic valve replacement (TAVR) is a major therapeutic option, rapidly replacing surgical aortic valve replacement (SAVR) in patients with aortic stenosis (AS) in recent years. However, the use of TAVR may vary with the socioeconomic status (SES) since new technologies are more likely to have the lower accessibility in some medico-social environments. In South Korean patients with AS, we investigated the difference in the use of TAVR based on SES and whether the difference influences clinical outcomes of patients with AS. Methods Between 2010 and 2020, 30,142 patients newly diagnosed with AS in a tertiary or regional center were investigated through the Korean National Health Insurance System (KNHIS). Patients were received either medical, SAVR or TAVR therapy for AS. The patients were categorized into 3 groups based on the insurance premium level (IPL) of the KNHIS (IPL1, <100 KW; IPL2, 100-249 KW; IPL3, ≥250KW). AS-related death was defined as death by AS, heart failure or ventricular arrhythmia. Cardiovascular (CV) death was defined as AS-related death or death by myocardial infarction or stroke. The study period was divided at year 2015, when the partial coverage for TAVR was implemented by the KNHIS. Results The numbers of patients referred to the tertiary/regional centers have continuously grown for the 11 years but the referring rate has grown even faster since 2015. The proportions of TAVR has increased while that of SAVR has decreased since 2015. TAVR was more frequently chosen by patients with a higher IPL (5.5%, 8.0% and 12.5%, respectively in the IPL1, IPL2 and IPL3, p<0.001), whereas the medical therapy appeared not affected by the IP levels. The patients in the IPL2 (odd ratio [OR] 1.33 [1.20-1.47]) and IPL3 (OR 1.65 [1.45-1.86]) had a higher chance to undergo TAVR than those in the IPL1 whereas the patients in the IPL3 was a lower chance to undergo SAVR than those in the IPL1 (OR 0.86 [0.78-0.94]). In patients with severe AS, the disparities between the IPL1 and IPL3 exaggerated (OR 1.99 [1.70-2.33]) (Figure 1). Higher IPLs were associated with lower risks of CV death and AS-related death. Time-varying Cox proportional hazard models showed that TAVR was associated with a lower risk of CV death than both medical therapy and SAVR in the entire study period and in year 2015 or later, whereas TAVR was associated with a lower risk of AS-related death than the both only in year 2015 or later, after adjustment of relevant covariates including the IPL (Figure 2). The choice of TAVR significantly medicated the associations between IPLs and the risk of CV death (responsible for 3.0% in the IPL2 and 4.1% in the IPL3). Conclusion The SES based on the IPL is independently associated with the choice of TAVR in patients with AS and the association has become stronger since 2015. The disparity in use of TAVR could mediate more frequent CV deaths in patients with the lower IPL.Figure 1Figure 2

Hemoglobin/creatinine ratio as long- term prognostic marker in acute coronary syndromes: a praise registry study

