Adjusting for bias introduced by instrumental variable estimation in the Cox Proportional Hazards Model

Instrumental variable (IV) methods are widely used for estimating average treatment effects in the presence of unmeasured confounders. However, the capability of existing IV procedures, and most notably the two-stage residual inclusion (2SRI) procedure recommended for use in nonlinear contexts, to account for unmeasured confounders in the Cox proportional hazard model is unclear. We show that instrumenting an endogenous treatment induces an unmeasured covariate, referred to as an individual frailty in survival analysis parlance, which if not accounted for leads to bias. We propose a new procedure that augments 2SRI with an individual frailty and prove that it is consistent under certain conditions. The finite sample-size behavior is studied across a broad set of conditions via Monte Carlo simulations. Finally, the proposed methodology is used to estimate the average effect of carotid endarterectomy versus carotid artery stenting on the mortality of patients suffering from carotid artery disease. Results suggest that the 2SRI-frailty estimator generally reduces the bias of both point and interval estimators compared to traditional 2SRI.Comment: 27 pages, 8 figures, 4 table

Finding the best thresholds of FEV1 and dyspnea to predict 5-year survival in COPD patients: the COCOMICS study

BACKGROUND: FEV1 is universally used as a measure of severity in COPD. Current thresholds are based on expert opinion and not on evidence. OBJECTIVES: We aimed to identify the best FEV1 (% predicted) and dyspnea (mMRC) thresholds to predict 5-yr survival in COPD patients. DESIGN AND METHODS: We conducted a patient-based pooled analysis of eleven COPD Spanish cohorts (COCOMICS). Survival analysis, ROC curves, and C-statistics were used to identify and compare the best FEV1 (%) and mMRC scale thresholds that predict 5-yr survival. RESULTS: A total of 3,633 patients (93% men), totaling 15,878 person-yrs. were included, with a mean age 66.4 ± 9.7, and predicted FEV1 of 53.8% (± 19.4%). Overall 975 (28.1%) patients died at 5 years. The best thresholds that spirometrically split the COPD population were: mild ≥ 70%, moderate 56-69%, severe 36-55%, and very severe ≤ 35%. Survival at 5 years was 0.89 for patients with FEV1 ≥ 70 vs. 0.46 in patients with FEV1 ≤ 35% (H.R: 6; 95% C.I.: 4.69-7.74). The new classification predicts mortality significantly better than dyspnea (mMRC) or FEV1 GOLD and BODE cutoffs (all p<0.001). Prognostic reliability is maintained at 1, 3, 5, and 10 years. In younger patients, survival was similar for FEV1 (%) values between 70% and 100%, whereas in the elderly the relationship between FEV1 (%) and mortality was inversely linear. CONCLUSIONS: The best thresholds for 5-yr survival were obtained stratifying FEV1 (%) by ≥ 70%, 56-69%, 36-55%, and ≤ 35%. These cutoffs significantly better predict mortality than mMRC or FEV1 (%) GOLD and BODE cutoffs

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019

Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease

Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC(ADO) - AUC(BODE) = 0.015 [95% confidence interval (CI) = - 0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research

Procedural Safety Comparison Between Transcarotid Artery Revascularization, Carotid Endarterectomy, and Carotid Stenting: Perioperative and 1‐Year Rates of Stroke or Death

Background Transcarotid artery revascularization (TCAR) was approved by the Food and Drug Administration in 2015 for patients with carotid artery stenosis. However, no randomized trial to evaluate TCAR has been performed to date, and previous reports have important limitations. Accordingly, we measured stroke or death after TCAR compared with carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF‐CAS). Methods and Results We used the Vascular Quality Initiative registry to study patients who underwent TCAR, CEA, or TF‐CAS from September 2016 to June 2021. Our primary outcomes were perioperative and 1‐year stroke or death. We used logistic regression for risk adjustment for perioperative outcomes and Cox regression for risk adjustment for 1‐year outcomes. We used a 2‐stage residual inclusion instrumental variable (IV) method to adjust for selection bias and other unmeasured confounding. Our instrument was a center's preference to perform TCAR versus CEA or TF‐CAS. We performed a subgroup analysis stratified by presenting neurologic symptoms. We studied 21 234 patients who underwent TCAR, 82 737 who underwent CEA, and 14 595 who underwent TF‐CAS across 662 centers. The perioperative rate of stroke or death was 2.0% for TCAR, 1.7% for CEA, and 3.7% for TF‐CAS (P<0.001). Compared with TCAR, the IV‐adjusted odds ratio of perioperative stroke or death for CEA was 0.74 (95% CI, 0.55–0.99) and for TF‐CAS was 1.66 (95% CI, 0.99–2.79). Results were similar among both symptomatic and asymptomatic patients. The 1‐year rate of stroke or death was 6.4% for TCAR, 5.2% for CEA, and 9.7% for TF‐CAS (P<0.001). Compared with TCAR, the IV‐adjusted hazard ratio of 1 year stroke or death for CEA was 0.97 (95% CI, 0.80–1.17), and for TF‐CAS was 1.45 (95% CI, 1.04–2.02). IV analysis further demonstrated that symptomatic patients with carotid stenosis had the lowest 1‐year likelihood of stroke or death with TCAR (compared with TCAR, symptomatic IV‐adjusted hazard ratio for CEA: 1.30 [95% CI, 1.04–1.64], and TF‐CAS: 1.86 [95% CI, 1.27–2.71]). Conclusions Perioperative stroke or death was greater following TCAR when compared with CEA. However, at 1 year there was no statistically significant difference in stroke or death between the 2 procedures. TCAR performed favorably compared with TF‐CAS at both time points. Although CEA remains the gold standard procedure for patients with carotid stenosis, TCAR appears to be a safe alternative to CEA and TF‐CAS when used selectively and may be useful when treating symptomatic patients