Abstract Introduction Anemia and renal impairment are key determinants of adverse outcomes in patients with acute coronary syndrome (ACS). The hemoglobin/creatinine (Hb/Cr) ratio, a simple and universally accessible index that combines these two factors, was found to predict adverse outcomes in patients with cardiovascular disease. There is limited evidence on the performance of the Hb/Cr ratio in predicting long-term adverse outcomes in the specific setting of ACS. Purpose To evaluate the long-term prognostic impact of the Hb/Cr ratio in patients with ACS. Methods Out of the 23,270 ACS patients enrolled in the international PRAISE registry between 2003 and 2019, 3.465 were excluded due to missing data and 19.805 were included in this analysis. The primary endpoint was all-cause mortality at one year follow-up. Secondary endpoints were major bleeding and the composite of all-cause mortality or reinfarction at one year follow-up. A cut-point analysis according to Liu’s method was run to evaluate the best discriminative value of the Hb/Cr ratio for the prediction of all-cause mortality. Results The cut-point analysis showed that a cut-off value of 13.79 represented the most discriminative in predicting all-cause mortality at one year (CI 13.35–14.23; AUC 0.66), and that mortality increased exponentially when the ratio was <12.4. On the basis of this discriminative value, we divided our population into low vs. high Hb/Cr groups. The former included 5,874 (29.7%) patients, while the latter included 13,931 (70.3%). Patients in the low Hb/Cr group were older, more frequently female, and had a higher prevalence of cardiovascular risk factors, comorbidities, and history of coronary artery disease. Conversely, patients in the high Hb/Cr group were mostly men and more frequently admitted with a STEMI diagnosis. One year post-discharge from ACS, all-cause mortality (8.3% vs. 2.3%; p < 0.001), major bleeding (5.4% vs. 2.2%; p < 0.001) and the composite of all-cause mortality or reinfarction (11.6% vs. 4.7%; p < 0.001) were significantly higher in the low Hb/Cr group. Bivariate regression analysis showed that Hb/Cr ratio was inversely associated with all-cause mortality (OR 0.85; CI 0.84 – 0.86; p < 0.0001), major bleeding (OR 0.91; CI 0.89-0.92; p < 0.0001), and the composite of all-cause mortality or reinfarction (OR 0.89; CI 0.88-0.90; p < 0.0001). This association held strongly true even after an extensive adjustment for several covariates, including cardiovascular risk factors, comorbidities, and discharge medical therapy: all-cause mortality (OR 0.95; CI 0.92 – 0.97; p < 0.0001), major bleeding (OR 0.92; CI 0.89-0.95; p < 0.0001), composite of all-cause mortality or reinfarction (OR 0.96; CI 0.94-0.98; p < 0.0001). Conclusions HB/Cr ratio appears to be inversely associated with long-term adverse outcomes among ACS patients. Further research is warranted before routinely considering this index in clinical practice.

The inverse relationship between Life’s Essential 8 and risk of metabolic syndrome: evidence from NHANES 2005-2018

BackgroundMetabolic syndrome (MetS) has a close association with cardiovascular diseases. Few studies have investigated the association of Life’s Essential 8 (LE8), the updated measurement of cardiovascular health (CVH), with MetS.MethodsThe National Health and Nutrition Examination Survey (2005–2018) data was extracted. The LE8 comprised 4 health behaviors (diet, physical activity, nicotine exposure, and sleep health) and 4 health factors [body mass index (BMI), blood lipids, blood glucose, and blood pressure (BP)]. The total LE8 score is the average of 8 metric scores (0-100), categorized into low (0–49), moderate (50–79), and high CVH (80–100) levels. Multivariable logistic regression models, restricted cubic spline models and stratified analyses were performed to examine the relationship between LE8 and MetS.ResultsIn this study, a total of 21,543 participants represented 146.6 million non-institutionalized U.S. adults. Following adjustment for various potential covariates, participants who attained a moderate [adjusted odds ratio (AOR) = 0.234, 95% CI: 0.209, 0.262] or a high CVH level (AOR = 0.026, 95% CI: 0.021, 0.032) exhibited an inverse correlation with MetS risks when comparing those with a low CVH level. An inverse linear dose-response relationship between LE8 scores and MetS risks was also identified (P for nonlinearity > 0.05).ConclusionsLE8 was inversely associated with the risk of MetS. Adhering to LE8 guidelines to sustain a higher CVH level may be beneficial for preventing MetS.

Personality and cardiovascular mortality risk: a multi-cohort analysis in individuals with and without pre-existing cardiovascular disease

AbstractThis study investigated the associations between personality traits of the Five Factor Model and cardiovascular mortality, with a specific focus on whether pre-existing cardiovascular conditions modified these associations. We used data from 43,027 participants across five cohort studies: Health and Retirement Study (HRS); Wisconsin Longitudinal Study (WLS); National Social Life, Health, and Aging Project (NSHAP); Midlife in the United States (MIDUS); Household, Income, and Labour Dynamics in Australia (HILDA) with a mean age 55.9 years and 6493 individuals with pre-existing cardiovascular disease. We conducted meta-analyses examining conscientiousness, emotional stability, agreeableness, openness to experience, and extraversion in relation to mortality due to coronary heart disease and stroke. During a mean follow-up of 12.1 years, 1620 participants died from coronary heart disease and 454 from stroke. Lower conscientiousness was associated with higher mortality risk from both coronary heart disease (hazard ratio per 1SD = 0.82, 95%CI = 0.75–0.90) and stroke (HR = 0.84, CI = 0.72–0.99). Lower emotional stability predicted increased coronary heart disease mortality (HR = 0.91, CI = 0.85–0.97). The association between conscientiousness and cardiovascular mortality did not differ between individuals with or without baseline cardiovascular conditions. In addition, adjustments for health behaviors and other covariates only slightly attenuated this association. Other personality traits were not associated with cardiovascular disease mortality. Our findings highlight the role of low conscientiousness, and to a lesser extent low emotional stability, in the development and progression of fatal cardiovascular disease through pathways that may extend beyond established health behaviors.

Effect of unprocessed and minimally processed foods on blood pressure in children

Abstract Background The poor eating habits of children, including a decrease in the consumption of unprocessed foods and an increase in the consumption of processed foods, have been associated with excess body weight, which is a well-established risk factor for cardiovascular diseases (CVDs), especially high blood pressure (BP). We aimed to investigate whether the consumption of unprocessed and minimally processed foods is associated with high BP in children at nine years of age. Methods Cross-sectional study of 142 Brazilian children participating in a cohort study conducted at the participant’s home. The child’s food consumption markers were evaluated using the Brazilian Food and Nutrition Surveillance System (SISVAN) and were classified by NOVA. Using a standardized procedure for approaching the child, BP was measured by the auscultatory method. Biological, socioeconomical, demographic, and anthropometric data of the mother and child were also collected. Logistic regression analysis adjusting for important predictors was used to evaluate the association between food consumption and BP. Results The prevalence of high BP in children was 20.4%, and the mean systolic and diastolic BP were significantly (p < 0.05) higher in children classified as high BP (110.1 and 71.3 mmHg, respectively). An important proportion (44.8%) of children had excess body weight (>85th percentile) and high BP when compared to eutrophic children. Not consuming healthy foods was associated with high systolic BP, even after adjustment for other important covariates (OR = 3.97; p = 0.028). Conclusions Not consuming healthy foods was associated with increased odds of children having high BP at nine years of age. Interventions promoting a healthy diet and the consumption of fruits and vegetables in childhood may contribute to preventing diseases associated with CVD, a global public health problem. Key messages • Educating parents to avoid processed foods and monitoring children’s BP are essential actions to prevent associated chronic diseases throughout life. • Public policies aimed at educating parents to encourage the consumption of healthy foods may significantly contribute to reducing adverse cardiovascular outcomes.

Long-term changes in cardiac geometry and mechanics after bariatric surgery- insights from the FatWest study