Sex-, race-and ethnicity-based differences in thromboembolic events among adults hospitalized with COVID-19

BACKGROUND: Patients hospitalized with COVID-19 have an increased risk of thromboembolic events. Whether sex, race or ethnicity impacts these events is unknown. We studied the association between sex, race, and ethnicity and venous and arterial thromboembolic events among adults hospitalized with COVID-19. METHODS AND RESULTS: We used the American Heart Association Cardiovascular Disease COVID-19 registry. Primary expo-sures were sex and race and ethnicity, as defined by the registry. Primary outcomes were venous thromboembolic events and arterial thromboembolic events. We used logistic regression for risk adjustment. We studied 21 528 adults hospitalized with COVID-19 across 107 centers (54.1% men; 38.1% non-Hispanic White, 25.4% Hispanic, 25.7% non-Hispanic Black, 0.5% Native American, 4.0% Asian, 0.4% Pacific Islander, and 5.9% other race and ethnicity). The rate of venous thromboembolic events was 3.7% and was more common in men (4.2%) than women (3.2%; P\u3c0.001), and in non-Hispanic Black patients (4.9%) than other races and ethnicities (range, 1.3%– 3.8%; P\u3c0.001). The rate of arterial thromboembolic events was 3.9% and was more common in men (4.3%) than women (3.5%; P=0.002), and in non-Hispanic Black patients (5.0%) than other races and ethnicities (range, 2.3%– 4.7%; P\u3c0.001). Compared with men, women were less likely to experience venous thromboem-bolic events (adjusted odds ratio [OR], 0.71; 95% CI, 0.61– 0.83) and arterial thromboembolic events (adjusted OR, 0.76; 95% CI, 0.66– 0.89). Compared with non-Hispanic White patients, non-Hispanic Black patients had the highest likelihood of venous thromboembolic events (adjusted OR, 1.27; 95% CI, 1.04–1.54) and arterial thromboembolic events (adjusted OR, 1.35; 95% CI, 1.11–1.65). CONCLUSIONS: Men and non-Hispanic Black adults hospitalized with COVID-19 are more likely to have venous and arterial thromboembolic events. These subgroups may represent at-risk patients more susceptible to thromboembolic COVID-19 complications

sj-jpg-1-vmj-10.1177_1358863X241237776 – Supplemental material for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease

Supplemental material, sj-jpg-1-vmj-10.1177_1358863X241237776 for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease by Stanislav Henkin, Stephen A Kearing, Pablo Martinez-Camblor, Nikolaos Zacharias, Mark A Creager, Michael N Young, Philip P Goodney and Jesse A Columbo in Vascular Medicine</p

sj-docx-1-vmj-10.1177_1358863X241237776 – Supplemental material for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease

Supplemental material, sj-docx-1-vmj-10.1177_1358863X241237776 for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease by Stanislav Henkin, Stephen A Kearing, Pablo Martinez-Camblor, Nikolaos Zacharias, Mark A Creager, Michael N Young, Philip P Goodney and Jesse A Columbo in Vascular Medicine</p

sj-jpg-2-vmj-10.1177_1358863X241237776 – Supplemental material for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease

Supplemental material, sj-jpg-2-vmj-10.1177_1358863X241237776 for The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease by Stanislav Henkin, Stephen A Kearing, Pablo Martinez-Camblor, Nikolaos Zacharias, Mark A Creager, Michael N Young, Philip P Goodney and Jesse A Columbo in Vascular Medicine</p