Abstract Background Patients with severe obesity have a high prevalence of subclinical cardiac organ damage including impaired longitudinal and radial cardiac mechanics. Previous studies on the impact of bariatric surgery on cardiac remodeling, most of them with short patient follow-up, have yielded inconsistent results. Purpose To assess progressive changes in cardiac geometry and mechanics up to five years following bariatric surgery. Methods In the prospective Bariatric Surgery on the West Coast of Norway (FatWest) study, cardiac remodeling was assessed by 2D echocardiography preoperatively and at six months, one year and five years after Roux-en-Y gastric bypass in a cohort of 97 patients (44±10 years, 72% women, body mass index [BMI] 41.8±4.8 kg/m²). Excess weight loss (EWL) was calculated as: absolute weight loss/(initial weight-ideal weight)x100. Left ventricular (LV) size was assessed by the LV mass/ height^2.7, LV longitudinal mechanics by the peak global longitudinal strain (GLS) and radial mechanics by the midwall shortening (MWS). LV myocardial oxygen demand was estimated from the LV mass-wall stress-heart rate product. Right ventricular diameter was measured in the basal one-third of the ventricular cavity. Left atrial (LA) reservoir function was assessed by the LA emptying fraction. Results After a mean follow-up of 63±13 months, the average postoperative EWL was 66%. Overall, both right ventricular diameter, LV mass index, LV GLS, myocardial oxygen demand and LAEF (68% vs. 64%) improved significantly at the 5-year follow-up (all p<0.05), while MWS remained unchanged (Figure). Prevalence of normal LV geometry increased gradually from 56% to 80%, while that of LV hypertrophy fell from 36% to 16% (p<0.001). Analyses of temporal trends showed that improvement in BMI, LV mass and LV GLS occurred during the first postoperative year (Figure). In Cox regression analysis, a low 5-year GLS was associated with preoperative hypertension after adjustment for age, sex, preoperative diabetes mellitus, and postoperative changes in BMI, mean blood pressure and myocardial oxygen demand (p<0.01). In a similar linear model, after adjustment for the same covariates, LV mass index at the 5-year follow-up was independently related to the magnitude of the postoperative BMI reduction (R² = 0.58, p<0.001). Conclusion Ventricular size and longitudinal mechanics are significantly improved 5 years after bariatric surgery, with the reverse remodeling occurring during the first postoperative year. Residual abnormal 5-year LV geometry and mechanics are related to preoperative hypertension and suboptimal BMI reduction.Figure

Prognostic significance of pre-procedure wall shear stress in the ascending aorta in patients with aortic stenosis undergoing transcatheter aortic valve replacement

Abstract Background Accurate prognostication before the procedure is challenging in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Recently, blood flow dynamics assessed by four-dimensional flow cardiovascular magnetic resonance imaging (4D-flow CMR) showed a significant reduction in average wall shear stress (WSS) in the ascending aorta (AAo) after TAVR. However, the prognostic value of pre-procedure average WSS in the AAo is controversial. Purpose We aimed to investigate whether pre-procedure average WSS was associated with clinical outcomes in patients with AS undergoing TAVR. Methods We prospectively examined 159 consecutive AS patients who underwent TAVR (57 males, mean age 83.6 ± 4.7 years, median left ventricular ejection fraction 63.4%) between May 2018 and May 2022. We assessed average WSS in the AAo before TAVR using 4D-flow CMR. We divided the patients into high WSS (≥6.60 Pa, n = 79) and low WSS (<6.60 Pa, n = 80) groups according to the median value of pre-TAVR WSS. The primary outcome of interest was a composite of all-cause death and hospitalization for worsening heart failure. Results Patients with high WSS had lower age compared to those with low WSS. There were no significant differences on sex, body mass index, systolic blood pressure, hemoglobin, serum albumin, N-terminal pro b-type natriuretic peptide, left ventricular ejection fraction, mean transaortic valvular gradient, annulus area in aortic valve and AAo diameter between the groups. During a median follow-up period of 19.8 months (interquartile range 6.0-37.1), the primary outcome more frequently occurred in patients with low WSS than in those with high WSS (28% vs 5%, P <0.001) (Figure 1). A multivariable Cox regression showed that lower WSS independently associated with increased risk of the primary outcome (hazard ratio 0.69, 95% confidence interval [CI] 0.53-0.91, P <0.001), even after adjustment for significant prognostic covariates including age, sex, serum albumin, history of chronic obstructive pulmonary disease, peripheral artery disease and malignancy, and estimated glomerular filtration rate. Predictive performance for the primary outcome was improved when adding the value of WSS in the AAo to representative prognostic factors (c-index 0.81 95%CI 0.72-0.90 vs. 0.77 95%CI 0.67-0.88) (Figure 2). Conclusions In patients with AS who underwent TAVR, lower average WSS in the AAo before procedure was associated with higher risk of worse clinical outcomes, suggesting that pre-TAVR average WSS in the AAo would be a surrogate marker and useful for the risk stratification.Survival analysis for primary outcomePredictive performance

When does adjusting covariate under randomization help? A comparative study on current practices

PurposeWe aim to thoroughly compare past and current methods that leverage baseline covariate information to estimate the average treatment effect (ATE) using data from of randomized clinical trials (RCTs). We especially focus on their performance, efficiency gain, and power.MethodsWe compared 6 different methods using extensive Monte-Carlo simulation studies: the unadjusted estimator, i.e., analysis of variance (ANOVA), the analysis of covariance (ANCOVA), the analysis of heterogeneous covariance (ANHECOVA), the inverse probability weighting (IPW), the augmented inverse probability weighting (AIPW), and the overlap weighting (OW) as well as the augmented overlap weighting (AOW) estimators. The performance of these methods is assessed using the relative bias (RB), the root mean square error (RMSE), the model-based standard error (SE) estimation, the coverage probability (CP), and the statistical power.ResultsEven with a well-executed randomization, adjusting for baseline covariates by an appropriate method can be a good practice. When the outcome model(s) used in a covariate-adjusted method is closer to the correctly specified model(s), the efficiency and power gained can be substantial. We also found that most covariate-adjusted methods can suffer from the high-dimensional curse, i.e., when the number of covariates is relatively high compared to the sample size, they can have poor performance (along with lower efficiency) in estimating ATE. Among the different methods we compared, the OW performs the best overall with smaller RMSEs and smaller model-based SEs, which also result in higher power when the true effect is non-zero. Furthermore, the OW is more robust when dealing with the high-dimensional issue.ConclusionTo effectively use covariate adjustment methods, understanding their nature is important for practical investigators. Our study shows that outcome model misspecification and high-dimension are two main burdens in a covariate adjustment method to gain higher efficiency and power. When these factors are appropriately considered, e.g., performing some variable selections if the data dimension is high before adjusting covariate, these methods are expected to be useful.

The fixed-effects model for robust analysis of stepped-wedge cluster trials with a small number of clusters and continuous outcomes: a simulation study

BackgroundStepped-wedge cluster trials (SW-CTs) describe a cluster trial design where treatment rollout is staggered over the course of the trial. Clusters are commonly randomized to receive treatment beginning at different time points in this study design (commonly referred to as a Stepped-wedge cluster randomized trial; SW-CRT), but they can also be non-randomized. Trials with this design regularly have a low number of clusters and can be vulnerable to covariate imbalance. To address such covariate imbalance, previous work has examined covariate-constrained randomization and analysis adjustment for imbalanced covariates in mixed-effects models. These methods require the imbalanced covariate to always be known and measured. In contrast, the fixed-effects model automatically adjusts for all imbalanced time-invariant covariates, both measured and unmeasured, and has been implicated to have proper type I error control in SW-CTs with a small number of clusters and binary outcomes.MethodsWe present a simulation study comparing the performance of the fixed-effects model against the mixed-effects model in randomized and non-randomized SW-CTs with small numbers of clusters and continuous outcomes. Additionally, we compare these models in scenarios with cluster-level covariate imbalances or confounding.ResultsWe found that the mixed-effects model can have low coverage probabilities and inflated type I error rates in SW-CTs with continuous outcomes, especially with a small number of clusters or when the ICC is low. Furthermore, mixed-effects models with a Satterthwaite or Kenward-Roger small sample correction can still result in inflated or overly conservative type I error rates, respectively. In contrast, the fixed-effects model consistently produced the target level of coverage probability and type I error rates without dramatically compromising power. Furthermore, the fixed-effects model was able to automatically account for all time-invariant cluster-level covariate imbalances and confounding to robustly yield unbiased estimates.ConclusionsWe recommend the fixed-effects model for robust analysis of SW-CTs with a small number of clusters and continuous outcomes, due to its proper type I error control and ability to automatically adjust for all potential imbalanced time-invariant cluster-level covariates and confounders.

A benchmark of RNA-seq data normalization methods for transcriptome mapping on human genome-scale metabolic networks

Genome-scale metabolic models (GEMs) cover the entire list of metabolic genes in an organism and associated reactions, in a tissue/condition non-specific manner. RNA-seq provides crucial information to make the GEMs condition-specific. Integrative Metabolic Analysis Tool (iMAT) and Integrative Network Inference for Tissues (INIT) are the two most popular algorithms to create condition-specific GEMs from human transcriptome data. The normalization method of choice for raw RNA-seq count data affects the model content produced by these algorithms and their predictive accuracy. However, a benchmark of the RNA-seq normalization methods on the performance of iMAT and INIT algorithms is missing in the literature. Another important phenomenon is covariates such as age and gender in a dataset, and they can affect the predictivity of analysis. In this study, we aimed to compare five different RNA-seq data normalization methods (TPM, FPKM, TMM, GeTMM, and RLE) and covariate adjusted versions of the normalized data by mapping them on a human GEM using the iMAT and INIT algorithms to generate personalized metabolic models. We used RNA-seq data for Alzheimer’s disease (AD) and lung adenocarcinoma (LUAD) patients. The results demonstrated that RNA-seq data normalized by the RLE, TMM, or GeTMM methods enabled the production of condition-specific metabolic models with considerably low variability in terms of the number of active reactions compared to the within-sample normalization methods (FPKM, TPM). Using these models, we could more accurately capture the disease-associated genes (average accuracy of ~0.80 for AD and ~0.67 for LUAD) for the RLE, TMM, and GeTMM normalization methods. An increase in the accuracies was observed for all the methods when covariate adjustment was applied. We found a similar accuracy trend when we compared the metabolites of perturbed reactions to metabolome data for AD. Together, our benchmark study shows that the between-sample RNA-seq normalization methods reduce false positive predictions at the expense of missing some true positive genes when mapped on GEMs.

Bayesian Response Adaptive Randomization for Randomized Clinical Trials With Continuous Outcomes: The Role of Covariate Adjustment.

Study designs incorporate interim analyses to allow for modifications to the trial design. These analyses may aid decisions regarding sample size, futility, and safety. Furthermore, they may provide evidence about potential differences between treatment arms. Bayesian response adaptive randomization (RAR) skews allocation proportions such that fewer participants are assigned to the inferior treatments. However, these allocation changes may introduce covariate imbalances. We discuss two versions of Bayesian RAR (with and without covariate adjustment for a binary covariate) for continuous outcomes analyzed using change scores and repeated measures, while considering either regression or mixed models for interim analysis modeling. Through simulation studies, we show that RAR (both versions) allocates more participants to better treatments compared to equal randomization, while reducing potential covariate imbalances. We also show that dynamic allocation using mixed models for repeated measures yields a smaller allocation proportion variance while having a similar covariate imbalance as regression models. Additionally, covariate imbalance was smallest for methods using covariate-adjusted RAR (CARA) in scenarios with small sample sizes and covariate prevalence less than 0.3. Covariate imbalance did not differ between RAR and CARA in simulations with larger sample sizes and higher covariate prevalence. We thus recommend a CARA approach for small pilot/exploratory studies for the identification of candidate treatments for further confirmatory studies.

A Unified Framework for Covariate Adjustment Under Stratified Randomisation

ABSTRACTRandomisation, as a key technique in clinical trials, can eliminate sources of bias and produce comparable treatment groups. In randomised experiments, the treatment effect is a parameter of general interest. Researchers have explored the validity of using linear models to estimate the treatment effect and perform covariate adjustment and thus improve the estimation efficiency. However, the relationship between covariates and outcomes is not necessarily linear, and is often intricate. Advances in statistical theory and related computer technology allow us to use nonparametric and machine learning methods to better estimate the relationship between covariates and outcomes and thus obtain further efficiency gains. However, theoretical studies on how to draw valid inferences when using nonparametric and machine learning methods under stratified randomisation are yet to be conducted. In this paper, we discuss a unified framework for covariate adjustment and corresponding statistical inference under stratified randomisation and present a detailed proof of the validity of using local linear kernel‐weighted least squares regression for covariate adjustment in treatment effect estimators as a special case. In the case of high‐dimensional data, we additionally propose an algorithm for statistical inference using machine learning methods under stratified randomisation, which makes use of sample splitting to alleviate the requirements on the asymptotic properties of machine learning methods. Finally, we compare the performances of treatment effect estimators using different machine learning methods by considering various data generation scenarios, to guide practical research.

Sexual violence affecting female sex workers in Côte d’Ivoire: prevalence, context, and associated mental health and substance use outcomes

BackgroundFemale sex workers are disproportionately affected by sexual violence, which is associated with an increased risk of poor mental health outcomes, substance use, and decreased access to health resources. Understanding the pathways through which sexual violence impacts these outcomes can inform strategies that appropriately and effectively meet the health needs of sex workers.MethodsThis study investigated the prevalence of sexual violence among female sex workers in Côte d’Ivoire, and the relationship between sexual violence and adverse mental health and substance use outcomes. We examined survey data from female sex workers recruited between November 2019 and May 2020 across five regions of Côte d’Ivoire using respondent driven sampling (RDS), as part of an integrated bio-behavioral survey. The primary exposure of interest was self-reported lifetime experience of sexual violence, and the main outcomes of interest included depression, suicidal ideation, counselling seeking, alcohol consumption, and substance use. Multivariable logistic regression models investigated associations between exposure to sexual violence and the key mental health and substance use outcomes of interest. For each outcome, a directed acyclic graph was developed to identify a minimally sufficient set of covariates for adjustment. Additional sociodemographic characteristics, experiences, and sex work-related behaviors were explored in descriptive analyses using crude and RDS adjusted estimates.ResultsOut of 1,177 participants, 376 (31.9%; RDS weighted: 30.5%; 95% CI: 24.7, 36.3) reported having experienced sexual violence in their lifetime, and of those 31.9% (RDS weighted: 31.2%; 95% CI: 21.3, 41.1) had experienced sexual violence within the previous 12 months. Experience of sexual violence was associated with an increased odds of suicidal ideation (aOR: 1.95; 95% CI: 1.48, 2.55), illicit drug use in the last 12 months (aOR: 2.40; 95% CI: 1.50, 3.86), daily alcohol use (aOR: 1.63; 95% CI: 0.99, 2.67), and having spoken to a counselor or confidant (aOR: 1.90; 95% CI: 1.34, 2.68).ConclusionFindings confirm a high burden of sexual violence among female sex workers in Côte d’Ivoire, and a need to implement large structural changes that enable female sex workers to seek protection as well as health resources after experiencing sexual violence. This may include reform in the form of targeted social, clinical and mental health resources, along with community development opportunities.

Discharge Communication and the Achievement of Lifestyle and Behavioral Changes Post-Stroke in the Transitions of Care Stroke Disparities Study

Objectives: This study identifies the association between patient perception of discharge education/resources and adequate transitions of care (ATOC) (i.e., patient achievement of at least 75% of recommended positive behaviors and activities within 30 days post-stroke hospitalization). Methods: The analysis measured the association between sufficient discharge communication (SDC) (i.e., patient receipt of sufficient diet education, sufficient toxic habit cessation education, if applicable, and scheduled medical follow-up appointment) and ATOC within 30 days post-discharge overall and by race/ethnicity [non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic] in the Transitions of Care Stroke Disparities Study (TCSD-S) (2018-2023). Results: In our sample (N = 1151, Average Age 64+/−14 years, 57% Men, 54% NHW, 24% NHB, 23% Hispanic), 31% overall, as well as 22% of NHW, 43% of NHB, and 41% of Hispanics reported SDC. After covariate adjustment, patients reporting SDC had increased likelihood of accomplishing ATOC when compared to patients not reporting SDC overall (OR = 1.97; 95% CI: 1.42-2.74) and among NHW (OR = 2.76; 95% CI: 1.64-4.64) and NHB (OR = 2.29; 95% CI: 1.16-4.53). The association among Hispanic participants was not statistically significant. Conclusion: Our findings reinforce the importance of providing quality communication to patients to ensure a successful transition of care from hospital to home or rehabilitation facility.

Volume and Permeability of White Matter Hyperintensity on Cognition: A DCE Imaging Study of an Older Cohort With and Without Cognitive Impairment.

The impact of blood-brain barrier (BBB) leakage on white matter hyperintensity (WMH) subtypes (location) and its association with clinical factors and cognition remains unclear. To investigate the relationship between WMH volume, permeability, clinical factors, and cognition in older individuals across the cognitive spectrum. Prospective, cross-sectional. A total of 193 older adults with/without cognitive impairment; 128 females; mean age 70.1 years (standard deviation 6.8). 3 T, GE Dynamic contrast-enhanced, three-dimensional (3D) Magnetization-prepared rapid gradient-echo (MPRAGE T1WI), 3D fluid-attenuated inversion recovery (FLAIR). Periventricular WMH (PWMH), deep WMH (DWMH), and normal-appearing white matter (NAWM) were segmented using FMRIB automatic segmentation tool algorithms on 3D FLAIR. Hippocampal volume and cortex volume were segmented on 3D T1WI. BBB permeability (Ktrans) and blood plasma volume (Vp) were determined using the Patlak model. Vascular risk factors and cognition were assessed. Univariate and multivariate analyses were performed to identify factors associated with WMH permeability. Logistic regression analysis assessed the association between WMH imaging features and cognition, adjusting for age, sex, apolipoprotein E4 status, education, and brain volumes. A P-value <0.05 was considered significant. PWMH exhibited higher Ktrans (0.598 ± 0.509 × 10-3 minute-1) compared to DWMH (0.496 ± 0.478 × 10-3 minute-1) and NAWM (0.476 ± 0.398 × 10-3 minute-1). Smaller PWMH volume and cardiovascular disease (CVD) history were significantly associated with higher Ktrans in PWMH. In DWMH, higher Ktrans were associated with CVD history and cortical volume. In NAWM, it was linked to CVD history and dyslipidemia. Larger PWMH volume (odds ratio [OR] 1.106, confidence interval [CI]: 1.021-1.197) and smaller hippocampal volume (OR 0.069; CI: 0.019-0.253) were independently linked to worse global cognition after covariate adjustment. Elevated BBB leakage in PWMH was associated with lower PWMH volume and prior CVD history. Notably, PWMH volume, rather than permeability, was correlated with cognitive decline, suggesting that BBB leakage in WMH may be a consequence of CVD rather than indicate disease progression. 2 TECHNICAL EFFICACY: Stage 3.

Birth Outcomes After Pertussis and Influenza Diagnosed in Pregnancy: A Retrospective, Population-Based Study.

Adverse birth outcomes and the maternal severity of influenza in pregnancy are well documented but information on pertussis is limited. Population-based linkage data were collected during 2001-2016. New South Wales, Australia. A total of 1 453 037 singleton births. Cox regression was used to estimate the associations between pertussis or influenza during pregnancy and birth outcomes with adjustment of covariates. Adverse birth outcomes (preterm birth and low birth weight). Among 1 453 037 singleton births over 16 years, we identified pertussis in 925 (49; 5.3% hospitalised) and influenza in 2850 (1092; 38.3% hospitalised) women during pregnancy. Cases of pertussis were similarly distributed by trimester (32% 3rd) whereas 46% of influenza cases were in the 3rd trimester. Younger age, previous birth, and being overseas-born were associated with both pertussis and influenza, whereas identifying as Aboriginal or Torres Strait Islander, hypertension or diabetes before and during pregnancy, and a number of other factors were only associated with influenza. Both pertussis and influenza in pregnancy were associated with increased risk of preterm birth (pertussis: aHR = 1.30, 95% CI 1.01-1.68; influenza: aHR = 1.56, 95% CI 1.36-1.79) and these increased risks were greater when infections in the period within 2 weeks of birth were considered (pertussis: aHR = 2.36, 95% CI 1.26-4.41; influenza: aHR = 2.29, 95% CI 1.78-2.96). Maternal pertussis and influenza infections close to the time of birth were associated with adverse birth outcomes. These findings highlight the benefits of vaccination during pregnancy.